その他の認知症予防に関する報告④


Midlife Vascular Risk Factors
football
Neither cholesterol nor egg intake
vitamin A
Aluminium
high frequency of sauna bathing
statin
イソα酸―ホップ由来―
高機能茶「サンルージュ」
Chronic low-dose-rate ionising radiation
disaster
Androgen deprivation therapy
caffeine intake
smaller hippocampus
poorly controlled warfarin
depression
rosacea
anticholinergic
Colonic diverticular disease
NSAID
periodontitis
Using a computer
Proton Pump Inhibitors (PPI)
bexarotene
Lipid-based Diets
Taser’s Electric Shock
SEAFOOD
living alone as non-marrieds
β-N-methylamino-L-alanine (BMAA)
chronic anxiety
Oestrogen


Midlife Vascular Risk Factors

April 11, 2017 JAMA
Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition
Rebecca F. Gottesman, MD, PhD1,2; Andrea L. C. Schneider, MD, PhD1; Yun Zhou, PhD3; et al Josef Coresh, MD, PhD2; Edward Green, MD4; Naresh Gupta, MD5; David S. Knopman, MD6; Akiva Mintz, MD7; Arman Rahmim, PhD3; A. Richey Sharrett, MD, DrPH2; Lynne E. Wagenknecht, DrPH8; Dean F. Wong, MD, PhD3,9,10,11; Thomas H. Mosley, PhD12
Author Affiliations
JAMA. 2017;317(14):1443-1450. doi:10.1001/jama.2017.3090

Question Are midlife vascular risk factors associated with late-life brain amyloid deposition?

Findings In a prospective cohort study of 346 members of the community-based Atherosclerosis Risk in Communities (ARIC)?PET cohort without dementia, having 2 or more midlife vascular risk factors compared with none was significantly associated with elevated amyloid deposition in the brain (61.2% vs 30.8%). There was no significant association for late-life risk factors.

Meaning These findings are consistent with a role of vascular disease in the development of Alzheimer disease.

Abstract
Importance Midlife vascular risk factors have been associated with late-life dementia. Whether these risk factors directly contribute to brain amyloid deposition is less well understood.

Objective To determine if midlife vascular risk factors are associated with late-life brain amyloid deposition, measured using florbetapir positron emission tomography (PET).

Design, Setting, and Participants The Atherosclerosis Risk in Communities (ARIC)?PET Amyloid Imaging Study, a prospective cohort study among 346 participants without dementia in 3 US communities (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi) who have been evaluated for vascular risk factors and markers since 1987-1989 with florbetapir PET scans in 2011-2013. Positron emission tomography image analysis was completed in 2015.

Exposures Vascular risk factors at ARIC baseline (age 45-64 years; risk factors included body mass index ?30, current smoking, hypertension, diabetes, and total cholesterol ?200 mg/dL) were evaluated in multivariable models including age, sex, race, APOE genotype, and educational level.

Main Outcomes and Measures Standardized uptake value ratios (SUVRs) were calculated from PET scans and a mean global cortical SUVR was calculated. Elevated florbetapir (defined as a SUVR >1.2) was the dependent variable.

Results Among 322 participants without dementia and with nonmissing midlife vascular risk factors at baseline (mean age, 52 years; 58% female; 43% black), the SUVR (elevated in 164 [50.9%] participants) was measured more than 20 years later (median follow-up, 23.5 years; interquartile range, 23.0-24.3 years) when participants were between 67 and 88 (mean, 76) years old. Elevated body mass index in midlife was associated with elevated SUVR (odds ratio [OR], 2.06; 95% CI, 1.16-3.65). At baseline, 65 participants had no vascular risk factors, 123 had 1, and 134 had 2 or more; a higher number of midlife risk factors was associated with elevated amyloid SUVR at follow-up (30.8% [n?=?20], 50.4% [n?=?62], and 61.2% [n?=?82], respectively). In adjusted models, compared with 0 midlife vascular risk factors, the OR for elevated SUVR associated with 1 vascular risk factor was 1.88 (95% CI, 0.95-3.72) and for 2 or more vascular risk factors was 2.88 (95% CI, 1.46-5.69). No significant race × risk factor interactions were found. Late-life vascular risk factors were not associated with late-life brain amyloid deposition (for ?2 late-life vascular risk factors vs 0: OR, 1.66; 95% CI, 0.75-3.69).

Conclusions and Relevance An increasing number of midlife vascular risk factors was significantly associated with elevated amyloid SUVR; this association was not significant for late-life risk factors. These findings are consistent with a role of vascular disease in the development of Alzheimer disease.


football

Acta Neuropathologica
Mixed pathologies including chronic traumatic encephalopathy account for dementia in retired association football (soccer) players
Authors
Helen LingHuw R. MorrisJames W. NealAndrew J. LeesJohn HardyJanice L. HoltonEmail authorTamas ReveszEmail authorDavid D. R. Williams
Open AccessOriginal Paper
First Online: 15 February 2017
DOI: 10.1007/s00401-017-1680-3
Cite this article as:
Ling, H., Morris, H.R., Neal, J.W. et al. Acta Neuropathol (2017). doi:10.1007/s00401-017-1680-3
Abstract
In retired professional association football (soccer) players with a past history of repetitive head impacts, chronic traumatic encephalopathy (CTE) is a potential neurodegenerative cause of dementia and motor impairments. From 1980 to 2010, 14 retired footballers with dementia were followed up regularly until death. Their clinical data, playing career, and concussion history were prospectively collected. Next-of-kin provided consent for six to have post-mortem brain examination. Of the 14 male participants, 13 were professional and 1 was a committed amateur. All were skilled headers of the ball and had played football for an average of 26 years. Concussion rate was limited in six cases to one episode each during their careers. All cases developed progressive cognitive impairment with an average age at onset of 63.6 years and disease duration of 10 years. Neuropathological examination revealed septal abnormalities in all six post-mortem cases, supportive of a history of chronic repetitive head impacts. Four cases had pathologically confirmed CTE; concomitant pathologies included Alzheimer’s disease (N = 6), TDP-43 (N = 6), cerebral amyloid angiopathy (N = 5), hippocampal sclerosis (N = 2), corticobasal degeneration (N = 1), dementia with Lewy bodies (N = 1), and vascular pathology (N = 1); and all would have contributed synergistically to the clinical manifestations. The pathological diagnosis of CTE was established in four individuals according to the latest consensus diagnostic criteria. This finding is probably related to their past prolonged exposure to repetitive head impacts from head-to-player collisions and heading the ball thousands of time throughout their careers. Alzheimer’s disease and TDP-43 pathologies are common concomitant findings in CTE, both of which are increasingly considered as part of the CTE pathological entity in older individuals. Association football is the most popular sport in the world and the potential link between repetitive head impacts from playing football and CTE as indicated from our findings is of considerable public health interest. Clearly, a definitive link cannot be established in this clinico-pathological series, but our findings support the need for further systematic investigation, including large-scale case?control studies to identify at risk groups of footballers which will justify for the implementation of protective strategies.


Neither cholesterol nor egg intake

Association of dietary cholesterol and egg intakes with the risk of incident dementia or Alzheimer disease: the Kuopio Ischaemic Heart Disease Risk Factor Study1,2

First published January 4, 2017, doi: 10.3945/?ajcn.116.146753
Am J Clin Nutr
ajcn146753

Maija PT Ylilauri3, Sari Voutilainen3, Eija L?nnroos3, Jaakko Mursu3, Heli EK Virtanen3, Timo T Koskinen3, Jukka T Salonen4, Tomi-Pekka Tuomainen3, and Jyrki K Virtanen3,*
+ Author Affiliations

3Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; and
4Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland
+ Author Notes

?1 The authors reported no funding received for this study.

?2 Supplemental Figure 1 is available from the “Online Supporting Material” link in the online posting of the article and from the same link in the online table of contents at http://ajcn.nutrition.org.

?*To whom correspondence should be addressed. E-mail: jyrki.virtanen@uef.fi.

Abstract

Background: There is little information about the associations of intakes of cholesterol and eggs, a major source of dietary cholesterol, with the risk of cognitive decline in general populations or in carriers of apolipoprotein E ?4 (APO-E4), a major risk factor for dementia.

Objective: We investigated the associations of cholesterol and egg intakes with incident dementia, Alzheimer disease (AD), and cognitive performance in middle-aged and older men from Eastern Finland.

Design: A total of 2497 dementia-free men, aged 42?60 y in 1984?1989 at the baseline examinations of the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study, were included in the study. Information on the apolipoprotein E (Apo-E) phenotype was available for 1259 men. Data on cognitive performance tests at the 4-y re-examinations were available for 480 men. Dietary intakes were assessed with the use of 4-d food records at baseline. Dementia and AD diagnoses were based on Finnish health registers. Cox regression and ANCOVA were used for the analyses.

Results: During the 21.9-y follow-up, 337 men were diagnosed with dementia, and 266 men were diagnosed with AD. Neither cholesterol nor egg intake was associated with a higher risk of incident dementia or AD. For example, when evaluated continuously, each intake of 100 mg cholesterol/d was associated with a multivariable-adjusted HR of 0.90 (95% CI: 0.79, 1.02) for incident dementia, and each additional 0.5 egg (27 g)/d was associated with an HR of 0.89 (95% CI: 0.78, 1.01). However, egg intake was associated with better performance on neuropsychological tests of the frontal lobe and executive functioning, the Trail Making Test, and the Verbal Fluency Test. The Apo-E4 phenotype did not modify the associations of cholesterol or egg intake (P-interactions > 0.11).

Conclusions: Neither cholesterol nor egg intake is associated with an increased risk of incident dementia or AD in Eastern Finnish men. Instead, moderate egg intake may have a beneficial association with certain areas of cognitive performance.


vitamin A

Acta Neuropathologica
Marginal vitamin A deficiency facilitates Alzheimer’s pathogenesis

Authors and affiliations
Jiaying ZengLi ChenZhe WangQian ChenZhen FanHongpeng JiangYili WuLan RenJie ChenTingyu LiEmail authorWeihong SongEmail author
Original Paper
First Online: 27 January 2017
DOI: 10.1007/s00401-017-1669-y
Abstract
Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the unique pathological hallmark of Alzheimer’s disease (AD). Aβ is derived from amyloid β precursor protein (APP) by β- and γ-secretase cleavages and turned over by glia in the central nervous system (CNS). Vitamin A deficiency (VAD) has been shown to affect cognitive functions. Marginal vitamin A deficiency (MVAD) is a serious and widespread public health problem among pregnant women and children in developing countries. However, the role of MVAD in the pathogenesis of AD remains elusive. Our study showed that MVAD is approximately twofold more prevalent than VAD in the elderly, and increased cognitive decline is positively correlated with lower VA levels. We found that MVAD, mostly prenatal MVAD, promotes beta-site APP cleaving enzyme 1 (BACE1)-mediated Aβ production and neuritic plaque formation, and significantly exacerbates memory deficits in AD model mice. Supplementing a therapeutic dose of VA rescued the MVAD-induced memory deficits. Taken together, our study demonstrates that MVAD facilitates AD pathogenesis and VA supplementation improves cognitive deficits. These results suggest that VA supplementation might be a potential approach for AD prevention and treatment.


Aluminium

Aluminium in brain tissue in familial Alzheimer’s disease

Ambreen Mirzaa, Andrew Kingb, c, Claire Troakesc, Christopher Exleya, ,
http://dx.doi.org/10.1016/j.jtemb.2016.12.001
Journal of Trace Elements in Medicine and Biology
Volume 40, March 2017, Pages 30?36

Abstract
The genetic predispositions which describe a diagnosis of familial Alzheimer’s disease can be considered as cornerstones of the amyloid cascade hypothesis. Essentially they place the expression and metabolism of the amyloid precursor protein as the main tenet of disease aetiology. However, we do not know the cause of Alzheimer’s disease and environmental factors may yet be shown to contribute towards its onset and progression. One such environmental factor is human exposure to aluminium and aluminium has been shown to be present in brain tissue in sporadic Alzheimer’s disease. We have made the first ever measurements of aluminium in brain tissue from 12 donors diagnosed with familial Alzheimer’s disease. The concentrations of aluminium were extremely high, for example, there were values in excess of 10 μg/g tissue dry wt. in 5 of the 12 individuals. Overall, the concentrations were higher than all previous measurements of brain aluminium except cases of known aluminium-induced encephalopathy. We have supported our quantitative analyses using a novel method of aluminium-selective fluorescence microscopy to visualise aluminium in all lobes of every brain investigated. The unique quantitative data and the stunning images of aluminium in familial Alzheimer’s disease brain tissue raise the spectre of aluminium’s role in this devastating disease.


high frequency of sauna bathing

Visit sauna regularly to stave off dementia, 20 year study suggests

Sarah Knapton, science editor
18 MARCH 2016
telegraph

Visiting the sauna regularly could reduce the risk of dementia, a new study has found.

Scientists at the University of East Finland followed more than 2,000 middle-aged men for 20 years to find out what factors influenced how many developed cognitive problems in later life.

They found that those who used the sauna between four and seven times a week were 66 per cent less likely to be diagnosed with dementia during the study period compared with those taking a sauna just once a week or less.

It is the first time that anyone has found a link between sauna use and dementia although previous studies have shown that regular use reduces the risk of dying from all causes and seems to improve heart health.

Professor Jari Laukkaben, the study leader, said that sauna bathing may protect both the heart and memory in similar ways.

“It is known that cardiovascular health affects the brain as well,” he said. "The sense of well-being and relaxation experience during sauna-bathing may also play a role."

Dementia charities said saunas might work by reducing blood pressure and improving circulation.

Dr Clare Walton, Research Manager at the Alzheimer’s Society said: “With dementia now the biggest killer across England and Wales, finding ways to reduce the risk of developing the condition is a top priority.

“Saunas are thought to improve circulation and reduce blood pressure, both of which could go some way to reducing your risk of getting dementia.

“Currently the best evidence to reduce the risk of dementia is to exercise regularly, eat a healthy, balanced diet and avoid smoking.”

Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK, added: “Although sauna bathing isn’t a common hobby for men in the UK, this study suggests men who use saunas several times a week may also have a lower dementia risk.

“As this study does not look at other groups of people such as women or people who do not use saunas, we don’t know how this risk compares to the general population and or what might be behind it.

“These kinds of studies can’t unpick cause and effect, but they are important for highlighting trends in how lifestyle factors may influence our risk of dementia for more detailed follow-up.”

The research was published in the journal of Age and Ageing.


Sauna bathing is inversely associated with dementia and Alzheimer's disease in middle-aged Finnish men

Tanjaniina Laukkanen1, Setor Kunutsor2, Jussi Kauhanen1 and Jari Antero Laukkanen1

1Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
2School of Clinical Sciences, University of Bristol, Bristol, UK
Address correspondence to: L. Tanjaniina. Tel: +358505053013. Email: tanjaniina.laukkanen@uef.fi
Received January 27, 2016.
Abstract

Background there are no previous studies linking repeated heat exposure of sauna and the risk of memory diseases. We aimed to investigate whether frequency of sauna bathing is associated with risk of dementia and Alzheimer's disease.

Setting prospective population-based study.

Methods the frequency of sauna bathing was assessed at baseline in the Kuopio Ischaemic Heart Disease population-based prospective cohort study of 2,315 apparently healthy men aged 42?60 years at baseline, with baseline examinations conducted between 1984 and 1989. Hazard ratios (HRs) with 95% confidence intervals (CIs) for dementia and Alzheimer's disease were ascertained using Cox-regression modelling with adjustment for potential confounders.

Results during a median follow-up of 20.7 (interquartile range 18.1?22.6) years, a total of 204 and 123 diagnosed cases of dementia and Alzheimer's disease were respectively recorded. In analysis adjusted for age, alcohol consumption, body mass index, systolic blood pressure, smoking status, Type 2 diabetes, previous myocardial infarction, resting heart rate and serum low-density lipoprotein cholesterol, compared with men with only 1 sauna bathing session per week, the HR for dementia was 0.78 (95% CI: 0.57?1.06) for 2?3 sauna bathing sessions per week and 0.34 (95% CI: 0.16?0.71) for 4?7 sauna bathing sessions per week. The corresponding HRs for Alzheimer's disease were 0.80 (95% CI: 0.53?1.20) and 0.35 (95% CI: 0.14?0.90).

Conclusion in this male population, moderate to high frequency of sauna bathing was associated with lowered risks of dementia and Alzheimer's disease. Further studies are warranted to establish the potential mechanisms linking sauna bathing and memory diseases.


statin

Original Investigation
December 12, 2016
Sex and Race Differences in the Association Between Statin Use and the Incidence of Alzheimer Disease
Julie M. Zissimopoulos, PhD1; Douglas Barthold, PhD1; Roberta Diaz Brinton, PhD1,2; et al Geoffrey Joyce, PhD1
Author Affiliations Article Information
JAMA Neurol. Published online December 12, 2016. doi:10.1001/jamaneurol.2016.3783
Key Points
Question What is the association between statin use and the incidence of Alzheimer disease among male and female Medicare beneficiaries?

Findings In this study, high vs low exposure to statins was associated with a lower incidence of Alzheimer disease for women and men, respectively. The reduction in incidence of Alzheimer disease varied across race/ethnicity and type of statin.

Meaning Statins may potentially affect Alzheimer disease risk, so physicians should consider which statin is prescribed to their patients.

Abstract
Importance To our knowledge, no effective treatments exist for Alzheimer disease, and new molecules are years away. However, several drugs prescribed for other conditions have been associated with reducing its risk.

Objective To analyze the association between statin exposure and Alzheimer disease incidence among Medicare beneficiaries.

Design, Setting, and Participants We examined the medical and pharmacy claims of a 20% sample of Medicare beneficiaries from 2006 to 2013 and compared rates of Alzheimer disease diagnosis for 399 979 statin users 65 years of age or older with high or low exposure to statins and with drug molecules for black, Hispanic, and non-Hispanic white people, and men and women of Asian, Native American, or unkown race/ethnicity who are referred to as “other.”

Main Outcomes and Measures The main outcome was incident diagnosis of Alzheimer disease based on the International Classification of Diseases, Ninth Revision, Clinical Modification. We used Cox proportional hazard models to analyze the association between statin exposure and Alzheimer disease diagnosis for different sexes, races and ethnicities, and statin molecules.

Results The 399 979 study participants included 7794 (1.95%) black men, 24 484 (6.12%) black women, 11 200 (2.80%) Hispanic men, 21 458 (5.36%) Hispanic women, 115 059 (28.77%) white men, and 195 181 (48.80%) white women. High exposure to statins was associated with a lower risk of Alzheimer disease diagnosis for women (hazard ratio [HR], 0.85; 95% CI, 0.82-0.89; P<.001) and men (HR, 0.88; 95% CI, 0.83-0.93; P<.001). Simvastatin was associated with lower Alzheimer disease risk for white women (HR, 0.86; 95% CI, 0.81-0.92; P<.001), white men (HR, 0.90; 95% CI, 0.82-0.99; P=.02), Hispanic women (HR, 0.82; 95% CI, 0.68-0.99; P=.04), Hispanic men (HR, 0.67; 95% CI, 0.50-0.91; P=.01), and black women (HR, 0.78; 95% CI, 0.66-0.93; P=.005). Atorvastatin was associated with a reduced risk of incident Alzheimer disease diagnosis for white women(HR, 0.84, 95% CI, 0.78-0.89), black women (HR, .081, 95% CI, 0.67-0.98), and Hispanic men (HR, 0.61, 95% CI, 0.42-0.89) and women (HR, 0.76, 95% CI, 0.60-0.97). Pravastatin and rosuvastatin were associated with reduced Alzheimer disease risk for white women only (HR, 0.82, 95% CI, 0.70-0.95 and HR, 0.81, 95% CI, 0.67-0.98, respectively). High statin exposure was not associated with a statistically significant lower Alzheimer disease risk among black men.

Conclusions and Relevance The reduction in Alzheimer disease risk varied across statin molecules, sex, and race/ethnicity. Clinical trials that include racial and ethnic groups need to confirm these findings. Because statins may affect Alzheimer disease risk, physicians should consider which statin is prescribed to each patient.


イソα酸―ホップ由来―

ホップ由来のビール苦味成分であるイソα酸のアルツハイマー病予防に関する作用機序を解明 ~世界で初めてビール苦味成分の予防効果を確認~

2016年11月28日
キリン株式会社

キリン株式会社(社長 磯崎功典)の健康技術研究所(所長 近藤恵二)は、東京大学、学習院大学と共同で、ホップ由来のビール苦味成分であるイソα酸のアルツハイマー病予防に関する作用機序を世界で初めて解明しました。当社はこの研究成果を12月1日(木)から3日(土)に開催される「第35回日本認知症学会学術集会」にて発表します。

現在、高齢者の増加に伴い、日本では460万人、世界では2,430万人近くの方が認知症を患っているとされ、国内外で大きな社会課題となっています。一方、アルツハイマー病に代表される認知症には十分な治療方法が開発されておらず、日々の生活を通じた予防に注目が集まっています。
これまでの疫学などの研究では、適度な量の酒類の摂取は認知症の防御因子として報告されています。特に赤ワインのポリフェノールは認知症への効果に関して多く研究報告がありますが、ビールの成分についてはあまり研究が進んでいませんでした。

ビールに華やかな香りと爽やかな苦味をもたらすホップは、ビールの原料として1,000年以上にわたって使用されており、当社ではこれまでホップ成分の肥満抑制効果、発がん抑制効果、骨密度低下抑制効果などを解明してきました。
今回、認知症の予防に関する研究開発において、ホップ由来のビール苦味成分であるイソα酸にアルツハイマー病の進行を抑制する作用があることを見出しました。また、この作用は、脳内の老廃物を除去するミクログリアと呼ばれる細胞の活性化および、アルツハイマー病の原因物質とされるβアミロイドの蓄積や脳内の炎症抑制により生じることを明らかにしました。
なお、本成分摂取のヒトの脳機能への作用は、内閣府の革新的研究開発推進プログラムImPACTでの実証試験※1で確認しています。
※1 50-70代男女25名にイソα酸を4週間摂取していただき、脳活動の変化をfMRI(ヒトおよび動物の脳や脊髄の活動に関連した血流動態反応を視覚化する方法の一つ)にて測定する試験。結果は2016年3月にImPACTから公開。
方法
アルツハイマー病モデルマウスにイソα酸を含む飼料を3カ月間混餌投与しました。
行動薬理試験※2で認知機能を評価した後、脳内に含まれるアルツハイマー病の原因物質の1つとされるβアミロイドの量やサイトカインなどの炎症物質、神経細胞のシナプス量を測定しました。また、脳内の老廃物を除去するミクログリアの活性化状態を併せて評価しました。
※2 新奇物体認識試験というエピソード記憶などを評価する行動試験

結果
イソα酸投与群では対照群と比較して脳内のβアミロイドの量が有意に低下しました。
脳内の炎症が緩和され、ミクログリアの老廃物除去活性および抗炎症活性が高進していました。
神経細胞のシナプス量が有意に増加し、行動薬理評価の結果、認知機能が有意に改善しました。
以上の結果により、イソα酸は脳内の老廃物を除去するミクログリアを活性化することでアルツハイマー病の進行を抑制する効果があることが示唆されました。

1.発表演題名ビール苦味成分イソα酸のミクログリア機能亢進作用によるアルツハイマー病の予防効果2.学会名第35回日本認知症学会学術集会3.発表日2016年12月1日(木)‐3日(土)4.発表場所東京国際フォーラム(東京都千代田区)5.発表者キリン株式会社、東京大学、学習院大学


高機能茶「サンルージュ」

高機能茶「サンルージュ」の「加齢による認知機能の低下抑制効果」を動物試験で確認
アセチルコリンエステラーゼの阻害効果は「やぶきた」の4.4倍~主要緑茶43品種の中で最も優れた効果~


2016年11月18日
日本製紙株式会社

日本製紙株式会社(社長:馬城 文雄)は、九州大学(立花 宏文教授)との共同研究で、高機能茶「サンルージュ」の'アセチルコリンエステラーゼ'(注1)阻害効果が、「やぶきた」をはじめとする主要緑茶43品種の中で最も高いことを見出しました。さらに、老化促進モデルマウス(注2)を用いた評価では、サンルージュの継続的な摂取により、加齢による認知機能の低下が抑制されることが明らかになり、その効果がやぶきたよりも高いことを確認しました。
 これらの試験結果の詳細は、11月20日に「第21回日本フードファクター学会学術大会」(※)で発表する予定です。

近年、高齢化の進展により認知症高齢者の数は増加を続けており、厚生労働省の推計によると、2025年には700万人を超えるとされています。認知症の予防については、さまざまな観点からアプローチされていますが、その中で、複数の研究機関から、緑茶を習慣的に摂取することによる予防効果が指摘されており、また、緑茶成分と脳機能との関連についても様々な研究結果が報告されています。

 そこで、当社は高機能茶「サンルージュ」について九州大学と共同研究を実施し、認知症予防効果を検証しました。
 サンルージュは主要緑茶43品種の中で、神経伝達物質である'アセチルコリン'(注1)を分解する酵素'アセチルコリンエステラーゼ'の働きを阻害する効果が最も高く、「やぶきた」の4.4倍、最も低い「さえみどり」の10倍以上の効果を示すことが確認できました(グラフ1)。
 また、老化促進モデルマウスを用いた試験では、サンルージュの継続的な摂取により、加齢による長期記憶能力の低下が抑制されること(グラフ2)と、学習能力の低下が抑制されること(グラフ3)が明らかになり、その効果が「やぶきた」よりも高いことが確認できました。同時に、サンルージュは、認知症を引き起こす原因物質とされる'b-アミロイド'(注3)の脳への蓄積を抑制することや、b-アミロイドの蓄積に関連する遺伝子の発現に影響を与えることも確認できました。

 サンルージュは、農業・食品産業技術総合研究機構 果樹茶業研究部門が育種した高機能茶品種ですが、挿し木増殖が難しいという課題がありました。そこで、当社は農林水産省の基礎研究推進事業に協力し、当社独自技術である「容器内挿し木技術」(注4)を活用してサンルージュの挿し木増殖法を開発し、サンルージュの普及に取り組んできました。
 サンルージュについては、緑茶特有の機能性成分であるカテキンと赤い色素である機能性成分アントシアニンの両方を含むことから、これらの相乗効果による抗疲労・抗ストレス作用や眼精疲労改善の効果が得られることがわかっていましたが、当社が昨年実施した九州大学との共同研究では、メタボリックシンドロームの予防効果があることも確認されました。さらにヒト臨床試験の結果、食事と共にサンルージュを摂取することで「食後の血糖値の上昇が抑制される効果」を確認しています。
 今回の試験で行ったサンルージュの成分分析では、'ケルセチン'や'ミリセチン'(注5)といった植物由来の機能性成分を多く含むことが明らかになり、これらのサンルージュに特徴的な成分が、認知症予防に効果を発揮するのではないかと考えられています。

 当社は、「サンルージュ」の認知症予防効果について、今後も九州大学と共同で調査を進めてまいります。また、当社が展開するアグリ事業において、「サンルージュ」の機能性を広める活動を行い、早期の普及に向けた取り組みを進めてまいります。


Chronic low-dose-rate ionising radiation

Concern that radiation may contribute to development of Alzheimer's

Date:October 27, 2016
https://www.sciencedaily.com/
Source:University of Southern Denmark
Summary:More humans than ever are exposed to higher levels of ionizing radiation from medical equipment, airplanes, etc. A new study suggests that this kind of radiation may be a confounding factor in the neurodegenerative disease Alzheimer's.

More humans than ever are exposed to higher levels of ionizing radiation from medical equipment, airplanes, etc. A new study suggests that this kind of radiation may be a confounding factor in the neurodegenerative disease Alzheimer´s.

Alzheimer's disease is the leading cause for dementia in the elderly, and its global prevalence is supposed to increase dramatically in the following decade -- up to 80 million patients by 2040.

"It is crucial that we investigate the potential factors behind this disease," says postdoc Stefan J. Kempf, University of Southern Denmark. His research focuses on possible connections between radiation and cognitive impairments.

In a new study, he and an international consortia involving colleagues from Italy, Japan, Germany and Denmark show that low doses of ionizing radiation induce molecular changes in the brain that resemble the pathologies of Alzheimer's.

The study has been published in Oncotarget. Co-authors are from Institute of Radiation Biology/Institute of Pathology, Helmholtz Zentrum M?nchen, German Research Center for Environmental Health and Institute for Environmental Sciences in Japan.

Large numbers of people of all age groups are increasingly exposed to ionizing radiation from various sources. Many receive chronic occupational exposure from nuclear technologies or airline travel. The use of medical diagnostics and therapeutic radiology has increased rapidly -- for example more than 62 million CT scans per year are currently carried out in USA.

Approximately one third of all diagnostic CT examinations are scans of the head region.

"All these kinds of exposures are low dose and as long as we talk about one or a few exposures in a lifetime I do not see cause for concern. What concerns me is that modern people may be exposed several times in their lifetime and that we don't know enough about the consequences of accumulated doses," says Stefan J. Kempf.

Recent data suggest that even relatively low radiation doses, similar to those received from a few CT scans, could trigger molecular changes associated with cognitive dysfunction.

In their new study, the researchers have elucidated molecular alterations in the hippocampus of mice. The hippocampus is an important brain region responsible for learning and memory formation and it is known to be negatively affected in Alzheimer´s.

The authors induced changes in the hippocampus by two kinds of chronic low-dose-rate ionizing radiation treatments. The mice were exposed to cumulative doses of 0.3 Gy or 6.0 Gy given at low dose rates of 1 mGy over 24 hours or 20 mGy over 24 hours for 300 days.

"Both dose rates are capable of inducing molecular features that are reminiscent of those found in the Alzheimer's disease neuropathology," says Stefan J. Kempf.

When a patient gets a head scan, the doses varies between 20 and 100 mGy and lasts for around one minute. When a person flies, he or she gets exposure to ionizing radiation coming from space but the rates are by far smaller than a CT scan.

"When you compare these figures you will find that we exposed the mice to a more than 1000 times smaller cumulative dose than what a patient gets from a single CT scan in the same time interval. And even then we could see changes in the synapses within the hippocampus that resemble Alzheimer´s pathology."

According to Stefan J. Kempf, the data indicate that chronic low-dose-rate radiation targets the integration of newborn neurons in existing synaptic wires.

Story Source: Materials provided by University of Southern Denmark. Original written by Birgitte Svennevig. Note: Content may be edited for style and length.

Journal Reference: Stefan J. Kempf, Dirk Janik, Zarko Barjaktarovic, Ignacia Braga-Tanaka III, Satoshi Tanaka, Frauke Neff, Anna Saran, Martin R. Larsen, Soile Tapio. Chronic low-dose-rate ionising radiation affects the hippocampal phosphoproteome in the ApoE?/? Alzheimer´s mouse model. Oncotarget, 2016; DOI: 10.18632/oncotarget.12376


Chronic low-dose-rate ionising radiation affects the hippocampal phosphoproteome in the ApoE?/? Alzheimer mouse model

Article (PDF Available)?in?Oncotarget ? September 2016?with?63 Reads

1st Stefan J Kempf
23.97 ? University of Southern Denmark
Abstract
Accruing data indicate that radiation-induced consequences resemble pathologies of neurodegenerative diseases such as Alzheimer´s. The aim of this study was to elucidate the effect on hippocampus of chronic low-dose-rate radiation exposure (1 mGy/day or 20 mGy/day) given over 300 days with cumulative doses of 0.3 Gy and 6.0 Gy, respectively. ApoE deficient mutant C57Bl/6 mouse was used as an Alzheimer´s model. Using mass spectrometry, a marked alteration in the phosphoproteome was found at both dose rates. The radiation-induced changes in the phosphoproteome were associated with the control of synaptic plasticity, calcium-dependent signalling and brain metabolism. An inhibition of CREB signalling was found at both dose rates whereas Rac1-Cofilin signalling was found activated only at the lower dose rate. Similarly, the reduction in the number of activated microglia in the molecular layer of hippocampus that paralleled with reduced levels of TNFα gene expression and lipid peroxidation was significant only at the lower dose rate. Adult neurogenesis, investigated by Ki67, GFAP and NeuN staining, and cell death (activated caspase-3) were not influenced at any dose or dose rate. This study shows that several molecular targets induced by chronic low-dose-rate radiation overlap with those of Alzheimer´s pathology. It may suggest that ionising radiation functions as a contributing risk factor to this neurodegenerative disease.


disaster

Elderly may face increased dementia risk after a disaster Japan tsunami destruction

October 24, 2016
Harvard T.H. Chan School of Public Health News

Boston, MA ? Elderly people who were uprooted from damaged or destroyed homes and who lost touch with their neighbors after the 2011 tsunami in Japan were more likely to experience increased symptoms of dementia than those who were able to stay in their homes, according to a new study from Harvard T.H. Chan School of Public Health. The study was the first to look at dementia as a potential health risk in the aftermath of a disaster.

The study was published online October 24, 2016 in an Early Edition of the Proceedings of the National Academy of Sciences journal (PNAS).

“In the aftermath of disasters, most people focus on mental health issues like PTSD,” said Hiroyuki Hikichi, research fellow at Harvard Chan School and lead author of the study. “But our study suggests that cognitive decline is also an important issue. It appears that relocation to a temporary shelter after a disaster may have the unintended effect of separating people not just from their homes but from their neighbors?and both may speed up cognitive decline among vulnerable people.”

The Harvard Chan researchers, working with colleagues in Japan, were able to conduct a “natural experiment” among a group of elderly residents of the coastal city of Iwanuma, located about 80 kilometers west of the earthquake epicenter, where nearly half the land area was inundated by the tsunami. Seven months before the disaster, elderly residents of Iwanuma had been surveyed about their health as part of an ongoing study of aging called the Japan Gerontological Evaluation Study (JAGES). Two-and-a-half years after the tsunami, the researchers conducted a follow-up survey among the same group.

Out of 3,566 survivors of the tsunami disaster aged 65 or older?some who were able to remain in their homes and some who were forced out?38.0% said they lost relatives and/or friends and 58.9% reported property damage. In the pre-tsunami survey, 4.1% of respondents had been assessed with dementia symptoms; after the tsunami, the percentage jumped to 11.5%. The prevalence of stroke increased, from 2.8% to 6.5%, as did the prevalence of hypertension (54.0% to 57.2%). The percentage of people who reported not interacting with their neighbors?not even with greetings?nearly doubled, from 1.5% to 2.9%.

Those who wound up in temporary housing after their houses were either destroyed or sustained major damage had the highest levels of cognitive decline. There was a strong dose-response association: People whose houses were more severely damaged experienced more cognitive decline. Depression and declines in informal social interactions with friends and neighbors appeared to play a role in the link.

By contrast, loss of relatives and/or friends did not seem to impact cognitive abilities.

Other Harvard Chan School authors included S V Subramanian and Ichiro Kawachi, senior author of the study.

Funding for the study came from the National Institutes of Health (R01 AG042463); Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI 23243070, KAKENHI 22390400, and KAKENHI 24390469); a Health Labour Sciences Research Grant from the Japanese Ministry of Health, Labour and Welfare (H24-Choju-Wakate-009); and a grant from the Strategic Research Foundation Grant-Aided Project for Private Universities from the Japanese Ministry of Education, Culture, Sports, Science and Technology (S0991035).

“Increased risk of dementia in the aftermath of the 2011 Great East Japan Earthquake and Tsunami,” Hiroyuki Hikichi, Jun Aida, Katsunori Kondo, Toru Tsuboya, Yusuke Matsuyama, S.V. Subramanian, and Ichiro Kawachi, PNAS, online October 24, 2016, doi: 10.1073/pnas.1607793113

For more information:

Todd Datz
Harvard T.H. Chan School of Public Health
tdatz@hsph.harvard.edu
617.432.8413

###

Increased risk of dementia in the aftermath of the 2011 Great East Japan Earthquake and Tsunami

Hiroyuki Hikichia,1, Jun Aidab, Katsunori Kondoc,d, Toru Tsuboyab, Yusuke Matsuyamab, S. V. Subramaniana, and Ichiro Kawachia
Author Affiliations

Edited by Susan T. Fiske, Princeton University, Princeton, NJ, and approved September 16, 2016 (received for review May 15, 2016)

Significance

Recovery after major disaster poses potential risks of dementia for the elderly population. However, no previous studies have examined exposure to natural disaster and changes in risk factors as predictors of deterioration in cognitive function. We prospectively examined whether housing damage and loss of relatives or friends were associated with cognitive decline in the aftermath of the 2011 Great East Japan Earthquake and Tsunami. In this study, which included 3,566 survivors who are 65 y old or older, the severity of housing damage was significantly associated with cognitive decline after controlling changes of covariates and risk factors during the follow-up period. The cognitive decline should be listed as a health risk of older survivors in the aftermath of natural disasters.

Abstract
No previous study has been able to examine the association by taking account of risk factors for dementia before and after the disaster. We prospectively examined whether experiences of a disaster were associated with cognitive decline in the aftermath of the 2011 Great East Japan Earthquake and Tsunami. The baseline for our natural experiment was established in a survey of older community-dwelling adults who lived 80 km west of the epicenter 7 mo before the earthquake and tsunami. Approximately 2.5 y after the disaster, the follow-up survey gathered information about personal experiences of disaster as well as incidence of dementia from 3,594 survivors (82.1% follow-up rate). Our primary outcome was dementia diagnosis ascertained by in-home assessment during the follow-up period. Among our analytic sample (n = 3,566), 38.0% reported losing relatives or friends in the disaster, and 58.9% reported property damage. Fixed-effects regression indicated that major housing damage and home destroyed were associated with cognitive decline: regression coefficient for levels of dementia symptoms = 0.12, 95% confidence interval (CI): 0.01 to 0.23 and coefficient = 0.29, 95% CI: 0.17 to 0.40, respectively. The effect size of destroyed home is comparable to the impact of incident stroke (coefficient = 0.24, 95% CI: 0.11 to 0.36). The association between housing damage and cognitive decline remained statistically significant in the instrumental variable analysis. Housing damage appears to be an important risk factor for cognitive decline among older survivors in natural disasters.


Androgen deprivation therapy

Association Between Androgen Deprivation Therapy and Risk of Dementia

Kevin T. Nead, MD, MPhil1,2; Greg Gaskin, BS1; Cariad Chester, BS3; et al Samuel Swisher-McClure, MD, MSHP2; Nicholas J. Leeper, MD4; Nigam H. Shah, PhD, MBBS1
JAMA Oncol. Published online
October 13, 2016
doi:10.1001/jamaoncol.2016.3662

Key Points
Questions Is there evidence of an association between use of androgen deprivation therapy in the treatment of prostate cancer and future dementia and can applied clinical informatics tools help identify relevant population cohorts?

Findings This cohort study applied a novel text-processing analytic approach to the electronic medical records of 9272 individuals with prostate cancer. There was a statistically significant association between androgen deprivation therapy and increased risk of dementia.

Meaning Future prospective studies are needed to further investigate the association of androgen deprivation therapy and risk of dementia.

Abstract
Importance A growing body of evidence supports a link between androgen deprivation therapy (ADT) and cognitive dysfunction, including Alzheimer disease. However, it is currently unknown whether ADT may contribute to the risk of dementia more broadly.

Objective To use an informatics approach to examine the association of ADT as a treatment for prostate cancer with the subsequent development of dementia (eg, senile dementia, vascular dementia, frontotemporal dementia, and Alzheimer dementia).

Design, Setting, and Participants In this cohort study, a text-processing method was used to analyze electronic medical record data from an academic medical center from 1994 to 2013, with a median follow-up of 3.4 years (interquartile range, 1.0-7.2 years). We identified 9455 individuals with prostate cancer who were 18 years or older at diagnosis with data recorded in the electronic health record and follow-up after diagnosis. We excluded 183 patients with a previous diagnosis of dementia. Our final cohort comprised 9272 individuals with prostate cancer, including 1826 men (19.7%) who received ADT.

Main Outcomes and Measures We tested the effect of ADT on the risk of dementia using propensity score?matched Cox proportional hazards regression models and Kaplan-Meier survival analysis.

Results Among 9272 men with prostate cancer (mean [SD] age, 66.9 [10.9] years; 5450 [58.8%] white), there was a statistically significant association between use of ADT and risk of dementia (hazard ratio, 2.17; 95% CI, 1.58-2.99; P?<?.001). In sensitivity analyses, results were similar when excluding patients with Alzheimer disease (hazard ratio, 2.32; 95% CI, 1.73-3.12; P?<?.001). The absolute increased risk of developing dementia among those who received ADT was 4.4% at 5 years (7.9% among those who received ADT vs 3.5% in those who did not receive ADT). Analyses stratified by duration of ADT found that individuals with at least 12 months of ADT use had the greatest absolute increased risk of dementia (hazard ratio, 2.36; 95% CI, 1.64-3.38; P?<?.001). Kaplan-Meier analysis demonstrated that ADT users 70 years or older had the lowest cumulative probability of remaining dementia free (log-rank P?<?.001).

Conclusions and Relevance Androgen deprivation therapy in the treatment of prostate cancer may be associated with an increased risk of dementia. This finding should be further evaluated in prospective studies.


caffeine intake

Relationships Between Caffeine Intake and Risk for Probable Dementia or Global Cognitive Impairment: The Women’s Health Initiative Memory Study
Ira Driscoll1, Sally A. Shumaker2, Beverly M. Snively3, Karen L. Margolis4, JoAnn E. Manson5, Mara Z. Vitolins6, Rebecca C. Rossom4 and Mark A. Espeland3

1 Department of Psychology, University of Wisconsin?Milwaukee.
2 Department of Social Sciences and Health Policy and
3 Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.
4 Health Partners Institute for Education and Research, Minneapolis, Minnesota.
5 Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
6 Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Address correspondence to Ira Driscoll, PhD, Department of Psychology, University of Wisconsin?Milwaukee, 224 Garland Hall, 2441 East Hartford Avenue, Milwaukee, WI 53211. Email: driscoli@uwm.edu
Received December 1, 2015.
Accepted April 7, 2016.
J Gerontol A Biol Sci Med Sci (2016)
doi: 10.1093/gerona/glw078
First published online: September 27, 2016

Abstract

Background: Nonhuman studies suggest a protective effect of caffeine on cognition. Although human literature remains less consistent, reviews suggest a possible favorable relationship between caffeine consumption and cognitive impairment or dementia. We investigated the relationship between caffeine intake and incidence of cognitive impairment or probable dementia in women aged 65 and older from the Women’s Health Initiative Memory Study.

Methods: All women with self-reported caffeine consumption at enrollment were included (N = 6,467). In 10 years or less of follow-up with annual assessments of cognitive function, 388 of these women received a diagnosis of probable dementia based on a 4-phase protocol that included central adjudication. We used proportional hazards regression to assess differences in the distributions of times until incidence of probable dementia or composite cognitive impairment among women grouped by baseline level of caffeine intake, adjusting for risk factors (hormone therapy, age, race, education, body mass index, sleep quality, depression, hypertension, prior cardiovascular disease, diabetes, smoking, and alcohol consumption).

Results: Women consuming above median levels (mean intake = 261mg) of caffeine intake for this group were less likely to develop incident dementia (hazard ratio = 0.74, 95% confidence interval [0.56, 0.99], p = .04) or any cognitive impairment (hazard ratio = 0.74, confidence interval [0.60, 0.91], p = .005) compared to those consuming below median amounts (mean intake = 64mg) of caffeine for this group.

Conclusion: Our findings suggest lower odds of probable dementia or cognitive impairment in older women whose caffeine consumption was above median for this group and are consistent with the existing literature showing an inverse association between caffeine intake and age-related cognitive impairment.


smaller hippocampus

Unmasking Alzheimer's risk in young adults

By Jacqueline Howard, CNN
July 6, 2016

(CNN)The risk for developing devastating Alzheimer's disease may be detectable in healthy adults younger than expected, and new studies reveal how.

Tests already exist to determine a genetic risk for familial Alzheimer's disease, which is typically early-onset and less common than sporadic Alzheimer's disease. Both types cause dementia. However, identifying risk for the sporadic variety of Alzheimer's -- which accounts for about 95% of all Alzheimer's cases -- is not as simple.
A study published in the journal Neurology on Wednesday suggests that the risk factors for sporadic Alzheimer's can be detected early in adulthood and might make a person more susceptible to cognitive decline.

One of the easiest ways to identify this risk might be to take a close look at images of a patient's hippocampus, a brain region associated with memory, the study suggests.
Younger adults with various genetic risk factors for Alzheimer's have a smaller hippocampal volume, said Elizabeth Mormino, a researcher at Massachusetts General Hospital and lead author of the study.
"However, we are not able to determine whether these young subjects with elevated risk actually progress to dementia late in life, since that sort of extended followup is not available," she added. "Nevertheless, this finding informs our understanding of disease mechanisms by revealing an impact of common risk variants decades before clinical symptoms would be present."

A surprising link
For the study, researchers used MRI images to analyze the hippocampi of 166 people with dementia and 1,026 people without dementia. The average age was 75. The researchers also determined the polygenic risk of Alzheimer's disease for each person by probing their DNA for specific gene variants associated with a high risk of developing Alzheimer's disease. A polygenic risk score is a numeric score based on whether a person has several of those gene variants.
Next, the researchers calculated the same risk score and hippocampal volume in 1,322 healthy adults between the ages of 18 and 35.

The researchers found a small association between a higher risk score and having a smaller hippocampal volume within both older and younger groups. Within young adults, the risk score accounted for about 0.2% of the variance in hippocampal volume.
"I was surprised that we identified a link between our polygenic risk scores and hippocampal volume among young adults, decades before any clinical symptoms of the disease would be present," Mormino said. "This implies that changes early in life may impact risk of dementia late in life and that these changes have a genetic basis."
Additionally, the researchers found that among older adults who did not enter the study with dementia, a higher risk score was tied to worse memory function over time and a greater likelihood of being diagnosed with dementia during a subsequent doctor's visit.

"Alzheimer's disease starts in the brain many decades before the first symptoms of memory loss appear, but what's happened over time is that most people don't realize their risk until they start having memory loss," said Dr. Richard Isaacson, director of the Alzheimer's Prevention Clinic at Weill Cornell Medicine and NewYork-Presbyterian Hospital, who was not involved in the study.
"Before that, you can have metabolic or functional changes in the brain as well as structural changes. The size of the hippocampus, or memory center of the brain, may start to shrink in the 30s or younger," he added. "As the science expands, we'll be better able to understand the true nature of sporadic versus genetic Alzheimer's."

Brain scans hold clues
The new findings seem to confirm what was shown in a separate study, published in the journal Biological Psychiatry in March, in which brain scans also revealed structural differences in the hippocampi of young adults with high and low risk scores.
Those researchers analyzed the association between genetic risk scores and brain images of about 300 healthy young adults.
"We had expected to see changes in the hippocampus in relation to risk for Alzheimer's disease based on the existing anatomical literature but were still somewhat surprised to see them in a relatively young cohort," said David Linden, professor of translational neuroscience at Cardiff University in Wales and a co-author of the study.

"Similar effects of reduced hippocampal volume in relation to increased polygenic Alzheimer's disease risk have now been reported for unrelated participants by other research groups," he added, "which inspires confidence into the robustness of these findings."
To diagnose Alzheimer's disease, doctors may perform brain-imaging tests, but those tests are typically to rule out other possible causes for a patient's symptoms.
Additionally, brain imaging can help doctors identify the disease once there has been damage to a patient's brain tissue. There still isn't a way to detect and clinically diagnose Alzheimer's using brain imaging alone.

How to reduce risk
A majority of adults 60 and older tend to be most concerned about developing Alzheimer's disease, according to a YouGov survey conducted in the UK last year. Fear of Alzheimer's even took precedence over cancer and financial concerns in the survey. As the world mourned legendary women's college basketball coach Pat Summitt, who died at age 64 last week after battling Alzheimer's, such concerns probably have heightened.
Yet, there's hope. More research not only could help physicians with using brain imaging and other methods to better identify dementia risk, it might lead to future preventative treatments, Mormino said.

Fear can be paralyzing, Isaacson said.
But "the field of Alzheimer's risk reduction and disease prevention is exploding," he added.
"It's really important that people are not fearful and that younger people don't think there's nothing a person can do to reduce their risk and protect their brain," Isaacson said. "Recent studies finally get us passed the dogma of 'there's nothing you can do.' There are so many things you can do."
For instance, at-risk young adults can alter their diets to include foods that benefit brain health, as well as focus on getting a healthy amount of exercise and sleep.
"The earlier you detect risk, the better," Isaacson said. "And the notion that there's nothing you can do is false."


Polygenic risk of Alzheimer disease is associated with early- and late-life processes

Elizabeth C. Mormino, PhD, Reisa A. Sperling, MD, Avram J. Holmes, PhD, Randy L. Buckner, PhD, Philip L. De Jager, MD, PhD, Jordan W. Smoller, MD, ScD, Mert R. Sabuncu, PhD; For the Alzheimer's Disease Neuroimaging Initiative
+SHOW AFFILIATIONS| + SHOW FULL DISCLOSURES
Correspondence to Dr. Mormino: bmormino@nmr.mgh.harvard.edu
Published online before print July 6, 2016, doi: http:/?/?dx.?doi.?org/?10.?1212/?WNL.?0000000000002922
Neurology 10.1212/WNL.0000000000002922
AbstractFull Text (PDF)
Also available: Data Supplement Coinvestigators

ABSTRACT

Objective: To examine associations between aggregate genetic risk and Alzheimer disease (AD) markers in stages preceding the clinical symptoms of dementia using data from 2 large observational cohort studies.

Methods: We computed polygenic risk scores (PGRS) using summary statistics from the International Genomics of Alzheimer's Project genome-wide association study of AD. Associations between PGRS and AD markers (cognitive decline, clinical progression, hippocampus volume, and β-amyloid) were assessed within older participants with dementia. Associations between PGRS and hippocampus volume were additionally examined within healthy younger participants (age 18?35 years).

Results: Within participants without dementia, elevated PGRS was associated with worse memory (p = 0.002) and smaller hippocampus (p = 0.002) at baseline, as well as greater longitudinal cognitive decline (memory: p = 0.0005, executive function: p = 0.01) and clinical progression (p < 0.00001). High PGRS was associated with AD-like levels of β-amyloid burden as measured with florbetapir PET (p = 0.03) but did not reach statistical significance for CSF β-amyloid (p = 0.11). Within the younger group, higher PGRS was associated with smaller hippocampus volume (p = 0.05). This pattern was evident when examining a PGRS that included many loci below the genome-wide association study (GWAS)?level significance threshold (16,123 single nucleotide polymorphisms), but not when PGRS was restricted to GWAS-level significant loci (18 single nucleotide polymorphisms).

Conclusions: Effects related to common genetic risk loci distributed throughout the genome are detectable among individuals without dementia. The influence of this genetic risk may begin in early life and make an individual more susceptible to cognitive impairment in late life. Future refinement of polygenic risk scores may help identify individuals at risk for AD dementia.

Received December 24, 2015.
Accepted in final form April 22, 2016.
? 2016 American Academy of Neurology


poorly controlled warfarin

Warfarin, AF May Each Contribute to Dementia Risk in Atrial Fibrillation

Marlene Busko
May 05, 2016
http://www.medscape.com/

SAN FRANCISCO, CA ? In more than 10,000 patients with different diseases who were receiving warfarin therapy to prevent clots and stroke, those who had atrial fibrillation (AF) as opposed to thromboembolism or a mechanical heart valve were more likely to develop dementia. including Alzheimer's disease, during about a 7-year follow-up[1]. A total of 2.8% of patients with AF vs 0.9% of the other patients developed Alzheimer's disease.

Dr T Jared Bunch (Intermountain Medical Center Heart institute, Salt Lake City, UT) presented this study May 5, 2016 at the Heart Rhythm Society (HRS) 2016 Scientific Sessions.

The study confirmed that AF patients had more baseline risk factors for dementia (such as hypertension, diabetes, prior stroke) than non-AF patients. However, in a subgroup analysis that corrected for this, the patients with AF still had a higher risk of all types of dementia.

In addition, the risk of dementia was higher when warfarin was poorly controlled, regardless of whether or not the patients had AF.

This study shows that "we really have to be careful in our prescribing practices of anticoagulation," Bunch told heartwire from Medscape. "Patients on warfarin who show erratic biologic results . . . need to be transitioned to other agents, if possible, or to potential nonpharmacologic approaches," he said.

Studies such as this one are important as guideline writers grapple with the issue of prophylaxis with anticoagulants for low-risk patients with a CHADS score of 1 or a CHA2DS2-VASc score of 1 or 2 to determine how best to lower the risk of clots and stroke, while keeping patients safe from large bleeds requiring transfusion and repeated small brain bleeds.

Is It the Warfarin or the AF That Increases Risk of Dementia?

In previous research, the group found that Alzheimer's disease risk was more likely in younger patients with AF when warfarin levels were poorly controlled compared with older anticoagulated patients. They also reported that among patients who were taking a concomitant antiplatelet agent (mostly aspirin) as well as warfarin, those who spent more time in a supratherapeutic warfarin range were at increased risk of dementia.

But it was unclear whether AF increased risk of dementia, independent of the anticoagulant treatment strategy.

To investigate this, the researchers analyzed data from patients whose warfarin was managed by the Intermountain Healthcare Clinical Pharmacist Anticoagulation Service. They identified 10,537 patients with no dementia who had received warfarin prophylaxis in the past decade, including 4460 patients with AF, 5868 patients with thromboembolism (deep vein thrombosis or pulmonary embolism), and 209 patients with a mechanical heart valve.

Compared with the patients without AF, those with AF were older and had higher rates of hypertension, diabetes, prior MI, and prior stroke. The patients in the AF group were followed for a mean of 6.3 years, and the others were followed for a mean of 8.2 years, for an overall follow-up of about 7 years.

Patients with AF were 1.6 times more likely than other patients to develop dementia, which was diagnosed by a neurologist; they had higher rates of total dementia (5.8% vs 1.6%), Alzheimer's disease (2.8% vs 0.9%), and vascular dementia (1.0% vs 0.2%) (all P<0.0001).

For patients in both groups, the risk for dementia grew incrementally higher as time in therapeutic range (TTR) worsened.

In a propensity analysis of 3015 patients with AF and 3015 patients without AF with similar baseline characteristics, the patients with AF still had significantly higher rates of total dementia (5.2% vs 2.6%), Alzheimer's disease (2.4% vs 1.4%), and vascular dementia (0.9% vs 0.3%%).

Risk of Dementia in AF Patients vs Other Patients on Warfarin Therapy*

Outcome HR (95% CI) P
Total dementia 2.42 (1.85?3.18) <0.0001
Alzheimer's disease 2.04 (1.40?2.98) <0.0001
Vascular dementia 3.47 (1.62?7.42) 0.0001
*In about 7 years of follow-up
There was a threefold increased risk of dementia in the AF group that continued to increase with time.

"Anticoagulation clearly has a role as far as long-term brain health and viability," Bunch said. Based on the propensity analysis, "We learned as well that AF is an additive disease state, in that it increases risk beyond anticoagulation, so its management also becomes very important to lower dementia risk."

The authors acknowledge that this was an observational study and cannot determine cause and effect.

Bunch has no relevant financial relationships.

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depression

Worsening depression 'may predict dementia risk'

30 April 2016
BBC

A link between depression and dementia has been known for some time
Symptoms of depression that steadily increase over time in older age could indicate early signs of dementia, scientists have said.
Other patterns of symptoms, such as chronic depression, appear not to be linked, a study found.
Dutch researchers looked at different ways depression in older adults progressed over time and how this related to any risk.
They concluded worsening depression may signal the condition is taking hold.
The research, published in The Lancet Psychiatry, followed more than 3,000 adults aged 55 and over living in the Netherlands.
All had depression but no symptoms of dementia at the start of the study.
Dr M Arfan Ikram of the Erasmus University Medical Center in Rotterdam said depressive symptoms that gradually increase over time appear to be a better predictor of dementia later in life than other paths of depression.
"There are a number of potential explanations, including that depression and dementia may both be symptoms of a common underlying cause, or that increasing depressive symptoms are on the starting end of a dementia continuum in older adults," he said.
Only the group whose symptoms of depression increased over time were found to be at increased risk of dementia - about one in five of people (55 out of 255) in this group developed dementia.
Others who had symptoms that waxed and waned or stayed the same were not at increased risk.
For example, in those who experienced low but stable levels of depression, around 10% went on to develop dementia.
Prevention strategies?
The exact nature of depression on dementia risk remains unknown.
They often occur together, but the Dutch study is among the first to look at different patterns of depression symptoms.
Dr Simone Reppermund from the Centre for Healthy Brain Ageing at the University of New South Wales, Sydney, said more studies were needed to understand the link.
"A focus on lifestyle factors such as physical activity and social networks, and biological risk factors such as vascular disease, neuroinflammation, high concentrations of stress hormones, and neuropathological changes, might bring new treatment and prevention strategies a step closer," she wrote in a linked editorial in the journal.
Depression varies greatly from one person to another. Some experience depressive symptoms only briefly, others have remitting and relapsing depression and some people are depressed all the time.
Dr Simon Ridley, director of research at Alzheimer's Research UK, said anyone concerned about either condition should seek help.
"The findings suggest that low levels of depression or fluctuating symptoms may not affect dementia risk but that a worsening of symptoms in the over-55s may be an early indicator of diseases like Alzheimer's," he said.
"It's important to remember that only a relatively small number of people experiencing symptoms of depression went on to develop dementia during this 11-year study, but anyone concerned about either condition should talk to their GP."


10-year trajectories of depressive symptoms and risk of dementia: a population-based study

Saira Saeed Mirza, MD, Frank J Wolters, MD, Sonja A Swanson, ScD, Prof Peter J Koudstaal, PhD, Prof Albert Hofman, PhD, Prof Henning Tiemeier, PhD, Dr M Arfan Ikram, MDcorrespondenceemail
Published Online: 29 April 2016
DOI: http://dx.doi.org/10.1016/S2215-0366(16)00097-3 |

Summary
Background
Late-life depressive symptoms have been extensively studied for their relationship with incident dementia, but have been typically assessed at a single timepoint. Such an approach neglects the course of depression, which, given its remitting and relapsing nature, might provide further insights into the complex association of depression with dementia. We therefore repeatedly measured depressive symptoms in a population of adults over a decade to study the subsequent risk of dementia.

Methods
Our study was embedded in the Rotterdam Study, a population-based study of adults aged 55 years or older in Rotterdam (Netherlands), ongoing since 1990. The cohort is monitored continuously for major events by data linkage between the study database and general practitioners. We examined a cohort of participants who were free from dementia, but had data for depressive symptoms from at least one examination round in 1993?95, 1997?99, or 2002?04. We assessed depressive symptoms with the validated Dutch version of the Center for Epidemiology Depression Scale (CES-D) and the Hospital Anxiety and Depression Scale-Depression. We used these data to identify 11-year trajectories of depressive symptoms by latent class trajectory modelling. We screened participants for dementia at each examination round and followed up participants for 10 years for incident dementia by latent trajectory from the third examination round to 2014. We calculated hazard ratios (HR) for dementia by assigned trajectory using two Cox proportional hazards models (model 1 adjusted for age and sex only, and model 2 adjusted additionally for APOE?4 carrier status, educational level, body-mass index, smoking, alcohol consumption, cognitive score, use of antidepressants, and prevalent disease status at baseline). We repeated the analyses censoring for incident stroke, restricting to Alzheimer's disease as an outcome, and accounting for mortality as a competing risk for dementia.

Findings
From 1993?2004, we obtained data for depressive symptoms from at least one examination round for 3325 participants (median age: 74?88 years [IQR 70?62?80?06], 1995 [60%] women). We identified five trajectories of depressive symptoms in these 3325 individuals, characterised by maintained low CES-D scores (low; 2441 [73%]); moderately high starting scores but then remitting (decreasing; 369 [11%]); low starting scores, increasing, then remitting (remitting; 170 [5%]); low starting scores that steadily increased (increasing; 255 [8%]); and maintained high scores (high; 90 [3%]). During 26?330 person-years, 434 participants developed incident dementia. Only the trajectory with increasing depressive symptoms was associated with a higher risk of dementia compared with the low depressive symptom trajectory, using model 2 (HR 1?42, 95% CI 1?05?1?94; p=0?024). Additionally, only the increasing trajectory was associated with a higher risk of dementia compared with the low trajectory after censoring for incident stroke (1?58, 1?15?2?16; p=0?0041), restricting to Alzheimer's disease as an outcome (1?44, 1?03?2?02; p=0?034), and accounting for mortality as a competing risk (1?45, 1?06?1?97; p=0?019).

Interpretation
Risk of dementia differed with different courses of depression, which could not be captured by a single assessment of depressive symptoms. The higher risk of dementia only in the increasing trajectory suggests depression might be a prodrome of dementia.

Funding
Erasmus Medical Center; ZonMw; the Netherlands Ministry of Education Culture and Science; and the Netherlands Ministry for Health, Welfare and Sports.


rosacea

28-APR-2016http://www.eurekalert.org/

Rosacea linked to a slightly increased risk of dementia

A new study has uncovered an increased risk of dementia--in particular Alzheimer's disease--in patients with rosacea. Importantly, the risk was highest in older patients and in patients where rosacea was diagnosed by a hospital dermatologist. The findings are published in the Annals of Neurology, a journal of the American Neurological Association and Child Neurology Society.

Rosacea is a common chronic inflammatory skin disorder that is characterized by elevated expression of certain proteins--including matrix metalloproteinases and antimicrobial peptides--that are also involved in various neurodegenerative disorders such as Alzheimer's disease and other forms of dementia. Because of this potential link, a team led by Alexander Egeberg, MD, PhD, of University of Copenhagen, investigated the association between rosacea and dementia in Danish registers.

There were 5,591,718 Danish citizens aged ?18 between 1997 to 2012, including 82,439 patients with rosacea. Individuals were followed until December 31, 2012, migration, a diagnosis of dementia, or death from any cause, whichever came first. A total of 99,040 individuals developed dementia, of which 29,193 were diagnosed with Alzheimer's disease. After adjustments for potential confounding factors, patients with rosacea had a 7 percent increased risk of dementia and a 25 percent increased risk of Alzheimer's disease compared with individuals without rosacea. Stratified by sex, women had a 28 percent increased risk of Alzheimer's disease and men had a 16 percent increased risk if they had rosacea. When results were stratified by age at study entry, the risk of Alzheimer's disease was only significantly increased in individuals ?60 years (who had a 20 percent increased risk). When analyses were limited to patients with a hospital dermatologist diagnosis of rosacea only, the increased risks of dementia and Alzheimer's disease were 42 percent and 92 percent, respectively.

"A subtype of patients have prominent neurological symptoms such as burning and stinging pain in the skin, migraines, and neuropsychiatric symptoms, suggesting a link between rosacea and neurological diseases," explained Dr. Egeberg. "Indeed, emerging evidence suggests that rosacea may be linked with neurological disorders including Parkinson's disease and now also Alzheimer's disease. There are certain mechanistic overlaps between rosacea and Alzheimer's disease that may explain the observed association, albeit the pathogenic links between these conditions are still unclear."

Dr. Egeberg noted that it is important for patients to remember that having rosacea does not necessarily mean that they will develop dementia; however, the results may provide new insights into the link between the skin and neurodegenerative disorders. Further research is warranted to examine whether treating rosacea may also modify patients' risk of developing dementia.

###

Full citation: "Patients with rosacea have increased risk of dementia." Alexander Egeberg, Peter R. Hansen, Gunnar H. Gislason, and Jacob P. Thyssen. Annals of Neurology; Published Online: April 28, 2016 (DOI:10.1002/ana.24645).

URL Upon Publication: http://doi.wiley.com/10.1002/ana.24645

Author Contact: Lead author, Dr. Alexander Egeberg from the University of Copenhagen at alexander.egeberg@gmail.com.

About the Journal

Annals of Neurology, the official journal of the American Neurological Association and the Child Neurology Society, publishes articles of broad interest with potential for high impact in understanding the mechanisms and treatment of diseases of the human nervous system. All areas of clinical and basic neuroscience, including new technologies, cellular and molecular neurobiology, population sciences, and studies of behavior, addiction, and psychiatric diseases are of interest to the journal. The journal is published by Wiley on behalf of the American Neurological Association and Child Neurology Society. For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/ana.

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Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.


Patients with rosacea have increased risk of dementia
Alexander Egeberg MD1,2,*, Peter R. Hansen MD2, Gunnar H. Gislason MD2,3,4 andJacob P. Thyssen MD1
Article first published online: 28 APR 2016
DOI: 10.1002/ana.24645
? 2016 American Neurological Association

Objective
Rosacea is a common chronic inflammatory skin disorder where upregulation of matrix metalloproteinases (MMPs) and antimicrobial peptides (AMPs) is observed. Notably, inflammation, MMPs, and AMPs are also involved in the etiopathogenesis of neurodegenerative disorders including certain forms of dementia such as Alzheimer disease (AD). Based on several clinical observations, we investigated the association between rosacea and dementia, including AD in Danish registers.

Methods
All Danish citizens aged ?18 years between January 1, 1997 and December 31, 2012 were linked at the individual level through administrative registers. Cox regression was used to calculate unadjusted and adjusted hazard ratios (HRs).

Results
The study comprised a total of 5,591,718 individuals, including 82,439 patients with rosacea. A total of 99,040 individuals developed dementia (any form) in the study period, of whom 29,193 were diagnosed with AD. The adjusted HRs of dementia and AD were 1.07 (95% confidence interval [CI] = 1.01?1.14), and 1.25 (95% CI = 1.14?1.37), respectively, in patients with rosacea. Stratified by sex, the HRs of AD were 1.28 (95% CI = 1.15?1.45) and 1.16 (95% CI = 1.00?1.35) in women and men, respectively. When results were stratified by age at study entry, the risk of AD was only significantly increased in individuals ?60 years old (adjusted HR = 1.20, 95% CI = 1.08?1.32). When analyses were limited to patients with a hospital dermatologist diagnosis of rosacea only, the adjusted HRs of dementia and AD were 1.42 (95% CI = 1.17?1.72) and 1.92 (95% CI = 1.44?2.58), respectively.

Interpretation
Rosacea is significantly associated with dementia, particularly AD. Increased focus on symptoms of cognitive dysfunction in older patients with rosacea may be relevant. Ann Neurol 2016


anticholinergic

Common over-the-counter drugs can hurt your brain

CNN
April 18, 2016

(CNN)From allergies to insomnia, there's a pill for just about every problem. The problem is, those pills often come with a lengthy list of potential side effects.
And in the quest to cure what ails us as quickly as possible, those warnings are too often overlooked.
A new study, published Monday, offers the most definite proof yet of what scientists have known for at least a decade: that anticholinergic drugs (PDF) are linked with cognitive impairment and an increased risk of dementia.
Though you may have never heard of this class of drug, you've certainly heard of the medications themselves, including Benadryl, Demerol, Dimetapp, Dramamine, Paxil, Unisom and VESIcare. They are sold over the counter and by prescription as sleep aids and for chronic diseases including hypertension, cardiovascular disease and chronic obstructive pulmonary disease (COPD).
The new study is the first to examine the physical changes that serve as the catalyst for cognitive decline. Using brain imaging techniques, researchers at the Indiana University School of Medicine found (PDF) lower metabolism and reduced brain sizes among study participants taking anticholinergic drugs.
"These findings provide us with a much better understanding of how this class of drugs may act upon the brain in ways that might raise the risk of cognitive impairment and dementia," said Shannon Risacher, an assistant professor of radiology and imaging sciences.
The study looked at 451 people, with an average age of 73. Sixty of them were taking at least one medication with medium or high anticholinergic activity. To identify physical and physiological changes that could be associated with the reported effects, researchers assessed the results of memory and cognitive tests; PET scans, to measure brain metabolism; and MRI scans, to assess brain structure.
The cognitive tests revealed that people taking anticholinergic drugs performed worse on short-term memory tests, as well as on some tests of executive function, including verbal reasoning, planning and problem-solving.
Anticholinergic drug users also showed lower levels of glucose metabolism -- a biomarker for brain activity -- both in the brain overall and in the hippocampus, a region of the brain associated with memory and which has been identified as affected early by Alzheimer's disease. The participants using anticholinergic drugs were also found to have reduced brain volume and larger ventricles, the cavities inside the brain.
"These findings might give us clues to the biological basis for the cognitive problems associated with anticholinergic drugs, but additional studies are needed if we are to truly understand the mechanisms involved," Risacher said.
A 2013 study by scientists at the Indiana University Center for Aging Research (PDF) found that drugs with a strong anticholinergic effect cause cognitive problems when taken continuously for as few as 60 days. Drugs with a weaker effect could cause impairment within 90 days.
"Given all the research evidence, physicians might want to consider alternatives to anticholinergic medications, if available, when working with their older patients," Risacher said.
Of course, never start or stop taking a medication without first consulting your doctor.


Original Investigation | April 18, 2016
Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults
ONLINE FIRST

Shannon L. Risacher, PhD1,2; Brenna C. McDonald, PsyD, MBA1,2,3; Eileen F. Tallman, BS1,2; John D. West, MS1,2; Martin R. Farlow, MD2,3; Fredrick W. Unverzagt, PhD2,4; Sujuan Gao, PhD2,5; Malaz Boustani, MD, MPH2,6,7,8; Paul K. Crane, MD, MPH9; Ronald C. Petersen, MD, PhD10; Clifford R. Jack Jr, MD11; William J. Jagust, MD12; Paul S. Aisen, MD13; Michael W. Weiner, MD14,15; Andrew J. Saykin, PsyD1,2 ; for the Alzheimer’s Disease Neuroimaging Initiative
JAMA Neurol. Published online April 18, 2016. doi:10.1001/jamaneurol.2016.0580 Text

ABSTRACT
The use of anticholinergic (AC) medication is linked to cognitive impairment and an increased risk of dementia. To our knowledge, this is the first study to investigate the association between AC medication use and neuroimaging biomarkers of brain metabolism and atrophy as a proxy for understanding the underlying biology of the clinical effects of AC medications.

Objective To assess the association between AC medication use and cognition, glucose metabolism, and brain atrophy in cognitively normal older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Indiana Memory and Aging Study (IMAS).

Design, Setting, and Participants The ADNI and IMAS are longitudinal studies with cognitive, neuroimaging, and other data collected at regular intervals in clinical and academic research settings. For the participants in the ADNI, visits are repeated 3, 6, and 12 months after the baseline visit and then annually. For the participants in the IMAS, visits are repeated every 18 months after the baseline visit (402 cognitively normal older adults in the ADNI and 49 cognitively normal older adults in the IMAS were included in the present analysis). Participants were either taking (hereafter referred to as the AC+ participants [52 from the ADNI and 8 from the IMAS]) or not taking (hereafter referred to as the AC? participants [350 from the ADNI and 41 from the IMAS]) at least 1 medication with medium or high AC activity. Data analysis for this study was performed in November 2015.

Main Outcomes and Measures Cognitive scores, mean fludeoxyglucose F 18 standardized uptake value ratio (participants from the ADNI only), and brain atrophy measures from structural magnetic resonance imaging were compared between AC+ participants and AC? participants after adjusting for potential confounders. The total AC burden score was calculated and was related to target measures. The association of AC use and longitudinal clinical decline (mean [SD] follow-up period, 32.1 [24.7] months [range, 6-108 months]) was examined using Cox regression.

Results The 52 AC+ participants (mean [SD] age, 73.3 [6.6] years) from the ADNI showed lower mean scores on Weschler Memory Scale?Revised Logical Memory Immediate Recall (raw mean scores: 13.27 for AC+ participants and 14.16 for AC? participants; P?=?.04) and the Trail Making Test Part B (raw mean scores: 97.85 seconds for AC+ participants and 82.61 seconds for AC? participants; P?=?.04) and a lower executive function composite score (raw mean scores: 0.58 for AC+ participants and 0.78 for AC? participants; P?=?.04) than the 350 AC? participants (mean [SD] age, 73.3 [5.8] years) from the ADNI. Reduced total cortical volume and temporal lobe cortical thickness and greater lateral ventricle and inferior lateral ventricle volumes were seen in the AC+ participants relative to the AC? participants.

Conclusions and Relevance The use of AC medication was associated with increased brain atrophy and dysfunction and clinical decline. Thus, use of AC medication among older adults should likely be discouraged if alternative therapies are available.


Colonic diverticular disease

Colonic Diverticular Disease May Increase Dementia Risk

http://www.psychiatryadvisor.com/
April 11, 2016

Researchers found an elevated risk of dementia after adjustment for age, sex, and comorbidities.Researchers found an elevated risk of dementia after adjustment for age, sex, and comorbidities.

HealthDay News ? Colonic diverticular disease appears to be associated with increased risk of dementia in a population from Taiwan, according to a study published online March 31 in the Journal of Gastroenterology and Hepatology.
Yen-Chun Peng, MD, from the Taichung Veterans General Hospital in Taipei, Taiwan, and colleagues used data from Taiwan's National Health Insurance Research Database to examine the potential increased risk for dementia in colonic diverticular disease. Data were included for 66 377 sex-, age-, and index year-matched patients with colonic diverticular disease and 265 508 control patients without colonic diverticular disease. Incident cases of dementia were identified from 2000 to 2011.

The researchers identified 1057 dementia cases in the diverticular disease cohort during 315 171 person-years of follow-up. The overall incidence rate of dementia was 3.35 per 1000 person-years in the diverticular disease cohort versus 2.43 per 1000 person-years in the control group (P < 0.001). After adjustment for age, sex, and comorbidities, the adjusted hazard ratio for dementia was 1.24 for colonic diverticular disease patients.
"We demonstrated that diverticular disease and associated comorbidities are risk factors, with joint effects, for dementia," the authors wrote. "Dementia prevention may be possible by controlling risk factors at the population level. Such risk factors may include diverticular disease and comorbidities."

Reference
Peng Y, Lin C, Yeh H, Tung C, Chang C, Kao C..
Diverticular disease and additional comorbidities associated with increased risk of dementia.
J Gastroen Hepatol. 2016; doi:10.1111/jgh.13389.

Abstract
Objectives
Colonic diverticular disease may cause a chronic systemic effect, but its role in the development of dementia remains unclear. The purpose of this study was to investigate the potential increased risk for dementia in colonic diverticular disease.
Methods
We conducted a population-based cohort study using data from Taiwan's National Health Insurance Research Database. A total of 66,377 sex-, age-, and index year-matched (1:4) pairs of patients with colonic diverticular disease and 265,508 patients without colonic diverticular disease, who served as controls, were selected from all potential participants aged 20?years or older in the database. Each subject was individually tracked from 2000 to 2011 to identify incident cases of dementia. Cox proportional hazards regression was employed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between colonic diverticular disease and dementia.
Results
There were 1057 dementia cases in the diverticular disease cohort during the follow-up period of 315,171 person-years; the overall incidence rate of dementia differed from that of the control group (3.35 vs. 2.43 per 1000 person-years, p?<?0.001). The adjusted HR for dementia was 1.24 (95% CI 1.15?1.33) for diverticular disease patients after adjusting for age, sex, and comorbidities.
Conclusions
Colonic diverticular disease may be associated with increased risk for dementia.


NSAID

March 24, 2016
http://www.neurologyadvisor.com/

Decreased Risk of Dementia With Prolonged NSAID Exposure in RA

In this patient population, no significant association was observed between risk of dementia and RA development.

A longer period of treatment with non-steroid anti-inflammatory drugs (NSAIDs) was associated with a decreased risk of dementia among patients with rheumatoid arthritis (RA) in a large population-based cohort, according to recent findings published in Medicine.
Previous studies have suggested that early inflammation, cardiovascular disease, and depression are associated with increased risk of dementia. The authors of the study noted that NSAIDs are “commonly used for treating RA, and several studies suggest that NSAIDs reduce the risk of Alzheimer disease (AD) or dementia in patients with RA.”
Using data from the Registry of the Catastrophic Illnesses Patient Database, a Taiwanese nationwide database created to track major illnesses, researchers examined a cohort of 33 229 patients at least 20 years of age with newly diagnosed RA between 2000 and 2011. A second cohort of 132 916 patients without RA was frequency matched with the RA cohort according to age, sex, and year of RA diagnosis.

The risk of dementia among participants with RA was not significantly higher than the participants without RA (3.34 vs 3.74 per 1000 person years; adjusted hazard ratio [HR]: 0.95; 95% confidence interval [CI]: 0.87-1.02).
When researchers compared duration of NSAID treatment, the risk of dementia was significantly lower for participants with RA who used NSAIDs for more than 2191 days compared with the participants who used NSAIDs for less than 730 days (HR: 0.56; 95% CI: 0.45-0.68).
“Our findings reveal no significant association between the risk of dementia and RA,” the authors concluded. “Nevertheless, it is suggested that prolonged use of NSAIDs reduces the risk of dementia in patients with RA. Because of the limitations of the NHIRD [National Health Insurance Research Database], it is necessary to conduct an experimental study determining the mechanism underlying the association of dementia risk with NSAID treatment in patients with RA.”
Summary and Clinical Applicability
NSAIDs are commonly used to alleviate RA-associated chronic pain, inflammation and swelling. Researchers conducted a study to evaluate the association between dementia risk and NSAID treatment in individuals with RA. While there was no observed association between RA risk and dementia risk, prolonged NSAID treatment was associated with reduced incidence of dementia.
The true baseline risk of dementia in RA patients, however, was difficult to estimate, limited by the availability of data from the NHIRD. Results from testing for neurocognitive pathology such as serum electrolytes, electroencephalograms, and neuroimaging were lacking in the database.
Further research should be conducted to determine the mechanism causing the association between dementia risk and NSAID treatment.
Reference
Chang KH, Hsu YC, Hsu CC, et al. Prolong Exposure of NSAID in Patients with RA Will Decrease Risk of Dementia. Medicine. 2016; 95(10):1-6. doi: 10.1097/MD.0000000000003056.
This article originally appeared on Rheumatology Advisor.

Medicine (Baltimore). 2016 Mar;95(10):e3056. doi: 10.1097/MD.0000000000003056.
Prolong Exposure of NSAID in Patients With RA Will Decrease the Risk of Dementia: A Nationwide Population-Based Cohort Study.
Chang KH1, Hsu YC, Hsu CC, Lin CL, Hsu CY, Lee CY, Chong LW, Liu HC, Lin MC, Kao CH.
Author information
Abstract
Rheumatoid arthritis (RA), a chronic, systemic inflammatory disorder, primarily affects joints. Several studies have indicated that early inflammation, cardiovascular disease, and depression in patients were associated with a considerably increased risk of dementia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for treating RA. NSAIDs facilitate alleviating RA-associated chronic pain, inflammation, and swelling. Therefore, we conducted this nationwide study for evaluating the association between the dementia risk and NSAID treatment in patients with RA.The RA cohort comprised patients aged 20 years and older who were newly diagnosed with RA between 2000 and 2011, with data obtained from the Registry of Catastrophic Illnesses Patient Database (RCIPD). Patients without RA were frequency matched with the RA cohort at a 1:4 ratio according to age, sex, and year of RA diagnosis. The relative risks of dementia were estimated using Cox proportional hazard models.The risk of dementia in the RA cohort was not significantly higher than that in the non-RA cohort (adjusted HR [hazard ratio]?=?0.95, 95% confidence interval [CI]?=?0.87-1.02). Regarding the duration of NSAID treatment, the risk of dementia was significantly lower when the RA cohort used NSAIDs for >2191 days (HR?=?0.56, 95% CI?=?0.45-0.68).A longer duration of NSAID treatment possibly reduces the risk of dementia. Additional studies are warranted for verifying the association of dementia risk with NSAID treatment in patients with RA.


periodontitis

Gum disease link to Alzheimer's, research suggests
By Dominic Howell
BBC News
10/03/2016

Gum disease has been linked to a greater rate of cognitive decline in people with Alzheimer's disease, early stage research has suggested.
The small study, published in PLOS ONE, looked at 59 people who were all deemed to have mild to moderate dementia.
It is thought the body's response to gum inflammation may be hastening the brain's decline.
The Alzheimer's Society said if the link was proven to be true, then good oral health may help slow dementia.
The body's response to inflammatory conditions was cited as a possible reason for the quicker decline.
Inflammation causes immune cells to swell and has long been associated with Alzheimer's. Researchers believe their findings add weight to evidence that inflammation in the brain is what drives the disease.
'Six-fold increase'
The study, jointly led by the University of Southampton and King's College London, cognitively assessed the participants, and took blood samples to measure inflammatory markers in their blood.
Their oral health was also assessed by a dental hygienist who was unaware of the cognitive outcomes.
Of the sample group, 22 were found to have considerable gum disease while for the remaining 37 patients the disease was much less apparent. The average age of the group with gum disease was 75, and in the other group it was 79.
A majority of participants - 52 - were followed up at six months, and all assessments were repeated.
The presence of gum disease - or periodontitis as it is known - was associated with a six-fold increase in the rate of cognitive decline, the study suggested.
'Quite scary'
Dentist Dr Mark Ide from King's College London told the BBC News website he was "surprised" by the rate of decline, and said that as patients with gum disease chew on their teeth they were effectively giving themselves "mini-injections" of bacteria into their bloodstream.
"In just six months you could see the patients going downhill - it's really quite scary," he said.
Higher levels of antibodies to periodontal bacteria are associated with an increase in levels of inflammatory molecules elsewhere in the body - which in turn have been linked to greater rates of cognitive decline in Alzheimer's disease.
Prof Clive Holmes, senior author from the University of Southampton, said the results were "very interesting" and proved that this study needed to be carried out again but using a larger number of participants.
"However, if there is a direct relationship between periodontitis and cognitive decline, as this current study suggests, then treatment of gum disease might be a possible treatment option for Alzheimer's," he said.
He also said his researchers had taken into account the fact that gum disease may become more common in those people with Alzheimer's, because of a reduced ability to take care of oral hygiene as the disease progresses.
Cause or effect?
Dr Doug Brown, director of research and development at the Alzheimer's Society, also recognised that the study "adds evidence to the idea that gum disease could potentially be a contributing factor to Alzheimer's".
"If this is proven to be the case, better dental hygiene would offer a relatively straightforward way to help slow the progression of dementia and enable people to remain independent for longer," he said.
But he also described the study as "small" and said it was currently "unclear" whether the gum disease was the cause or the effect.
"We don't know if the gum disease is triggering the faster decline of dementia, or vice versa," he said.
In the UK around 80% of adults over 55 years old had evidence of gum disease, according to the adult dental survey of 2009, which is the latest data available.
There are around half a million people living with Alzheimer's disease in the UK .


Periodontitis and Cognitive Decline in Alzheimer’s Disease
Mark Ide , Marina Harris , Annette Stevens , Rebecca Sussams , Viv Hopkins , David Culliford , James Fuller , Paul Ibbett , Rachel Raybould , Rhodri Thomas , Ursula Puenter , Jessica Teeling , V. Hugh Perry , Clive Holmes

Published: March 10, 2016DOI: 10.1371/journal.pone.0151081

Abstract

Periodontitis is common in the elderly and may become more common in Alzheimer’s disease because of a reduced ability to take care of oral hygiene as the disease progresses. Elevated antibodies to periodontal bacteria are associated with an increased systemic pro-inflammatory state. Elsewhere raised serum pro-inflammatory cytokines have been associated with an increased rate of cognitive decline in Alzheimer’s disease. We hypothesized that periodontitis would be associated with increased dementia severity and a more rapid cognitive decline in Alzheimer’s disease. We aimed to determine if periodontitis in Alzheimer’s disease is associated with both increased dementia severity and cognitive decline, and an increased systemic pro inflammatory state. In a six month observational cohort study 60 community dwelling participants with mild to moderate Alzheimer’s Disease were cognitively assessed and a blood sample taken for systemic inflammatory markers. Dental health was assessed by a dental hygienist, blind to cognitive outcomes. All assessments were repeated at six months. The presence of periodontitis at baseline was not related to baseline cognitive state but was associated with a six fold increase in the rate of cognitive decline as assessed by the ADAS-cog over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state over the six month follow up period. Our data showed that periodontitis is associated with an increase in cognitive decline in Alzheimer’s Disease, independent to baseline cognitive state, which may be mediated through effects on systemic inflammation.


Using a computer

Logging on 'could reduce dementia risk': Elderly who use a computer once a week are 42% less likely to develop mild impairment that is warning sign

Experts found using a computer as you age may help keep memory intact
Those who used a computer at least once a week were 42 per cent less likely than those who didn't to develop mild cognitive impairment
Reading magazines saw the likelihood reduced by 30 per cent, attending social events by 23 per cent and crafts such as knitting by 16 per cent

By BEN SPENCER MEDICAL CORRESPONDENT
THE DAILY MAIL
4 March 2016

Using a computer as you age may help keep your memory intact, experts found.
Scientists have linked numerous activities with preserving brain power in the elderly ? but logging on seems particularly effective.
The American study found that those who used a computer at least once a week were 42 per cent less likely than those who didn't to develop mild cognitive impairment, which is often a warning sign for dementia.

By comparison, reading magazines saw the likelihood reduced by 30 per cent, attending social events by 23 per cent and crafts such as knitting by 16 per cent.
The findings come from a team at the Mayo Clinic in Arizona, who spent four years tracking nearly 2,000 people over 70.
Study leader Dr Janina Krell-Roesch, whose work is to be presented at the American Academy of Neurology annual meeting in Vancouver, Canada, next month, said: 'The results show the importance of keeping the mind active as we age.
'While this study only shows association, not cause and effect, as people age, they may want to consider participating in activities like these because they may keep a mind healthier, longer.'
Dr Clare Walton, of the UK Alzheimer's Society, said: 'There is increasing evidence that staying mentally and socially active is an important way to keep our brains healthy as we age.
'This could include activities such as regularly doing puzzles, trying out arts and crafts or joining a book group.
'Although this research is only preliminary, it should be encouraging to today' s generation of silver surfers that using a computer might also help to keep memory sharp.'

She added: 'Dementia, however, is a complex condition and we do not know what effect these activities have on the risk of developing it.
'Currently, the best evidence for reducing your risk of dementia is to exercise regularly, avoid smoking and eating a healthy, balanced diet.'
The results come after separate research, published last week, found that people who keep mentally active through middle age have less of a build-up of toxins in the brain.
That study, also led by the Mayo Clinic, may suggest why people with higher levels of education are slightly less likely to develop Alzheimer's.
The team found that people with at least 14 years of education, and who kept mentally active in middle age, had smaller build-ups of amyloid plaques, brain toxins that are thought to be instrumental in causing Alzheimer's.


Proton Pump Inhibitors (PPI)

Proton Pump Inhibitors Linked to Dementia

Pauline Anderson
February 15, 2016
Medscape Medical News

A new study has confirmed an association between proton pump inhibitors (PPIs) ? drugs that treat heartburn, peptic ulcers, and other acid-related disorders of the upper gastrointestinal tract ? and increased risk for dementia in older patients.

An earlier study by the same researchers found the same connection between PPI use and dementia risk, although the current study is larger and based on information from a pharmaceutical database rather than on medical records, as the previous one was.

The new study, by Willy Gomm, PhD, from the German Center for Neurodegenerative Diseases, Bonn, Germany, and colleagues and published online February 15 in JAMA Neurology, is important, as PPIs are among the most frequently prescribed drugs and their use has been increasing sharply, especially among the elderly.

"Unfortunately, overprescribing of PPIs is reported frequently," said study coauthor Britta Haenisch, PhD, also from the German Center for Neurodegenerative Diseases.

According to some research, up to 70% of all PPI prescriptions could be inappropriate, she told Medscape Medical News.

"In general, clinicians should follow guidelines for PPI prescription to avoid overprescribing PPIs and inappropriate use."

The study used the largest mandatory public health insurer in Germany, which includes one third of the overall population and as much as 50% of the elderly population. Its database includes information on diagnoses and drug prescriptions.

The analysis included 73,679 subjects aged 75 years or older who initially did not have dementia at baseline. Over the course of the study (2004 - 2011), 29,510 subjects were diagnosed with dementia. More than half (59.0%) had a diagnosis of at least two different types of dementia.

Researchers focused on regular PPI prescription for at least 18 months. They looked at intervals starting with a 1-year baseline in 2004 followed by 18-month intervals, with the last interval lasting 12 months.

Regular PPI use was defined as at least one prescription per quarter in these intervals of omeprazole, pantoprazole, lansoprazole, esomeprazole, or rabeprazole.

The results showed that 2950 patients were regularly using a PPI. These users had a significantly higher risk for dementia compared with those not taking this drug (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.36 - 1.52; P < .001).

Depression and Stroke

Several confounding factors were significantly associated with increased dementia risk; for example, depression (HR, 1.28; 95% CI, 1.24 - 1.32; P < .001) and stroke (HR, 1.37; 95% CI, 1.29 - 1.46; P < .001).

Having diabetes and being prescribed five or more drugs other than the PPI (defined as polypharmacy) were also associated with significantly elevated dementia risk.

"In our analysis, polypharmacy elevated the risk for occurrence of dementia by about 16%," commented Dr Haenisch.

For the three most prescribed PPIs (omeprazole, pantoprazole, and esomeprazole), researchers performed subgroup analyses and found similar results.

To examine the effect of duration of PPI use, the researchers analyzed occasional use, defined as a prescription in less than six quarters within an interval. They found a lower HR for occasional use (HR, 1.16; 95% CI, 1.13 - 1.19). Continue Reading

The risk for dementia with PPI use gradually decreased with age, with the highest HR among those aged 75 to 79 years. Depression and stroke also had lower effect sizes with increasing age.

"This might reflect the decreasing influence of external and internal factors on dementia progression with age, possibly owing to an already initiated disease process," the authors write.

Researchers are not clear on how PPI use might raise dementia risk. Evidence suggests some PPIs may cross the blood?brain barrier and interact with brain enzymes and, in mice, may increase beta amyloid levels in the brain.

Although the current study did not include vitamin B12 levels, other research has linked PPI use to vitamin B12 deficiency, which has been shown to be associated with cognitive decline, Dr Haenisch noted.

The new results coincide with those of the research group's earlier study: the German Study on Aging, Cognition and Dementia in Primary Care Patients (AgeCoDe). That study, which included 3327 community-dwelling patients aged 75 years and older, also found a link between PPI use and dementia, with an HR of 1.38 (95% CI, 1.04 - 1.84).

Because the claims data used in the current study lack detailed sociodemographic parameters, the researchers could not integrate education levels into the analysis.

"This is a limitation of the study that has to be taken into account when interpreting the results," commented Dr Haenisch. "In the previous AgeCoDe study, we were able to include education into the analysis, and it did not mainly affect the result."

Also unlike the earlier study, the current one did not assess the effect of APOE 4 status.

There are several alternatives to PPIs to treat gastrointestinal disorders in the elderly. According to Dr Haenisch, these include histamine H2 receptor antagonists, prostaglandins, and antacids.

Dr Haenisch stressed that the study can only provide a statistical association between PPI prescription and occurrence of dementia and does not prove that PPIs cause dementia. To evaluate the cause-and-effect relationships in the elderly, randomized, prospective clinical trials are needed, she said.

More People With Dementia

In his accompanying editorial, Lewis H. Kuller, MD, DrPH, from the Graduate School of Public Health, Department of Epidemiology, University of Pittsburgh, Pennsylvania, notes that even a relatively small increased risk for dementia could translate into many more people in the population having dementia.

For example, he writes, a 1.4-fold increased risk, as suggested by the study, would increase the estimated incidence rate of dementia from 6.0% to about 8.4% per year.

In the United States, 13.5 million people are in the 75- to 84-year-old age bracket. If 3% of them were receiving PPIs, this could result in an increase of about 10,000 new cases of incident dementia per year in this age group alone, said Dr Kuller.

Dr Kuller also pointed to evidence of PPIs possibly increasing both production and degradation of amyloid, at least in animals, and of reduced B12 and other nutrients among PPI users, which could be tied to dementia risk. However, he said, it is possible that the association between PPI use and dementia is not causal.

Older people, said Dr Kuller, often take many drugs, which may reflect the extent of disease and comorbidities. Specific drugs may be associated with both PPI use and dementia.

The authors, said Dr Kuller, "have provided an important and interesting challenge" to evaluate the possible association between PPI use and dementia risk. Their study raises the issue of "whether a careful evaluation of cognitive changes and/or neuropathology should be a component of the evaluation of drugs that are widely used among the elderly," he concludes.

There was no outside funding for the study. The authors and Dr Kuller have disclosed no relevant financial relationships.

JAMA Neurol. Published online February 15, 2016. Article abstract, Editorial extract

Association of Proton Pump Inhibitors With Risk of Dementia A Pharmacoepidemiological Claims Data Analysis
ONLINE FIRST
Willy Gomm, PhD1; Klaus von Holt, MD, PhD1; Friederike Thom?, MSc1; Karl Broich, MD2; Wolfgang Maier, MD1,3; Anne Fink, MSc1,4; Gabriele Doblhammer, PhD1,4,5,6; Britta Haenisch, PhD1
[+] Author Affiliations
JAMA Neurol. Published online February 15, 2016. doi:10.1001/jamaneurol.2015.4791

ABSTRACT
Importance Medications that influence the risk of dementia in the elderly can be relevant for dementia prevention. Proton pump inhibitors (PPIs) are widely used for the treatment of gastrointestinal diseases but have also been shown to be potentially involved in cognitive decline.

Objective To examine the association between the use of PPIs and the risk of incident dementia in the elderly.

Design, Setting, and Participants We conducted a prospective cohort study using observational data from 2004 to 2011, derived from the largest German statutory health insurer, Allgemeine Ortskrankenkassen (AOK). Data on inpatient and outpatient diagnoses (coded by the German modification of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision) and drug prescriptions (categorized according to the Anatomical Therapeutic Chemical Classification System) were available on a quarterly basis. Data analysis was performed from August to November 2015.

Exposures Prescription of omeprazole, pantoprazole, lansoprazole, esomeprazole, or rabeprazole.

Main Outcomes and Measures The main outcome was a diagnosis of incident dementia coded by the German modification of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. The association between PPI use and dementia was analyzed using time-dependent Cox regression. The model was adjusted for potential confounding factors, including age, sex, comorbidities, and polypharmacy.

Results A total of 73?679 participants 75 years of age or older and free of dementia at baseline were analyzed. The patients receiving regular PPI medication (n?=?2950; mean [SD] age, 83.8 [5.4] years; 77.9% female) had a significantly increased risk of incident dementia compared with the patients not receiving PPI medication (n?=?70?729; mean [SD] age, 83.0 [5.6] years; 73.6% female) (hazard ratio, 1.44 [95% CI, 1.36-1.52]; P?<?.001).

Conclusions and Relevance The avoidance of PPI medication may prevent the development of dementia. This finding is supported by recent pharmacoepidemiological analyses on primary data and is in line with mouse models in which the use of PPIs increased the levels of β-amyloid in the brains of mice. Randomized, prospective clinical trials are needed to examine this connection in more detail.


bexarotene

GM worm study provides 'powerful first step' towards preventing Alzheimer's

12 February 2016
theguardian

Research is at a very early stage, but scientists are hopeful that a ‘neurostatin’ preventative drug for neurological conditions will become a reality

Scientists working on genetically modified worms have made what they hope are the first steps towards developing a preventative treatment for Alzheimer’s disease.

The study, published in the journal Science Advances and presented at the American Association for the Advancement of Science conference, describes how researchers modified nematode worms to develop Alzheimer’s-like symptoms, and then applied the existing anti-cancer drug, bexarotene, at various stages of the disease.

“We showed that these worms that were doomed to develop Alzheimer’s disease could be rescued,” said study author Michele Vendruscolo, of the University of Cambridge.

“It is a powerful first step,” he said. “It is very exciting, but at the same time we are very aware it the first step and many things can go wrong.”

Researchers believe that Alzheimer’s destroys brain function through a catastrophic cascade of events: natural proteins start folding and glomming onto each other in dysfunctional ways, a process that in turn creates the toxic molecules thought to kill brain cells.

When the proteins started malfunctioning in the worms, the drug could do nothing to save them. But if administered before symptoms developed, it prevented the first stage of the process.

Vendruscolo said that timing and dosage would be critical to any potential drug ? as would far more testing and a greater understanding of Alzheimer’s. The disease is believed to be caused by both genetics and environmental factors, but remains poorly understood in many ways, especially for identifying people at risk.

“If you have a genetic change, we know you are at risk,” he said. “But this is maybe 5% of cases.”

He said that “the spirit” of a drug to prevent neurological conditions would be similar to the way statins are used to prevent heart disease: “given to people that are more at risk of disease and given fairly early, ideally one or two decades before the symptoms appear.”

Bexarotene was the first of about a dozen potential drug compounds identified by the research.

Vendruscolo and other researchers agreed that any possible preventative requires extensive testing on mice or miniature balls of cells that mimic human brains reprogrammed for the disease.

Kenneth Langa, a professor at the University of Michigan, said he was skeptical of any claims to have identified a ‘neurostatin’.

The study “only looked at the first step in a hypothetical disease process that might lead to Alzheimer’s,” he said. “To me, this looks like the first step in a million-mile journey.”

But Vendruscolo remains hopeful. “We get Alzheimer’s and other neurodegenerative diseases in old age because it is when our natural defenses start to crumble,” he said. “The dream would be to find a compound which is cheap and safe and therefore can be given early to everybody.”

Dr Rosa Sancho, lead scientist of Alzheimer’s Research UK, noted that a recent clinical trial of bexarotene with people who have Alzheimer’s was not successful. “But this new work in worms suggests the drug may need to be given very early in the disease,” she said.

The accumulation of the amyloid proteins is “a hallmark feature” of the disease, she said, adding that drugs to protect nerve cells from them could be consequential.

“We will now need to see whether this new preventative approach could halt the earliest biological events in Alzheimer’s and keep damage at bay in further animal and human studies.”


An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer’s disease
Johnny Habchi1, Paolo Arosio1, Michele Perni1, Ana Rita Costa1, Maho Yagi-Utsumi1, Priyanka Joshi1, Sean Chia1, Samuel I. A. Cohen1, Martin B. D. M?ller2, Sara Linse3, Ellen A. A. Nollen2, Christopher M. Dobson1,*, Tuomas P. J. Knowles1,* and Michele Vendruscolo1,*
+ Author Affiliations
?*Corresponding author. E-mail: mv245@cam.ac.uk (M.V.); tpjk2@cam.ac.uk (T.P.J.K.); cmd44@cam.ac.uk (C.M.D.)
Science Advances 12 Feb 2016:
Vol. 2, no. 2, e1501244
DOI: 10.1126/sciadv.1501244

Abstract

The conversion of the β-amyloid (Aβ) peptide into pathogenic aggregates is linked to the onset and progression of Alzheimer’s disease. Although this observation has prompted an extensive search for therapeutic agents to modulate the concentration of Aβ or inhibit its aggregation, all clinical trials with these objectives have so far failed, at least in part because of a lack of understanding of the molecular mechanisms underlying the process of aggregation and its inhibition. To address this problem, we describe a chemical kinetics approach for rational drug discovery, in which the effects of small molecules on the rates of specific microscopic steps in the self-assembly of Aβ42, the most aggregation-prone variant of Aβ, are analyzed quantitatively. By applying this approach, we report that bexarotene, an anticancer drug approved by the U.S. Food and Drug Administration, selectively targets the primary nucleation step in Aβ42 aggregation, delays the formation of toxic species in neuroblastoma cells, and completely suppresses Aβ42 deposition and its consequences in a Caenorhabditis elegans model of Aβ42-mediated toxicity. These results suggest that the prevention of the primary nucleation of Aβ42 by compounds such as bexarotene could potentially reduce the risk of onset of Alzheimer’s disease and, more generally, that our strategy provides a general framework for the rational identification of a range of candidate drugs directed against neurodegenerative disorders.


Lipid-based Diets

Lipid-based Diets Effectively Combat Alzheimer's Disease In Mouse Model

February 10th 2016
science20

Alzheimer´s disease (AD) is the most common disease underlying memory problems and dementia in the elderly. One of the invariable pathologies in AD is degeneration of cholinergic synapses in brain cortex and hippocampus. Despite enormous effort to find out an efficient treatment, current pharmacological interventions are limited to a few drugs that alleviate symptoms but do not slow down the underlying disease processes. These drugs include inhibitors of cholinesterases, enzymes that degrade the neurotransmitter acetylcholine, or memantine, a modulator of glutamate neurotransmission.

It is generally accepted that lifestyle and particularly dietary habits influence mental health, and prevalence and progression of AD. Numerous epidemiological studies have revealed profitable effects of dietary intake of especially fish oil on cognitive decline during aging and dementia.

Within the EU-funded project LipiDiDiet (FP7-211696, therapeutic and preventive impact of nutritional lipids on neuronal and cognitive performance in aging, Alzheimer´s disease and vascular dementia, researchers devised several lipid-based diets aimed at slowing down progression and relieving symptoms of AD. Short-term (3 weeks) feeding of young adult APPswe/PS1dE9 mice (transgenic mouse model of AD) with experimental diets containing fish oil or stigmasterol reversed the decrease in responsiveness of hippocampal muscarinic receptors to acetylcholine compared to their non-transgenic littermates. Only fish oil based diet enriched with nutrients supporting neuroprotection (Fortasyn diet) increased in addition the density of muscarinic receptors and cholinergic synapses in the hippocampus.

Researchers have devised several lipid-based diets aimed at slowing down progression and relieving symptoms of Alzheimer's disease.

These findings yield important proof-of-principle evidence that regular intake of specific dietary components may help to prevent some of the key early functional changes that take place in the Alzheimer brain. These findings support viability of the dietary approach in AD.

source: Bentham Science Publishers

Lipid-Based Diets Improve Muscarinic Neurotransmission in the Hippocampus of Transgenic APPswe/PS1dE9 Mice

Current Alzheimer Research, 12(10): 923-931.

Author(s): Helena Janickova, Vladimir Rudajev, Eva Dolejsi, Hennariikka Koivisto, Jan Jakubik, Heikki Tanila, Esam E. El-Fakahany and Vladimir Dolezal.

Affiliation: Institute of Physiology CAS, Department of Neurochemistry, V?denska 1083, 14220 Prague 4, Czech Republic.

Abstract

Transgenic APPswe/PS1dE9 mice modeling Alzheimer’s disease demonstrate ongoing accumulation of β-amyloid fragments resulting in formation of amyloid plaques that starts at the age of 4-5 months. Buildup of β-amyloid fragments is accompanied by impairment of muscarinic transmission that becomes detectable at this age, well before the appearance of cognitive deficits that manifest around the age of 12 months. We have recently demonstrated that long-term feeding of trangenic mice with specific isocaloric fish oil-based diets improves specific behavioral parameters. Now we report on the influence of short-term feeding (3 weeks) of three isocaloric diets supplemented with Fortasyn (containing fish oil and ingredients supporting membrane renewal), the plant sterol stigmasterol together with fish oil, and stigmasterol alone on markers of cholinergic neurotransmission in the hippocampus of 5-month-old transgenic mice and their wild-type littermates. Transgenic mice fed normal diet demostrated increase in ChAT activity and attenuation of carbachol-stimulated GTP-γ35S binding compared to wild-type mice. None of the tested diets compared to control diet influenced the activities of ChAT, AChE, BuChE, muscarinic receptor density or carbachol-stimulated GTP-γ35S binding in wild-type mice. In contrast, all experimental diets increased the potency of carbachol in stimulating GTP-γ35S binding in trangenic mice to the level found in wild-type animals. Only the Fortasyn diet increased markers of cholinergic synapses in transgenic mice. Our data demonstrate that even short-term feeding of transgenic mice with chow containing specific lipid-based dietary supplements can influence markers of cholinergic synapses and rectify impaired muscarinic signal transduction that develops in transgenic mice.


Taser’s Electric Shock

Taser’s Electric Shock Causes Dementia-Like Symptoms, Undermines Police Interrogations, Study Says

BY HIMANSHU GOENKA
02/05/16
http://www.ibtimes.com/

The burst of electricity from a stun gun can disrupt the functioning of the brain, negatively affecting “a person’s ability to remember and process information,” according to a new study carried out by Drexel University and Arizona State University (ASU).

In the first-of-its-kind study, researchers subjected participants to 50,000-volt Taser shocks and then tested them for cognitive impairment. Some test participants showed “short-term declines in cognitive functioning comparable to dementia,” according to a statement on the Drexel University website. Given the use of stun guns by 17,000 police departments across the United States, the study raised “serious questions about the ability of police suspects to understand their rights at the point of arrest.”

Authored by Professor Robert J. Kane of Drexel, and Professor Michael D. White and Assistant Professor Justin Ready of ASU, the study was funded by the U.S. Department of Justice’s National Institute of Justice. It was the first time that Taser was going through “a major randomized clinical trial outside the purview of Taser International,” the statement added.

Researchers recruited 142 participants who were tested for drug use, cardiac ailments and psychiatric problems, and other “significant protections in place to insure participant safety,” White said. The participants were divided randomly into four groups of 37, 32, 35 and 38 people, and each group was put through different “treatments.”

Participants were tested on a variety of cognitive instruments at five stages, the first being at the time of selection, followed by before they were subjected to their varying “treatments” and then being tested again immediately after. The tests were repeated an hour later and once again after a week.

The greatest variability showed up on the Hopkins Verbal Learning Test, which measures a person’s ability to learn new information, like a string of words, and to subsequently recall that information after different intervals of time. According to the study, “Taser exposure caused statistically significant reductions in verbal learning and memory. The effects lasted, on average, less than one hour.”

While each group had a mean score above the national average on the cognitive tests before being exposed to their “treatment,” a fourth of each group subjected to Taser shocks showed a mean level of cognitive function equal to 79-year-old adults, suggesting mild cognitive impairment. Additionally, participants who were Tased also reported difficulty in concentrating, increased levels of anxiety and the feeling of being overwhelmed.

“The findings from this study suggest that people who have been shocked with a Taser may be unable to understand and rationally act upon his or her legal rights, and may be more likely to waive their Miranda rights directly after Taser exposure or to give inaccurate information to investigators,” Kane said.

The study, “TASER Exposure and Cognitive Impairment: Implications for Valid Miranda Waivers and the Timing of Police Custodial Interrogations,” was published in the journal Criminology & Public Policy.

Research Summary
This study reports findings from a randomized controlled trial that examined the effects of the TASER® (a conducted energy weapon sold by TASER International, Scottsdale, Arizona) on several dimensions of cognitive functioning. The research demonstrated that in a sample of healthy human volunteer participants, TASER exposure led to significant and substantial reductions in (a) short-term auditory recall and (b) abilities to assimilate new information through auditory processes. The effects lasted up to 1 hour for most subjects, almost all of whom returned to baseline 60 minutes postexposure.


SEAFOOD

Could SEAFOOD slow the progression of dementia? Patients who eat even one portion a week 'have less brain damage'

Scientists have long thought seafood has benefits for the brain
Have now found it may also delay the progression of severe dementia
People with certain gene who ate 1-3 servings showed less brain damage
All types of seafood appear to have beneficial effect, say Chicago experts

By BEN SPENCER MEDICAL CORRESPONDENT
DAILY MAIL
3 February 2016

Eating seafood just once a week may slow the course of Alzheimer’s disease, new research suggests.
Scientists have long thought that seafood has benefits for the brain, but researchers have found it may also delay the progression of severe dementia.
They say all types have appear to have a beneficial effect.
Experts from Rush University Medical Centre in Chicago examined the brains of 286 people who had recently died with Alzheimer’s.
They found that those who ate between one and three meals containing seafood each week, and also carried a certain gene, showed less damage as a result of the Alzheimer’s disease

The team, whose work is published in the JAMA medical journal, suspect that the omega-3 fatty acids in seafood may be responsible.
But they also found that people who consumed fish oil supplements, rather than seafood itself, did not benefit from the same protection.
Seafood eaters who showed the least damage had a gene called APOE ε4, which is carried by 36 per cent of Alzheimer’s patients.
Experts had previously feared that seafood might actually be bad for Alzheimer’s patients, because it is a source of mercury, a neurotoxin thought to impair the brain

But the new study found that while those who had regularly eaten seafood did, indeed, have high levels of mercury in the brain, they had no signs of the expected damage.
They said the mercury toxicity may have been reduced by selenium, a nutrient present in seafood.
The team wrote: ‘To our knowledge, this is the first study to report on the relationship between brain concentrations of mercury and brain neuropathology or diet.
‘The finding of no deleterious correlations of mercury on the brain is supported by a number of case-control studies that found no difference between Alzheimer disease patients and controls in mercury concentrations in the brain, serum, or whole blood.’

Dr Laura Phipps at Alzheimer’s Research UK, said: ‘The omega-3 fatty acids found in oily fish are an important part of a balanced diet, and previous studies suggest they could play an important role in keeping the brain healthy.
‘This study links moderate seafood consumption with lower levels of Alzheimer’s-related brain changes in elderly people who carry a risk gene for the disease, but we must be careful when drawing conclusions about the wider population.
‘Current research is underway to investigate the benefits of a diet rich in omega-3 fatty acids in those at risk of memory and thinking problems, but at this time there is no evidence to suggest fish oil supplements could prevent dementia.
‘Dementia risk is a complex mix of age, genetics and lifestyle factors.
'The best current evidence suggests that what’s good for your heart is good for your head and that getting plenty of exercise, eating a healthy balanced diet, not smoking and keeping blood pressure and cholesterol in check could help reduce dementia risk.’
Dr James Pickett, head of research at Alzheimer’s Society, added: ‘Eating seafood has often been associated with improved memory and better health - but the research into whether eating fish can prevent or delay dementia has produced conflicting results.
‘The fact that the presence of mercury in the brain ? which has been linked to eating a lot of seafood ? was not associated with signs of Alzheimer’s is encouraging news for fish lovers.
‘However, given the relatively small size of this study, these findings are by no means conclusive. We look forward to seeing more results in this area of research.’

February 2, 2016
Association of Seafood Consumption, Brain Mercury Level, and APOE ε4 Status With Brain Neuropathology in Older Adults
Martha Clare Morris, ScD1; John Brockman, PhD2; Julie A. Schneider, MD, MPH3,4,5; Yamin Wang, PhD1; David A. Bennett, MD3,4; Christy C. Tangney, PhD6; Ondine van de Rest, PhD7
[+] Author Affiliations
JAMA. 2016;315(5):489-497. doi:10.1001/jama.2015.19451. Text Size: A A A

ABSTRACT |
Importance Seafood consumption is promoted for its many health benefits even though its contamination by mercury, a known neurotoxin, is a growing concern.

Objective To determine whether seafood consumption is correlated with increased brain mercury levels and also whether seafood consumption or brain mercury levels are correlated with brain neuropathologies.

Design, Setting, and Participants Cross-sectional analyses of deceased participants in the Memory and Aging Project clinical neuropathological cohort study, 2004-2013. Participants resided in Chicago retirement communities and subsidized housing. The study included 286 autopsied brains of 554 deceased participants (51.6%). The mean (SD) age at death was 89.9 (6.1) years, 67% (193) were women, and the mean (SD) educational attainment was 14.6 (2.7) years.

Exposures Seafood intake was first measured by a food frequency questionnaire at a mean of 4.5 years before death.

Main Outcomes and Measures Dementia-related pathologies assessed were Alzheimer disease, Lewy bodies, and the number of macroinfarcts and microinfarcts. Dietary consumption of seafood and n-3 fatty acids was annually assessed by a food frequency questionnaire in the years before death. Tissue concentrations of mercury and selenium were measured using instrumental neutron activation analyses.

Results Among the 286 autopsied brains of 544 participants, brain mercury levels were positively correlated with the number of seafood meals consumed per week (ρ?=?0.16; P?=?.02). In models adjusted for age, sex, education, and total energy intake, seafood consumption (??1 meal[s]/week) was significantly correlated with less Alzheimer disease pathology including lower density of neuritic plaques (β?=??0.69 score units [95% CI, ?1.34 to ?0.04]), less severe and widespread neurofibrillary tangles (β?=??0.77 score units [95% CI, ?1.52 to ?0.02]), and lower neuropathologically defined Alzheimer disease (β?=??0.53 score units [95% CI, ?0.96 to ?0.10]) but only among apolipoprotein E (APOE ε4) carriers. Higher intake levels of α-linolenic acid (18:3 n-3) were correlated with lower odds of cerebral macroinfarctions (odds ratio for tertiles 3 vs 1, 0.51 [95% CI, 0.27 to 0.94]). Fish oil supplementation had no statistically significant correlation with any neuropathologic marker. Higher brain concentrations of mercury were not significantly correlated with increased levels of brain neuropathology.

Conclusions and Relevance In cross-sectional analyses, moderate seafood consumption was correlated with lesser Alzheimer disease neuropathology. Although seafood consumption was also correlated with higher brain levels of mercury, these levels were not correlated with brain neuropathology.


living alone as non-marrieds

Marital Status May Be Risk Factor For Early- And Late-Onset Dementia

Jan 24, 2016
medicaldaily

Being single really could be worse for our health ? at least by the time we reach our golden years.

A recent population study of Swedish residents published this January in BMJ Open has found being unmarried may up the risk for developing dementia, a broad and often misunderstood term used to describe the severe cognitive decline that usually afflicts the elderly. Of the various unmarried groups detailed, divorced individuals were twice as likely to develop early-onset dementia, and 40 percent more likely to develop late-onset dementia compared to those who were married.

"Our results suggest that those living alone as non-marrieds may be at risk for early-onset and late-onset dementia," wrote the authors. "Although more research is needed to understand the underlying mechanism by which marital status is associated with dementia, this suggests that social relationships should be taken seriously as a risk factor for dementia and that social-based interventions may provide an opportunity to reduce the overall dementia risk."

As The Heart Goes

Previous research has found a similar connection between marital status and dementia risk. According to the authors, though, these studies haven't been able to differentiate between people who are unmarried because of divorce, death, or eternal singledom. To remedy that, the authors turned to Sweden, a small-developed country known for its meticulous medical records. This allowed the researchers to track down nearly all-native Swedish citizens from the ages of 50 to 74 living without dementia as of late 1997, a total of 2.2 million individuals.

They then followed these people for a 10-year period, by which time about 32,000 had been diagnosed with dementia. For further clarification, researchers separated these cases as either early-onset (occurring in people 50 to 64) or late-onset (65 to 74).

The absolute threat of dementia was low; only 0.38 percent of people in danger of early-onset and 3.4 percent of late-onset actually came down with it. But across the board, those unmarried were at greater risk, even after accounting for factors like age and socioeconomic status. People who stayed single or became widowed were the second and third most at risk for dementia after divorcees, respectively. Unlike earlier research, though, the current study authors found no significant increase in risk for men over women once these sorts of factors were taken into account.

There are plenty of theories for why marriage seems to be a buffer against dementia. "[A] person who lives with someone may be less lonely and receive more social support, which is found to reduce psychological distress, including anxiety and depression," the authors wrote. "Individuals with more social support also have access to better resources for coping with stressors and are less prone to assess stressors as threatening."

It might also be that, simply, avoiding the likely life-changing and stressful events of divorce or the death of a spouse can help to steady both our bodies and brains.

"Further studies are required to develop a better understanding of the mechanisms and pathways through which marriage plays a protective role regarding dementia in different age cohorts," they concluded. "Until then, the results of this study suggest opportunities for social-based interventions that target people living alone that may delay or even reduce the risk of dementia."

If nothing else, these findings are yet more support for the idea that a difficult or otherwise stressful life can take its toll on our minds as we age.

Source: Sundstr?m A, Westerlund O, Kotyrlo E. Marital status and risk of dementia: a nationwide population-based prospective study from Sweden. BMJ Open. 2016.



BMJ Open 2016;6:e008565 doi:10.1136/bmjopen-2015-008565

Neurology

Marital status and risk of dementia: a nationwide population-based prospective study from Sweden

Anna Sundstr?m1,2, Olle Westerlund2,3, Elena Kotyrlo2

+
Author Affiliations

1Department of Psychology, Ume? University, Ume?, Sweden
2Centre for Demographic and Ageing Research, Ume? University, Ume?, Sweden
3Ume? School of Business and Economics, Ume? University, Ume?, Sweden

Correspondence to Dr Anna Sundstr?m; anna.sundstrom@umu.se

Received 21 April 2015
Revised 7 September 2015
Accepted 21 October 2015
Published 4 January 2016

Abstract

Objectives To examine the association between marital status and dementia in a cohort of young-old (50?64) and middle-old (65?74) adults, and also whether this may differ by gender.

Design Prospective population-based study with follow-up time of up to 10?years.

Setting Swedish national register-based study.

Participants 2?288?489 individuals, aged 50?74?years, without prior dementia diagnosis at baseline. Dementia was identified using the Swedish National Patient Register and the Cause of Death Register.

Outcome measures The influence of marital status on dementia was analysed using Cox proportional hazards models, adjusted stepwise for multiple covariates (model 1: adjusted for age and gender; and model 2: additionally adjusted for having adult children, education, income and prior cardiovascular disease).

Results During follow-up, 31?572 individuals in the study were identified as demented. Cox regression showed each non-married subcategory to be associated with a significantly higher risk of dementia than the married group, with the highest risk observed among people in the young-old age group, especially among those who were divorced or single (HRs 1.79 vs 1.71, fully adjusted model). Analyses stratified by gender showed gender differences in the young-old group, with indications of divorced men having a higher relative risk compared with divorced women (HRs 2.1 vs 1.7, only-age adjusted model). However, in the fully adjusted model, these differences were attenuated and there was no longer any significant difference between male and female participants.

Conclusions Our results suggest that those living alone as non-marrieds may be at risk for early-onset and late-onset dementia. Although more research is needed to understand the underlying mechanism by which marital status is associated with dementia, this suggests that social relationships should be taken seriously as a risk factor for dementia and that social-based interventions may provide an opportunity to reduce the overall dementia risk.


β-N-methylamino-L-alanine (BMAA)

Exposure to environmental toxin ups Alzheimer’s risk
A down-side of living in a polluted city is its infamous smog, which is a factor in respiratory conditions such as asthma, bronchitis and COPD.
By: ANI
January 24, 2016
http://www.financialexpress.com/

A down-side of living in a polluted city is its infamous smog, which is a factor in respiratory conditions such as asthma, bronchitis and COPD. Now, a new study has revealed a link between exposure to air pollution and Alzheimer’s disease and other neurodegenerative illnesses.
The study indicates that chronic exposure to an environmental toxin may increase risk of neurodegenerative illness. Conducted by scientists at the Institute for EthnoMedicine, a non-profit medical research organization, and the University of Miami Brain Endowment Bank, the study provides a foundation for future research in Alzheimer’s disease, ALS and Parkinson’s disease.
Brain tangles and amyloid deposits are the hallmarks of both Alzheimer’s disease and an unusual illness suffered by Chamorro villagers on the Pacific Island of Guam, whose diet is contaminated by the environmental toxin BMAA. Pacific Islanders with this unusual condition also suffer from dementia and symptoms similar to Alzheimer’s disease, ALS and Parkinson’s disease.
The cause of neurodegenerative disease remains largely unknown, and the role of environmental factors in these illnesses is poorly understood. However, scientists have suspected a link between BMAA, a neurotoxin found in some harmful algal blooms, and neurodegenerative illness.
The findings show that chronic exposure to BMAA can trigger Alzheimer’s-like brain tangles and amyloid deposits, said lead author Paul Alan Cox, adding that this is the first time researchers have been able to successfully produce brain tangles and amyloid deposits in an animal model through exposure to an environmental toxin.
The study is published in the journal Proceedings of the Royal Society B.
First Published on January 24, 2016 12:05 am


Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain

Paul Alan Cox, David A. Davis, Deborah C. Mash, James S. Metcalf, Sandra Anne Banack
Published 20 January 2016.DOI: 10.1098/rspb.2015.2397
Proceedings of the Royal Society B

Abstract

Neurofibrillary tangles (NFT) and β-amyloid plaques are the neurological hallmarks of both Alzheimer's disease and an unusual paralytic illness suffered by Chamorro villagers on the Pacific island of Guam. Many Chamorros with the disease suffer dementia, and in some villages one-quarter of the adults perished from the disease. Like Alzheimer's, the causal factors of Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) are poorly understood. In replicated experiments, we found that chronic dietary exposure to a cyanobacterial toxin present in the traditional Chamorro diet, β-N-methylamino-L-alanine (BMAA), triggers the formation of both NFT and β-amyloid deposits similar in structure and density to those found in brain tissues of Chamorros who died with ALS/PDC. Vervets (Chlorocebus sabaeus) fed for 140 days with BMAA-dosed fruit developed NFT and sparse β-amyloid deposits in the brain. Co-administration of the dietary amino acid L-serine with L-BMAA significantly reduced the density of NFT. These findings indicate that while chronic exposure to the environmental toxin BMAA can trigger neurodegeneration in vulnerable individuals, increasing the amount of L-serine in the diet can reduce the risk.


chronic anxiety

Severe stress in middle age can lead to Alzheimer's by damaging the brain, experts warn

Stress in middle age could cause dementia by damaging the brain
Mid-life stress has been previously linked to a higher risk
Therapy and exercise might be ways to reduce the risk of Alzheimer' s

By COLIN FERNANDEZ
THE DAILY MAIL
23 January 2016

Stress in middle age could cause dementia by damaging the brain, according to new research.
Neurons involved in chronic anxiety and fear 'extensively overlap' in areas also associated with Alzheimer's disease, say scientists.
Mid-life stress has been previously linked to a higher risk of Alzheimer's disease.
The latest research shows the mechanism of how chronic stress physically damages the brain ? potentially leading to dementia

Chronic stress is defined as 'prolonged activation' of the normal stress response ? in other words stress over long periods of time.
The study suggests reducing chronic stress by therapy, exercise or mindfulness training ? a form of meditation ? might be ways to reduce the risk of Alzheimer' s.
A Canadian team reviewed animal and human studies that have already been published and found brain areas affected by chronic anxiety, fear and stress were linked.
This could explain the development of neuropsychiatric disorders, including depression and Alzheimer's, they argue.

Psychiatrist Dr Linda Mah, of the University of Toronto, said: 'Pathological anxiety and chronic stress are associated with structural degeneration and impaired functioning of the hippocampus and the prefrontal cortex (PFC), which may account for the increased risk of developing neuropsychiatric disorders, including depression and dementia.'
In Alzheimer's the hippocampus, the brain's memory hub, is one of the first regions to shrink. Those who suffer from depression also have a smaller hippocampus. The PFC also wastes away in both conditions.
The research, published in the journal Current Opinion in Psychiatry, pooled data from studies of lab animals along with brain scans of humans, focusing on chemicals sparked by fear and anxiety in three brain areas: the amygdala, medial prefrontal cortex and hippocampus.

When subjected to chronic stress there were similar patterns of abnormal brain activity including an overactive amygdala, an area associated with emotional responses, and an underactive PFC, that helps regulate them through thinking.
This 'see-saw relationship' was first identified in a landmark study by world renowned neurologist and depression researcher Dr Helen Mayberg more than a decade ago.
But Dr May said stress induced damage to the hippocampus and PFC can be combated or even reversed with anti-depressants and physical activity that have both been found to improve the hippocampus.
She said: 'Looking to the future we need to do more work to determine whether interventions, such as exercise, mindfulness training and cognitive behavioural therapy, can not only reduce stress but decrease the risk of developing neuropsychiatric disorders.'
Dr Mah's study follows on the heels of her previous one published in October 2014 which found some of the strongest evidence yet that anxiety may accelerate the development of Alzheimer's disease in people diagnosed with mild cognitive impairment, minor memory loss that can lead to the condition.
Experiencing anxiety, fear and stress is considered a normal part of life when it is occasional and temporary, such as feeling anxious and stressed before an exam or a job interview.
But when those acute emotional reactions become more frequent or chronic, they can significantly interfere with daily living activities such as work, school and relationships.

Current Opinion in Psychiatry:
January 2016 - Volume 29 - Issue 1 - p 56?63
Can anxiety damage the brain?
Mah, Lindaa,b; Szabuniewicz, Claudiab; Fiocco, Alexandra J.c

Abstract
Purpose of review: Stress exacerbates mental illnesses such as depression but also appears to increase risk of dementia, suggesting a common mechanism for development of stress-induced affective and cognitive impairment. The purpose of this review is to address the question of whether anxiety ‘damages’ the brain, and to identify potential mechanisms for the link between stress and neuropsychiatric illness.

Recent findings: Anxiety disorders are associated with alterations in fear neurocircuitry such that ‘bottom-up’ processes in the amygdala which respond to threat are exaggerated, and regulation of these processes by the prefrontal cortex (PFC) and hippocampus is impaired. Chronic stress exposure similarly alters fear neurocircuitry by enhancing amygdalar functioning while causing structural degeneration in the PFC and hippocampus thereby inhibiting PFC/hippocampus control over the stress response. Pharmacological (e.g., antidepressant medications) and nonpharmacological interventions (cognitive-behavioral therapy, exercise) may reverse stress-induced damage in the brain.

Summary: Pathological anxiety and chronic stress lead to structural degeneration and impaired functioning of the hippocampus and the PFC, which may account for the increased risk of developing neuropsychiatric disorders, including depression and dementia. Longitudinal studies are needed to determine whether reversal of stress-induced brain changes by interventions such as cognitive-behavioral therapy can reduce risk of neuropsychiatric illness.


Oestrogen

Oestrogen supplements could reduce dementia risk in women

January 22, 2016
http://www.news-medical.net/

Women who take oestrogen supplements from before or at the start of menopause and continue with them for a few years have better preserved brain structure, which may reduce the risk of dementia.

Globally, one new person is affected by dementia every four seconds. In 2010, 36 million people were estimated to have dementia.

Now, findings in a doctoral thesis from the Norwegian University of Science and Technology (NTNU) show that oestrogen supplements can reduce the risk of dementia in women.

"Oestrogen supplements can have a positive effect against dementia if women start early enough with treatment," says Carl Pintzka, a medical doctor and PhD candidate at NTNU.

The finding has been just published in the journal Neurobiology of Aging.

A sample of 80 women who had used oestrogen supplements through menopause was compared with 80 women who had never used oestrogen supplements. All had participated in the Nord-Tr?ndelag Health Study (HUNT), a general population-based study in mid-Norway.

The brain shrinks with less oestrogen

Following menopause, womens' oestrogen levels drop significantly compared to levels before menopause.

MRIs of the brains of the women in the study showed that those who had taken oestrogen supplements throughout menopause had a larger hippocampus. The hippocampus is one of the most important structures for memory and sense of place, and is one of the structures that is affected early in the progression of Alzheimer's disease.

"We also examined the shape of the hippocampus and found that areas where hormone therapy had the greatest effect are the same areas that are affected by Alzheimer's disease in its early stages," says Pintzka.

Other studies have shown that women who start oestrogen supplements several years after menopause do not benefit from the same positive effect on the hippocampus.

Must start oestrogen from the late 40s

Pintzka's findings show that boosting oestrogen levels increases the volume of the hippocampus. As of yet there are no drugs that stop or prevent the course of Alzheimer's disease, and the focus has shifted towards strategies to prevent or delay the onset of dementia.

Successful strategies are thought to be those that increase brain volume, and that in particular preserve the hippocampus. The risk of dementia may therefore be reduced for women taking estrogen supplements around the time of menopause, according to Asta H?berg, a Professor of Neuroscience at NTNU and Pintzka's supervisor.

Until 2002, many women in Norway and internationally took oestrogen supplements during and after menopause. The reasons for boosting oestrogen levels are to reduce hot flashes and osteoporosis and to prevent cardiovascular disease. Then the number of women taking supplements fell dramatically.

The studies that scared women

Pintzka points to two specific studies as the reason for the steep decline in the use of oestrogen supplements. In the summer of 2002, a large study of menopausal women conducted by the "Womens Health Initiative" was published.

This study landed like a bombshell in professional circles and the media. The conclusion was that the disadvantages of long-term treatment with oestrogen far outweighed the benefits.

The study included 16,000 women and showed that the combination of oestrogen and progestin increased the risk of both heart disease and breast cancer. Furthermore, the study showed that those who took oestrogen supplements had poorer memory and greater risk for dementia than the control group.

Soon after, The Journal of the American Medical Association published another study, which had followed 44,000 women for 20 years. This study showed that oestrogen therapy increased the risk of ovarian cancer if treatment persisted for over 10 years.

Some risks increase, others drop

"It's true that the risk of some cancers increases with oestrogen supplements, but we also know, for example, that the risk of hip fractures and colorectal cancer drops with their use," says Pintzka.

According to H?berg, it's a big question whether the findings of the American studies can be transferred to Norwegian women, because women [in the American studies] started using oestrogen at a later age. "Oestrogen supplements used in the United States are also different from the ones used in Europe," she says.

More recent studies suggest that boosting oestrogen levels has protective effects on the brain if started around menopause, but that the same treatment could be harmful for women if they start supplements later than a few years after menopause.

"The women who participated in the Women's Health Initiative study started with oestrogen supplementation 15-30 years after menopause. This was probably too late to expect a positive effect," Pintzka says.

More and more people will be affected by dementia

According to Norway's 2014 Public Health Report, Norway has approximately 70 000 people with dementia, and that number is anticipated to increase greatly in the coming years due to a growing population and higher average age.

Norway is not alone in facing this development, which is associated with the increasing average age of the population.

The World Health Organization has identified the fight against neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, as some of the biggest health challenges society faces in the coming years.

Women should start early with oestrogen if they decide to use it

H?berg believes that positive effects on the brain from using oestrogen supplements are highly probable, but whether supplements eventually protect against dementia remains unclear.

"Women who want to take oestrogen supplements should start early to benefit from the positive effect on the brain," says H?berg.

Pintzka points out that none of the participants in his doctoral thesis had dementia at the start of the study, nor have any developed the disease since the MRIs were taken. He adds that neither he nor his supervisor know how many participants may develop dementia as they continue to age. An NTNU research group plans to follow up on this question in the next HUNT study.

Source:
Norwegian University of Science and Technology


September 2015Volume 36, Issue 9, Pages 2555?2562
Perimenopausal hormone therapy is associated with regional sparing of the CA1 subfield: a HUNT MRI study
Abstract
Observational studies support a neuroprotective role of hormone therapy (HT) in the perimenopause, with hippocampal size being a widely used biomarker. We investigated the effect of HT started before the onset of menopause and lasting for at least 3 years on hippocampal volume and shape in 80 postmenopausal women and 80 controls matched on age and intracranial volume taken from a large community-based sample (Nord-Tr?ndelag Health Study?magnetic resonance imaging). The main effect of hormone group showed a statistically significant difference in hippocampal volumes (p = 0.028). Both the right (3.2%) and left (2.8%) hippocampal volumes were larger in the HT group but only significant for the right hippocampus (p = 0.023). Shape analysis revealed significant regional sparing of the medial aspect of the right hippocampal head and lateral aspect of the body extending to the tail, corresponding to the cornu ammonis, including part of the subiculum, in the HT group. A similar nonsignificant pattern was observed in the left hippocampus. The present study provides support for the critical window theory demonstrating that HT initiated in the perimenopause has neuroprotective properties