Feedback and insights from individuals with early-stage dementia helped shape this new collection, as well as activity suggestions from national and international dementia programs. As a result, the activities include a new focus on diversity and multiculturalism. Also featured are topics of interest to participants in their 50s and 60s, such as the Internet, advocacy, and community service.

Participants, staff, and family members will enjoy fresh ideas for creative art projects, interactive games, and evening activities. New themes to explore in Volume 2 include activities related to the kitchen and food, life story sharing and reminiscence, religious and spiritual traditions, and wellness. Adaptations for people in the early and late stages of Alzheimer s disease, preventive measures to avoid unwanted surprises, and conversation tips make these activities particularly versatile.

Use this resource to extend the benefits you already enjoy from Best Friends programming or discover for the first time how this groundbreaking approach can transform activities and daily interactions.

Author: Virginia Bell, David Troxel, Tonya Cox, and Robin Hamon
Paperback: 256 pages
Company: Health Professions Pr (2007-12-21)
ISBN: 1932529268
List Price: $36.95
Amazon Price: $24.31
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"Credentials don't come much loftier than Fotuhi's."

--Washington Post

"The book is a message of hope and reassurance for laymen, especially aging members of the baby-boom generation alarmed by all the attention being paid to Alzheimer's and imagining worst-case scenarios for themselves."

--Washington Times

Dr. Majid Fotuhi, one of the world's foremost experts in the field of Alzheimer's Disease and brain function, outlines a highly effective plan to guard against memory loss.

In The Cox-2 Connection, pharmacist and naturalist James B. LaValle shares a thorough overview of treatment options for a variety of disorders for which inflammation is a primary symptom--from osteoarthritis, bursitis, and fibromyalgia to rheumatoid arthritis, gout and dysbiosis. He clearly explains the physiological mechanism that leads to inflammation and pain and includes an in-depth section on pain-management strategies useful for anyone who is experiencing this discomfort, whether temporary or chronic.

Cox-2--or cyclooxygenase-2--is the key enzyme responsible for the body's inflammation and pain response in conditions such as arthritis and bursitis, and it is also linked to the inflammation that may play a significant role in the progression of Alzheimer's and cancer. The Cox-2 Connection, however, goes further than other pain management books by dealing with not only the synthetic, anti-inflammatory Cox-2 inhibitors, such as Celebrex and Vioxx, but also with their natural counterparts that have been used for thousands of years by people all over the world. The author thoughtfully evaluates the effectiveness of these inhibitors as well as their side effects and presents exciting new studies that indicate their possible role in preventing Alzheimer's and cancer. 

The Cox-2 Connection is an essential and timely reference for anyone trying to understand and manage inflammation and pain and make sense of the exploding availability and potential of ways to deal with them.

This groundbreaking book has been written especially for patients, caregivers, family members, and allied healthcare professionals. Dr. Isaacson writes in easy to understand terms and easy to read (larger-type) print to help educate and inform those confronting AD. He outlines his comprehensive and scientifically-based approach that includes a ccomprehenisve 9-week diet and nutrition plan, with examples of what to eat, what not to eat, and a food terminology guide to help read and understand nutrition labels. He discusses the available medications, supplements, vitamins, and medical foods, as well as the proven non-drug approaches that have been shown to help in treatment and prevention.

This book is a resource to empower families to understand the latest in AD. Remember: Knowledge is Power - Get informed, Get Educated. The fight against AD is a battle we must win.

Sample Chapters:
"In 2012, what are the best strategies for treating and preventing AD?"
"Where can I turn to for help and should I get a second opinion?"
"I have a family member with Alzheimer's and am concerned about developing AD. What strategies do you suggest for prevention?"

Dr. Isaacson has appeared widely in the media, including the Today Show, CBS, ABC, Wall Street Journal, USA Today, US News and World Report, CNN.com and Univision.

This new 2012 edition is revised and expanded from his groundbreaking approach first published last year, was highlighted twice on the NBC Today Show (interviews by Meredith Vieira, and Kathie Lee and Hoda), Fox Good Day L.A., and a myriad of other television and radio programs throughout the United States.

Author: Dr. Richard S Isaacson MD
Paperback: 274 pages Large Print
Company: AD Education Consultants, Incorporated (2011-11-15)
ISBN: 0983186979
List Price: $19.95
Amazon Price: $19.95

Written primarily for physicians, psychiatrists and other mental health professionals who treat people with Alzheimer's disease, this book is also important reading for anyone who has a family member with the infirmity to learn what can be done to alleviate patient suffering and help reduce family burden and stress.

Hardcover: 160 pages
Company: Routledge (1988-09-01)
ISBN: 0876305192
List Price: $49.95
Amazon Price: $26.99
Used Price: $0.01

Section two is a representative list, by state and city, of home care providers and assisted living, adult day care and long-term residential treatment facilities, noting location, special accommodations, certifications, number of beds, accreditations, insurance information, and URL if available.

Section three is a state-by-state list of the National Institute of Aging’s Alzheimer’s Disease Centers along with numerous other government, clinical and university affiliated treatment and research centers.

Section four is a guide to a wide selection of resources including books, journals, support groups, organizations, and Internet sites.

Author: Elaine A. Moore, Lisa Moore
Hardcover: 413 pages
Company: Mcfarland & Co Inc Pub (2003-01-08)
ISBN: 0786414383
List Price: $95.00
Amazon Price: $66.50
Used Price: $0.58

Drawing on the most up-to-date information available on the disease as well as experiences from his clinical practice, Dr. Marwan Sabbagh, a leading expert in Alzheimer's research, translates the current ideas driving Alzheimer's treatment into practical information you can use to determine your risk and develop a prevention strategy. You'll find tools for assessing your personal Alzheimer's risk and "What You Can Do" sections to help you keep your brain and body healthy, plus information on the treatment of Alzheimer's and its complications.Gives you the most up-to-date information on Alzheimer's and Alzheimer's preventionWritten by a neurologist specializing in geriatric neurology and dementia who is one of the country's leading experts in Alzheimer's researchIncludes exciting revelations, such as finding that early onset Alzheimer's can be significantly slowed in its progress, giving the patient as many as ten to fifteen added years of quality life

There are an estimated 5.2 million people living with Alzheimer's in America today. If you or someone you love is at risk of developing the disease or wishes to slow its advancement, this book will give you vital information to help you reduce risk and safeguard health and quality of life.

Author: Marwan Sabbagh
Kindle Edition: 322 pages Kindle eBook
Company: John Wiley & Sons, Inc. (2008-02-11) (2008-02-08)
List Price: $24.95
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"This book...provides important information on best practices and appropriate ways to care for a person with Alzheimer's and advanced dementia. Drs. Martin and Sabbagh have assembled a team of experts to help craft recommendations that should ultimately become standards that all professional caregivers adopt."

This book testifies that caregivers can have a monumental impact on the lives of persons with advanced dementia. Through specialized programming and a renewed effort toward patient-centered care, caregivers can profoundly enrich the quality of life for these persons. Providing guidelines for health care professionals, caregivers, and family members, this book introduces palliative care programs and protocols for the treatment of people with advanced dementia.

The book is designed to guide professional caregivers in meeting the needs of patients and their families, providing insight into the philosophy, assessment, planning, implementation, and evaluation measures involved in interdisciplinary palliative care. The chapter authors offer guidelines and standards of care based on contributions from nurses, physical therapists, social workers, dietitions, psychologists, family caregivers and pastors. An exhibit at the end of every chapter clearly articulates the standards of care appropriate for all advanced dementia facilities and health care staff.

Enhance the physiological, psychological, social, and spiritual well-being of the patient and the patient's family Anticipate and meet the patient's basic human needs: hunger, thirst, body positioning, hygiene, continence, and management of any pain Ensure that the patient's surroundings are safe, comfortable, and homelike Address health care decisions that will support the patient's right to self-determination until the end of life

Paperback: 350 pages
Company: Springer Publishing Company (2010-07-23)
ISBN: 0826106757
List Price: $60.00
Amazon Price: $50.95
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BACE (β-site of APP cleaving enzyme) is a critical component in Alzheimer's Disease (AD), and the development of BACE inhibitors shows great potential as a therapy for the disease. BACE: Lead Target for Orchestrated Therapy of Alzheimer's Disease covers virtually all aspects of BACE from initial identification, discovery of inhibitors, and challenges in clinical development, while providing a global understanding essential for productive and successful drug discovery.

This book details the story of the discovery of BACE and its role in AD and comprehensively discusses:

The development of BACE inhibitors as therapeutics for Alzheimer's disease

The research that led to the identification of BACE

New BACE inhibitors currently being clinically tested

ADME (absorption, distribution, metabolism, excretion) and clinical trial design—topics not addressed in current field literature

Cutting-edge technology such as high-throughput screening, structure-based drug design, and QSAR in context of BACE inhibitors and Alzheimer's drug discovery

Other approaches to BACE inhibition based on interaction with the precursor protein APP

By enhancing the reader's understanding of the various aspects of the BACE drug-discovery process, this much-needed reference will serve as a key resource for all scientists involved in Alzheimer's research—and inspire new approaches to treatment of AD.

Author: Varghese John
Hardcover: 266 pages
Company: Wiley (2010-03-15)
ISBN: 047029342X
List Price: $104.95
Amazon Price: $80.98
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Hundreds of Activities for Men and Women with Alzheimer's Disease and Related Disorders

Contains an incredible compilation of creative activities and fascinating information that will benefit both Alzheimer's caregivers and patients. The 288-page, idea-packed book has suggestions for everyday and special-occasion activities, and facilitates communication between caregiver and AD patient with helpful details about social eras the patient may have experienced during his or her lifetime, U.S. holidays, religious holy days, and modern invention timelines. In addition, there are topic-appropriate questions to ask the patient, tips for successful activities, caregivers' anecdotes, resource lists, encouraging words, and much more. (See Contents below).

Author: B. J. Fitzray
Hardcover: 288 pages Lists of activities to stimulate the mind and muscle groups.
Company: Rayve Productions (2001-06-01)
ISBN: 1877810800
List Price: $29.95
Amazon Price: $8.50
Used Price: $6.65

Originally published in 1981, The 36-Hour Day was the first book of its kind. Thirty years later, with dozens of other books on the market, it remains the definitive guide for people caring for someone with dementia. Now in a new and updated edition, this best-selling book features thoroughly revised chapters on the causes of dementia, managing the early stages of dementia, the prevention of dementia, and finding appropriate living arrangements for the person who has dementia when home care is no longer an option.

"We are foolish, those of us who think we can escape the traps of aging," writes Tom DeBaggio. "I was one of them, dreaming of a perfect and healthy old age....Now, at fifty-eight, I realize the foolishness of my dreams as I watch my brain self-destruct from Alzheimer's." Losing My Mind is DeBaggio's extraordinary account of his early onset Alzheimer's, a disease that "silently hollows the brain" and slowly "gobbles memory and destroys life." But with DeBaggio's curse came an unexpected blessing: the ability to chart the mechanics and musings of his failing mind.

Whether describing the happy days of his youth or lamenting over the burden his disease has placed upon his loved ones, DeBaggio manages to inspire the reader with his ability to function, to think, and ultimately to survive. By turns an autobiography, a medical history, and a book of meditations, Losing My Mind is a testament to the splendor of memory and a triumphant celebration of the human spirit.

Author: Thomas DeBaggio
Paperback: 224 pages Bargain Price
Company: Free Press (2003-02-25)
List Price: $14.00
Amazon Price: $5.59
Used Price: $3.75

This is one daughter's story of Lois and Ralph Pearson, whose love of life and each other transcended the darkest moments of war, separation, heartache, and family tragedy to achieve a memorable state of grace spanning six decades of marriage.

Paddock recalls her parents' early lives together on St. Paul's East Side, including their playful courtship on the city's ice rinks, as well as her own fond recollections of growing up in the post-war glow of the 1950s and '60s. Reflecting in part on the nature of memory, her book examines the confounding mysteries surrounding Alzheimer's as manifested in Lois and Ralph's experience, while remembering some of the stories that marked one family's journey through life.

As scientists, researchers, and health-care professionals seek solutions for a growing ''epidemic'' of dementia in an aging population, families from all walks of life face a litany of issues for caring for their failing loved ones, including rising costs, social and political cross-currents, and institutional inertia in the nursing-home industry, among many. Against the odds, A Song at Twilight seeks ''the perfect place'' of care, dignity, and respect for our elders.

At once tribute, chronicle, meditation, and self-exploration amid great uncertainty, A Song at Twilight searches for meaning in fading photographs and memories while celebrating the ties that bind. For Nancy Paddock, the quest becomes an exploration of the map of her own heart, a journey of struggle, spirit, discovery, and surprise--in gratitude for life's gift of renewal found even in the harshest regions of experience--the story of how love indeed endures.

Author: Nancy Paddock
Paperback: 304 pages
Company: Blueroad Press (2011-07-01)
ISBN: 0979650941
List Price: $18.00
Amazon Price: $9.95
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What do you do when your outspoken, passionate, and quick-witted mother starts fading into a forgetful, fearful woman?

Revised in 2006 for its twenty-fifth anniversary, this best-selling book is the "bible" for families caring for people with Alzheimer disease, offering comfort and support to millions worldwide. In addition to the practical and compassionate guidance that have made The 36-Hour Day invaluable to caregivers, the fourth edition is the only edition currently available that includes new information on medical research and the delivery of care.

The new edition includes:

- new information on diagnostic evaluation
- resources for families and adult children who care for people with dementia
- updated legal and financial information
- the latest information on nursing homes and other communal living arrangements
- new information on research, medications, and the biological causes and effects of dementia

Over 4 million Americans suffer from Alzheimer's disease, which is an organic disorder that is progressive, debilitating, and irreversible. The economic cost of treating and providing care for those with Alzheimer's is over $40 billion a year. The emotional cost to the sufferers and their families is beyond estimation. Yet Alzheimer's is often misdiagnosed, mistreated, and mismanaged. The purpose of this book is to help physicians, health care administrators, graduate students and researchers better understand diagnostic procedures, treatment and management factors related to Alzheimer's disease and other dementias in the elderly.

Originally published in 1981, The 36-Hour Day was the first book of its kind. Thirty years later, with dozens of other books on the market, it remains the definitive guide for people caring for someone with dementia. Now in a new and updated edition, this best-selling book features thoroughly revised chapters on the causes of dementia, managing the early stages of dementia, the prevention of dementia, and finding appropriate living arrangements for the person who has dementia when home care is no longer an option.

Cold Spring Harb Perspect Med. 2012 Jan; 2(1): a006346
Wyss-Coray T, Rogers J

Biochemical and neuropathological studies of brains from individuals with Alzheimer disease (AD) provide clear evidence for an activation of inflammatory pathways, and long-term use of anti-inflammatory drugs is linked with reduced risk to develop the disease. As cause and effect relationships between inflammation and AD are being worked out, there is a realization that some components of this complex molecular and cellular machinery are most likely promoting pathological processes leading to AD, whereas other components serve to do the opposite. The challenge will be to find ways of fine tuning inflammation to delay, prevent, or treat AD.

Behav Brain Res. 2012 Jan 31;
Yang Y, Cheng XR, Zhang GR, Zhou WX, Zhang YX

The autocrine motility factor receptor (AMFR) is a multifunctional protein involved in cellular adhesion, proliferation, motility and apoptosis. Our study showed that increased AMFR protein expression in the hippocampus of KM mice correlated with enhanced capacity for learning and memory following the shuttle-box test and was significantly elevated in the highest score group. Also, AMF and AMFR mRNA expression positively correlates with the mRNA expression of the synapse marker synaptophysin (Syp). Aging studies in the senescence-accelerated mouse strain (SAM) prone/8 (SAMP8), an animal model of Alzheimer's disease (AD), revealed significantly decreased mRNA and protein expression of AMF and AMFR in the hippocampus. This is especially true for AMFR and AMF protein expression compared with age-matched SAM resistant/1 (SAMR1) mouse strain as the control. Additionally, the low mRNA expression of AMFR could be up-regulated by the four nootropic traditional Chinese medicinal prescriptions (TCMPs): Ba-Wei-Di-Huang decoction (BW), Huang-Lian-Jie-Du decoction (HL), Dang-Gui-Shao-Yao-San (DSS) and Tiao-Xin-Fang decoction (TXF). AMFR protein expression could be up-regulated by two TCMPs, Liu-Wei-Di-Huang decoction (LW) and BW. This indicated that AMFR is involved in the process of learning and memory in the central nervous system. These results may provide useful clues for understanding the etiology of AD.

Cold Spring Harb Perspect Med. 2012 Jan; 2(1): a006304
De Strooper B, Iwatsubo T, Wolfe MS

Presenilins were first discovered as sites of missense mutations responsible for early-onset Alzheimer disease (AD). The encoded multipass membrane proteins were subsequently found to be the catalytic components of γ-secretases, membrane-embedded aspartyl protease complexes responsible for generating the carboxyl terminus of the amyloid β-protein (Aβ) from the amyloid protein precursor (APP). The protease complex also cleaves a variety of other type I integral membrane proteins, most notably the Notch receptor, signaling from which is involved in many cell differentiation events. Although γ-secretase is a top target for developing disease-modifying AD therapeutics, interference with Notch signaling should be avoided. Compounds that alter Aβ production by γ-secretase without affecting Notch proteolysis and signaling have been identified and are currently at various stages in the drug development pipeline.

J Cereb Blood Flow Metab. 2012 Feb 8;
Shiino A, Watanabe T, Shirakashi Y, Kotani E, Yoshimura M, Morikawa S, Inubushi T, Akiguchi I

Alzheimer's disease (AD) and subcortical ischemic vascular dementia (SIVD) have overlapping pathologies and risk factors, but their underlying neurodegenerative mechanisms are basically different. We performed magnetic resonance spectroscopy (MRS) to study metabolite differences between the two diseases in vivo. The subjects were 31 patients with SIVD and 99 with AD. Additionally, 45 elderly subjects were recruited as controls. We measured N-acetylaspartate (NAA), glutamine and glutamate (Glx), and myoinositol (mIns) concentration quantitatively using a 1.5-T MR scanner. N-acetylaspartate and Glx concentrations decreased in the hippocampus and cingulate/precuneal cortices (PCC) in both AD and SIVD patients, and the NAA decrease in the hippocampus was more prominent in AD than in SIVD. Interestingly, the pattern of mIns concentration changes differed between the two disorders; mIns was increased in AD but not increased in SIVD. If one differentiates between AD and SIVD by the mIns concentration in the hippocampus, the area under the receiver operating characteristic curve was 0.95, suggesting a high potential for discrimination. Our results suggest that proton MRS can provide useful information to differentiate between AD and SIVD. The difference of mIns concentrations in the hippocampus and PCC seems to reflect the different neurodegenerative mechanisms of the two disorders.Journal of Cerebral Blood Flow & Metabolism advance online publication, 8 February 2012; doi:10.1038/jcbfm.2012.9.

J Chem Inf Model. 2012 Feb 8;
Kacker P, Masetti M, Mangold M, Bottegoni G, Cavalli A

The ability of BACE-1 catalytic dyad to adopt multiple protonation states and the conformational flexibility of the active site have hampered the reliability of computational screening campaigns carried out on this drug target for Alzheimer's disease. Here, we propose a protocol that, for the first time, combining quantum mechanical calculations, molecular dynamics, and conformational ensemble virtual ligand screening, addresses these issues simultaneously. The encouraging results prefigure this approach as a valuable tool for future drug discovery campaigns.

Aging Cell. 2012 Feb 7;
Yang YR, Song M, Lee H, Jeon Y, Choi EJ, Jang HJ, Moon HY, Byun HY, Kim EK, Kim DH, Lee MN, Koh A, Ghim J, Choi JH, Lee-Kwon W, Kim KT, Ryu SH, Suh PG

Dysregulation of O-GlcNAc modification catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) contributes to the etiology of chronic diseases of aging, including cancer, cardiovascular disease, type 2 diabetes, and Alzheimer's disease. Here we found that natural aging in wild-type mice was marked by a decrease in OGA and OGT protein levels and an increase in O-GlcNAcylation in various tissues. Genetic disruption of OGA resulted in constitutively elevated O-GlcNAcylation in embryos and led to neonatal lethality with developmental delay. Importantly, we observed that serum-stimulated cell cycle entry induced increased O-GlcNAcylation and decreased its level after release from G2/M arrest, indicating that O-GlcNAc cycling by OGT and OGA is required for precise cell cycle control. Constitutively elevated O-GlcNAcylation by OGA disruption impaired cell proliferation and resulted in mitotic defects with downregulation of mitotic regulators. OGA loss led to mitotic defects including cytokinesis failure and binucleation, increased lagging chromosomes, and micronuclei formation. These findings suggest an important role for O-GlcNAc cycling by OGA in embryonic development and the regulation of the maintenance of genomic stability linked to the aging process. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Dement Geriatr Cogn Disord. 2012 Feb 3; 32(5): 351-361
Silveira de Souza A, de Oliveira-Souza R, Moll J, Tovar-Moll F, Andreiuolo PA, Bottino CM

Background/Aims: The diagnosis of mild or questionable Alzheimer's disease (AD) depends on clinical criteria that often leave a margin for doubt. We aim to verify the diagnostic accuracy of amnestic mild cognitive impairment (aMCI) and AD with proton spectroscopy ((1)H-MRS) combined with brief cognitive-functional scales. Methods: The relationship between (1)H-MRS of the posterior cingulate cortex and the cognitive performance in Mini Mental State Examination, Blessed-Roth Dementia Rating and Functional Assessment Staging of Alzheimer Disease scales were investigated in 25 AD, 10 aMCI and 33 normal control (NC) individuals. Results: The N-acetylaspartate (NAA)/creatine and myoinositol/NAA ratios distinguished AD patients from NC (p < 0.005), and added value in diagnostic accuracy and specificity by discriminant function analysis when combined to clinical diagnosis and simple neuropsychiatric scales; an increase of 3.7% (for aMCI patients) and of 5% (for AD individuals) was observed in diagnostic accuracy, and one of 5.5% (aMCI) and of 11.1% (AD) in specificity. Conclusion:(1)H-MRS combined with brief cognitive-functional scales provided maximum diagnostic accuracy of AD patients, and can be useful when subtle cognitive and memory dysfunction is present.

Alzheimer Dis Assoc Disord. 2012 Feb 6;
Mioshi E, Foxe D, Leslie F, McLinneuro SS, Hsieh S, Miller L, Hodges JR, Piguet O

Caregiver burden is greater in frontotemporal dementia (FTD) than in Alzheimer disease (AD). However, little is known of the impact of the 3 main clinical variants of FTD- behavioral-variant frontotemporal dementia (bvFTD), semantic dementia (SemDem), and progressive nonfluent aphasia (PNFA)-or the role of disease severity in caregiver burden. The Zarit Burden Inventory was used to measure caregiver burden of bvFTD (n=17), SemDem (n=20), PNFA (n=20), and AD (n=19) patients. Symptom duration, caregiver age, and relationship type were matched across groups. Moreover, a number of caregiver (mood, social network) and patient variables (functional disability, behavioral changes, relationship with caregiver, and dementia stage) were addressed to investigate their impact on caregiver burden. Caregivers of bvFTD patients reported the highest burden, whereas SemDem and PNFA caregivers reported burden similar to AD. A regression analysis revealed that caregiver burden in FTD, regardless of subtype, was explained by a model combining disease staging, relationship changes, and caregiver depression. Burden increased with disease severity in FTD. This study is the first to show that caregivers of SemDem, PNFA, and AD patients show similar burden, while confirming that bvFTD caregivers show higher burden than AD caregivers. More importantly, this study demonstrates that burden worsens with disease progression in FTD.

Rev Neurol. 2012 Feb 16; 54(4): 193-8
Turro-Garriga O, Lopez-Pousa S, Vilalta-Franch J, Garre-Olmo J

AIMS. To compare the prevalence of anosognosia in patients with Alzheimer's disease (AD) using two different evaluation methodologies, to analyse the discrepancy between them and to determine the variables associated with this discrepancy. PATIENTS AND METHODS. The methodology involved a cross-sectional, observational study conducted in patients with AD. The Anosognosia Questionnaire-Dementia (AQ-D) and the Experimenter Rating Scale (ERS) were administered. Clinical and sociodemographic information was recorded about both the patient and his/her caregiver by means of standardised instruments. Prevalence was determined with each instrument and the degree of agreement between them was then established. A variable called 'agreement/non-agreement' was created and a logistic regression model was adjusted to determine the variables associated to the discrepancy. RESULTS. The prevalence of anosognosia in the mild cases was 13.6% (95% confidence interval, 95% CI = 5.5-21.7) and 17.3% (95% CI = 8.4-26.1), and 44.2% (95% CI = 28.2-60.2) and 55.8% (95% CI = 38.8-71.8) in the moderate cases, according to the ERS and the AQ-D, respectively. The degree of agreement between the two measurements yielded a kappa-value of 0.7. The regression model with the discrepancy between the ERS and the AQ-D as the dependent variable was associated to a lower functional capacity (odds ratio = 0.080; 95% CI = 0.855-0.997; p = 0.042). CONCLUSIONS. The data from the study showed an increase in the prevalence of anosognosia linked to the severity and a higher disagreement in its evaluation with two different methods as the degree of the patient's functional disability increased.

Mol Biol Rep. 2012 Feb 8;
Dong H, Mao S, Wei J, Liu B, Zhang Z, Zhang Q, Yan M

For the aging populations of any nation, Dementia is becoming a primary problem and Alzheimer's dementia (AD) is the most common type. However, until now, there is no effective treatment for AD. Tanshinone IIA (Tan IIA) has been reported for neuroprotective potential to against amyloid β peptides (Aβ)-induced cytotoxicity in the rat pheochromocytoma cell line PC-12, which is widely used as AD research model, but the mechanism still remains unclear. To investigate the effect of Tan IIA and the possible molecular mechanism in the apoptosis of PC12 cells, we induced apoptosis in PC12 cells with β-amyloid(25-35), and treated cells with Tan IIA. After 24 h treatment, we found that Tan IIA increased the cell viability and reduced the number of apoptotic cells induced by Aβ(25-35). However, neuroprotection of Tan IIA was abolished by PI3K inhibitor LY294002. Meanwhile, Treatment with lithium chloride, a phosphorylation inhibitor of GSK3β, which is a downstream target of PI3K/Akt, can block Aβ(25-35)-induced cell apoptosis in a Tan IIA-like manner. Our findings suggest that Tan IIA is an effective neuroprotective agent and a viable candidate in AD therapy and PI3K/Akt activation and GSK3β phosphorylation are involved in the neuroprotection of Tan IIA.

Mov Disord. 2012 Feb 7;
Alcalay RN, Gu Y, Mejia-Santana H, Cote L, Marder KS, Scarmeas N

BACKGROUND: Recent studies have demonstrated an association between a Mediterranean-type diet and Alzheimer's risk. We assessed the association between Mediterranean-type diet adherence and Parkinson's disease (PD) status. METHODS: Two hundred and fifty-seven PD participants and 198 controls completed the Willett semiquantitative questionnaire that quantifies diet during the past year. Scores were calculated using a 9-point scale; higher scores indicated greater adherence to the Mediterranean-type diet. Logistic regression models were used to assess the association between PD status and Mediterranean-type diet, adjusting for caloric intake, age, sex, education, and ethnicity. Adjusted linear regression models were used to examine the association between Mediterranean-type diet adherence and PD age at onset. RESULTS: Higher Mediterranean-type diet adherence was associated with reduced odds for PD after adjustment for all covariates (OR, 0.86; 95% CI, 0.77-0.97; P = .010). Lower Mediterranean-type diet score was associated with earlier PD age at onset (β = 1.09; P = .006). CONCLUSIONS: PD patients adhere less than controls to a Mediterranean-type diet. Dietary behavior may be associated with age at onset. © 2012 Movement Disorder Society.

J Biol Chem. 2012 Feb 7;
Hur JY, Teranishi Y, Kihara T, Yamamoto NG, Inoue M, Hosia W, Hashimoto M, Winblad B, Frykman S, Tjernberg LO

In Alzheimer's disease (AD), oligomeric amyloid β-peptide (Aβ) species lead to synapse loss and neuronal death. γ-Secretase, the transmembrane protease complex that mediates the final catalytic step that liberates Aβ from its precursor protein (APP), has a multitude of substrates and therapeutics aimed at reducing Aβ production should ideally be specific for APP cleavage. It has been shown that APP can be processed in lipid rafts and γ-secretase associated proteins can affect Aβ production. Here, we identify by affinity purification using a biotinylated γ-secretase inhibitor and mass spectrometry novel γ-secretase associated proteins in detergent resistant membranes (DRMs) from brain. Furthermore, we show by small interfering RNA mediated knockdown of gene expression that a subset of the γ-secretase associated proteins, in particular voltage-dependent anion channel 1 (VDAC1) and contactin associated protein 1 (CNTNAP1), reduced Aβ production (Aβ40 and Aβ42) by around 70% while knockdown of presenilin 1, one of the essential γ-secretase complex components, reduced Aβ production by 50%. Importantly, these proteins had a less pronounced effect on Notch processing. We conclude that VDAC1 and CNTNAP1 associate with γ-secretase in DRMs and affect APP processing, and suggest that molecules that interfere with this interaction could be of therapeutic use for AD.

J Amino Acids. 2011; 2011: 265084
Popiel HA, Burke JR, Strittmatter WJ, Oishi S, Fujii N, Takeuchi T, Toda T, Wada K, Nagai Y

Misfolding and abnormal aggregation of proteins in the brain are implicated in the pathogenesis of various neurodegenerative diseases including Alzheimer's, Parkinson's, and the polyglutamine (polyQ) diseases. In the polyQ diseases, an abnormally expanded polyQ stretch triggers misfolding and aggregation of the disease-causing proteins, eventually resulting in neurodegeneration. In this paper, we introduce our therapeutic strategy against the polyQ diseases using polyQ binding peptide 1 (QBP1), a peptide that we identified by phage display screening. We showed that QBP1 specifically binds to the expanded polyQ stretch and inhibits its misfolding and aggregation, resulting in suppression of neurodegeneration in cell culture and animal models of the polyQ diseases. We further demonstrated the potential of protein transduction domains (PTDs) for in vivo delivery of QBP1. We hope that in the near future, chemical analogues of aggregation inhibitor peptides including QBP1 will be developed against protein misfolding-associated neurodegenerative diseases.

PLoS One. 2012; 7(2): e31039
Cruchaga C, Chakraverty S, Mayo K, Vallania FL, Mitra RD, Faber K, Williamson J, Bird T, Diaz-Arrastia R, Foroud TM, Boeve BF, Graff-Radford NR, St Jean P, Lawson M, Ehm MG, Mayeux R, Goate AM,

Pathogenic mutations in APP, PSEN1, PSEN2, MAPT and GRN have previously been linked to familial early onset forms of dementia. Mutation screening in these genes has been performed in either very small series or in single families with late onset AD (LOAD). Similarly, studies in single families have reported mutations in MAPT and GRN associated with clinical AD but no systematic screen of a large dataset has been performed to determine how frequently this occurs. We report sequence data for 439 probands from late-onset AD families with a history of four or more affected individuals. Sixty sequenced individuals (13.7%) carried a novel or pathogenic mutation. Eight pathogenic variants, (one each in APP and MAPT, two in PSEN1 and four in GRN) three of which are novel, were found in 14 samples. Thirteen additional variants, present in 23 families, did not segregate with disease, but the frequency of these variants is higher in AD cases than controls, indicating that these variants may also modify risk for disease. The frequency of rare variants in these genes in this series is significantly higher than in the 1,000 genome project (p = 5.09×10(-5); OR = 2.21; 95%CI = 1.49-3.28) or an unselected population of 12,481 samples (p = 6.82×10(-5); OR = 2.19; 95%CI = 1.347-3.26). Rare coding variants in APP, PSEN1 and PSEN2, increase risk for or cause late onset AD. The presence of variants in these genes in LOAD and early-onset AD demonstrates that factors other than the mutation can impact the age at onset and penetrance of at least some variants associated with AD. MAPT and GRN mutations can be found in clinical series of AD most likely due to misdiagnosis. This study clearly demonstrates that rare variants in these genes could explain an important proportion of genetic heritability of AD, which is not detected by GWAS.

PLoS One. 2012; 7(2): e31302
Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C, Duff K

Tauopathy in the brain of patients with Alzheimer's disease starts in the entorhinal cortex (EC) and spreads anatomically in a defined pattern. To test whether pathology initiating in the EC spreads through the brain along synaptically connected circuits, we have generated a transgenic mouse model that differentially expresses pathological human tau in the EC and we have examined the distribution of tau pathology at different timepoints. In relatively young mice (10-11 months old), human tau was present in some cell bodies, but it was mostly observed in axons within the superficial layers of the medial and lateral EC, and at the terminal zones of the perforant pathway. In old mice (>22 months old), intense human tau immunoreactivity was readily detected not only in neurons in the superficial layers of the EC, but also in the subiculum, a substantial number of hippocampal pyramidal neurons especially in CA1, and in dentate gyrus granule cells. Scattered immunoreactive neurons were also seen in the deeper layers of the EC and in perirhinal and secondary somatosensory cortex. Immunoreactivity with the conformation-specific tau antibody MC1 correlated with the accumulation of argyrophilic material seen in old, but not young mice. In old mice, axonal human tau immunoreactivity, especially at the endzones of the perforant pathway, was greatly reduced. Relocalization of tau from axons to somatodendritic compartments and propagation of tauopathy to regions outside of the EC correlated with mature tangle formation in neurons in the EC as revealed by thioflavin-S staining. Our data demonstrate propagation of pathology from the EC and support a trans-synaptic mechanism of spread along anatomically connected networks, between connected and vulnerable neurons. In general, the mouse recapitulates the tauopathy that defines the early stages of AD and provides a model for testing mechanisms and functional outcomes associated with disease progression.

J Amino Acids. 2011; 2011: 198430
Butterfield DA, Sultana R

Alzheimer disease (AD) is an age-related progressive neurodegenerative disorder. This devastating disease is characterized by the presence of senile plaques (SP), neurofibrillary tangles (NFTs), and loss of synapses. Amyloid beta-peptide 1-42 (Aβ(1-42)) is the main component of SP and is pivotal to AD pathogenesis. Brain of subjects with AD and arguably its earliest manifestation, mild cognitive impairment (MCI), demonstrate increased levels of oxidative stress markers. Our laboratory combined these two aspects of AD and MCI and proposed the Aβ(1-42)-associated free radical oxidative stress hypothesis to explain oxidative stress under which the MCI and AD brain exist and the loss of synapses in both disorders. A large number of in vitro and in vivo studies showed that Aβ causes protein oxidation, lipid peroxidation, reactive oxygen species formation, and cell death in neuronal and synaptosomal systems. Methionine located at residue 35 of Aβ(1-42) is an important contributor to the oxidative stress associated with this neurotoxic peptide. In this paper, we summarize studies involving Met-35 of Aβ(1-42). Understanding the role of the single methionine residue of Aβ(1-42) may help in understanding underlying disease mechanisms in AD and MCI.

Arch Neurol. 2012 Feb 6;
Morris JC

OBJECTIVE: To evaluate the potential impact of revised criteria for mild cognitive impairment (MCI), developed by a work group sponsored by the National Institute on Aging and the Alzheimer's Association, on the diagnosis of very mild and mild Alzheimer disease (AD) dementia. DESIGN: Retrospective review of ratings of functional impairment across diagnostic categories. SETTING: Alzheimer's Disease Centers and the National Alzheimer's Coordinating Center. PARTICIPANTS: Individuals (N = 17 535) with normal cognition, MCI, or AD dementia. MAIN OUTCOME MEASURES: The functional ratings of individuals with normal cognition, MCI, or AD dementia who were evaluated at Alzheimer's Disease Centers and submitted to the National Alzheimer's Coordinating Center were assessed in accordance with the definition of "functional independence" allowed by the revised criteria. Pairwise demographic differences between the 3 diagnostic groups were tested using t tests for continuous variables and χ(2) for categorical variables. RESULTS: Almost all (99.8%) individuals currently diagnosed with very mild AD dementia and the large majority (92.7%) of those diagnosed with mild AD dementia could be reclassified as having MCI with the revised criteria, based on their level of impairment in the Clinical Dementia Rating domains for performance of instrumental activities of daily living in the community and at home. Large percentages of these individuals with AD dementia also meet the revised "functional independence" criterion for MCI as measured by the Functional Assessment Questionnaire. CONCLUSIONS: The categorical distinction between MCI and milder stages of AD dementia has been compromised by the revised criteria. The resulting diagnostic overlap supports the premise that "MCI due to AD" represents the earliest symptomatic stage of AD.

Environ Health Perspect. 2012 Feb 7;
Mazumdar M, Xia W, Hofmann O, Gregas M, Ho Sui S, Hide W, Yang T, Needleman HL, Bellinger DC

Background: Animal studies suggest that early life lead exposure influences gene expression and production of proteins associated with Alzheimer's disease (AD). Objectives: We attempted to assess the relationship between early life lead exposure and potential biomarkers for AD among young adults. We also attempted to assess whether early life lead exposure was associated with changes in expression of AD-related genes. Methods: We used sandwich enzyme-linked immunosorbent assays (ELISA) to measure plasma Aβ40 and Aβ42 concentrations among 55 adults who had participated as newborns and young children in a prospective cohort study of the effects of lead exposure on development. We used RNA microarray techniques to analyze gene expression. Results: Mean plasma Aβ42 concentrations were lower among 13 participants with high umbilical cord blood lead concentrations (≥10 μg/dL) than in 42 participants with lower cord blood lead concentrations (p=0.08). Among 10 participants with high prenatal lead exposure, we found evidence of an inverse relationship between umbilical cord lead concentration and expression of ADAM9, RTN4 and LRPAP1, genes whose products are believed to affect Aβ production and deposition. Gene network analysis suggested enrichment in gene sets involved in nerve growth and general cell development. Conclusions: Data from our exploratory study suggest that prenatal lead exposure may influence Aβ-related biological pathways that have been implicated in AD onset. Gene network analysis identified further candidates to study the mechanisms of developmental lead neurotoxicity.

Cold Spring Harb Perspect Med. 2012 Jan; 2(1): a011460
Selkoe D, Mandelkow E, Holtzman D

Alzheimer disease represents an insidious impairment of intellect and emotional well-being. However, recent advances in biochemical pathology and human genetics offer promise that effective therapeutic agents may soon be developed.

DNA Cell Biol. 2012 Feb 7;
Irier HA, Jin P

Gene expression is modulated by epigenetic factors that come in varying forms, such as DNA methylation, histone modifications, microRNAs, and long noncoding RNAs. Recent studies reveal that these epigenetic marks are important regulatory factors in brain function. In particular, DNA methylation dynamics are found to be essential components of epigenetic regulation in the mammalian central nervous system. In this review, we provide an overview of the literature on DNA methylation in neurodegenerative diseases, with a special focus on methylation of 5-position of cytosine base (5mC) and hydroxymethylation of 5-position of cytosine base (5hmC) in the context of neurodegeneration associated with aging and Alzheimer's disease.