BrainBlog

From Pharmalot blog, a good read about the Amyvid approval decision: Should FDA Have Approved Lilly Alzheimer’s Agent? Pharmalot By Ed Silverman April 9th, 2012 // 11:23 am Read the full blog post

Multicenter, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending Dose Study of the Oral γ-Secretase Inhibitor BMS-708163 (Avagacestat): Tolerability Profile, Pharmacokinetic Parameters, and Pharmacodynamic Markers Clin Ther. 2012 Feb 28; Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, Castaneda L, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens RC Abstract BACKGROUND: γ-Secretase inhibitors (GSIs) are being investigated for their potential to modify the progression of Alzheimer disease based on their ability to regulate amyloid-β (Aβ) accumulation. BMS-708163 (avagacestat) is an oral GSI designed for selective inhibition of Aβ synthesis currently in development for the treatment of mild to moderate and predementia AD. In addition to the desired effect on Aβ synthesis, GSIs affect Notch processing, which is thought to mediate some toxic adverse effects reported with this drug class. Avagacestat produced up to 190-fold greater selectivity for Aβ synth...

Discussions about Targretin (bexarotene): From The Wall Street Journal : Alzheimer's Families Clamor for Drug By Shirley S. Wang 11 February 2012 Read the article From the In The Pipeline blog: Bexarotene for Alzheimer's 13 February 2012 Read the blog posting

From The Independent : Switzerland's 'Dementiaville' designed to mirror the past Plan to build 1950s-style village for Alzheimer's sufferers divides geriatric-care experts TONY PATERSON TUESDAY 24 JANUARY 2012 [snip] "Its detractors may end up dubbing it "Dementiaville", but Switzerland is brushing aside a debate raging among geriatric-care experts with plans to build a mock-1950s village catering exclusively for elderly sufferers of Alzheimer's and other debilitating mental illnesses." [snip] Read the full article

This blog post from the New York Times discusses "The 36-hour Day": The Caregivers’ Bookshelf: An Alzheimer’s Classic The New Old Age Blog The New York Times by Paula Span January 20, 2012, 2:27 PM Read the full blog entry

Subjective Cognitive Complaints of Older Adults at the Population Level: An Item Response Theory Analysis Alzheimers Disease and Associated Disorders. 2011 Dec 20; Snitz BE, Yu L, Crane PK, Chang CC, Hughes TF, Ganguli M Abstract Subjective cognitive complaints (SCCs) are increasingly a focus in studies on prodromal Alzheimer disease (AD) and risk for dementia. Little is known about the optimal approach to measure SCCs. We used item response theory (IRT) to examine the characteristics of 24 SCC items in a sample of 3495 older adults pooled from 4 community-based studies. We investigated the potential advantages of IRT scoring over conventional scoring on the basis of participants' item response patterns. Items most likely endorsed by individuals low in SCC severity relate to word retrieval and general subjective memory decline. Items likely endorsed only by individuals high in SCC severity relate to nonepisodic memory changes, such as decline in comprehension, judgment and executi...

Measuring Alzheimer disease progression with transition probabilities: Estimates from NACC-UDS Curr Alzheimer Res. 2011 Nov 28; Spackman DE, Kadiyala S, Neumann PJ, Veenstra DL, Sullivan SD Abstract Objectives: Estimate the probabilities, for Alzheimer's disease (AD) patients, of transitioning between stages of disease severity (mild, moderate, severe, dead) and care settings (community, institutional). Methods: Data were compiled by the National Alzheimer Coordinating Center. The main analyses were limited to 3,852 patients who were >50 years old, diagnosed with possible/probable AD and had at least two center visits. A multinomial logistic model accounting for patient and center level correlation was used to calculate transition probabilities between stages of the Clinical Dementia Rating (CDR). Separately we calculated the probabilities of being institutionalized based on CDR stage. Both analyses controlled for baseline age, time between visits, sex, marital status, whether ...

From Bloomberg : Eli Lilly Shares Rise on Alzheimer’s Drug Hopes By Drew Armstrong and Robert Langreth Dec 6, 2011 [snip] "Solanezumab is an antibody designed to clear protein fragments called beta amyloid that clutter the brains of patients with Alzheimer’s disease. Pfizer Inc. (PFE), Johnson & Johnson and Elan are testing bapineuzumab, a similar drug." [snip] Read the article

Hippocampal hyperactivation associated with cortical thinning in Alzheimer's disease signature regions in non-demented elderly adults Journal of Neuroscience. 2011 Nov 30; 31(48): 17680-17688 Putcha D, Brickhouse M, O'Keefe K, Sullivan C, Rentz D, Marshall G, Dickerson B, Sperling R Abstract Alzheimer's disease (AD) is associated with functional and structural alterations in a distributed network of brain regions supporting memory and other cognitive domains. Functional abnormalities are present in mild cognitive impairment (MCI) with evidence of early hyperactivity in medial temporal lobe regions, followed by failure of hippocampal activation as dementia develops. Atrophy in a consistent set of cortical regions, the "cortical signature of AD," has been reported at the stage of dementia, MCI, and even in clinically normal (CN) older individuals predicted to develop AD. Despite multiple lines of evidence for each of these findings, the relationship between this st...

Just noticeable difference in olfaction: A discriminative tool between healthy elderly and patients with cognitive disorders associated with dementia Rhinology. 2011 15 1; 49(5): 513-518. Chopard G, Galmiche J, Jacquot L, Brand G Abstract Olfactory dysfunction appears to be one of the earliest signs of several age-related neurodegenerative disorders, including Alzheimer`s disease (AD) or Parkinson`s disease (PD). To rate performance and olfactory deficits in patients with cognitive disorders, various olfactory tasks have been used such as odor detection, discrimination, recognition memory, identification and naming but no study has been focused on just noticeable difference (JND), a sensitive tool of detection. The aim of this study was to investigate and compare variations in JNDs in healthy elderly and in patients with cognitive disorders associated with dementia. The results showed significantly higher olfactory JNDs in a population with cognitive disorders associated with dementia...

Alzheimer’s Disease and Dementia Leadership Council Holds Inaugural Meeting Council convenes at the New York Academy of Sciences to discuss strategies for tackling barriers to translation in dementia. Posted 11/28/2011 "NEW YORK, November 23, 2011- The newly created Alzheimer's Disease and Dementia Leadership Council gathered for its inaugural meeting at the New York Academy of Sciences on Tuesday, November 15. The leadership council, consisting of key opinion leaders in industry, academia, and government, is charged with creating strategic objectives for the Academy's Translational Science Initiative, which aims to accelerate the transfer of basic scientific discoveries into new methods for diagnosis, treatment, and prevention of disease, initially focused on Alzheimer's disease and dementia." Read the full NYAS press release From the One Mind for Research organization: Read the press release

Hippocampal Subregions are Differentially Affected in the Progression to Alzheimer's Disease Anat Rec (Hoboken). 2011 Nov 18; Greene SJ, Killiany RJ, Abstract Atrophy within the hippocampus (HP) as measured by magnetic resonance imaging (MRI) is a promising biomarker for the progression to Alzheimer's disease (AD). Subregions of the HP along the longitudinal axis have been found to demonstrate unique function, as well as undergo differential changes in the progression to AD. Little is known of relationships between such HP subregions and other potential biomarkers, such as neuropsychological (NP), genetic, and cerebral spinal fluid (CSF) beta amyloid and tau measures. The purpose of this study was to subdivide the hippocampus to determine how the head, body, and tail were affected in normal control, mild cognitively impaired, and AD subjects, and investigate relationships with HP subregions and other potential biomarkers. MRI scans of 120 participants of the Alzheimer's Di...

Increasing the diagnostic accuracy of medial temporal lobe atrophy in Alzheimer's disease Journal of Alzheimer's Disease . 2011;25(3):477-90 Jacobs HI, Van Boxtel MP, van der Elst W, Burgmans S, Smeets F, Gronenschild EH, Verhey FR, Uylings HB, Jolles J Abstract Medial temporal lobe (MTL) atrophy is considered to be one of the most important predictors of Alzheimer's disease (AD). This study investigates whether atrophy in parietal and prefrontal areas increases the predictive value of MTL atrophy in three groups of different cognitive status. Seventy-five older adults were classified as cognitively stable (n = 38) or cognitively declining (n = 37) after three years follow-up. At follow-up, the grey matter of the MTL, inferior prefrontal cortex (IPC), and inferior parietal lobule (IPL) was delineated on MRI scans. Six years later, a dementia assessment resulted in distinguishing and separating a third group (n = 9) who can be considered as preclinical AD cases at scan time....

The measurement of everyday cognition: Development and validation of a short form of the Everyday Cognition scales Alzheimers Dement . 2011 Nov; 7(6): 593-601. Tomaszewski Farias S, Mungas D, Harvey DJ, Simmons A, Reed BR, Decarli C Abstract BACKGROUND: This study describes the development and validation of a shortened version of the Everyday Cognition (ECog) scales [Tomaszewski Farias et al. Neuropsychology 2008;22:531-44], an informant-rated questionnaire designed to detect cognitive and functional decline. METHODS: External, convergent, and divergent validities and internal consistency were examined. Data were derived from informant ratings of 907 participants who were either cognitively normal, had mild cognitive impairment (MCI), or had dementia. RESULTS: Twelve items were included in the shortened version (ECog-12). The ECog-12 strongly correlated with established functional measures and neuropsychological scores, only weakly with age and education, and demonstrated high internal...

Reliability of repeated cognitive assessment of dementia using a brief computerized battery American Journal of Alzheimers Disease and Other Dementias. 2011 Jun; 26(4): 326-333. Hammers D, Spurgeon E, Ryan K, Persad C, Heidebrink J, Barbas N, Albin R, Frey K, Darby D, Giordani B Abstract OBJECTIVE: The aim of this study was to evaluate the short-term stability and reliability of a brief computerized cognitive battery in established dementia types. METHOD: Patients were administered the computerized battery twice with administrations approximately 2 hours apart, with intervening conventional neuropsychological tests. Patients were classified clinically, via consensus conference, as healthy controls (n = 23), mild cognitive impairment (n = 20), Alzheimer's disease (n = 52), dementia with Lewy Bodies ([DLB], n = 10), or frontotemporal dementia (n = 9). RESULTS: Minimal practice effects were evident across Cog-State test administrations. Small magnitude improvements were seen across a...

Relationships Between Behavioral Syndromes and Cognitive Domains in Alzheimer Disease: The Impact of Mood and Psychosis American Journal of Geriatric Psychiatry . 2011 Nov 1; Koppel J, Goldberg TE, Gordon ML, Huey E, Davies P, Keehlisen L, Huet S, Christen E, Greenwald BS Abstract OBJECTIVES:: Behavioral disturbances occur in nearly all Alzheimer disease (AD) patients together with an array of cognitive impairments. Prior investigations have failed to demonstrate specific associations between them, suggesting an independent, rather than shared, pathophysiology. The objective of this study was to reexamine this issue using an extensive cognitive battery together with a sensitive neurobehavioral and functional rating scale to correlate behavioral syndromes and cognitive domains across the spectrum of impairment in dementia. DESIGN:: Cross-sectional study of comprehensive cognitive and behavioral ratings in subjects with AD and mild cognitive impairment. SETTING:: Memory disorders researc...

New pharmacological strategies for treatment of Alzheimer's disease: focus on disease-modifying drugs British Journal of Clinical Pharmacology. 2011 Oct 28; Salomone S, Caraci F, Leggio GM, Fedotova J, Drago F Abstract Current approved drug treatments for Alzheimer disease (AD) include cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the NMDA receptor antagonist memantine. These drugs provide symptomatic relief but poorly affect the progression of the disease. Drug discovery has been directed, in the last ten years, to develop "disease-modifying drugs" hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success, it is crucial to have biomarkers for early detection of AD-related brain dysfunction, usable before clinical onset. Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy, with specifi...

Predictive value of APOE-ε4 allele for progression from MCI to AD-type dementia: A meta-analysis Journal of Neurology Neurosurgery and Psychiatry. 2011 Oct; 82(10): 1149-1156. Elias-Sonnenschein LS, Viechtbauer W, Ramakers IH, Verhey FR, Visser PJ Abstract BACKGROUND: The identification of subjects with mild cognitive impairment (MCI) at high risk for Alzheimer's disease (AD) is important for prognosis and early intervention. The APOE-ε4 allele is the strongest known genetic risk factor for AD. The authors performed a meta-analysis to establish the predictive accuracy of the APOE-ε4 allele for progression from MCI to AD-type dementia. METHODS: The authors included 35 prospective cohort studies of subjects with MCI, including 6095 subjects, of whom 1236 progressed to AD-type dementia after 2.9 years of follow-up. Pooled estimates of the OR, sensitivity, specificity, positive and negative predictive values (PPV and NPV), and positive and negative likelihood ratios (LR+ and LR-) were ...

Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation Neuron . 2011 Sep 8; 71(5): 833-844. Kummer MP, Hermes M, Delekarte A, Hammerschmidt T, Kumar S, Terwel D, Walter J, Pape HC, König S, Roeber S, Jessen F, Klockgether T, Korte M, Heneka MT Abstract Part of the inflammatory response in Alzheimer's disease (AD) is the upregulation of the inducible nitric oxide synthase (NOS2) resulting in increased NO production. NO contributes to cell signaling by inducing posttranslational protein modifications. Under pathological conditions there is a shift from the signal transducing actions to the formation of protein tyrosine nitration by secondary products like peroxynitrite and nitrogen dioxide. We identified amyloid β (Aβ) as an NO target, which is nitrated at tyrosine 10 (3NTyr(10)-Aβ). Nitration of Aβ accelerated its aggregation and was detected in the core of Aβ plaques of APP/PS1 mice and AD brains. NOS2 deficiency or oral treatment with the NOS2 inh...

An NIH Public Access Author Manuscript: Richard J. O’Brien and Philip C. Wong Amyloid Precursor Protein Processing and Alzheimer’s Disease Published in final edited form as: Annu Rev Neurosci. 2011 ; 34: 185–204. doi:10.1146/annurev-neuro-061010-113613. Download the free-access pdf here This looks like a fine overview of our current knowledge.