Latha Velayudhan

Association of Plasma Clusterin Concentration With Severity, Pathology, and Progression in Alzheimer Disease

CONTEXT Blood-based analytes may be indicators of pathological processes in Alzheimer disease (AD). OBJECTIVE To identify plasma proteins associated with AD pathology using a combined proteomic and neuroimaging approach. DESIGN Discovery-phase proteomics to identify plasma proteins associated with correlates of AD pathology. Confirmation and validation using immunodetection in a replication set and an animal model. SETTING A multicenter European study (AddNeuroMed) and the Baltimore Longitudinal Study of Aging. PARTICIPANTS Patients with AD, subjects with mild cognitive impairment, and healthy controls with standardized clinical assessments and structural neuroimaging. MAIN OUTCOME MEASURES Association of plasma proteins with brain atrophy, disease severity, and rate of clinical progression. Extension studies in humans and transgenic mice tested the association between plasma proteins and brain amyloid. RESULTS Clusterin/apolipoprotein J was associated with atrophy of the entorhinal cortex, baseline disease severity, and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater fibrillar amyloid-beta burden in the medial temporal lobe. Subjects with AD had increased clusterin messenger RNA in blood, but there was no effect of single-nucleotide polymorphisms in the gene encoding clusterin with gene or protein expression. APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin, as well as amyloid and clusterin colocalization in plaques. CONCLUSIONS These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of AD.

A feasibility and tolerability study of lithium in Alzheimer's disease

To assess the safety and feasibility of prescribing long term lithium to elderly people with mild to moderate Alzheimers disease (AD).

Risk of developing dementia in people with diabetes and mild cognitive impairment

BACKGROUND Diabetes mellitus is associated with cognitive dysfunction, but it is not clear whether the disorder increases the risk of conversion from mild cognitive impairment to dementia. AIMS To determine the association between diabetes mellitus and dementia conversion in people with mild cognitive impairment (Petersons criteria) in a prospective community-based study. METHOD People over 65 years old were approached through primary care practices in south London, UK, and those with mild cognitive impairment (n = 103) were followed up for 4 years. Presence of diabetes was established from self-report and information from general practitioners. RESULTS Nineteen participants progressed to dementia, with the predominant diagnosis being probable or possible Alzheimers disease (in 84%). Only diabetes mellitus was associated with progression to dementia (hazard ratio 2.9, 95% CI 1.1-7.3) after adjustment for sociodemographic factors, APOE4, premorbid IQ and other health conditions. CONCLUSIONS Diabetes mellitus increases not only the risks of dementia and mild cognitive impairment but also the risk of progression from such impairment to dementia.

Review of brief cognitive tests for patients with suspected dementia

Background: As the population ages, it is increasingly important to use effective short cognitive tests for suspected dementia. We aimed to review systematically brief cognitive tests for suspected dementia and report on their validation in different settings, to help clinicians choose rapid and appropriate tests. Methods: Electronic search for face-to-face sensitive and specific cognitive tests for people with suspected dementia, taking ≤ 20 minutes, providing quantitative psychometric data. Results: 22 tests fitted criteria. Mini-Mental State Examination (MMSE) and Hopkins Verbal Learning Test (HVLT) had good psychometric properties in primary care. In the secondary care settings, MMSE has considerable data but lacks sensitivity. 6-Item Cognitive Impairment Test (6CIT), Brief Alzheimers Screen, HVLT, and 7 Minute Screen have good properties for detecting dementia but need further validation. Addenbrookes Cognitive Examination (ACE) and Montreal Cognitive Assessment are effective to detect dementia with Parkinsons disease and Addenbrookes Cognitive Examination-Revised (ACE-R) is useful for all dementias when shorter tests are inconclusive. Rowland Universal Dementia Assessment scale (RUDAS) is useful when literacy is low. Tests such as Test for Early Detection of Dementia, Test Your Memory, Cognitive Assessment Screening Test (CAST) and the recently developed ACE-III show promise but need validation in different settings, populations, and dementia subtypes. Validation of tests such as 6CIT, Abbreviated Mental Test is also needed for dementia screening in acute hospital settings. Conclusions: Practitioners should use tests as appropriate to the setting and individual patient. More validation of available tests is needed rather than development of new ones.

Entorhinal Cortex Thickness Predicts Cognitive Decline in Alzheimer's Disease

Biomarkers for Alzheimers disease (AD) based on non-invasive methods are highly desirable for diagnosis, disease progression, and monitoring therapeutics. We aimed to study the use of hippocampal volume, entorhinal cortex (ERC) thickness, and whole brain volume (WBV) as predictors of cognitive change in patients with AD. 120 AD subjects, 106 mild cognitive impairment (MCI), and 99 non demented controls (NDC) from the multi-center pan-European AddNeuroMed study underwent MRI scanning at baseline and clinical evaluations at quarterly follow-up up to 1 year. The rate of cognitive decline was estimated using cognitive outcomes, Mini-Mental State Examination (MMSE) and Alzheimer disease assessment scale-cognitive (ADAS-cog) by fitting a random intercept and slope model. AD subjects had smaller ERC thickness and hippocampal and WBV volumes compared to MCI and NDC subjects. Within the AD group, ERC > WBV was significantly associated with baseline cognition (MMSE, ADAS-cog) and disease severity (Clinical Dementia Rating). Baseline ERC thickness was associated with both longitudinal MMSE and ADAS-cog score changes and WBV with ADAS-cog decline. These data indicate that AD subjects with thinner ERC had lower baseline cognitive scores, higher disease severity, and predicted greater subsequent cognitive decline at one year follow up. ERC is a region known to be affected early in the disease. Therefore, the rate of atrophy in this structure is expected to be higher since neurodegeneration begins earlier. Focusing on structural analyses that predict decline can identify those individuals at greatest risk for future cognitive loss. This may have potential for increasing the efficacy of early intervention.

Plasma Transthyretin as a Candidate Marker for Alzheimer's Disease

Diagnosis of the progressive neurodegenerative disorder Alzheimers disease (AD) can only definitively be made postmortem. The most promising AD biomarkers identified to date are found in cerebrospinal fluid (CSF). Among these, one of the most interesting candidates is transthyretin (TTR), the carrier of thyroxine and retinol, which also binds with amyloid-β (Aβ), and it has been suggested that it protects against Aβ deposition. A biomarker detectable in plasma would have great diagnostic value and could be of use for determining disease progression and the monitoring of therapeutic efficacy due to its greater accessibility over CSF-based markers. We aimed to validate TTR as a prognostic marker in AD and to determine its relation with cognitive measures. We examined the plasma protein levels of TTR in 90 people with late-onset AD and 50 age-matched non-demented controls (NDC) by immunoblotting and found lower plasma TTR levels in AD compared to NDC (p = 0.004). We then quantified plasma TTR by enzyme-linked immunosorbent assays in a larger independent cohort (n = 270) including subjects with mild to severe AD. Plasma TTR levels were significantly lower in AD cases with rapid cognitive decline and with severe cognitive impairment. Regression analyses showed plasma TTR levels also predicted cognitive decline over the ensuing 6 months. These data indicate that plasma TTR is a strong candidate AD biomarker that should be included in the development of blood based biomarker panels for disease diagnosis and also suggests that plasma TTR is a marker of disease severity and progression.

Smell identification function as a severity and progression marker in Alzheimer's disease.

BACKGROUND Olfactory dysfunction, impaired smell identification in particular, is known as a diagnostic and a marker of conversion in Alzheimers disease (AD). We aimed to evaluate the associations of olfactory identification impairments with cognition, illness severity, and progression in AD patients. METHODS Fifty-seven outpatients with late onset mild to moderate AD and 24 elderly non-demented controls (NDC) were assessed, at baseline and after three months, for Mini-Mental State Examination (MMSE), University of Pennsylvania Smell Identification Test (UPSIT), and Bristol Activities of Daily Living and Neuropsychiatry Inventory. AD participants were classified as Rapid Cognitive Decliners (RCD) defined on a priori with a loss of ≥2 points in MMSE within the previous six months. RESULTS AD participants had lower olfactory scores than NDC. RCD had lower olfaction scores compared with Non-Rapid Cognitive Decliners (NRCD). Although the baseline UPSIT scores were associated with baseline MMSE scores, it did not interact significantly with change in MMSE over the follow-up period. Using a median split for olfactory scores, the AD participants were classified as Rapid Olfactory Progressors (ROP) (UPSIT ≤ 15) and Slow Olfactory Progressors correlating significantly with RCD/NRCD groups. The ROP group with higher olfactory impairment indicated more symptomatic illness or severity, i.e. lower cognition, higher functional dependence, and presence of behavioral symptoms. CONCLUSIONS Our study supports association of smell identification function with cognition and its utility as an adjunct clinical measure to assess severity in AD. Further work, including larger longitudinal studies, is needed to explore its value in predicting AD progression.

Smell Identification Test as a Treatment Response Marker in Patients With Alzheimer Disease Receiving Donepezil

Background: Olfactory dysfunction, impaired odor identification in particular, is known to occur in Alzheimer disease (AD). The entorhinal cortex and the olfactory bulb, critical areas for olfactory function, are rich in acetylcholine, the neurotransmitter implicated in AD pathology and treatment. In view of the common anatomical substrate, we aimed to determine whether performance on an olfaction test can be used as a clinical marker for monitoring the efficacy of donepezil in elderly people with AD. Methods: Twenty-five participants with mild to moderate AD, planned for donepezil treatment, were recruited from mental health services for older adults in this open-labeled study. Assessments before commencing donepezil included Mini-Mental State Examination, Neuropsychiatric Inventory, Bristol Activities of Daily Living, and the University of Pennsylvania Smell Identification Test. After 3 months of treatment, the primary outcome measure, the Clinician Interview Based Impression of Change plus caregiver input (CIBIC-plus), was completed, and the baseline assessments were repeated. Results: Eighteen patients continued to receive donepezil at follow-up. The CIBIC-plus outcome correlated with changes in University of Pennsylvania Smell Identification Test and Bristol Activities of Daily Living scores from the baseline (r = 0.7, P < 0.01). In addition, it was the change in smell identification function after treatment that best predicted CIBIC-plus outcome (P < 0.05) on ordinal regression analysis. Conclusions: Smell identification function could be useful as a clinical measure to assess treatment response with donepezil in AD. This is a nonblind uncontrolled study, and the outcome indicates the need for a controlled study.

Association of blood lipids with Alzheimer's disease: A comprehensive lipidomics analysis

The aim of this study was to (1) replicate previous associations between six blood lipids and Alzheimers disease (AD) (Proitsi et al 2015) and (2) identify novel associations between lipids, clinical AD diagnosis, disease progression and brain atrophy (left/right hippocampus/entorhinal cortex).

Therapeutic potential of cannabinoids in neurodegenerative disorders: a selective review.

The endocannabinoid system (ECS) is now recognised as an important modulator of various central nervous system processes. More recently, an increasing body of evidence has accumulated to suggest antioxidant, anti-inflammatory and neuroprotective roles of ECS. In this review we discuss the role and therapeutic potential of ECS in neurodegenerative disorders such as Alzheimers disease (AD), Parkinsons disease, multiple sclerosis, Huntingtons disease, Tourettes syndrome, brain ischemia and amyotrophic lateral sclerosis (ALS). Elements of the ECS, such as fatty acid amide hydrolase or the cannabinoid receptors are now considered as promising pharmacological targets for some diseases. Although still preliminary, recent reports suggest that modulation of the ECS may constitute a novel approach for the treatment of AD. There are windows of opportunity in conditions caused by acute events such as trauma and ischemia as well in conditions that may involve altered functionality of the target receptors of the ECS, such as in AD. The ECS changes in Parkinsons disease could be compensatory as well as pathogenic of the illness process and needs further understanding and clinical studies are still in the preliminary stage. There is not enough evidence to support use of cannabinoids in treating Huntingtons disease, tics and obsessive compulsive behaviour in Tourettes syndrome. Evidence on therapeutic use of cannabinoids in multiple sclerosis and ALS is currently limited. A major challenge for future research is the development of novel compounds with more selectivity for various components of the ECS which could target different neurotoxic pathways and be used in combination therapy.