Faculty Bibliography

OBJECTIVE:The preeminent in vivo cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are amyloid β 1-42 (Aβ42), phosphorylated Tau (p-tau), and total Tau (t-tau). The goal of this study was to examine how well traditional (total and delayed recall) and process-based (recency ratio [Rr]) measures derived from Rey's Auditory Verbal Learning test (AVLT) were associated with these biomarkers. METHOD/METHODS: RESULTS:= 3.57). CONCLUSIONS:Our findings suggest that Rr may be a better cognitive measure than commonly used AVLT scores to assess CSF levels of p-tau and t-tau in nondemented individuals. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

BACKGROUND/UNASSIGNED:Wordlist and story recall tests are routinely employed in clinical practice for dementia diagnosis. In this study, our aim was to establish how well-standard clinical metrics compared to process scores derived from wordlist and story recall tests in predicting biomarker determined Alzheimer's disease, as defined by CSF ptau/Aβ42 ratio. METHODS/UNASSIGNED:Data from 295 participants (mean age = 65 ± 9.) were drawn from the University of Wisconsin - Madison Alzheimer's Disease Research Center (ADRC) and Wisconsin Registry for Alzheimer's Prevention (WRAP). Rey's Auditory Verbal Learning Test (AVLT; wordlist) and Logical Memory Test (LMT; story) data were used. Bayesian linear regression analyses were carried out with CSF ptau/Aβ42 ratio as outcome. Sensitivity analyses were carried out with logistic regressions to assess diagnosticity. RESULTS/UNASSIGNED:LMT generally outperformed AVLT. Notably, the best predictors were primacy ratio, a process score indexing loss of information learned early during test administration, and recency ratio, which tracks loss of recently learned information. Sensitivity analyses confirmed this conclusion. CONCLUSIONS/UNASSIGNED:Our study shows that story recall tests may be better than wordlist tests for detection of dementia, especially when employing process scores alongside conventional clinical scores.

Type 2 diabetes mellitus DM (T2DM) is associated with a 70% increased risk for dementia, including Alzheimer's disease (AD). Insulin resistance has been proposed to play a pivotal role in both T2DM and AD and the concept of "brain insulin resistance" has been suggested as an interpretation to the growing literature regarding cognitive impairment and T2DM. Subjects with T2DM present an abnormal platelet reactivity that together with insulin resistance, hyperglycaemia and dyslipidaemia effect the vascular wall by a series of events including endothelial dysfunction, oxidative stress and low-grade inflammation. Activated platelets directly contribute to cerebral amyloid angiopathy (CAA) by promoting the formation of β-amyloid (Aβ) aggregates and that Aβ, in turn, activates platelets, creating a feed-forward loop suggesting the involvement of platelets in the AD pathogenesis. Moreover, islet amyloid polypeptide deposition, co-localized with Aβ deposits, is a common finding in the brain of patients with T2DM. These observations raise the intriguing prospect that traditional or novel antiplatelet therapeutic strategies may alleviate fibril formation and could be used in the prevention or treatment of AD subjects with diabetes.

Depressed individuals are twice as likely to develop Alzheimer's disease (AD) as compared to controls. Brain amyloid-β (Aβ) deposition is believed to have a major role in AD pathogenesis but studies also suggest associations of Aβ dynamics and depression. The aim of this study was to test if plasma Aβ levels are longitudinally associated to late-life depression. We measured plasma levels of amyloid-β_1-40 (Aβ40) and amyloid-β_1-42 (Aβ42) peptides longitudinally for three consecutive years in 48 cognitively intact elderly subjects with late-life major depressive disorder (LLMD) and 45 age-matched cognitively healthy controls. We found that the Aβ42/Aβ40 plasma ratio was significantly and steadily lower in depressed subjects compared to controls (p < 0.001). At screening, Aβ42/Aβ40 plasma did not correlate with depression severity (as measured with Hamilton Depression Scale) or cognitive performance (as measured with Mini-Mental State Examination) but was associated to depression severity at 3 years after adjustment for age, education, cognitive performance, and antidepressants use. This study showed that reduced plasma Aβ42/Aβ40 ratio is consistently associated with LLMD diagnosis and that increased severity of depression at baseline predicted low Aβ42/Aβ40 ratio at 3 years. Future studies are needed to confirm these findings and examine if the consistently lower plasma Aβ42/Aβ40 ratio in LLMD reflects increased brain amyloid deposition, as observed in AD subjects, and an increased risk for progressive cognitive decline and AD.

Background Vascular function is compromised in Alzheimer disease (AD) years before amyloid and tau pathology are detected and a substantial body of work shows abnormal platelet activation states in patients with AD. The aim of our study was to investigate whether platelet function in middle age is independently associated with future risk of AD. Methods and Results We examined associations of baseline platelet function with incident dementia risk in the community-based FHS (Framingham Heart Study) longitudinal cohorts. The association between platelet function and risk of dementia was evaluated using the cumulative incidence function and inverse probability weighted Cox proportional cause-specific hazards regression models, with adjustment for demographic and clinical covariates. Platelet aggregation response was measured by light transmission aggregometry. The final study sample included 1847 FHS participants (average age, 53.0 years; 57.5% women). During follow-up (median, 20.5 years), we observed 154 cases of incident dementia, of which 121 were AD cases. Results from weighted models indicated that platelet aggregation response to adenosine diphosphate 1.0 µmol/L was independently and positively associated with dementia risk, and it was preceded in importance only by age and hypertension. Sensitivity analyses showed associations with the same directionality for participants defined as adenosine diphosphate hyper-responders, as well as the platelet response to 0.1 µmol/L epinephrine. Conclusions Our study shows individuals free of antiplatelet therapy with a higher platelet response are at higher risk of dementia in late life during a 20-year follow-up, reinforcing the role of platelet function in AD risk. This suggests that platelet phenotypes may be associated with the rate of dementia and potentially have prognostic value.

BACKGROUND:Inflammation has been described as a key pathogenic event in Alzheimer's disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies. OBJECTIVE:To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum. METHODS:We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum. RESULTS:We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ42/ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small. CONCLUSION:Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples.

One of the central lesions in the brain of subjects with Alzheimer's disease (AD) is represented by aggregates of β-amyloid (Aβ), a peptide of 40-42 amino acids derived from the amyloid precursor protein (APP). The reasons why Aβ accumulates in the brain of individuals with sporadic forms of AD are unknown. Platelets are the primary source of circulating APP and, upon activation, can secrete significant amounts of Aβ into the blood which can be actively transported to the brain across the blood-brain barrier and promote amyloid deposition. Increased platelet activity can stimulate platelet adhesion to endothelial cells, trigger the recruitment of leukocytes into the vascular wall and cause perivascular inflammation, which can spread inflammation in the brain. Neuroinflammation is fueled by activated microglial cells and reactive astrocytes that release neurotoxic cytokines and chemokines. Platelet activation is also associated with the progression of carotid artery disease resulting in an increased risk of cerebral hypoperfusion which may also contribute to the AD neurodegenerative process. Platelet activation may thus be a pathophysiological mechanism of AD and for the strong link between AD and cerebrovascular diseases. Interfering with platelet activation may represent a promising potential adjunct therapeutic approach for AD.

BACKGROUND:Inflammatory mechanisms are believed to contribute to the manifestation of major depressive disorder (MDD). Central cholinergic activity may moderate this effect. Here, we tested if volume of the cholinergic basal forebrain is associated with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglial activation in people with late life MDD. METHODS:Basal forebrain volume was determined from structural MRI scans and levels of CSF sTREM2 with immunoassay in 29 people with late-life MDD and 20 healthy older controls at baseline and 3 years follow-up. Associations were determined using Bayesian analysis of covariance. RESULTS:and total tau. Evidence was in favor of absence of an effect for baseline levels of CSF sTREM2 in MDD cases and for baseline and follow up data in controls. LIMITATIONS/CONCLUSIONS:The sample size of repeated CSF examinations was relatively small. Therefore, we used Bayesian sequential analysis to assess if effects were affected by sample size. Still, the number of cases was too small to stratify effects for different antidepressive treatments. CONCLUSIONS:Our data agree with the assumption that central cholinergic system integrity may contribute to regulation of microglia activity in late-life MDD.