Cláudia Y. Santos

Pathophysiologic relationship between Alzheimer's disease, cerebrovascular disease, and cardiovascular risk: A review and synthesis

As the population ages due to demographic trends and gains in life expectancy, the incidence and prevalence of dementia increases, and the need to understand the etiology and pathogenesis of dementia becomes ever more urgent. Alzheimers disease (AD), the most common form of dementia, is a complex disease, the mechanisms of which are poorly understood. The more we learn about AD, the more questions are raised about our current conceptual models of disease. In the absence of a cure or the means by which to slow disease progress, it may be prudent to apply our current knowledge of the intersection between AD, cardiovascular disease, and cerebrovascular disease to foster efforts to delay or slow the onset of AD. This review discusses our current understanding of the epidemiology, genetics, and pathophysiology of AD, the intersection between AD and vascular causes of dementia, and proposes future directions for research and prevention.

Nonvascular retinal imaging markers of preclinical Alzheimer's disease

In patients with Alzheimers disease (AD) and mild cognitive impairment, structural changes in the retina (i.e., reduced thicknesses of the ganglion cell and retinal nerve fiber layers and inclusion bodies that appear to contain beta‐amyloid protein [Ab]) have been previously reported. We sought to explore whether anatomic retinal changes are detectable in the preclinical stage of AD.

Resting-State Cardiac Workload is Related to Both Increased Neocortical Aggregation of Amyloid-β and Relative Impairments in Spatial Working Memory in Pre-Clinical Alzheimer's Disease.

We sought to determine whether there is any association between a cardiac workload marker, rate pressure product (RPP), working memory, and cortical amyloid-β (Aβ) burden in 63 cognitively normal midlife adults (Mage = 62.8 years; range = 55 to 75 years) at risk for Alzheimers disease (AD). The results show a small-to-moderate relationship between increasing cardiac workload (at rest) and neocortical amyloidosis in individuals at the preclinical stage of AD. Moreover, increasing RPP was linearly related to increasing relative impairments on a spatial working memory task (R2 = 0.30), but only for those individuals with neuroimaging evidence suggestive of preclinical AD. These results support a relationship between the aggregation of Aβ protein plaques in the neocortex, increased cognitive impairment, and more inefficient myocardial oxygen use in the absence of significant metabolic demands.

Change in retinal structural anatomy during the preclinical stage of Alzheimer's disease

We conducted a 27‐month longitudinal study of mid‐life adults with preclinical Alzheimers disease (AD), using spectral domain optical coherence tomography to compare changes in volume and thickness in all retinal neuronal layers to those of age‐matched healthy control subjects.

DISRUPTION OF CHOLINERGIC NEUROTRANSMISSION, WITHIN A COGNITIVE CHALLENGE PARADIGM, PREDICTS Aβ-RELATED COGNITIVE IMPAIRMENT IN PRECLINICAL ALZHEIMER’S DISEASE AFTER A 27-MONTH DELAY INTERVAL

Figure 1. Performance on the International Shopping List (ISLT) Delayed Recall Task, by participants who either failed the scopolamine challenge test (SCT) at baseline (N 1⁄4 28, at end of study) vs. those who passed the SCTat baseline (N1⁄4 30, at end of study), modeled over all four study visits. Dark lines indicate group mean scores at each visit, with SE bars provided. Both betweenand within-subject variation is represented in each group, by displaying individual subject change over time, with each case yoked to the group baseline mean score. Danielle Goldfarb, Peter J. Snyder, Paul Maruff, Cl audia Y. Santos, Brian R. Ott, Stephen Salloway, Don C. Yoo, Richard B. Noto, Jessica Alber, Louisa I. Thompson, Alex Song, Alpert Medical School of Brown University, Providence, RI, USA; University of Rhode Island, Kingston, RI, USA; The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia; Cogstate Ltd., Melbourne, Australia; Lifespan, Providence, RI, USA; Butler Hospital, Providence, RI, USA; Brown University, Providence, RI, USA. Contact e-mail: dagoldfarb9@gmail.com

Discontinuation and nonpublication of interventional clinical trials conducted in patients with mild cognitive impairment and Alzheimer's disease

Discontinuation and nonpublication of interventional clinical trials represents a waste of already scarce resources. We sought to identify the prevalence of discontinuation and nonpublication of interventional clinical trials conducted in patients afflicted by mild cognitive impairment and Alzheimers disease.

Autonomic Cardiac Function in Preclinical Alzheimer’s Disease

To explore early autonomic cardiac changes in pre-clinical Alzheimers disease (AD), we have evaluated electrocardiologic measures of vagal tone for 63 adults (ages 55-75) at rest, during cognitive testing, and then again at rest. All subjects had multiple risk factors for AD, and all completed amyloid PET scans (18F-Florbetapir) to determine amyloid positivity (Aβ+). No change in electrocardiographic measures were observed for Aβ+ participants under each testing condition, whereas Aβ-subjects showed an expected increase in vagal tone during the cognitive stress condition. These findings suggest an early relationship between cortical Aβ accumulation, a precursor to AD development, and autonomic cardiac function.

RETINAL NERVE FIBER LAYER AND GANGLION CELL LAYER VOLUME CHANGES IN PRECLINICAL ALZHEIMER'S DISEASE OVER 27 MONTHS

hippocampus and cortex in an APP/PSEN1 mouse. Methods:We utilize a cell-specific inducible system to express human TDP-43 and nuclear localization signal defective TDP-43DNLS in hippocampal and cortical neuronal populations using the Camk2a tetracycline transactivator (Camk2a-tTA) in an APP/PSEN1 background. The effect of TDP-43 on cognition and neurotoxicity was evaluated through novel object recognition, Y-maze, pathology, electron microscopy, immunofluorescence, primary cortical neuronal cultures, proteomics, and Western blotting. Results: We describe functional changes in short and long-term memory associated with TDP-43 expression. In addition, we describe pathological changes in AB plaques, tau aggregation, and phosphorylated TDP-43. Conclusions: Collectively, our data lead us to conclude that TDP-43 contributes to functional changes in memory, Ab plaque formation, tau aggregation, and accumulation of phosphorylated TDP-43. Our current data suggest that TDP-43 could be a putative target of therapeutic intervention in AD affecting both AB plaques and tauopathy.