Sharon J. Sha

The clinical presentations of early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS) described EOAD as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the phenotypic range of EOAD presentation, we applied a neuropsychological data-driven method to subtype the LEADS cohort. Neuropsychological test performance from 169 amyloid-positive EOAD participants were analyzed. Education-corrected normative comparisons were made using a sample of 98 cognitively normal participants. Comparing the relative levels of impairment between each cognitive domain, we applied a cut-off of 1 SD below all other domain scores to indicate a phenotype of “predominant” impairment in a given cognitive domain. Individuals were otherwise considered to have multidomain impairment. Whole-cortex general linear modeling of cortical atrophy was applied as an MRI-based validation of these distinct clinical phenotypes. We identified 6 phenotypic subtypes of EOAD: Dysexecutive Predominant (22% of sample), Amnestic Predominant (11%), Language Predominant (11%), Visuospatial Predominant (15%), Mixed Amnestic/Dysexecutive Predominant (11%), and Multidomain (30%). These phenotypes did not differ by age, sex, or years of education. The APOE ɛ4 genotype was enriched in the Amnestic Predominant group, who were also rated as least impaired. Cortical thickness analysis validated these clinical phenotypes with dissociations in atrophy patterns observed between the Dysexecutive and Amnestic Predominant groups. In contrast to the heterogeneity observed from our neuropsychological data-driven approach, diagnostic classifications for this same sample based solely on clinical judgment indicated that 82% of individuals were amnestic-predominant, 9% were non-amnestic, 4% met criteria for Posterior Cortical Atrophy, and 5% met criteria for Primary Progressive Aphasia. A neuropsychological data-driven method to phenotype EOAD individuals uncovered a more detailed understanding of the presenting heterogeneity in this atypical AD sample compared to clinical judgment alone. Clinicians and patients may over-report memory dysfunction at the expense of non-memory symptoms. These findings have important implications for diagnostic accuracy and treatment considerations.

Age-related episodic memory decline is characterized by striking heterogeneity across individuals. Hippocampal pattern completion is a fundamental process supporting episodic memory. Yet, the degree to which this mechanism is impaired with age, and contributes to variability in episodic memory, remains unclear. We combine univariate and multivariate analyses of fMRI data from a large cohort of cognitively normal older adults (N=100; 60-82 yrs) to measure hippocampal activity and cortical reinstatement during retrieval of trial-unique associations. Trial-wise analyses revealed that hippocampal activity predicted cortical reinstatement strength, and these two metrics of pattern completion independently predicted retrieval success. However, increased age weakened cortical reinstatement and its relationship to memory behaviour. Critically, individual differences in the strength of hippocampal activity and cortical reinstatement explained unique variance in performance across multiple assays of episodic memory. These results indicate that fMRI indices of hippocampal pattern completion explain within- and across-individual memory variability in older adults.

The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator’s meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics.

Alzheimer disease (AD) is a progressive neurodegenerative disease that affects cognition and function. There is no known disease-modifying therapy, making drug discovery an area of unmet medical need. The increasing number of patients with AD warrants a pursuit of treatments that can improve or maintain cognitive function.

Introduction: Frontotemporal lobar degeneration–causing mutations in the progranulin ( GRN ) gene reduce progranulin protein (PGRN) levels, suggesting that restoring PGRN in mutation carriers may be therapeutic. Nimodipine, a Food and Drug Administration–approved blood‐brain barrier‐penetrant calcium channel blocker, increased PGRN levels in PGRN‐deficient murine models. We sought to assess safety and tolerability of oral nimodipine in human GRN mutation carriers. Methods: We performed an open‐label, 8‐week, dose‐finding, phase 1 clinical trial in eight GRN mutation carriers to assess the safety and tolerability of nimodipine and assayed fluid and radiologic markers to investigate therapeutic endpoints. Results: There were no serious adverse events; however, PGRN concentrations (cerebrospinal fluid and plasma) did not change significantly following treatment (percent changes of −5.2 ± 10.9% in plasma and −10.2 ± 7.8% in cerebrospinal fluid). Measurable atrophy within the left middle frontal gyrus was observed over an 8‐week period. Discussion: While well tolerated, nimodipine treatment did not alter PGRN concentrations or secondary outcomes.

Introduction: Group comparisons demonstrate greater visuospatial and memory deficits and temporoparietal-predominant degeneration on neuroimaging in patients with corticobasal syndrome (CBS) found to have Alzheimer’s disease (AD) pathology versus those with underlying frontotemporal lobar degeneration (FTLD). The value of these features in predicting underlying AD pathology in individual patients is unknown. The goal of this study is to evaluate the utility of modified clinical criteria and visual interpretations of magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) for predicting amyloid deposition (as a surrogate of Alzheimer’s disease neuropathology) in patients presenting with CBS. Methods: In total, 25 patients meeting CBS core criteria underwent amyloid (Pittsburgh compound B; PIB) PET scans. Clinical records, MRI, and FDG scans were reviewed blinded to PIB results. Modified clinical criteria were used to classify CBS patients as temporoparietal variant CBS (tpvCBS) or frontal variant CBS (fvCBS). MRI and FDG-PET were classified based on the predominant atrophy/hypometabolism pattern (frontal or temporoparietal). Results: A total of 9 out of 13 patients classified as tpvCBS were PIB+, compared to 2out of 12 patients classified as fvCBS (P < 0.01, sensitivity 82%, specificity 71% for PIB+ status). Visual MRI reads had 73% sensitivity and 46% specificity for PIB+ status with moderate intra-rater reliability (Cohen’s kappa = 0.42). Visual FDG reads had higher sensitivity (91%) for PIB+ status with perfect intra-rater reliability (kappa = 1.00), though specificity was low (50%). PIB results were confirmed in all 8 patients with available histopathology (3 PIB+ with confirmed AD, 5 PIB- with FTLD). Conclusions: Splitting CBS patients into frontal or temporoparietal clinical variants can help predict the likelihood of underlying AD, but criteria require further refinement. Temporoparietal-predominant neuroimaging patterns are sensitive but not specific for AD.