Hassenstab, Jason

Abstract Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer’s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. We evaluated plasma, serum, and CSF GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Plasma GFAP elevations appear a decade before expected symptom onset, after β-amyloid accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished β-amyloid-positive from β-amyloid-negative ADAD participants and showed a stronger relationship with β-amyloid load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Our findings support a role for plasma GFAP as a clinical biomarker for β-amyloid-associated cognitive deterioration in AD.

AbstractIntroductionAs knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD.MethodsFrequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers.ResultsAD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1%. Cross‐sectionally, mutation carriers with AD neurological examination findings showed a more than two‐fold faster cognitive decline and had greater parieto‐temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time.DiscussionADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs.

AbstractThe extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of ‘sporadic’ late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease.We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer’s Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset.Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants.These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.

AbstractINTRODUCTIONAs the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others.METHODSWe used hierarchical clustering to group 19 cross‐sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation.RESULTSThree primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors.DISCUSSIONThese results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.

AbstractIntroductionThis study established the psychometric properties and preliminary validity of the Stricker Learning Span (SLS), a novel computer adaptive word list memory test designed for remote assessment and optimized for smartphone use.MethodsWomen enrolled in the Mayo Clinic Specialized Center of Research Excellence (SCORE) were recruited via e‐mail or phone to complete two remote cognitive testing sessions. Convergent validity was assessed through correlation with previously administered in‐person neuropsychological tests (n = 96, ages 55–79) and criterion validity through associations with magnetic resonance imaging measures of neurodegeneration sensitive to Alzheimer's disease (n = 47).ResultsSLS performance significantly correlated with the Auditory Verbal Learning Test and measures of neurodegeneration (temporal meta‐regions of interest and entorhinal cortical thickness, adjusting for age and education). Test–retest reliabilities across two sessions were 0.71–0.76 (two‐way mixed intraclass correlation coefficients).DiscussionThe SLS is a valid and reliable self‐administered memory test that shows promise for remote assessment of aging and neurodegenerative disorders.

AbstractBackgroundThough pathogenic variations in PSEN1 leading to Autosomal Dominant Alzheimer's disease (ADAD) are all highly penetrant, there is substantial inter‐individual variability in the rates of cognitive decline and biomarker change observed in ADAD. We hypothesized that this inter‐individual variability may be associated with the location of the pathogenic variant within PSEN1. We tested this hypothesis using biomarker and cognitive data from the Dominantly Inherited Alzheimer Network (DIAN) observational study.MethodPSEN1 pathogenic variant carriers [grouped based on whether their ADAD genotype affected transmembrane (PSEN1 TM; N = 125) or cytoplasmic (PSEN1 CY; N = 62) domains] and non‐carriers [NC; N = 176] enrolled in DIAN underwent clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF). Linear mixed effects models with a restricted cubic spline were used to determine cross‐sectional differences in clinical and biomarker measures between NC, PSEN1 TM, and PSEN1 CY groups, across the disease course (estimated years to symptom onset; EYO).ResultBackground characteristics are reported in Table 1. PSEN1 CY and PSEN1 TM groups had elevated β‐amyloid (PiB‐PET) and phosphorylated‐tau levels (CSF pTauT181) compared to NC, but these biomarker measures were not different between PSEN1 TM and CY groups (Figure 1a‐b). Additionally, the PSEN1 TM group had decreased glucose metabolism compared to NC but was similar to the PSEN1 CY group (Figure 1c). However, we observed that PSEN1 TM carriers had significantly smaller hippocampal volume, greater lateral ventricle volume, and greater cognitive impairment (Figure 1d‐f) across EYO as compared to PSEN1 CY carriers.ConclusionDespite similar β‐amyloid PET and CSF pTauT181 levels across EYO, individuals with pathogenic variants affecting transmembrane domains in PSEN1 may have more rapid progression of disease as measured by cognitive function and neurodegeneration as compared to those with variants affecting cytoplasmic domains. These results have implications both for understanding the heterogeneity in ongoing ADAD clinical trials and for better understanding the pathobiology of ADAD.

AbstractBackgroundMayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform for remote self‐administered assessment for novel (Stricker Learning Span; SLS) and open access (Symbols Test) cognitive measures. The SLS is a computer adaptive word‐list memory test that matches test difficulty to user performance. The SLS visually presents words for learning exposures and 4‐choice recognition to test encoding across 5 trials. Symbols is a measure of processing speed being used in many remote assessment studies and typically employs a burst design; in MTD participants complete 4 trials (12‐items each). We examine validity and reliability of the SLS and Symbols via MTD.MethodForty‐five women enrolled in an ongoing study of the Sex‐Specific Effects of Endocrine Disruption on Aging and Alzheimer’s Disease were recruited via email or phone. The Auditory Verbal Learning Test (AVLT) and Digit Symbol Coding (Coding), administered in person within the past 2 years (Mean=11 months), were used to establish construct validity. Participants (91.3% White, Mean age=66.2 years, Mean education=15.3 years) were emailed a link to complete the SLS and Symbols remotely at their convenience on their own device and emailed to repeat testing after approximately 1 week. Pearson correlations (n=45) and 2‐way mixed intraclass correlation coefficients (ICC; n=42) determined construct validity and test‐retest reliability, respectively. Significance was set at p<.05.ResultAcross all test sessions initiated, 97% were successfully completed. Most were completed at home (92.6%; vs. at work or in a public space), and device type varied (48% smartphone, 2% tablet, 50% PC). Median session completion time was 15 minutes. SLS learning scores (max span, total correct trials 1‐5) significantly correlated with AVLT 1‐5 total (r’s .37‐.39) and AVLT Trial 5 (r’s .51‐.52). SLS delay significantly correlated with AVLT delay (r=0.45) and recognition (r=0.61). Symbols time‐based scores averaged across trials were significantly correlated with Coding (r’s=‐.48‐(‐).50). Test‐retest reliabilities across 2 sessions were high for SLS (ICC’s=.80‐.88) and Symbols (ICC’s=.81‐.82).ConclusionSLS and Symbols are valid and reliable self‐administered remote tests in older females. Future work will examine effects of Alzheimer’s disease neuroimaging biomarkers and risk factors on these tests.

AbstractAs prevention trials advance with autosomal dominant Alzheimer disease (ADAD) participants, understanding the similarities and differences between ADAD and “sporadic” late‐onset AD (LOAD) is critical to determine generalizability of findings between these cohorts. Cognitive trajectories of ADAD mutation carriers (MCs) and autopsy‐confirmed LOAD individuals were compared to address this question. Longitudinal rates of change on cognitive measures were compared in ADAD MCs (n = 310) and autopsy‐confirmed LOAD participants (n = 163) before and after symptom onset (estimated/observed). LOAD participants declined more rapidly in the presymptomatic (preclinical) period and performed more poorly at symptom onset than ADAD participants on a cognitive composite. After symptom onset, however, the younger ADAD MCs declined more rapidly. The similar but not identical cognitive trajectories (declining but at different rates) for ADAD and LOAD suggest common AD pathologies but with some differences.