Pedraza, Otto

AbstractBackgroundAs new anti‐amyloid immunotherapies emerge for Alzheimer’s disease (AD), it is clear that early diagnosis of AD pathology is crucial for treatment success. This can be challenging in atypical presentations of AD and, together with our reliance on CSF or PET scans, can, at times, lead to delayed diagnosis. Here, we further explore the possible role of plasma tau phosphorylated at threonine 217 (P‐tau217) for the detection of primary AD or AD co‐pathology when frontotemporal dementia spectrum disorders are the main clinical presentation.MethodParticipants were recruited through ALLFTD, a North American multisite research consortium for the longitudinal assessment of frontotemporal lobar degeneration. After excluding cases with known FTD‐causing mutations, 573 participants with sporadic disease, mild cognitive/behavioral impairment, or healthy familial controls evaluated between 2014 and 2023 were included in this analysis (45.8% female, median age 66 years). 39 of those cases underwent neuropathological evaluation. Plasma P‐tau217 was measured with the Eli Lilly electrochemiluminescence‐based assay. P‐tau217 concentrations were compared by phenotype, disease severity, genotype, and, when available, neuropathological diagnosis with non‐parametric tests. Its diagnostic performance was tested with ROC curves. Associations between plasma P‐tau217 concentrations and clinical scales of global cognition, memory, executive function, motor function, and social cognition with linear regressions and non‐parametric tests.ResultPlasma P‐tau217 concentrations were higher in logopenic variant primary progressive aphasia (lvPPA) and amnestic dementia (AmDem), compared to participants with normal cognition or other FTD phenotypes. P‐tau217 concentrations were higher in APOE e4 carriers, compared to non‐carriers, regardless of phenotype, but were not affected by disease severity. P‐tau217 concentrations showed associations with clinical measures of global cognition, memory, and executive function, but had no associations with measures of motor function or social cognition. Plasma P‐tau217 concentrations were elevated in high and intermediate ADNC scoring, or more advanced Braak stages, even when AD was not the primary pathology.ConclusionEven when FTD is suspected, high plasma p‐tau 217 concentrations are strongly associated with underlying AD as primary pathology or contributing co‐pathology. Plasma P‐tau217 could be a tool to support the development of disease‐modifying therapies for atypical Alzheimer’s disease presentations or for FTD cases with Alzheimer’s disease co‐pathology.

Background: Identifying individuals at risk for mild cognitive impairment (MCI) is of urgent clinical need. Objective: This study aimed to determine whether machine learning approaches could harness longitudinal neuropsychology measures, medical data, and APOE ɛ4 genotype to identify individuals at risk of MCI 1 to 2 years prior to diagnosis. Methods: Data from 676 individuals who participated in the ‘APOE in the Predisposition to, Protection from and Prevention of Alzheimer’s Disease’ longitudinal study (N = 66 who converted to MCI) were utilized in supervised machine learning algorithms to predict conversion to MCI. Results: A random forest algorithm predicted conversion 1–2 years prior to diagnosis with 97% accuracy (p = 0.0026). The global minima (each individual’s lowest score) of memory measures from the ‘Rey Auditory Verbal Learning Test’ and the ‘Selective Reminding Test’ were the strongest predictors. Conclusions: This study demonstrates the feasibility of using machine learning to identify individuals likely to convert from normal cognition to MCI.

Abstract Background and purpose Cognitive complaints are common in patients recovering from Coronavirus Disease 2019 (COVID-19), yet their etiology is often unclear. We assess factors that contribute to cognitive impairment in ambulatory versus hospitalized patients during the sub-acute stage of recovery. Methods Participants were prospectively recruited from a hospital-wide registry. All patients tested positive for SARS-CoV-2 infection using a real-time reverse transcriptase polymerasechain-reaction assay. Patients ≤ 18 years-of-age and those with a pre-existing major neurocognitive disorder were excluded. Participants completed an extensive neuropsychological questionnaire and a computerized cognitive screen via remote telemedicine platform. Rates of subjective and objective neuropsychological impairment were compared between the ambulatory and hospitalized groups. Factors associated with impairment were explored separately within each group. Results A total of 102 patients (76 ambulatory, 26 hospitalized) completed the symptom inventory and neurocognitive tests 24 ± 22 days following laboratory confirmation of SARSCoV-2 infection. Hospitalized and ambulatory patients self-reported high rates of cognitive impairment (27-40%), without differences between the groups. However, hospitalized patients showed higher rates of objective impairment in visual memory (30% vs. 4%; p=0.001) and psychomotor speed (41% vs. 15%; p=0.008). Objective cognitive test performance was associated with anxiety, depression, fatigue, and pain in the ambulatory but not the hospitalized group. Conclusions Focal cognitive deficits are more common in hospitalized than ambulatory patients. Cognitive performance is associated with neuropsychiatric symptoms in ambulatory but not hospitalized patients. Objective neurocognitive measures can provide essential information to inform neurologic triage and should be included as endpoints in clinical trials.