Linking Type and Extent of Head Trauma to Cavum Septum Pellucidum in Older Adults With and Without Alzheimer Disease and Related Dementias.

BACKGROUND AND OBJECTIVES: Cavum septum pellucidum (CSP) is a common but nonspecific MRI finding in individuals with prior head trauma. The type and extent of head trauma related to CSP, CSP features specific to head trauma, and the impact of brain atrophy on CSP are unknown. We evaluated CSP cross-sectionally and longitudinally in healthy and clinically impaired older adults who underwent detailed lifetime head trauma characterization. METHODS: This is an observational cohort study of University of California, San Francisco Memory and Aging Center participants (healthy controls [HCs], those with Alzheimer disease or related dementias [ADRDs], subset with traumatic encephalopathy syndrome [TES]). We characterized traumatic brain injury (TBI) and repetitive head impacts (RHI) through contact/collision sports. Study groups were no RHI/TBI, prior TBI only, prior RHI only, and prior RHI + TBI. We additionally looked within TBI (1, 2, or 3+) and RHI (1-4, 5-10, and 11+ years). All underwent baseline MRI, and 67% completed a second MRI (median follow-up = 5.4 years). CSP measures included grade (0-4) and length (millimeters). Groups were compared on likelihood of CSP (logistic regression, odds ratios [ORs]) and whether CSP length discriminated groups (area under the curve [AUC]). RESULTS: Our sample included 266 participants (N = 160 HCs, N = 106 with ADRD or TES; age 66.8 ± 8.2 years, 45.3% female). Overall, 123 (49.8%) participants had no RHI/TBI, 52 (21.1%) had TBI only, 41 (16.6%) had RHI only, 31 (12.6%) had RHI + TBI, and 20 were classified as those with TES (7.5%). Compared with no RHI/TBI, RHI + TBI (OR 3.11 [1.23-7.88]) and TES (OR 11.6 [2.46-54.8]) had greater odds of CSP. Approximately 5-10 years (OR 2.96 [1.13-7.77]) and 11+ years of RHI (OR 3.14 [1.06-9.31]) had higher odds of CSP. CSP length modestly discriminated participants with 5-10 years (AUC 0.63 [0.51-0.75]) and 11+ years of prior RHI (AUC 0.69 [0.55-0.84]) from no RHI/TBI (cut point = 6 mm). Strongest effects were noted in analyses of American football participation. Longitudinally, CSP grade was unchanged in 165 (91.7%), and length was unchanged in 171 (95.5%) participants. DISCUSSION: Among older adults with and without neurodegenerative disease, risk of CSP is driven more by duration (years) of RHI, especially American football, than number of TBI. CSP length (≥6 mm) is relatively specific to individuals who have had substantial prior RHI. Neurodegenerative disease and progressive atrophy do not clearly influence development or worsening of CSP.

Plasma Alzheimer's biomarkers and brain amyloid in Hispanic and non-Hispanic older adults.

INTRODUCTION: Alzheimer's disease studies often lack ethnic diversity. METHODS: We evaluated associations between plasma biomarkers commonly studied in Alzheimer's (p-tau181, GFAP, and NfL), clinical diagnosis (clinically normal, amnestic MCI, amnestic dementia, or non-amnestic MCI/dementia), and Aß-PET in Hispanic and non-Hispanic older adults. Hispanics were predominantly of Cuban or South American ancestry. RESULTS: Three-hundred seventy nine participants underwent blood draw (71.9 ± 7.8 years old, 60.2% female, 57% Hispanic of which 88% were Cuban or South American) and 240 completed Aß-PET. P-tau181 was higher in amnestic MCI (p = 0.004, d = 0.53) and dementia (p < 0.001, d = 0.97) than in clinically normal participants and discriminated Aß-PET[+] and Aß-PET[-] (AUC = 0.86). P-tau181 outperformed GFAP and NfL. There were no significant interactions with ethnicity. Among amnestic MCI, Hispanics had lower odds of elevated p-tau181 than non-Hispanic (OR = 0.41, p = 0.006). DISCUSSION: Plasma p-tau181 informs etiological diagnosis of cognitively impaired Hispanic and non-Hispanic older adults. Hispanic ethnicity may relate to greater likelihood of non-Alzheimer's contributions to memory loss. HIGHLIGHTS: Alzheimer's biomarkers were measured in Hispanic and non-Hispanic older adults. Plasma p-tau181 related to amnestic cognitive decline and brain amyloid burden. AD biomarker associations did not differ between Hispanic and non-Hispanic ethnicity. Hispanic individuals may be more likely to have non-Alzheimer causes of memory loss.

Plasma phosphorylated tau-217 exhibits sex-specific prognostication of cognitive decline and brain atrophy in cognitively unimpaired adults.

INTRODUCTION: Accumulating evidence indicates disproportionate tau burden and tau-related clinical progression in females. However, sex differences in plasma phosphorylated tau (p-tau)217 prediction of subclinical cognitive and brain changes are unknown. METHODS: We measured baseline plasma p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]). In CU, linear mixed effects models examined sex differences in plasma biomarker prediction of longitudinal domain-specific cognitive decline and brain atrophy. Cognitive models were repeated in MCI. RESULTS: In CU females, baseline plasma p-tau217 predicted verbal memory and medial temporal lobe trajectories such that trajectories significantly declined once p-tau217 concentrations surpassed 0.053 pg/ml, a threshold that corresponded to early levels of cortical amyloid aggregation in secondary amyloid positron emission tomography analyses. CU males exhibited similar rates of cognitive decline and brain atrophy, but these trajectories were not dependent on plasma p-tau217. Plasma GFAP and NfL exhibited similar female-specific prediction of medial temporal lobe atrophy in CU. Plasma p-tau217 exhibited comparable prediction of cognitive decline across sex in MCI. DISCUSSION: Plasma p-tau217 may capture earlier Alzheimer's disease (AD)-related cognitive and brain atrophy hallmarks in females compared to males, possibly reflective of increased susceptibility to AD pathophysiology.

Alzheimer's pathology is associated with altered cognition, brain volume, and plasma biomarker patterns in traumatic encephalopathy syndrome.

BACKGROUND: Traumatic encephalopathy syndrome (TES) is a clinical phenotype sensitive but non-specific to underlying chronic traumatic encephalopathy (CTE) neuropathology. However, cognitive symptoms of TES overlap with Alzheimer's disease (AD), and features of AD pathology like beta-amyloid (Aß) plaques often co-occur with CTE, making clinical-to-pathological conclusions of TES diagnoses challenging. We investigated how Alzheimer's neuropathological changes associated with cognition, brain volume, and plasma biomarkers in patients with repetitive head impacts (RHI)/TES, clinical AD, or typically aging controls. METHODS: We studied 154 participants including 33 with RHI/TES (age 61.5 ± 11.5, 100% male, 11/33 Aß[ +]), 62 with AD and no known prior RHI (age 67.1 ± 10.2, 48% male, 62/62 Aß[ +]), and 59 healthy controls without RHI (HC; age 73.0 ± 6.2, 40% male, 0/59 Aß[ +]). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (voxel-based morphometry analysis), and provided plasma samples analyzed for GFAP, NfL, IL-6, IFN-γ, and YKL-40. For cognition and plasma biomarkers, patients with RHI/TES were stratified as Aß[ +] or Aß[ -] and compared to each other plus the AD and HC groups (ANCOVA adjusting for age and sex). Differences with at least a medium effect size (Cohen's d > 0.50) were interpreted as potentially meaningful. RESULTS: Cognitively, within the TES group, Aß[ +] RHI/TES performed worse than Aß[-] RHI/TES on visuospatial (p = .04, d = 0.86) and memory testing (p = .07, d = 0.74). Comparing voxel-wise brain volume, both Aß[ +] and Aß[ -] RHI/TES had lower medial and anterior temporal lobe volume than HC and did not significantly differ from AD. Comparing plasma biomarkers, Aß[ +] RHI/TES had higher plasma GFAP than HC (p = .01, d = 0.88) and did not significantly differ from AD. Conversely, Aß[ -] RHI/TES had higher NfL than HC (p = .004, d = 0.93) and higher IL-6 than all other groups (p's ≤ .004, d's > 1.0). CONCLUSIONS: Presence of Alzheimer's pathology in patients with RHI/TES is associated with altered cognitive and biomarker profiles. Patients with RHI/TES and positive Aß-PET have cognitive and plasma biomarker changes that are more like patients with AD than patients with Aß[ -] RHI/TES. Measuring well-validated Alzheimer's biomarkers in patients with RHI/TES could improve interpretation of research findings and heighten precision in clinical management.

Evaluation of Plasma Phosphorylated Tau217 for Differentiation Between Alzheimer Disease and Frontotemporal Lobar Degeneration Subtypes Among Patients With Corticobasal Syndrome.

Importance: Plasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)-associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology. Objective: To validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS. Design, Setting, and Participants: This multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort. Main Outcome and Measures: Plasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-ß (Aß) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling. Results: Of 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aß PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aß PET of 0.87 (95% CI, 0.76-0.98; P < .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P < .001). At baseline, individuals with CBS-AD (n = 12), defined by a PET-validated plasma p-tau217 cutoff 0.25 pg/mL or greater, had increased temporoparietal atrophy at baseline compared to individuals with CBS-FTLD (n = 39), whereas longitudinally, individuals with CBS-FTLD had faster brainstem atrophy rates. Individuals with CBS-FTLD also progressed more rapidly on a modified version of the PSP Rating Scale than those with CBS-AD (mean [SD], 3.5 [0.5] vs 0.8 [0.8] points/year; P = .005). Conclusions and Relevance: In this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aß or FTP PET positivity within CBS with likely underlying AD pathology. Plasma P-tau217 may be a useful and inexpensive biomarker to select patients for CBS clinical trials.

Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.

BACKGROUND: Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD). METHODS: We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL). RESULTS: We studied 394 participants (non-carriers=143, C9orf72=117, GRN=62, MAPT=72). In MAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (ß=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR2=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007). CONCLUSIONS: Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.

Roles of physical activity and diet in cognitive aging: is more better?

Objective: To determine the synergistic effects of nutrition, specifically adherence to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, and physical activity on cognition and brain outcomes in a cross-sectional healthy aging cohort. Methods: A total of 132 adults (age range 52-91; Clinical Dementia Rating = 0) from the UCSF Brain Aging Project completed a 15-item MIND diet food frequency questionnaire and an 11-item self-report measure of weekly physical activity (Physical Activity Scale [PASE]). Cognitive outcomes included executive functioning, episodic memory, and language. Neuroimaging outcomes consisted of total grey matter volume and total white matter volume, adjusted for total intracranial volumes. All regression interaction models adjusted for age, sex, education, and a composite vascular burden score. Results: There was a significant interaction between PASE and MIND on executive functioning and total grey matter volume. Low levels of both related to disproportionately poorer cognitive and brain structural outcomes. Increasing levels of either, but not both, PASE or MIND related to better executive functioning and gray matter outcomes. For memory, language, and total white matter volume, the interaction between PASE and MIND showed the same directionality but did not reach statistical significance. Conclusions: Higher levels of physical activity associated with better executive functioning and gray matter volume, particularly when diet was poor. Similarly, higher levels of MIND diet adherence were associated with better brain and cognitive outcomes when physical activity was low. However, highest levels of physical activity and MIND diet together did not necessarily lead to disproportionately better cognitive and brain volume outcomes.

Feasibility and Acceptability of a Multidisciplinary Academic Telemedicine System for Memory Care in Response to COVID-19.

Background and Objectives: In response to the restrictions imposed by the COVID-19 pandemic, the University of California San Francisco Memory and Aging Center (UCSF MAC) has deployed a comprehensive telemedicine model for the diagnosis and management of Alzheimer disease and related dementias. This review summarizes a large academic behavioral neurology clinic's experience transitioning to telemedicine services, including the impact on clinic care indicators, access metrics, and provider's experience. We compared these outcomes from 3 years before COVID-19 to 12 months after the transition to video teleconferencing (VTC) encounters. Methods: Patient demographics and appointment data (dates, visit types, and departments) were extracted from our institution's electronic health record database from January 1, 2017, to May 1, 2021. We present data as descriptive statistics and comparisons using Wilcoxon rank-sum tests and Fisher exact tests. The results of anonymous surveys conducted among the clinic's providers are reported as descriptive findings. Results: After the implementation of telemedicine services, the proportion of clinic encounters completed via VTC increased from 1.9% to 86.4%. There was a statistically significant decline in both the percentage of scheduled appointments that were canceled (32.9% vs 27.9%; p < 0.01) and total cancelations per month (mean 240.3 vs 179.4/mo; p < 0.01). There was an increase in the percentage of completed scheduled appointments (60.2% vs 64.8%; p < 0.01) and an increase in the average estimated commuting distance patients would need to drive for follow-up appointments (mean 49.8 vs 54.7 miles; p < 0.01). The transition to telemedicine services did not significantly affect the clinic's patient population as measured by age, gender, estimated income, area deprivation index, or self-reported racial/ethnic identity. The results of the provider survey revealed that physicians reported a more positive experience relative to neuropsychologists. Both types of providers reported telemedicine services as a reasonable equivalent and acceptable alternative to in-person evaluations with notable caveats. Discussion: UCSF MAC's comprehensive integration of telemedicine services maintained critical ambulatory care to patients living with dementia during the COVID-19 pandemic. The recognized benefits of our care model suggest dementia telemedicine may be used as a feasible and equivalent alternative to in-person ambulatory care in the after COVID-19 era.

Combined Effects of Synaptic and Axonal Integrity on Longitudinal Gray Matter Atrophy in Cognitively Unimpaired Adults.

BACKGROUND AND OBJECTIVES: Synaptic dysfunction and degeneration is a predominant feature of brain aging and synaptic preservation buffers against Alzheimer's disease (AD) protein-related brain atrophy. We tested whether cerebrospinal fluid (CSF) synaptic protein concentrations similarly moderate the effects of axonal injury, indexed via CSF neurofilament light [NfL], on brain atrophy in clinically normal adults. METHODS: Clinically normal older adults enrolled in the observational Hillblom Aging Network study at the UCSF Memory and Aging Center completed baseline lumbar puncture and longitudinal brain MRI (Mean scan [follow-up]=2.6 [3.7 years]). CSF was assayed for synaptic proteins (synaptotagmin-1, synaptosomal-associated protein 2 [SNAP-25], neurogranin, growth associated protein 43 [GAP-43]), axonal injury (NfL), and core AD biomarkers (ptau181/Aß42 ratio; reflecting AD proteinopathy). Ten bilateral temporo-parietal gray matter ROIs shown to be sensitive to clinical AD were summed to generate a composite temporo-parietal ROI. Linear mixed-effects models tested statistical moderation of baseline synaptic proteins on baseline NfL-related temporo-parietal trajectories, controlling for ptau181/Aß42 ratios. RESULTS: Forty-six clinically normal older adults (Mean age=70; 43% female) were included. Synaptic proteins exhibited small to medium correlations with NfL (r range: .10 to .36). Higher baseline NfL, but not ptau181/Aß42 ratios, predicted steeper temporo-parietal atrophy (NfL x time: ß=-0.08, p<.001; ptau181/Aß42 x time: ß=-0.02, p=.31). SNAP-25, neurogranin, and GAP-43 significantly moderated NfL-related atrophy trajectories (-0.07≤ßs≥-0.06, ps<.05) such that NfL was associated with temporo-parietal atrophy at high (more abnormal) but not low (more normal) synaptic protein concentrations. At high NfL concentrations, atrophy trajectories were 1.5 to 4.5 times weaker when synaptic protein concentrations were low (ß range: -0.21 to -0.07) than high (ß range: -0.33 to -0.30). CONCLUSIONS: The association between baseline CSF NfL and longitudinal temporo-parietal atrophy is accelerated by synaptic dysfunction and buffered by synaptic integrity. Beyond AD proteins, concurrent examination of in vivo axonal and synaptic biomarkers may improve detection of neural alterations that precede overt structural changes in AD-sensitive brain regions.

Hepatic and renal function impact concentrations of plasma biomarkers of neuropathology.

Introduction: The impact of hepatorenal function on plasma biomarkers of neuropathology is unknown. Herein, we measured several plasma biomarkers in patients with cirrhosis. Methods: Plasma phosphorylated tau (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau), and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) were measured in 135 adults with cirrhosis and 22 healthy controls using Simoa. Within cirrhosis, associations between biomarkers and hepatorenal function were explored using linear regression. Results: p-tau181, NfL, t-tau, and UCHL1 were increased 2- to 4-fold in cirrhosis, whereas GFAP was not increased. Within cirrhosis, creatinine moderately correlated with p-tau181 (ß = 0.75, P < .01), NfL (ß = 0.32, P < .01), and t-tau (ß = 0.31, P < .01), but not GFAP (ß = -0.01, P = .88) or UCHL1 (ß = -0.05, P = .60), whereas albumin showed weak, inverse correlations: p-tau181 (ß = -0.18, P < .01), NfL (ß = -0.22, P < .01), GFAP (ß = -0.17, P < .05), t-tau (ß = -0.20, P = .02), and UCHL1 (ß = -0.15, P = .09). Conclusions: Elevated p-tau181, NfL, and t-tau in cirrhosis were associated with renal impairment and hypoalbuminemia, suggesting that hepatorenal function may be important when interpreting plasma biomarkers of neuropathology.

Amyloid, tau and metabolic PET correlates of cognition in early and late-onset Alzheimer's disease.

Early-onset (age < 65) Alzheimer's disease is associated with greater non-amnestic cognitive symptoms and neuropathological burden than late-onset disease. It is not fully understood whether these groups also differ in the associations between molecular pathology, neurodegeneration and cognitive performance. We studied amyloid-positive patients with early-onset (n = 60, mean age 58 ± 4, MMSE 21 ± 6, 58% female) and late-onset (n = 53, mean age 74 ± 6, MMSE 23 ± 5, 45% female) Alzheimer's disease who underwent neurological evaluation, neuropsychological testing, 11C-Pittsburgh compound B PET (amyloid-PET) and 18F-flortaucipir PET (tau-PET). 18F-fluorodeoxyglucose PET (brain glucose metabolism PET) was also available in 74% (n = 84) of participants. Composite scores for episodic memory, semantic memory, language, executive function and visuospatial domains were calculated based on cognitively unimpaired controls. Voxel-wise regressions evaluated correlations between PET biomarkers and cognitive scores and early-onset versus late-onset differences were tested with a PET × Age group interaction. Mediation analyses estimated direct and indirect (18F-fluorodeoxyglucose mediated) local associations between 18F-flortaucipir binding and cognitive scores in domain-specific regions of interest. We found that early-onset patients had higher 18F-flortaucipir binding in parietal, lateral temporal and lateral frontal cortex; more severe 18F-fluorodeoxyglucose hypometabolism in the precuneus and angular gyrus; and greater 11C-Pittsburgh compound B binding in occipital regions compared to late-onset patients. In our primary analyses, PET-cognition correlations did not meaningfully differ between age groups.18F-flortaucipir and 18F-fluorodeoxyglucose, but not 11C-Pittsburgh compound B, were significantly associated with cognition in expected domain-specific patterns in both age groups (e.g. left perisylvian/language, frontal/executive, occipital/visuospatial). 18F-fluorodeoxyglucose mediated the relationship between 18F-flortaucipir and cognition in both age groups across all domains except episodic memory in late-onset patients. Additional direct effects of 18F-flortaucipir were observed for executive function in all age groups, language in early-onset Alzheimer's disease and in the total sample and visuospatial function in the total sample. In conclusion, tau and neurodegeneration, but not amyloid, were similarly associated with cognition in both early and late-onset Alzheimer's disease. Tau had an association with cognition independent of neurodegeneration in language, executive and visuospatial functions in the total sample. Our findings support tau PET as a biomarker that captures both the clinical severity and molecular pathology specific to Alzheimer's disease across the broad spectrum of ages and clinical phenotypes in Alzheimer's disease.

Plasma P-tau181 and P-tau217 in Patients With Traumatic Encephalopathy Syndrome With and Without Evidence of Alzheimer Disease Pathology.

BACKGROUND AND OBJECTIVES: Traumatic encephalopathy syndrome (TES) has overlapping clinical symptoms with Alzheimer disease (AD). AD pathology commonly co-occurs with chronic traumatic encephalopathy (CTE) pathology. There are currently no validated CTE biomarkers. AD-specific biomarkers such as plasma P-tau181 and P-tau217 may help to identify patients with TES who have AD pathology. METHODS: We measured plasma P-tau181 and P-tau217 (Meso Scale Discovery electrochemiluminescence) in patients with TES, mild cognitive impairment/dementia with biomarker-confirmed AD ("AD"), and healthy controls ("HC"). Patients underwent amyloid-beta (Aß)-PET and a subset underwent tau-PET using [18F]Flortaucipir. We compared plasma P-tau levels controlling for age and sex and also performed AUC analyses to evaluate the accuracy of group differentiation. In patients with TES, we evaluated associations between plasma P-tau, years of repetitive head impact exposure, and tau-PET. Four TES patients with autopsy-confirmed CTE were described qualitatively. RESULTS: The sample included 131 participants (TES, N = 18; AD, N = 65; HC, N = 48). Aß(+) patients with TES (N = 10), but not Aß(-) TES, had significantly higher plasma P-tau levels than HC (P-tau181: p < 0.001, d = 1.34; P-tau217: p < 0.001, d = 1.59). There was a trend for Aß(+) TES having higher plasma P-tau than Aß(-) TES (P-tau181: p = 0.06, d = 1.06; P-tau217: p = 0.09, d = 0.93). AUC analyses showed good classification of Aß(+) TES from HC for P-tau181 (AUC = 0.87 [0.71-1.00]) and P-tau217 (AUC = 0.93 [0.86-1.00]). Plasma P-tau217 showed fair differentiation of Aß(+) TES from Aß(-) TES (AUC = 0.79 [0.54-1.00], p = 0.04), whereas classification accuracy of P-tau181 was slightly lower and not statistically significant (AUC = 0.71 [0.46-0.96], p = 0.13). Patients with AD had higher tau-PET tracer uptake than Aß(+) TES and were well differentiated using P-tau181 (AUC = 0.81 [0.68-0.94]) and P-tau217 (AUC = 0.86 [0.73-0.98]). Plasma P-tau correlated with the tau-PET signal in Aß(+) TES but not in Aß(-) TES, and there was no association between plasma P-tau and years of repetitive head impact exposure. TES patients with severe CTE and no AD at autopsy had low P-tau181 and P-tau217 levels. DISCUSSION: Measuring P-tau181 and P-tau217 in plasma may be a feasible and scalable fluid biomarker for identifying AD pathology in TES. Low plasma P-tau levels may be used to increase clinical suspicion of CTE over AD as a primary pathology in TES. Currently, there is no support for P-tau181 or P-tau217 as in vivo biomarkers of CTE tau. Larger studies of patients with pathologically confirmed CTE are needed. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that (1) among patients with TES and abnormal Aß-PET scans, elevated plasma P-tau can differentiate between affected individuals and HCs; (2) low plasma P-tau may help identify patients with TES who do not have Alzheimer; and (3) plasma P-tau181 and P-tau217 are not useful biomarkers of patients with TES who do not have AD.

Multi-Modal Biomarkers of Repetitive Head Impacts and Traumatic Encephalopathy Syndrome: A Clinicopathological Case Series.

Traumatic encephalopathy syndrome (TES) criteria were developed to aid diagnosis of chronic traumatic encephalopathy (CTE) pathology during life. Interpreting clinical and biomarker findings in patients with TES during life necessitates autopsy-based determination of the neuropathological profile. We report a clinicopathological series of nine patients with previous repetitive head impacts (RHI) classified retrospectively using the recent TES research framework (100% male and white/Caucasian, age at death 49-84) who completed antemortem neuropsychological evaluations, T1-weighted magnetic resonance imaging, diffusion tensor imaging (n = 6), (18)F-fluorodeoxyglucose-positron emission tomography (n = 5), and plasma measurement of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau (n = 8). Autopsies were performed on all patients. Cognitively, low test scores and longitudinal decline were relatively consistent for memory and executive function. Medial temporal lobe atrophy was observed in all nine patients. Poor white matter integrity was consistently found in the fornix. Glucose hypometabolism was most common in the medial temporal lobe and thalamus. Most patients had elevated plasma GFAP, NfL, and total tau at their initial visit and a subset showed longitudinally increasing concentrations. Neuropathologically, five of the nine patients had CTE pathology (n = 4 "High CTE"/McKee Stage III-IV, n = 1 "Low CTE"/McKee Stage I). Primary neuropathological diagnoses (i.e., the disease considered most responsible for observed symptoms) were frontotemporal lobar degeneration (n = 2 FTLD-TDP, n = 1 FTLD-tau), Alzheimer disease (n = 3), CTE (n = 2), and primary age-related tauopathy (n = 1). In addition, hippocampal sclerosis was a common neuropathological comorbidity (n = 5) and associated with limbic-predominant TDP-43 proteinopathy (n = 4) or FTLD-TDP (n = 1). Memory and executive function decline, limbic system brain changes (atrophy, decreased white matter integrity, hypometabolism), and plasma biomarker alterations are common in RHI and TES but may reflect multiple neuropathologies. In particular, the neuropathological differential for patients with RHI or TES presenting with medial temporal atrophy and memory loss should include limbic TDP-43. Researchers and clinicians should be cautious in attributing cognitive, neuroimaging, or other biomarker changes solely to CTE tau pathology based on previous RHI or a TES diagnosis alone.

Risk factors and abnormal cerebrospinal fluid associate with cognitive symptoms after mild COVID-19.

Cognitive post-acute sequelae of SARS-CoV-2 (PASC) can occur after mild COVID-19. Detailed clinical characterizations may inform pathogenesis. We evaluated 22 adults reporting cognitive PASC and 10 not reporting cognitive symptoms after mild SARS-CoV-2 infection through structured interviews, neuropsychological testing, and optional cerebrospinal fluid (CSF) evaluations (53%). Delayed onset of cognitive PASC occurred in 43% and associated with younger age. Cognitive PASC participants had a higher number of pre-existing cognitive risk factors (2.5 vs. 0; p = 0.03) and higher proportion with abnormal CSF findings (77% vs. 0%; p = 0.01) versus controls. Cognitive risk factors and immunologic mechanisms may contribute to cognitive PASC pathogenesis.

Lower White Matter Volume and Worse Executive Functioning Reflected in Higher Levels of Plasma GFAP among Older Adults with and Without Cognitive Impairment.

OBJECTIVE: There are minimal data directly comparing plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in aging and neurodegenerative disease research. We evaluated associations of plasma NfL and plasma GFAP with brain volume and cognition in two independent cohorts of older adults diagnosed as clinically normal (CN), mild cognitive impairment (MCI), or Alzheimer's dementia. METHODS: We studied 121 total participants (Cohort 1: n = 50, age 71.6 ± 6.9 years, 78% CN, 22% MCI; Cohort 2: n = 71, age 72.2 ± 9.2 years, 45% CN, 25% MCI, 30% dementia). Gray and white matter volumes were obtained for total brain and broad subregions of interest (ROIs). Neuropsychological testing evaluated memory, executive functioning, language, and visuospatial abilities. Plasma samples were analyzed in duplicate for NfL and GFAP using single molecule array assays (Quanterix Simoa). Linear regression models with structural MRI and cognitive outcomes included plasma NfL and GFAP simultaneously along with relevant covariates. RESULTS: Higher plasma GFAP was associated with lower white matter volume in both cohorts for temporal (Cohort 1: ß = -0.33, p = .002; Cohort 2: ß = -0.36, p = .03) and parietal ROIs (Cohort 1: ß = -0.31, p = .01; Cohort 2: ß = -0.35, p = .04). No consistent findings emerged for gray matter volumes. Higher plasma GFAP was associated with lower executive function scores (Cohort 1: ß = -0.38, p = .01; Cohort 2: ß = -0.36, p = .007). Plasma NfL was not associated with gray or white matter volumes, or cognition after adjusting for plasma GFAP. CONCLUSIONS: Plasma GFAP may be more sensitive to white matter and cognitive changes than plasma NfL. Biomarkers reflecting astroglial pathophysiology may capture complex dynamics of aging and neurodegenerative disease.

Interbatch Reliability of Blood-Based Cytokine and Chemokine Measurements in Community-Dwelling Older Adults: A Cross-Sectional Study.

Blood-based inflammatory markers hold considerable promise for diagnosis and prognostication of age-related neurodegenerative disease, though a paucity of research has empirically tested how reliably they can be measured across different experimental runs ("batches"). We quantified the interbatch reliability of 13 cytokines and chemokines in a cross-sectional study of 92 community-dwelling older adults (mean age = 74; 48% female). Plasma aliquots from the same blood draw were parallelly processed in 2 separate batches using the same analytic platform and procedures (high-performance electrochemiluminescence by Meso Scale Discovery). Interbatch correlations (Pearson's r) ranged from small and nonsignificant (r = .13 for macrophage inflammatory protein-1 alpha [MIP-1α]) to very large (r > .90 for interferon gamma [IFNγ], interleukin-10 [IL-10], interferon gamma-induced protein 10 [IP-10], MIP-1ß, thymus and activation-regulated chemokine [TARC]) with most markers falling somewhere in between (.67 ≤ r ≤ .90 for IL-6, tumor necrosis factor alpha [TNF-α], Eotaxin, Eotaxin-3, monocyte chemoattractant protein-1 [MCP-1], MCP-4, macrophage-derived chemokine [MDC]). All markers, except for IL-6 and MCP-4, showed significant differences in absolute values between batches, with discrepancies ranging in effect size (Cohen's d) from small to moderate (0.2 ≤ |d| ≤ 0.5 for IL-10, IP-10, MDC) to large or very large (0.68 ≤ |d| ≤ 1.5 for IFNγ, TNF-α, Eotaxin, Eotaxin-3, MCP-1, MIP-1α, MIP-1ß, TARC). Relatively consistent associations with external variables of interest (age, sex, systolic blood pressure, body mass index, cognition) were observed across batches. Taken together, our results suggest heterogeneity in measurement reliability of blood-based cytokines and chemokines, with some analytes outperforming others. Future work is needed to evaluate the generalizability of these findings while identifying potential sources of batch effect measurement error.

Identifying degenerative effects of repetitive head trauma with neuroimaging: a clinically-oriented review.

BACKGROUND AND SCOPE OF REVIEW: Varying severities and frequencies of head trauma may result in dynamic acute and chronic pathophysiologic responses in the brain. Heightened attention to long-term effects of head trauma, particularly repetitive head trauma, has sparked recent efforts to identify neuroimaging biomarkers of underlying disease processes. Imaging modalities like structural magnetic resonance imaging (MRI) and positron emission tomography (PET) are the most clinically applicable given their use in neurodegenerative disease diagnosis and differentiation. In recent years, researchers have targeted repetitive head trauma cohorts in hopes of identifying in vivo biomarkers for underlying biologic changes that might ultimately improve diagnosis of chronic traumatic encephalopathy (CTE) in living persons. These populations most often include collision sport athletes (e.g., American football, boxing) and military veterans with repetitive low-level blast exposure. We provide a clinically-oriented review of neuroimaging data from repetitive head trauma cohorts based on structural MRI, FDG-PET, Aß-PET, and tau-PET. We supplement the review with two patient reports of neuropathology-confirmed, clinically impaired adults with prior repetitive head trauma who underwent structural MRI, FDG-PET, Aß-PET, and tau-PET in addition to comprehensive clinical examinations before death. REVIEW CONCLUSIONS: Group-level comparisons to controls without known head trauma have revealed inconsistent regional volume differences, with possible propensity for medial temporal, limbic, and subcortical (thalamus, corpus callosum) structures. Greater frequency and severity (i.e., length) of cavum septum pellucidum (CSP) is observed in repetitive head trauma cohorts compared to unexposed controls. It remains unclear whether CSP predicts a particular neurodegenerative process, but CSP presence should increase suspicion that clinical impairment is at least partly attributable to the individual's head trauma exposure (regardless of underlying disease). PET imaging similarly has not revealed a prototypical metabolic or molecular pattern associated with repetitive head trauma or predictive of CTE based on the most widely studied radiotracers. Given the range of clinical syndromes and neurodegenerative pathologies observed in a subset of adults with prior repetitive head trauma, structural MRI and PET imaging may still be useful for differential diagnosis (e.g., assessing suspected Alzheimer's disease).

Persistent COVID-19-associated neurocognitive symptoms in non-hospitalized patients.

As cases of coronavirus disease 2019 (COVID-19) mount worldwide, attention is needed on potential long-term neurologic impacts for the majority of patients who experience mild to moderate illness managed as outpatients. To date, there has not been discussion of persistent neurocognitive deficits in patients with milder COVID-19. We present two cases of non-hospitalized patients recovering from COVID-19 with persistent neurocognitive symptoms. Commonly used cognitive screens were normal, while more detailed testing revealed working memory and executive functioning deficits. An observational cohort study of individuals recovering from COVID-19 (14 or more days following symptom onset) identified that among the first 100 individuals enrolled, 14 were non-hospitalized patients reporting persistent cognitive issues. These 14 participants had a median age of 39 years (interquartile range: 35-56), and cognitive symptoms were present for at least a median of 98 days (interquartile range: 71-120 following acute COVID-19 symptoms); no participants with follow-up evaluation reported symptom resolution. We discuss potential mechanisms to be explored in future studies, including direct viral effects, indirect consequences of immune activation, and immune dysregulation causing auto-antibody production.