The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, β, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study.
Abstract Background Language impairment is common in progressive supranuclear palsy (PSP) and is often overlooked due to the severity of the motor symptoms. We investigated whether language can be used to predict PSP prognosis. Methods One hundred‐forty‐six patients with a diagnosis of possible or probable PSP from the Tilavonemab (ABBV‐8E12) clinical trial were evaluated at baseline and week 32 using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the PSP rating scale (PSPRS) and the Schwab and England Activities of Daily Living Scale (SEADL). Percentage of change was calculated for each measure. Using correlations, we evaluated relationships between all RBANS‐subscores (language, attention, memory and visuoconstructional), the PSPRS and SEADL scores at baseline; p‐values were FDR corrected. Linear regression analyses were performed between the RBANS‐language, RBANS‐delayed‐memory and RBANS‐executive at baseline and the percentage of change over time. Grey matter volumes were extracted from three regions of interest based on language (bilateral temporal poles and inferior frontal gyri), executive (bilateral dorsolateral and superior frontal gyri and frontal pole) and memory (bilateral hippocampus, inferior, middle and superior temporal gyri) areas. Results Mean age of PSP patients: 68.8 years (49‐86 years), 57 (39%) females. The RBANS language, executive and delayed memory scores at baseline were positively correlated with each other and with visuoconstructional and immediate memory score (all p<0.05). Only the RBANS‐language score at baseline predicted percentage of change in PSPRS (B = ‐0.63, p = 0.003). The percentage of change in the RBANS‐language score was predicted by the RBANS‐language at baseline (B = ‐0.59, p<0.001). Lower age at baseline was associated with a worsening in language score over time (B = 0.51, p = 0.009). Language grey matter volume was associated with the change in RBANS‐language score (B = 0.01, p = 0.02). Conclusions language impairment at baseline, in contrast to memory and executive functions, was predictive of functional decline as measured by PSPRS. Atrophy in language areas at baseline predicted language decline. Language impairment may be an independent prognostic factor in PSP. *Based on research using data from AbbVie that has been made available through Vivli, Inc. Vivli has not contributed to or approved, and is not in any way responsible for, the contents of this publication.
The hippocampus is one of the first brain structures affected by Alzheimer's disease (AD), and its atrophy is a strong indicator of the disease. This study investigates the ability of plasma biomarkers of AD and AD-related dementias-amyloid-β (Aβ42/40), phosphorylated tau-181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)-to predict hippocampal atrophy in adult individuals in Kinshasa, Democratic Republic of Congo (DRC).
Abstract Background Postoperative complications of major surgical interventions include delirium. Delirium is a risk factor for dementia, and in some cases, may signal underlying neuropathological processes. Cognitive tests that accurately predict post‐operative outcomes could identify patients with cognitive vulnerabilities who may benefit from preoperative counseling and postoperative interventions. Unfortunately, in‐person presurgical cognitive evaluations are often not available, but digital technologies may improve access. In this pilot study, we evaluate the feasibility of utilizing a smartphone app to conduct preoperative remote cognitive assessment in patients undergoing spine surgery. We also evaluate the relationship of app‐based assessments with subjective cognitive concerns. Method We enrolled 30 older adults ( = 65 years old) who were scheduled for elective spinal surgery anticipated to last at least three hours. On the ALLFTD Mobile App, participants completed a battery of cognitive tests, a measure of subjective cognitive concerns (12‐item self‐reported everyday cognition scale, Ecog‐12), and a user experience survey. A subset (N = 12) had a study partner complete the 41‐item Ecog, reporting on observed changes in cognitive function over a 10‐year period prior to the surgery. Linear regressions adjusted for age evaluated the associations between subjective cognitive concerns and the objective app‐based outcomes (Flanker task and a composite of several measures). Result Average age of participants was 71.2 years (SD = 4.4); 46.1% were women and 75% identified as White. Most (96%) participants indicated that the time required to complete the app assessments was acceptable, 77% indicated that the app instructions were clear, and all participants indicated that the text on the app was large enough to read comfortably. Participants' subjective cognitive concerns (ECog‐12) were significantly associated with a composite of app tasks (ß = ‐0.48, p = 0.01). The executive functioning domain of the study partner Ecog was significantly associated with patient performance on an app‐based executive functioning task (ß = 0.75, p = 0.007). Conclusion These findings support the feasibility of remote preoperative assessments in older adults using smartphones. The study also provides preliminary support that these measures can objectively quantify self‐ and partner‐reported cognitive concerns. Future work will explore associations with postoperative outcomes.
Abstract Background Traumatic brain injury (TBI) and repetitive head impacts (RHI) have been linked to increased risk for multiple types of neurodegenerative disease, higher dementia risk, and earlier age of dementia symptom onset, suggesting transdiagnostic implications for later-life brain health. Frontotemporal dementia (FTD) and primary progressive aphasia (PPA) represent a spectrum of clinical phenotypes that are neuropathologically diverse. FTD/PPA diagnoses bring unique challenges due to complex cognitive and behavioral symptoms that disproportionately present as an early-onset dementia (before age 65). We performed a detailed characterization of lifetime head trauma exposure in individuals with FTD and PPA compared to healthy controls to examine frequency of lifetime TBI and RHI and associated clinical implications. Methods We studied 132 FTD/PPA (age 68.9 ± 8.1, 65% male) and 132 sex-matched healthy controls (HC; age 73.4 ± 7.6). We compared rates of prior TBI and RHI (contact/collision sports) between FTD/PPA and HC (chi-square, logistic regression, analysis of variance). Within FTD/PPA, we evaluated associations with age of symptom onset (analysis of variance). Within behavioral variant FTD, we evaluated associations with cognitive function and neuropsychiatric symptoms (linear regression controlling for age, sex, and years of education). Results Years of participation were greater in FTD/PPA than HC for any contact/collision sport (8.5 ± 6.7yrs vs. 5.3 ± 4.5yrs, p = .008) and for American football (6.2yrs ± 4.3yrs vs. 3.1 ± 2.4yrs; p = .003). Within FTD/PPA, there were dose-dependent associations with earlier age of symptom onset for TBI (0 TBI: 62.1 ± 8.1, 1 TBI: 59.9 ± 6.9, 2 + TBI: 57.3 ± 8.4; p = .03) and years of American football (0yrs: 62.2 ± 8.7, 1-4yrs: 59.7 ± 7.0, 5 + yrs: 55.9 ± 6.3; p = .009). Within bvFTD, those who played American football had worse memory (z-score: -2.4 ± 1.2 vs. -1.4 ± 1.6, p = .02, d = 1.1). Conclusions Lifetime head trauma may represent a preventable environmental risk factor for FTD/PPA. Dose-dependent exposure to TBI or RHI influences FTD/PPA symptom onset and memory function in bvFTD. Clinico-pathological studies are needed to better understand the neuropathological correlates linking RHI or TBI to FTD/PPA onset and symptoms.
Abstract The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate ‘pro-aging’ or ‘pro-youthful’ effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer’s disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 3 years, range 1–7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer’s disease cohort included 35 adults with sporadic Alzheimer’s disease (Mage = 69.4; 60% female) and 56 controls (Mage = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting ‘pro-youthful’ levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer’s disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer’s disease and related dementias and warrant further investigation.
Western countries have provided reference values (RV) for Alzheimer's disease (AD) plasma biomarkers, but there are not available in Sub-Saharan African populations.
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease.We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects.Tau p.A152T significantly increases the risk for both FTD-s (n 5 2139, OR 5 3.0, CI: 1.6 -5.6, P 5 0.0005) and Alzheimer's disease (AD) (n 5 3345, OR 5 2.3, CI: 1.3 -4.2, P 5 0.004) compared with 9047 controls.Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers.However, there is a pronounced increase in the formation of tau oligomers.Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation.These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
Abstract Background The Uniform Data Set (UDS) neuropsychological battery, administered across Alzheimer’s Disease Centers (ADC), includes memory tests but lacks a list‐learning paradigm. ADCs often supplement the UDS with their own preferred list‐learning task. Given the importance of list‐learning for characterizing memory, we aimed to develop a harmonized memory score that incorporates UDS memory tests while allowing centers to contribute differing list‐learning tasks. Method We applied item‐banking confirmatory factor analysis to develop a composite memory score in 5,287 participants (mean age 67.1; SD = 12.2) recruited through 18 ADCs and four consortia (DiverseVCID, MarkVCID, ALLFTD, LEADS) who completed UDS memory tasks (used as linking‐items) and one of five list‐learning tasks. All analyses used linear regression. We tested whether memory scores were affected by which list‐learning task was administered. To assess construct validity, we tested associations of memory scores with demographics, disease severity (CDR Box Score), an independent memory task (TabCAT Favorites, n = 675), and hippocampal volume (n = 811). We compared performances between cognitively unimpaired (n = 279), AD‐biomarker+ MCI (n = 26), and AD‐biomarker+ dementia (n = 98). In a subsample with amyloid‐ and tau‐PET (n = 49), we compared memory scores from participants with positive vs negative scans determined using established quantitative cutoffs. Result Model fit indices were excellent (e.g., CFI = 0.998) and factor loadings were strong (0.43‐0.93). Differences in list‐learning task had a negligible effect on scores (average Cohen’s d = 0.11). Higher memory scores were significantly ( p ’s<.001) correlated with younger age (β = ‐0.18), lower CDR Box Scores (β = ‐0.63), female sex (β = 0.12), higher education (β = 0.19), larger hippocampal volume (β = 0.42), and an independent memory task (β = 0.71, p<0.001). The memory composite declined in a stepwise fashion by diagnosis (cognitively unimpaired>MCI>AD dementia, p<0.001). On average, amyloid‐PET positivity was associated with lower composite scores, but was not statistically significant (β = ‐0.34; p = 0.25; d = 0.40). Tau‐PET positivity was associated with worse performance, demonstrating a large effect size (β = ‐0.75; p<0.002; d = 0.91). Conclusion The harmonized memory score developed in a large national sample was stable regardless of contributing list‐learning task and its validity for cross‐cohort ADRD research is supported by expected associations with demographics, clinical measures, and Alzheimer’s biomarkers. A processing script will be made available to enhance cross‐cohort ADRD research.
Abstract Background Postoperative complications of major surgical interventions include delirium. Delirium is a risk factor for dementia, and in some cases, may signal underlying neuropathological processes. Cognitive tests that accurately predict post‐operative outcomes could identify patients with cognitive vulnerabilities who may benefit from preoperative counseling and postoperative interventions. Unfortunately, in‐person presurgical cognitive evaluations are often not available, but digital technologies may improve access. In this pilot study, we evaluate the feasibility of utilizing a smartphone app to conduct preoperative remote cognitive assessment in patients undergoing spine surgery. We also evaluate the relationship of app‐based assessments with subjective cognitive concerns. Method We enrolled 30 older adults (≥ 65 years old) who were scheduled for elective spinal surgery anticipated to last at least three hours. On the ALLFTD Mobile App, participants completed a battery of cognitive tests, a measure of subjective cognitive concerns (12‐item self‐reported everyday cognition scale, Ecog‐12), and a user experience survey. A subset (N = 12) had a study partner complete the 41‐item Ecog, reporting on observed changes in cognitive function over a 10‐year period prior to the surgery. Linear regressions adjusted for age evaluated the associations between subjective cognitive concerns and the objective app‐based outcomes (Flanker task and a composite of several measures). Result Average age of participants was 71.2 years (SD = 4.4); 46.1% were women and 75% identified as White. Most (96%) participants indicated that the time required to complete the app assessments was acceptable, 77% indicated that the app instructions were clear, and all participants indicated that the text on the app was large enough to read comfortably. Participants’ subjective cognitive concerns (ECog‐12) were significantly associated with a composite of app tasks (β = ‐0.48, p = 0.01). The executive functioning domain of the study partner Ecog was significantly associated with patient performance on an app‐based executive functioning task (β = 0.75, p = 0.007). Conclusion These findings support the feasibility of remote preoperative assessments in older adults using smartphones. The study also provides preliminary support that these measures can objectively quantify self‐ and partner‐reported cognitive concerns. Future work will explore associations with postoperative outcomes.
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