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1.
Neuroimage Clin ; 24: 102025, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31670152

RESUMO

OBJECTIVE: To characterize individual and group-level neuroimaging findings in patients at risk for Chronic Traumatic Encephalopathy (CTE). METHODS: Eleven male patients meeting criteria for Traumatic Encephalopathy Syndrome (TES, median age: 64) underwent neurologic evaluation, 3-Tesla MRI, and PET with [18F]-Flortaucipir (FTP, tau-PET) and [11C]-Pittsburgh compound B (PIB, amyloid-PET). Six patients underwent [18F]-Fluorodeoxyglucose-PET (FDG, glucose metabolism). We assessed imaging findings at the individual patient level, and in group-level comparisons with modality-specific groups of cognitively normal older adults (CN). Tau-PET findings in patients with TES were also compared to a matched group of patients with mild cognitive impairment or dementia due to Alzheimer's disease (AD). RESULTS: All patients with TES sustained repetitive head injury participating in impact sports, ten in American football. Three patients met criteria for dementia and eight had mild cognitive impairment. Two patients were amyloid-PET positive and harbored the most severe MRI atrophy, FDG hypometabolism, and FTP-tau PET binding. Among the nine amyloid-negative patients, tau-PET showed either mildly elevated frontotemporal binding, a "dot-like" pattern, or no elevated binding. Medial temporal FTP was mildly elevated in a subset of amyloid-negative patients, but values were considerably lower than in AD. Voxelwise analyses revealed a convergence of imaging abnormalities (higher FTP binding, lower FDG, lower gray matter volumes) in frontotemporal areas in TES compared to controls. CONCLUSIONS: Mildly elevated tau-PET binding was observed in a subset of amyloid-negative patients at risk for CTE, in a distribution consistent with CTE pathology stages III-IV. FTP-PET may be useful as a biomarker of tau pathology in CTE but is unlikely to be sensitive to early disease stages.

2.
JAMA Neurol ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31710340

RESUMO

Importance: Basket-design clinical trials that allow investigation of treatment effects on different clinical syndromes that share the same molecular pathophysiology have not previously been attempted in neurodegenerative disease. Objective: To assess the safety, tolerability, and pharmacodynamics of the microtubule stabilizer TPI-287 (abeotaxane) in Alzheimer disease (AD) or the 4-repeat tauopathies (4RT) progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). Design, Setting, and Participants: Two parallel-design, double-blind, placebo-controlled phase 1 randomized clinical trials in AD and 4RT were conducted from December 20, 2013, through May 4, 2017, at the University of California, San Francisco, and University of Alabama at Birmingham. A total of 94 patients with clinically diagnosed AD (n = 39) and 4RT (n = 55) were screened; of these, 3 refused to participate, and 10 with AD and 11 with 4RT did not meet inclusion criteria. A total of 29 patients with AD, 14 with PSP, and 30 with ß-amyloid-negative CBS (determined on positron emission tomography findings) were enrolled. Data were analyzed from December 20, 2013, through May 4, 2017, based on modified intention to treat. Interventions: Randomization was 8:3 drug to placebo in 3 sequential dose cohorts receiving 2.0, 6.3, or 20.0 mg/m2 of intravenous TPI-287 once every 3 weeks for 9 weeks, with an optional 6-week open-label extension. Main Outcomes and Measures: Primary end points were safety and tolerability (maximal tolerated dose) of TPI-287. Secondary and exploratory end points included TPI-287 levels in cerebrospinal fluid (CSF) and changes on biomarker, clinical, and neuropsychology measures. Results: A total of 68 participants (38 men [56%]; median age, 65 [range, 50-85] years) were included in the modified intention-to-treat analysis, of whom 26 had AD (14 women [54%]; median age, 63 [range, 50-76] years), and 42 had 4RT (16 women [38%]; median age, 69 [range, 54-83] years). Three severe anaphylactoid reactions occurred in TPI-287-treated patients with AD, whereas none were seen in patients with 4RT, leading to a maximal tolerated dose of 6.3 mg/m2 for AD and 20.0 mg/m2 for 4RT. More falls (3 in the placebo group vs 11 in the TPI-287 group) and a dose-related worsening of dementia symptoms (mean [SD] in the CDR plus NACC FTLD-SB [Clinical Dementia Rating scale sum of boxes with frontotemporal dementia measures], 0.5 [1.8] in the placebo group vs 0.7 [1.6] in the TPI-287 group; median difference, 1.5 [95% CI, 0-2.5]; P = .03) were seen in patients with 4RT. Despite undetectable TPI-287 levels in CSF, CSF biomarkers demonstrated decreased chitinase-3-like protein-1 (YKL-40) levels in the 4RT treatment arm (mean [SD], -8.4 [26.0] ng/mL) compared with placebo (mean [SD], 10.4 [42.3] ng/mL; median difference, -14.6 [95% CI, -30.0 to 0.2] ng/mL; P = .048, Mann-Whitney test). Conclusions and Relevance: In this randomized clinical trial, TPI-287 was less tolerated in patients with AD than in those with 4RT owing to the presence of anaphylactoid reactions. The ability to reveal different tau therapeutic effects in various tauopathy syndromes suggests that basket trials are a valuable approach to tau therapeutic early clinical development. Trial Registration: ClinicalTrials.gov identifiers: NCT019666666 and NCT02133846.

3.
Alzheimers Dement ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31672482

RESUMO

INTRODUCTION: Differential patterns of brain atrophy on structural magnetic resonance imaging (MRI) revealed four reproducible subtypes of Alzheimer's disease (AD): (1) "typical", (2) "limbic-predominant", (3) "hippocampal-sparing", and (4) "mild atrophy". We examined the neurobiological characteristics and clinical progression of these atrophy-defined subtypes. METHODS: The four subtypes were replicated using a clustering method on MRI data in 260 amyloid-ß-positive patients with mild cognitive impairment or AD dementia, and we subsequently tested whether the subtypes differed on [18F]flortaucipir (tau) positron emission tomography, white matter hyperintensity burden, and rate of global cognitive decline. RESULTS: Voxel-wise and region-of-interest analyses revealed the greatest neocortical tau load in hippocampal-sparing (frontoparietal-predominant) and typical (temporal-predominant) patients, while limbic-predominant patients showed particularly high entorhinal tau. Typical patients with AD had the most pronounced white matter hyperintensity load, and hippocampal-sparing patients showed the most rapid global cognitive decline. DISCUSSION: Our data suggest that structural MRI can be used to identify biologically and clinically meaningful subtypes of AD.

4.
Neurobiol Aging ; 83: 54-62, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31585367

RESUMO

Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials.

5.
Neuron ; 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31623919

RESUMO

Neurodegenerative diseases appear to progress by spreading via brain connections. Here we evaluated this transneuronal degeneration hypothesis by attempting to predict future atrophy in a longitudinal cohort of patients with behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA). We determined patient-specific "epicenters" at baseline, located each patient's epicenters in the healthy functional connectome, and derived two region-wise graph theoretical metrics to predict future atrophy: (1) shortest path length to the epicenter and (2) nodal hazard, the cumulative atrophy of a region's first-degree neighbors. Using these predictors and baseline atrophy, we could accurately predict longitudinal atrophy in most patients. The regions most vulnerable to subsequent atrophy were functionally connected to the epicenter and had intermediate levels of baseline atrophy. These findings provide novel, longitudinal evidence that neurodegeneration progresses along connectional pathways and, further developed, could lead to network-based clinical tools for prognostication and disease monitoring.

6.
Stem Cell Reports ; 13(5): 939-955, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31631020

RESUMO

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies.

7.
Acta Neuropathol Commun ; 7(1): 159, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640778

RESUMO

Tau aggregation is a hallmark feature in a subset of patients with frontotemporal dementia (FTD). Early and selective loss of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices (ACC) is observed in patients with sporadic behavioral variant FTD (bvFTD) due to frontotemporal lobar degeneration (FTLD), including FTLD with tau inclusions (FTLD-tau). Recently, we further showed that these specialized neurons show preferential aggregation of TDP-43 in FTLD-TDP. Whether VENs and fork cells are prone to tau accumulation in FTLD-tau remains unclear, and no previous studies of these neurons have focused on patients with pathogenic variants in the gene encoding microtubule-associated protein tau (FTLD-tau/MAPT). Here, we examined regional profiles of tau aggregation and neurodegeneration in 40 brain regions in 8 patients with FTLD-tau/MAPT and 7 with Pick's disease (PiD), a sporadic form of FTLD-tau that often presents with bvFTD. We further qualitatively assessed the cellular patterns of frontoinsular tau aggregation in FTLD-tau/MAPT using antibodies specific for tau hyperphosphorylation, acetylation, or conformational change. ACC and mid-insula were among the regions most affected by neurodegeneration and tau aggregation in FTLD-tau/MAPT and PiD. In these two forms of FTLD-tau, severity of regional neurodegeneration and tau protein aggregation were highly correlated across regions. In FTLD-tau/MAPT, VENs and fork cells showed disproportionate tau protein aggregation in patients with V337 M, A152T, and IVS10 + 16 variants, but not in patients with the P301L variant. As seen in FTLD-TDP, our data suggest that VENs and fork cells represent preferentially vulnerable neuron types in most, but not all of the MAPT variants we studied.

8.
JAMA Intern Med ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31566651

RESUMO

Importance: Few health systems have adopted effective dementia care management programs. The Care Ecosystem is a model for delivering care from centralized hubs across broad geographic areas to caregivers and persons with dementia (PWDs) independently of their health system affiliations. Objective: To determine whether the Care Ecosystem is effective in improving outcomes important to PWDs, their caregivers, and payers beyond those achieved with usual care. Design, Setting, and Participants: A single-blind, randomized clinical trial with a pragmatic design was conducted among PWDs and their caregivers. Each PWD-caregiver dyad was enrolled for 12 months between March 20, 2015, and February 28, 2017. Data were collected until March 5, 2018. Study interventions and assessments were administered over the telephone and internet by clinical and research teams in San Francisco, California, and Omaha, Nebraska. Of 2585 referred or volunteer PWD-caregiver dyads in California, Iowa, or Nebraska, 780 met eligibility criteria and were enrolled. A total of 512 PWD-caregiver dyads were randomized to receive care through the Care Ecosystem and 268 dyads to receive usual care. All eligible PWDs had a dementia diagnosis; were enrolled or eligible for enrollment in Medicare or Medicaid; and spoke English, Spanish, or Cantonese. Analyses were intention-to-treat. Intervention: Telephone-based collaborative dementia care was delivered by a trained care team navigator, who provided education, support and care coordination with a team of dementia specialists (advanced practice nurse, social worker, and pharmacist). Main Outcomes and Measures: Primary outcome measure: Quality of Life in Alzheimer's Disease based on caregiver's rating of 13 aspects of PWD's well-being (including physical health, energy level, mood, living situation, memory, relationships, and finances) on a 4-point scale (poor to excellent). Secondary outcomes: frequencies of PWDs' use of emergency department, hospitalization, and ambulance services; caregiver depression (score on 9-Item Patient Health Questionnaire; higher scores indicate more severe depression); and caregiver burden (score on 12-Item Zarit Burden Interview; higher scores indicate more severe caregiver burden). Results: The 780 PWDs (56.3% female; mean [SD] age, 78.1 [9.9] years) and 780 caregivers (70.9% female; mean [SD] age, 64.7 [12.0] years) lived in California (n = 452), Nebraska (n = 284), or Iowa (n = 44). Of 780 dyads, 655 were still active at 12 months, and 571 completed the 12-month survey. Compared with usual care, the Care Ecosystem improved PWD quality of life (B, 0.53; 95% CI, 0.25-1.30; P = .04), reduced emergency department visits (B, -0.14; 95% CI, -0.29 to -0.01; P = .04), and decreased caregiver depression (B, -1.14; 95% CI, -2.15 to -0.13; P = .03) and caregiver burden (B, -1.90; 95% CI, -3.89 to -0.08; P = .046). Conclusions and Relevance: Effective care management for dementia can be delivered from centralized hubs to supplement usual care and mitigate the growing societal and economic burdens of dementia. Trial Registration: ClinicalTrials.gov identifier: NCT02213458.

9.
Acta Neuropathol ; 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31542807

RESUMO

Common neurodegenerative diseases feature progressive accumulation of disease-specific protein aggregates in selectively vulnerable brain regions. Increasing experimental evidence suggests that misfolded disease proteins exhibit prion-like properties, including the ability to seed corruptive templating and self-propagation along axons. Direct evidence for transneuronal spread in patients, however, remains limited. To test predictions made by the transneuronal spread hypothesis in human tissues, we asked whether tau deposition within axons of the corticospinal and corticopontine pathways can be predicted based on clinical syndromes and cortical atrophy patterns seen in frontotemporal lobar degeneration (FTLD). Sixteen patients with Pick's disease, 21 with corticobasal degeneration, and 3 with FTLD-MAPT were included, spanning a range of clinical syndromes across the frontotemporal dementia (FTD) spectrum. Cortical involvement was measured using a neurodegeneration score, a tau score, and a composite score based on semiquantitative ratings and complemented by an MRI-based cortical atrophy W-map based on antemortem imaging. Midbrain cerebral peduncle and pontine base descending fibers were divided into three subregions, representing prefrontopontine, corticospinal, and parieto-temporo-occipital fiber pathways. Tau area fraction was calculated in each subregion and related to clinical syndrome and cortical measures. Within each clinical syndrome, there were predicted relationships between cortical atrophy patterns and axonal tau deposition in midbrain cerebral peduncle and pontine base. Between syndromes, contrasting and predictable patterns of brainstem axonal tau deposition emerged, with, for example, greater tau in prefrontopontine fibers in behavioral variant FTD and in corticospinal fibers in corticobasal syndrome. Finally, semiquantitative and quantitative cortical degeneration scores predicted brainstem axonal tau deposition based on anatomical principles. Taken together, these findings provide important human evidence in support of axonal tau spreading in patients with specific forms of tau-related neurodegeneration.

10.
Alzheimer Dis Assoc Disord ; 33(4): 327-330, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31513029

RESUMO

OBJECTIVE: A rare variant in TREM2 (p.R47H, rs75932628) has been consistently reported to increase the risk for Alzheimer disease (AD), while mixed evidence has been reported for association of the variant with other neurodegenerative diseases. Here, we investigated the frequency of the R47H variant in a diverse and well-characterized multicenter neurodegenerative disease cohort. METHODS: We examined the frequency of the R47H variant in a diverse neurodegenerative disease cohort, including a total of 3058 patients clinically diagnosed with AD, frontotemporal dementia spectrum syndromes, mild cognitive impairment, progressive supranuclear palsy syndrome, corticobasal syndrome, or amyotrophic lateral sclerosis and 5089 control subjects. RESULTS: We observed a significant association between the R47H variant and AD, while no association was observed with any other neurodegenerative disease included in this study. CONCLUSIONS: Our results support the consensus that the R47H variant is significantly associated with AD. However, we did not find evidence for association of the R47H variant with other neurodegenerative diseases.

11.
J Speech Lang Hear Res ; 62(8): 2723-2749, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31390290

RESUMO

Purpose Recent studies confirm the utility of speech-language intervention in primary progressive aphasia (PPA); however, long-term outcomes, ideal dosage parameters, and relative benefits of intervention across clinical variants warrant additional investigation. The purpose of this study was to determine whether naming treatment affords significant, lasting, and generalized improvement for individuals with semantic and logopenic PPA and whether dosage manipulations significantly affect treatment outcomes. Method Eighteen individuals with PPA (9 semantic and 9 logopenic variant) underwent lexical retrieval treatment designed to leverage spared cognitive-linguistic domains and develop self-cueing strategies to promote naming. One group (n = 10) underwent once-weekly treatment sessions, and the other group (n = 8) received the same treatment with 2 sessions per week and an additional "booster" treatment phase at 3 months post-treatment. Performance on trained and untrained targets/tasks was measured immediately after treatment and at 3, 6, and 12 months post-treatment. Results Outcomes from the full cohort of individuals with PPA showed significantly improved naming of trained items immediately post-treatment and at all follow-up assessments through 1 year. Generalized improvement on untrained items was significant up to 6 months post-treatment. The positive response to treatment was comparable regardless of session frequency or inclusion of a booster phase. Outcomes were comparable across PPA subtypes, as was maintenance of gains over the post-treatment period. Conclusion This study documents positive naming treatment outcomes for a group of individuals with PPA, demonstrating strong direct treatment effects, maintenance of gains up to 1 year post-treatment, and generalization to untrained items. Lexical retrieval treatment, in conjunction with daily home practice, had a strong positive effect that did not require more than 1 clinician-directed treatment session per week. Findings confirm that strategic training designed to capitalize on spared cognitive-linguistic abilities results in significant and lasting improvement, despite ongoing disease progression, in PPA.

12.
Alzheimers Dement ; 15(10): 1253-1263, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31416793

RESUMO

INTRODUCTION: Sleep-wake disturbances are a common and early feature in Alzheimer's disease (AD). The impact of early tau pathology in wake-promoting neurons (WPNs) remains unclear. METHODS: We performed stereology in postmortem brains from AD individuals and healthy controls to identify quantitative differences in morphological metrics in WPNs. Progressive supranuclear palsy (PSP) and corticobasal degeneration were included as disease-specific controls. RESULTS: The three nuclei studied accumulate considerable amounts of tau inclusions and showed a decrease in neurotransmitter-synthetizing neurons in AD, PSP, and corticobasal degeneration. However, substantial neuronal loss was exclusively found in AD. DISCUSSION: WPNs are extremely vulnerable to AD but not to 4 repeat tauopathies. Considering that WPNs are involved early in AD, such degeneration should be included in the models explaining sleep-wake disturbances in AD and considered when designing a clinical intervention. Sparing of WPNs in PSP, a condition featuring hyperinsomnia, suggest that interventions to suppress the arousal system may benefit patients with PSP.

13.
J Alzheimers Dis ; 71(1): 45-55, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31322558

RESUMO

BACKGROUND: Care navigation is an approach to personalized care management and care coordination that can help overcome barriers to care. Care navigation has not been extensively studied in dementia, where health care workforce innovations are needed as a result of increasing disease prevalence and resulting costs to the health care system. OBJECTIVE: To identify facilitators and barriers to care navigation in dementia and to assess dementia caregiver satisfaction with care navigation. METHODS: Methods include qualitative research (interviews, focus groups, observations) with "Care Team Navigators" (CTNs) who were part of a dementia care navigation program, the Care Ecosystem, and a quantitative survey with caregivers about their experiences with CTNs. Transcripts were analyzed to identify themes within the data. RESULTS: CTNs identified the following facilitators to care navigation in dementia: working closely with caregivers; providing emotional support; tailoring education and resources; and coordinating with a clinical team around issues ranging from clinical questions to financial and legal decision-making. The barriers CTNS identified included burn-out, the progressive nature of the disease; coordinating with primary care providers; and identifying resources for dyads who are low-income, do not speak English, or live in rural areas. Caregivers across both sites highly rated CTNs, though satisfaction was higher among those in Nebraska and Iowa. CONCLUSIONS: Innovative approaches to care delivery in dementia are crucial. Care navigation offers a feasible model to train unlicensed people to deliver care as a way to deliver larger-scale support for the growing population of adults living with dementia and their caregivers.

14.
Acta Neuropathol ; 138(5): 795-811, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31327044

RESUMO

Microsatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s-1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson's disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson's but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n = 354 cases, odds ratio = 3.59, p = 0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC-derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD.

15.
Sci Rep ; 9(1): 10854, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350420

RESUMO

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA's relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.

16.
Ann Clin Transl Neurol ; 6(7): 1352-1357, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31353851

RESUMO

Communication accommodation describes how individuals adjust their communicative style to that of their conversational partner. We predicted that interpersonal prosodic correlation related to pitch and timing would be decreased in behavioral variant frontotemporal dementia (bvFTD). We predicted that the interpersonal correlation in a timing measure and a pitch measure would be increased in right temporal FTD (rtFTD) due to sparing of the neural substrate for speech timing and pitch modulation but loss of social semantics. We found no significant effects in bvFTD, but conversations including rtFTD demonstrated higher interpersonal correlations in speech rate than healthy controls.

17.
JAMA Neurol ; 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31282955

RESUMO

Importance: Current attempts to gauge the acute care needs of patients with dementia have not effectively addressed the role of caregivers, despite their extensive involvement in decisions about acute care management. Objective: To determine whether caregiver depression is associated with increased use of the emergency department (ED) among patients with dementia. Design, Setting, and Participants: This longitudinal cohort study used data from the Care Ecosystem study, a randomized clinical trial examining telephone-based supportive care for patients with dementia and their caregivers. Patients were 45 years or older with any type of dementia. A total of 780 caregiver-patient dyads were enrolled from March 20, 2015, until February 28, 2017, and 663 dyads contributed baseline and 6-month data and were included in the analysis. Exposures: Caregiver depression (9-item Patient Health Questionnaire score of ≥10). Secondary analyses examined caregiver burden and self-efficacy. Main Outcomes and Measures: The primary outcome was the number of ED visits in a 6-month period. Results: Among the 663 caregivers (467 women and 196 men; mean [SD] age, 64.9 [11.8] years), 84 caregivers (12.7%) had depression at baseline. The mean incidence rate of ED visits was 0.9 per person-year. Rates of ED presentation were higher among dyads whose caregiver did vs did not have depression (1.5 vs 0.8 ED visits per person-year). In a Poisson regression model adjusting for patient age, sex, severity of dementia, number of comorbidities, and baseline ED use, as well as caregiver age and sex, caregiver depression continued to be associated with ED use, with a 73% increase in rates of ED use among dyads with caregivers with depression (adjusted incident rate ratio, 1.73; 95% CI, 1.30-2.30). Caregiver burden was associated with higher ED use in the unadjusted model, but this association did not reach statistical significance after adjustment (incident rate ratio, 1.19; 95% CI, 0.93-1.52). Caregiver self-efficacy was inversely proportional to the number of ED visits in the unadjusted and adjusted models (adjusted incident rate ratio, 0.96; 95% CI, 0.92-0.99). Conclusions and Relevance: Among patients with dementia, caregiver depression appears to be significantly associated with increased ED use, revealing a key caregiver vulnerability, which, if addressed with patient- and caregiver-centered dementia care, could improve health outcomes and lower costs for this high-risk population.

18.
Perspect Biol Med ; 62(2): 216-236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281119

RESUMO

Wisdom has been discussed for centuries in religious and philosophical texts. It is often viewed as a fuzzy psychological construct analogous to consciousness, stress, and resilience. This essay provides an understanding of wisdom as a scientific construct, based on empirical research starting in the 1970s. The focus is on practical rather than theoretical wisdom. While there are different conceptualizations of wisdom, it is best defined as a complex human characteristic or trait with specific components: social decision-making, emotional regulation, prosocial behavior (such as empathy and compassion), self-reflection, acceptance of uncertainty, decisiveness, and spirituality. These psychological processes involve the fronto-limbic circuitry. Wisdom is associated with positive life outcomes including better health, well-being, happiness, life satisfaction, and resilience. Wisdom tends to increase with active aging, facilitating a contribution of wise grandparents to promoting fitness of younger kin. Despite the loss of their own fertility and physical health, older adults help enhance their children's and grandchildren's well-being, health, longevity, and fertility-the "grandmother hypothesis" of wisdom. Wisdom has important implications at individual and societal levels and is a major contributor to human thriving. We need to place a greater emphasis on promoting wisdom through our educational systems from elementary to professional schools.

19.
Brain ; 142(7): 2082-2095, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31219516

RESUMO

Posterior cortical atrophy is a clinico-radiological syndrome characterized by progressive decline in visual processing and atrophy of posterior brain regions. With the majority of cases attributable to Alzheimer's disease and recent evidence for genetic risk factors specifically related to posterior cortical atrophy, the syndrome can provide important insights into selective vulnerability and phenotypic diversity. The present study describes the first major longitudinal investigation of posterior cortical atrophy disease progression. Three hundred and sixty-one individuals (117 posterior cortical atrophy, 106 typical Alzheimer's disease, 138 controls) fulfilling consensus criteria for posterior cortical atrophy-pure and typical Alzheimer's disease were recruited from three centres in the UK, Spain and USA. Participants underwent up to six annual assessments involving MRI scans and neuropsychological testing. We constructed longitudinal trajectories of regional brain volumes within posterior cortical atrophy and typical Alzheimer's disease using differential equation models. We compared and contrasted the order in which regional brain volumes become abnormal within posterior cortical atrophy and typical Alzheimer's disease using event-based models. We also examined trajectories of cognitive decline and the order in which different cognitive tests show abnormality using the same models. Temporally aligned trajectories for eight regions of interest revealed distinct (P < 0.002) patterns of progression in posterior cortical atrophy and typical Alzheimer's disease. Patients with posterior cortical atrophy showed early occipital and parietal atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion leading to tissue loss of comparable extent later. Hippocampal, entorhinal and frontal regions underwent a lower rate of change and never approached the extent of posterior cortical involvement. Patients with typical Alzheimer's disease showed early hippocampal atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion. Cognitive models showed tests sensitive to visuospatial dysfunction declined earlier in posterior cortical atrophy than typical Alzheimer's disease whilst tests sensitive to working memory impairment declined earlier in typical Alzheimer's disease than posterior cortical atrophy. These findings indicate that posterior cortical atrophy and typical Alzheimer's disease have distinct sites of onset and different profiles of spatial and temporal progression. The ordering of disease events both motivates investigation of biological factors underpinning phenotypic heterogeneity, and informs the selection of measures for clinical trials in posterior cortical atrophy.

20.
Neuroimage Clin ; 22: 101797, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31146321

RESUMO

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by semantic memory deficits with relatively preserved motor speech, syntax, and phonology. There is consistent evidence linking focal neurodegeneration of the anterior temporal lobes (ATL) to the semantic deficits observed in svPPA. Less is known about large-scale functional connectivity changes in this syndrome, particularly regarding the interplay between affected and spared language networks that leads to the unique cognitive dissociations typical of svPPA. Using whole-brain, seed-based connectivity on task-free Magnetic Resonance Imaging (MRI) data, we studied connectivity of networks anchored to three left-hemisphere regions crucially involved in svPPA symptomatology: ATL just posterior to the main atrophic area, opercular inferior frontal gyrus, and posterior inferior temporal lobe. First, in 32 healthy controls, these seeds isolated three networks: a ventral semantic network involving anterior middle temporal and angular gyri, a dorsal articulatory-phonological system involving inferior frontal and supramarginal regions, and a third functional connection between posterior inferior temporal and intraparietal regions likely involved in linking visual and linguistic processes. We then compared connectivity strength of these three networks between 16 svPPA patients and the 32 controls. In svPPA, decreased functional connectivity in the ventral semantic network correlated with weak semantic skills, while connectivity of the network seeded from the posterior inferior temporal lobe, though not significantly different between the two groups, correlated with pseudoword reading skills. Increased connectivity between the inferior frontal gyrus and the superior portion of the angular gyrus suggested possible adaptive changes. Our findings have two main implications. First, they support a functional subdivision of the left IPL based on its connectivity to specific language-related regions. Second, the unique neuroanatomical and linguistic profile observed in svPPA provides a compelling model for the functional interplay of these networks, being either up- or down- regulated in response to disease.

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