Cognitive trajectories in older adults with essential tremor.

Objective: Despite recent attention to the increased risk of cognitive impairment in older adults with essential tremor (ET), there are only limited data on the trajectories of cognitive change in ET or the demographic and motor predictors of such change.

Method: This study included 148 cognitively normal individuals with ET (mean age = 76.7 ± 9.

Design considerations for C9orf72 disease prevention trials.

The idea that it might be possible to prevent some forms of amyotrophic lateral sclerosis and frontotemporal dementia has finally come of age. The hexanucleotide repeat expansion in the C9orf72 gene accounts for ∼10% of all amyotrophic lateral sclerosis and 10-15% of all frontotemporal dementia diagnoses, with the two clinical syndromes co-manifesting in a significant number of patients. As a result, clinically unaffected carriers of pathogenic C9orf72 repeat expansions are currently the largest identifiable population at significantly elevated risk for both amyotrophic lateral sclerosis and frontotemporal dementia, and in whom it might be possible to prevent the emergence of clinically manifest disease.

Evaluation of Amyloid Removal as a Surrogate for Cognitive Decline: Pilot Analysis in Individual-Level Data from the A4 Study of Solanezumab.

Background: Amyloid removal has been used as a surrogate outcome in Alzheimer's disease trials, allowing accelerated approval of aducanumab and lecanemab. The A4 (Alzheimer's Clinical Trial Consortium A4/LEARN) trial's individual-level data supports novel methods to evaluate amyloid's validity as a surrogate for cognitive decline.

Methods: In 812 participants, cognitive and functional change was measured using the CDR-SB score.

Excessive emotional reactivity in a case of behavioral variant frontotemporal dementia with amyotrophic lateral sclerosis.

Although amyotrophic lateral sclerosis (ALS) is defined as a neuromuscular disease, cognitive and/or behavioral symptoms are relatively common, and a portion of ALS patients will meet criteria for behavioral variant frontotemporal dementia (bvFTD). In this report, we describe the case of a man with ALS with bvFTD (ALS-FTD) presenting with excessive emotional reactivity, including severe anger, aggression, and obsessive thoughts. We contrast this case with the decreased emotional reactivity that is usually observed in patients with bvFTD without ALS.

Ubiquitin-proteasome system in the different stages of dominantly inherited Alzheimer's disease.

Introduction: This study investigated the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining cerebrospinal fluid (CSF) levels of UPS proteins.

Method: The SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale.

Results: Subtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS-activating enzymes near symptom onset.

Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. Here we leveraged aptamer-based proteomics (>4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN and MAPT) compared with 39 non-carrier controls. Network analysis identified 31 protein co-expression modules.

The Diagnostic Landscape of Behavioral Variant Frontotemporal Dementia.

The behavioral variant of frontotemporal dementia (bvFTD) is a progressive, neurodegenerative disorder, characterized by profound changes in personality, behavior, and social comportment. Diagnosis of bvFTD is challenging, and it is frequently misdiagnosed as an idiopathic psychiatric disorder (e.g.

Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor.

Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia.

Introduction: Higher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females.

Methods: We included genetic and sporadic bvFTD patients from two multicenter cohorts.

Early increase of the synaptic blood marker β-synuclein in asymptomatic autosomal dominant Alzheimer's disease.

Introduction: β-synuclein is a promising blood marker to track synaptic degeneration in Alzheimer's disease (AD) but changes in preclinical AD are unclear.

Methods: We investigated serum β-synuclein in 69 cognitively unimpaired mutation non-carriers, 78 cognitively unimpaired AD mutation carriers (asymptomatic AD), and 31 symptomatic mutation carriers from the Dominantly Inherited Alzheimer Network.

Results: β-synuclein levels were already higher in asymptomatic AD mutation carriers compared to non-carriers and highest in symptomatic carriers.

Neuropsychiatric symptoms cluster and fluctuate over time in behavioral variant frontotemporal dementia.

Aim: Cognitive and behavioral phenomena define behavioral variant frontotemporal dementia (bvFTD), but neuropsychiatric symptoms (NPS) outside the core criteria are common throughout the illness. Identifying how NPS cluster in bvFTD may guide development of future therapies.

Methods: Participants (n = 354) with sporadic and genetic bvFTD were enrolled in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium.

Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders.

Background: Therapeutic development for frontotemporal dementia (FTD) is hindered by the lack of biomarkers that inform susceptibility/risk, prognosis, and the underlying causative pathology. Blood glial fibrillary acidic protein (GFAP) has garnered attention as a FTD biomarker. However, investigations of GFAP in FTD have been hampered by symptomatic and histopathologic heterogeneity and small cohort sizes contributing to inconsistent findings.

Neuropsychiatric and behavioral symptom clusters in frontotemporal dementia.

Background: Non-Alzheimer's disease dementias, including frontotemporal dementia (FTD) can be difficult to characterize due to the predominance of distinct behavioral and neuropsychiatric symptoms. Widely used measurement tools lack structure and objectivity.

Objective: The purpose of this study was to use systematic direct observation of neuropsychiatric and behavioral symptoms, via the Neurobehavioral Rating Scale (NBRS), to characterize clusters of behavioral and neuropsychiatric symptoms in FTD and examine how selected symptom clusters correlate with structural neuroimaging.

Parallel changes in cognition, neuropsychiatric symptoms, and amyloid in cognitively unimpaired older adults and those with mild cognitive impairment.

Introduction: Alzheimer's disease (AD) diagnosis centers on cognitive impairment despite other early indicators like neuropsychiatric symptoms (NPSs) and amyloid beta (Aβ) accumulation. This study examined how cognition, NPS, and Aβ changes are interrelated over time in individuals without dementia.

Methods: Participants were 1247 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI)-2 and -3 cohorts with at least 48 months of follow-up.

The landscape of autosomal-dominant Alzheimer's disease: global distribution and age of onset.

We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer's disease (ADAD). A total of 550 variants in the APP, PSEN1 and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature and public databases. Symptomatic age at onset (AAO) data were estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity and AAO.

Depressive Symptoms and Amyloid Pathology.

Importance: Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology.

Increasing hub disruption parallels dementia severity in autosomal dominant Alzheimer's disease.

Hub regions in the brain, recognized for their roles in ensuring efficient information transfer, are vulnerable to pathological alterations in neurodegenerative conditions, including Alzheimer's disease (AD). Computational simulations and animal experiments have hinted at the theory of activity-dependent degeneration as the cause of this hub vulnerability. However, two critical issues remain unresolved.

Longitudinal associations between exercise and biomarkers in autosomal dominant Alzheimer's disease.

Introduction: We investigated longitudinal associations between self-reported exercise and Alzheimer's disease (AD)-related biomarkers in individuals with autosomal dominant AD (ADAD) mutations.

Methods: Participants were 308 ADAD mutation carriers aged 39.7 ± 10.

Multimodal nonlinear correlates of behavioural symptoms in frontotemporal dementia.

Studies exploring the brain correlates of behavioral symptoms in the frontotemporal dementia spectrum (FTD) have mainly searched for linear correlations with single modality neuroimaging data, either structural magnetic resonance imaging (MRI) or fluoro-deoxy-D-glucose positron emission tomography (FDG-PET). We aimed at studying the two imaging modalities in combination to identify nonlinear co-occurring patterns of atrophy and hypometabolism related to behavioral symptoms. We analyzed data from 93 FTD patients who underwent T1-weighted MRI, FDG-PET imaging, and neuropsychological assessment including the Neuropsychiatric Inventory, Frontal Systems Behavior Scale, and Neurobehavioral Rating Scale.

Disentangling the genetic underpinnings of neuropsychiatric symptoms in Alzheimer's disease in the Alzheimer's Disease Sequencing Project: Study design and methodology.

Introduction: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). There are no effective treatments targeting these symptoms.

Methods: To facilitate identification of causative mechanistic pathways, we initiated an effort (NIH: U01AG079850) to collate, harmonize, and analyze all available NPS data (≈ 100,000 samples) of diverse ancestries with whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP).

Baseline Depressive Symptoms as a Predictor of Incident Dementia in a Prospectively Followed Cohort of Elders with Essential Tremor.

Introduction: Essential tremor (ET) patients may exhibit a variety of non-motor features, including cognitive decline and depressive symptoms. Studies of several neurodegenerative diseases link depression to cognitive decline, suggesting depression is an early marker of dementia. We examined whether baseline depressive symptoms predict incident dementia in elders with ET.