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 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm as the strongest overall FTLD-TDP risk factor and identify as a novel FTLD-TDP risk factor.

An attentional and working memory theory of hallucination vulnerability in frontotemporal dementia.

The rate and prevalence of hallucinations in behavioural variant frontotemporal dementia is well established. The mechanisms for underlying vulnerability however are the least well described in FTD compared with other neuropsychiatric conditions, despite the presence of these features significantly complicating the diagnostic process. As such, this present study aimed to provide a detailed characterization of the neural, cognitive and behavioural profile associated with a predisposition to hallucinatory experiences in behavioural variant frontotemporal dementia.

Examining the propensity and nature of criminal risk behaviours in frontotemporal dementia syndromes and Alzheimer's disease.

Introduction: Some people with dementia develop changes in behaviour and cognition that may lead to interactions with police or the legal system. However, large, prospective case-control studies examining these behaviours are lacking.

Methods: One hundred and forty-four people with dementia and 53 controls completed the Misdemeanours and Transgressions Screener.

Elevated GRO-α and IL-18 in serum and brain implicate the NLRP3 inflammasome in frontotemporal dementia.

Neuroinflammation is a hallmark of frontotemporal dementia (FTD), a heterogeneous group of proteinopathies characterized by the progressive degeneration of the frontal and temporal lobes. It is marked by microglial activation and subsequent cytokine release. Although cytokine levels in FTD brain and CSF have been examined, the number of cytokines measured in each study is limited and knowledge on cytokine concentrations in FTD serum is scarce.

Creating the Pick's disease International Consortium: Association study of H2 haplotype with risk of Pick's disease.

Background: Pick's disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by the gene.

Mapping behavioural, cognitive and affective transdiagnostic dimensions in frontotemporal dementia.

Two common clinical variants of frontotemporal dementia are the behavioural variant frontotemporal dementia, presenting with behavioural and personality changes attributable to prefrontal atrophy, and semantic dementia, displaying early semantic dysfunction primarily due to anterior temporal degeneration. Despite representing independent diagnostic entities, mounting evidence indicates overlapping cognitive-behavioural profiles in these syndromes, particularly with disease progression. Why such overlap occurs remains unclear.

Multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterized by the degeneration of motor neurons and loss of various muscular functions. Dyslipidaemia is prevalent in amyotrophic lateral sclerosis with aberrant changes mainly in cholesterol ester and triglyceride. Despite this, little is known about global lipid changes in amyotrophic lateral sclerosis or in relation to disease progression.

Distinct hypothalamic involvement in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum.

Background: Hypothalamic dysregulation plays an established role in eating abnormalities in behavioural variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis (ALS). Its contribution to cognitive and behavioural impairments, however, remains unexplored.

Methods: Correlation between hypothalamic subregion atrophy and cognitive and behavioural impairments was examined in a large sample of 211 participants (52 pure ALS, 42 mixed ALS-FTD, 59 bvFTD, and 58 age- and education- matched healthy controls).

Altered reward processing underpins emotional apathy in dementia.

Introduction: While apathy is broadly defined as a loss of motivation, it is increasingly recognised as a multidimensional syndrome spanning executive, emotional, and initiation domains. Emotional apathy is purportedly driven by deficits in using socioemotional rewards to guide behaviour, yet the link between these symptoms and reward processing, and their common neural correlates, has not been directly examined.

Methods: Sixty-four patients (33 behavioural-variant frontotemporal dementia, 14 Alzheimer's disease, 8 semantic dementia, 6 progressive nonfluent aphasia, 3 logopenic progressive aphasia) were classified into high (HEA; n = 36) and low (LEA; n = 28) emotional apathy groups based on emotional apathy subscale scores on the Dimensional Apathy Scale.

Distinct disease trajectories in frontotemporal dementia-motor neuron disease and behavioural variant frontotemporal dementia: A longitudinal study.

Background And Purpose: The heterogeneity of cognitive and behavioural disturbances in frontotemporal dementia-motor neuron disease (FTD-MND), and clinical differences between FTD-MND and FTD subtypes, have been illustrated cross-sectionally. This study aimed to examine the FTD-MND disease trajectory by comparing clinical features of FTD-MND and the behavioural variant FTD (bvFTD) longitudinally.

Methods: Neuropsychological and disease severity assessments were conducted in a cohort of FTD-MND (baseline, n = 42; follow-up, n = 18) and bvFTD (baseline, n = 116; follow-up, n = 111) using a longitudinal, case-control design.

A shared cognitive and neural basis underpinning cognitive apathy and planning in behavioural-variant frontotemporal dementia and Alzheimer's disease.

Apathy is the most common and disabling non-cognitive feature of dementia, affecting up to 90% of individuals over the disease course. Despite its prevalence, the underlying mechanisms of apathy remain elusive. This study aimed to investigate whether cognitive apathy and executive functioning have a shared cognitive and neural basis, in behavioural-variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD).

Plasma Oxytocin Is Not Associated with Social Cognition or Behavior in Frontotemporal Dementia and Alzheimer's Disease Syndromes.

Introduction: Changes in social behavior and emotion processing are common in frontotemporal dementia (FTD) and semantic dementia (SD), and less so in Alzheimer's disease (AD). Recent research has investigated oxytocin as a potential treatment for these symptoms; however, whether plasma oxytocin is associated with social-emotional symptoms of dementia remains underexplored.

Methods: Thirty behavioral-variant FTD (bvFTD), 28 SD, 39 AD, and 24 controls underwent blood sampling to measure oxytocin.

Thalamic and Cerebellar Regional Involvement across the ALS-FTD Spectrum and the Effect of .

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of the same disease spectrum. While thalamic−cerebellar degeneration has been observed in C9orf72 expansion carriers, the exact subregions involved across the clinical phenotypes of the ALS−FTD spectrum remain unclear. Using MRIs from 58 bvFTD, 41 ALS−FTD and 52 ALS patients compared to 57 controls, we aimed to delineate thalamic and cerebellar subregional changes across the ALS−FTD spectrum and to contrast these profiles between cases with and without C9orf72 expansions.

Biomarker discovery and development for frontotemporal dementia and amyotrophic lateral sclerosis.

Frontotemporal dementia refers to a group of neurodegenerative disorders characterized by behaviour and language alterations and focal brain atrophy. Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterized by loss of motor neurons resulting in muscle wasting and paralysis. Frontotemporal dementia and amyotrophic lateral sclerosis are considered to exist on a disease spectrum given substantial overlap of genetic and molecular signatures.

Cerebellar integrity and contributions to cognition in C9orf72-mediated frontotemporal dementia.

Background: The GGGGCC hexanucleotide repeat expansion in the non-coding region of the chromosome 9 open reading frame 72 gene (C9orf72) is the most common genetic cause of familial frontotemporal dementia (FTD). This study aims to clarify the patterns of cerebellar atrophy in FTD patients with and without a C9orf72 repeat expansion compared with healthy controls and determine whether associations between cerebellar atrophy and cognition differ between patient groups.

Methods: Thirty C9orf72 repeat expansion-positive FTD patients, 30 C9orf72 repeat expansion-negative FTD patients, and 30 age-, sex-, and education-matched healthy controls underwent brain MRI and cognitive assessments.

Examining the presence and nature of delusions in Alzheimer's disease and frontotemporal dementia syndromes.

Objectives: Abnormal beliefs and delusions have been reported in some people with dementia, however, the prevalence of delusions, and their neurocognitive basis has been underexplored. This study aimed to examine the presence, severity, content and neural correlates of delusions in a large, well-characterised cohort of dementia patients using a transdiagnostic, cross-sectional approach.

Methods: Four-hundred and eighty-seven people with dementia were recruited: 102 Alzheimer's disease, 136 behavioural-variant frontotemporal dementia, 154 primary progressive aphasia, 29 motor neurone disease, 46 corticobasal syndrome, 20 progressive supranuclear palsy.

Pathological manifestation of human endogenous retrovirus K in frontotemporal dementia.

Background: Behavioral variant frontotemporal dementia (bvFTD) is a common form of younger-onset dementia with a proportion of cases overlapping pathologically and genetically with amyotrophic lateral sclerosis (ALS). Previous studies have identified that the human endogenous retrovirus K (HERV-K) is elevated in ALS serum and is associated with ALS TDP-43 pathology. In contrast, little is known about HERV-K changes in bvFTD.

Tackling clinical heterogeneity across the amyotrophic lateral sclerosis-frontotemporal dementia spectrum using a transdiagnostic approach.

The disease syndromes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) display considerable clinical, genetic and pathological overlap, yet mounting evidence indicates substantial differences in progression and survival. To date, there has been limited examination of how profiles of brain atrophy might differ between clinical phenotypes. Here, we address this longstanding gap in the literature by assessing cortical and subcortical grey and white matter volumes on structural MRI in a large cohort of 209 participants.

Increased VLCFA-lipids and ELOVL4 underlie neurodegeneration in frontotemporal dementia.

Rare, yet biologically critical, lipids that contain very long chain fatty acids (VLCFA-lipids) are synthesized in the brain by the enzyme ELOVL4. High levels of VLCFA-lipids are toxic to cells and excess VLCFA-lipids are actively removed by ABCD1 in an ATP-dependent manner. Virtually nothing is known about the impact of VLCFA-lipids in neurodegenerative diseases.

Evidence for a pervasive autobiographical memory impairment in Logopenic Progressive Aphasia.

Although characterized primarily as a language disorder, mounting evidence indicates episodic amnesia in Logopenic Progressive Aphasia (LPA). Whether such memory disturbances extend to information encoded pre-disease onset remains unclear. To address this question, we examined autobiographical memory in 10 LPA patients, contrasted with 18 typical amnestic Alzheimer's disease and 16 healthy Control participants.