Self- versus caregiver-reported apathy across neurological disorders.

Apathy is a prevalent and persistent neuropsychiatric syndrome across many neurological disorders, significantly impacting both patients and caregivers. We systematically quantified discrepancies between self- and caregiver-reported apathy in 335 patients with a variety of diagnoses, such as frontotemporal dementia (behavioural variant and semantic dementia subtypes), Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, Alzheimer's disease dementia, mild cognitive impairment, small vessel cerebrovascular disease, subjective cognitive decline and autoimmune encephalitis. Using the Apathy Motivation Index (AMI) and its analogous caregiver version (AMI-CG), we found that caregiver-reported apathy consistently exceeded self-reported levels across all conditions.

GABAergic modulation of beta power enhances motor adaptation in frontotemporal lobar degeneration.

Introduction: We examined how abnormal prefrontal neurophysiology and changes in gamma-aminobutyric acid-ergic (GABAergic) neurotransmission contribute to behavioral impairments in disorders associated with frontotemporal lobar degeneration (FTLD).

Methods: We recorded magnetoencephalography during an adaptive visuomotor task from 11 people with behavioral-variant frontotemporal dementia, 11 with progressive supranuclear palsy, and 20 age-matched controls. We used tiagabine, a gamma-aminobutyric acid (GABA) re-uptake inhibitor, as a pharmacological probe to assess the role of GABA during motor-related beta power changes.

Behavioural changes in frontotemporal dementia and their cognitive and neuroanatomical correlates.

Behavioural changes are a central feature of frontotemporal dementia (FTD); they occur in both behavioural-variant (bvFTD) and semantic dementia (SD)/semantic-variant primary progressive aphasia subtypes. In this study, we addressed two current clinical knowledge gaps: (i) are there qualitative or clear distinctions between behavioural profiles in bvFTD and SD; and (ii) what are the precise roles of the prefrontal cortex and anterior temporal lobes in supporting social behaviour? Resolving these conundrums is crucial for improving diagnostic accuracy and for the development of targeted interventions to treat challenging behaviours in FTD. Informant questionnaires to assess behavioural changes included the Cambridge Behavioural Inventory-Revised and two targeted measures of apathy and impulsivity.

Impaired semantic control in the logopenic variant of primary progressive aphasia.

We investigated semantic cognition in the logopenic variant of primary progressive aphasia, including (i) the status of verbal and non-verbal semantic performance; and (ii) whether the semantic deficit reflects impaired semantic control. Our hypothesis that individuals with logopenic variant of primary progressive aphasia would exhibit semantic control impairments was motivated by the anatomical overlap between the temporoparietal atrophy typically associated with logopenic variant of primary progressive aphasia and lesions associated with post-stroke semantic aphasia and Wernicke's aphasia, which cause heteromodal semantic control impairments. We addressed the presence, type (semantic representation and semantic control; verbal and non-verbal), and progression of semantic deficits in logopenic variant of primary progressive aphasia.

Frontotemporal lobar degeneration changes neuronal beta-frequency dynamics during the mismatch negativity response.

The consequences of frontotemporal lobar degeneration include changes in prefrontal cortical neurophysiology, with abnormalities of neural dynamics reported in the beta frequency range (14-30 Hz) that correlate with functional severity. We examined beta dynamics in two clinical syndromes associated with frontotemporal lobar degeneration: the behavioral variant of frontotemporal dementia (bvFTD) and progressive supranuclear palsy (PSP). Whilst these two syndromes are partially convergent in cognitive effects, they differ in disease mechanisms such as molecular pathologies and prefrontal atrophy.

The impact of bilateral versus unilateral anterior temporal lobe damage on face recognition, person knowledge and semantic memory.

The functional importance of the anterior temporal lobes (ATLs) has come to prominence in two active, albeit unconnected literatures-(i) face recognition and (ii) semantic memory. To generate a unified account of the ATLs, we tested the predictions from each literature and examined the effects of bilateral versus unilateral ATL damage on face recognition, person knowledge, and semantic memory. Sixteen people with bilateral ATL atrophy from semantic dementia (SD), 17 people with unilateral ATL resection for temporal lobe epilepsy (TLE; left = 10, right = 7), and 14 controls completed tasks assessing perceptual face matching, person knowledge and general semantic memory.

The graded multidimensional geometry of phenotypic variation and progression in neurodegenerative syndromes.

Clinical variants of Alzheimer's disease and frontotemporal lobar degeneration display a spectrum of cognitive-behavioural changes varying between individuals and over time. Understanding the landscape of these graded individual/group level longitudinal variations is critical for precise phenotyping; however, this remains challenging to model. Addressing this challenge, we leverage the National Alzheimer's Coordinating Center database to derive a unified geometric framework of graded longitudinal phenotypic variation in Alzheimer's disease and frontotemporal lobar degeneration.

A neuroanatomical and cognitive model of impaired social behaviour in frontotemporal dementia.

Impaired social cognition is a core deficit in frontotemporal dementia (FTD). It is most commonly associated with the behavioural-variant of FTD, with atrophy of the orbitofrontal and ventromedial prefrontal cortex. Social cognitive changes are also common in semantic dementia, with atrophy centred on the anterior temporal lobes.

Synaptic density affects clinical severity via network dysfunction in syndromes associated with frontotemporal lobar degeneration.

There is extensive synaptic loss from frontotemporal lobar degeneration, in preclinical models and human in vivo and post mortem studies. Understanding the consequences of synaptic loss for network function is important to support translational models and guide future therapeutic strategies. To examine this relationship, we recruited 55 participants with syndromes associated with frontotemporal lobar degeneration and 24 healthy controls.

Syndromes associated with frontotemporal lobar degeneration change response patterns on visual analogue scales.

Self-report scales are widely used in cognitive neuroscience and psychology. However, they rest on the central assumption that respondents engage meaningfully. We hypothesise that this assumption does not hold for many patients, especially those with syndromes associated with frontotemporal lobar degeneration.

Neurochemistry-enriched dynamic causal models of magnetoencephalography, using magnetic resonance spectroscopy.

We present a hierarchical empirical Bayesian framework for testing hypotheses about neurotransmitters' concertation as empirical prior for synaptic physiology using ultra-high field magnetic resonance spectroscopy (7T-MRS) and magnetoencephalography data (MEG). A first level dynamic causal modelling of cortical microcircuits is used to infer the connectivity parameters of a generative model of individuals' neurophysiological observations. At the second level, individuals' 7T-MRS estimates of regional neurotransmitter concentration supply empirical priors on synaptic connectivity.

Neurophysiological consequences of synapse loss in progressive supranuclear palsy.

Synaptic loss occurs early in many neurodegenerative diseases and contributes to cognitive impairment even in the absence of gross atrophy. Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. We advocate that biophysical models of neurophysiology offer both a bridge from preclinical to clinical models of pathology and quantitative assays for experimental medicine.

Synaptic Loss in Frontotemporal Dementia Revealed by [ C]UCB-J Positron Emission Tomography.

Objective: Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [ C]UCB-J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity.

The neurophysiological effect of NMDA-R antagonism of frontotemporal lobar degeneration is conditional on individual GABA concentration.

There is a pressing need to accelerate therapeutic strategies against the syndromes caused by frontotemporal lobar degeneration, including symptomatic treatments. One approach is for experimental medicine, coupling neurophysiological studies of the mechanisms of disease with pharmacological interventions aimed at restoring neurochemical deficits. Here we consider the role of glutamatergic deficits and their potential as targets for treatment.

Proton magnetic resonance spectroscopy in frontotemporal lobar degeneration-related syndromes.

There is an urgent need for a better understanding of the pathophysiology of cognitive impairment in syndromes associated with frontotemporal lobar degeneration. Here, we used magnetic resonance spectroscopy to quantify metabolite deficits in sixty patients with a clinical syndrome associated with frontotemporal lobar degeneration (behavioral variant frontotemporal dementia n = 11, progressive supranuclear palsy n = 26, corticobasal syndrome n = 11, primary progressive aphasias n = 12), and 38 age- and sex-matched healthy controls. We measured nine metabolites in the right inferior frontal gyrus, superior temporal gyrus and right primary visual cortex.

GABAergic cortical network physiology in frontotemporal lobar degeneration.

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study.

Predicting loss of independence and mortality in frontotemporal lobar degeneration syndromes.

Objective: To test the hypothesis that in syndromes associated with frontotemporal lobar degeneration, behavioural impairment predicts loss of functional independence and motor clinical features predict mortality, irrespective of diagnostic group.

Methods: We used a transdiagnostic approach to survival in an epidemiological cohort in the UK, testing the association between clinical features, independence and survival in patients with clinical diagnoses of behavioural variant frontotemporal dementia (bvFTD n=64), non-fluent variant primary progressive aphasia (nfvPPA n=36), semantic variant primary progressive aphasia (svPPA n=25), progressive supranuclear palsy (PSP n=101) and corticobasal syndrome (CBS n=68). A principal components analysis identified six dimensions of clinical features.

GABA and glutamate deficits from frontotemporal lobar degeneration are associated with disinhibition.

Behavioural disinhibition is a common feature of the syndromes associated with frontotemporal lobar degeneration (FTLD). It is associated with high morbidity and lacks proven symptomatic treatments. A potential therapeutic strategy is to correct the neurotransmitter deficits associated with FTLD, thereby improving behaviour.

Clinical evaluation of a universal adhesive in non-carious cervical lesions.

Objectives: To compare the clinical performance of a universal adhesive in class V non-carious cervical lesions (NCCLs) using two surface treatment protocols (self-etch [SfE] vs selective-enamel-etch [SelE]).

Material And Methods: Thirty-three adults, each with ≥2 NCCLs, received one resin composite restoration utilizing a SfE universal adhesive and another utilizing the adhesive and SelE with 37% phosphoric acid. Restorations were evaluated for sensitivity, retention, marginal discoloration, marginal adaptation, and clinical acceptability through 24 months using Cochran-Mantel-Haenszel tests for stratified, ordered categorical outcomes.

Redefining the multidimensional clinical phenotypes of frontotemporal lobar degeneration syndromes.

The syndromes caused by frontotemporal lobar degeneration have highly heterogeneous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the past decade, but we propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, we examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia, non-fluent, and semantic variants of primary progressive aphasia (PPA), progressive supranuclear palsy and corticobasal syndrome.