Longitudinal effects of metabolic syndrome on Alzheimer and vascular related brain pathology.

Background/aimsThis study examines the longitudinal effect of metabolic syndrome (MetS) on brain-aging indices among cognitively normal (CN) and amnestic mild cognitive impairment (aMCI) groups [single-domain aMCI (saMCI) and multiple-domain aMCI (maMCI)].MethodsThe study population included 739 participants (CN = 226, saMCI = 275, and maMCI = 238) from the Alzheimer's Disease Neuroimaging Initiative, a clinic-based, multi-center prospective cohort. Confirmatory factor analysis was employed to determine a MetS latent composite score using baseline data of vascular risk factors. We examined the changes of two Alzheimer's disease (AD) biomarkers, namely [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) regions of interest and medial temporal lobe volume over 5 years. A cerebrovascular aging index, cerebral white matter (cWM) volume, was examined as a comparison.ResultsThe vascular risk was similar in all groups. Applying generalized estimating equation modeling, all brain-aging indices declined significantly over time. Higher MetS scores were associated with a faster decline of cWM in the CN and maMCI groups but with a slower decrement of regional glucose metabolism in FDG-PET in the saMCI and maMCI groups.ConclusionAt the very early stage of cognitive decline, the vascular burden such as MetS may be in parallel with or independent of AD pathology in contributing to cognitive impairment in terms of accelerating the disclosure of AD pathology

Anxious/depressed symptoms are related to microstructural maturation of white matter in typically developing youths

AbstractThere are multiple recent reports of an association between anxious/depressed (A/D) symptomatology and the rate of cerebral cortical thickness maturation in typically developing youths. We investigated the degree to which anxious/depressed symptoms are tied to age-related microstructural changes in cerebral fiber pathways. The participants were part of the NIH MRI Study of Normal Brain Development. Child Behavior Checklist A/D scores and diffusion imaging were available for 175 youths (84 males, 91 females; 241 magnetic resonance imagings) at up to three visits. The participants ranged from 5.7 to 18.4 years of age at the time of the scan. Alignment of fractional anisotropy data was implemented using FSL/Tract-Based Spatial Statistics, and linear mixed model regression was carried out using SPSS. Child Behavior Checklist A/D was associated with the rate of microstructural development in several white matter pathways, including the bilateral anterior thalamic radiation, bilateral inferior longitudinal fasciculus, left superior longitudinal fasciculus, and right cingulum. Across these pathways, greater age-related fractional anisotropy increases were observed at lower levels of A/D. The results suggest that subclinical A/D symptoms are associated with the rate of microstructural development within several white matter pathways that have been implicated in affect regulation, as well as mood and anxiety psychopathology.</jats:p

Mediterranean-type diet and brain structural change from 73 to 76 years in a Scottish cohort

STUDY FUNDING The data were collected by a Research into Ageing programme grant; research continues as part of the Age UK–funded Disconnected Mind project. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1), with funding from the BBSRC and Medical Research Council. Imaging and image analysis was performed at the Brain Research Imaging Centre (sbirc.ed.ac.uk/), Edinburgh, supported by the Scottish Funding Council SINAPSE Collaboration. Derivation of mean cortical thickness measures was funded by the Scottish Funding Council’s Postdoctoral and Early Career Researchers Exchange Fund awarded by SINAPSE to David Alexander Dickie. L.C.A.C. acknowledges funding from the Scottish Government's Rural and Environment Science and Analytical Services (RESAS) division.Peer reviewedPublisher PD

18 F-MK-6240 tau-PET in genetic frontotemporal dementia

Tau is one of several proteins associated with frontotemporal dementia. While knowing which protein is causing a patient\u27s disease is crucial, no biomarker currently exists for identifying tau in vivo in frontotemporal dementia. The objective of this study was to investigate the potential for the promising 18F-MK-6240 PET tracer to bind to tau in vivo in genetic frontotemporal dementia. We enrolled subjects with genetic frontotemporal dementia, who constitute an ideal population for testing because their pathology is already known based on their mutation. Ten participants (three with symptomatic P301L and R406W MAPT mutations expected to show tau binding, three with presymptomatic MAPT mutations and four with non-tau mutations who acted as disease controls) underwent clinical characterization, tau-PET scanning with 18F-MK-6240, amyloid-PET imaging with 18F-NAV-4694 to rule out confounding Alzheimer\u27s pathology, and high-resolution structural MRI. Tau-PET scans of all three symptomatic MAPT carriers demonstrated at least mild 18F-MK-6240 binding in expected regions, with particularly strong binding in a subject with an R406W MAPT mutation (known to be associated with Alzheimer\u27s like neurofibrillary tangles). Two asymptomatic MAPT carriers estimated to be 5 years from disease onset both showed modest 18F-MK-6240 binding, while one ∼30 years from disease onset did not exhibit any binding. Additionally, four individuals with symptomatic frontotemporal dementia caused by a non-tau mutation were scanned (two C9orf72; one GRN; one VCP): 18F-MK-6240 scans were negative for three subjects, while one advanced C9orf72 case showed minimal regionally non-specific binding. All 10 amyloid-PET scans were negative. Furthermore, a general linear model contrasting genetic frontotemporal dementia subjects to a set of 83 age-matched controls showed significant binding only in the MAPT carriers in selected frontal, temporal and subcortical regions. In summary, our findings demonstrate mild but significant binding of MK-6240 in amyloid-negative P301L and R406W MAPT mutation subjects, with higher standardized uptake value ratio in the R406W mutation associated with the presence of NFTs, and little non-specific binding. These results highlight that a positive 18F-MK-6240 tau-PET does not necessarily imply a diagnosis of Alzheimer\u27s disease and point towards a potential use for 18F-MK-6240 as a biomarker in certain tauopathies beyond Alzheimer\u27s, although further patient recruitment and autopsy studies will be necessary to determine clinical applicability

A Review and Expert Opinion on the Neuropsychiatric Assessment of Motor Functional Neurological Disorders

Functional neurological (conversion) disorder (FND) is a prevalent and disabling condition at the intersection of neurology and psychiatry. Advances have been made in elucidating an emerging pathophysiology for motor FND, as well as in identifying evidenced-based physiotherapy and psychotherapy treatments. Despite these gains, important elements of the initial neuropsychiatric assessment of functional movement disorders (FND-movt) and functional limb weakness/paresis (FND-par) have yet to be established. This is an important gap from both diagnostic and treatment planning perspectives. In this article, the authors performed a narrative review to characterize clinically relevant variables across FND-movt and FND-par cohorts, including time course and symptom evolution, precipitating factors, medical and family histories, psychiatric comorbidities, psychosocial factors, physical examination signs, and adjunctive diagnostic tests. Thereafter, the authors propose a preliminary set of clinical content that should be assessed during early-phase patient encounters, in addition to identifying physical signs informing diagnosis and potential use of adjunctive tests for challenging cases. Although clinical history should not be used to make a FND diagnosis, characteristics such as acute onset, precipitating events (e.g., injury and surgery), and a waxing and waning course (including spontaneous remissions) are commonly reported. Active psychiatric symptoms (e.g., depression and anxiety) and ongoing psychosocial stressors also warrant evaluation. Positive physical examination signs (e.g., Hoover's sign and tremor entrainment) are key findings, as one of the DSM-5 diagnostic criteria. The neuropsychiatric assessment proposed emphasizes diagnosing FND by using "rule-in" physical signs while also considering psychiatric and psychosocial factors to aid in the development of a patient-centered treatment plan

Differences in sex distribution between genetic and sporadic FTD

AbstractBackgroundThe reported sex distribution differs between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that have resulted in variable findings. Our aim was to determine the sex distribution in a large international retrospective cohort of sporadic and genetic FTD.MethodWe included patients with probable and definite behavioural variant frontotemporal dementia (bvFTD), non‐fluent variant primary progressive aphasia (nfvPPA), semantic variant primary progressive aphasia (svPPA) and right temporal variant frontotemporal dementia (rtvFTD) from the Amsterdam Dementia Cohort, the Montreal Neurological Institute Cohort, the University of Ulm and Technical University of Munich Cohort (part of the German Consortium of Frontotemporal Lobal Degeneration), the Policlinico Milan Cohort and the Sydney FRONTIER Cohort. We compared sex distribution between genetic and sporadic FTD using χ2 tests.ResultA total of 910 subjects were included (56.3% male), of whom 654 had bvFTD, 99 nfvPPA, 117 svPPA and 40 rtvFTD. Of these, 215 had genetic FTD and the sex distribution was equal (51.2% male), which did not differ significantly from sporadic FTD (57.8% male, χ2 p=0.081). In the sporadic bvFTD subgroup, we found a male predominance (61.6% males compared to 52.9% males in the bvFTD genetic group, χ 2 p=0.04). No sex distribution differences between sporadic and genetic cases were found in the other clinical FTD subgroups (all p>0.05).ConclusionDifferences in sex distribution between genetic and sporadic behavioural variant of FTD may provide important clues for its differential pathogenesis and warrants further research

Interactive effects of dehydroepiandrosterone and testosterone on cortical thickness during early brain development

Humans and the great apes are the only species demonstrated to exhibit adrenarche, a key endocrine event associated with prepubertal increases in the adrenal production of androgens, most significantly dehydroepiandrosterone (DHEA) and to a certain degree testosterone. Adrenarche also coincides with the emergence of the prosocial and neurobehavioral skills of middle childhood and may therefore represent a human-specific stage of development. Both DHEA and testosterone have been reported in animal and in vitro studies to enhance neuronal survival and programmed cell death depending on the timing, dose, and hormonal context involved, and to potentially compete for the same signaling pathways. Yet no extant brain-hormone studies have examined the interaction between DHEA- and testosterone-related cortical maturation in humans. Here, we used linear mixed models to examine changes in cortical thickness associated with salivary DHEA and testosterone levels in a longitudinal sample of developmentally healthy children and adolescents 4–22 years old. DHEA levels were associated with increases in cortical thickness of the left dorsolateral prefrontal cortex, right temporoparietal junction, right premotor and right entorhinal cortex between the ages of 4–13 years, a period marked by the androgenic changes of adrenarche. There was also an interaction between DHEA and testosterone on cortical thickness of the right cingulate cortex and occipital pole that was most significant in prepubertal subjects. DHEA and testosterone appear to interact and modulate the complex process of cortical maturation during middle childhood, consistent with evidence at the molecular level of fast/nongenomic and slow/genomic or conversion-based mechanisms underlying androgen-related brain development

Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart

Aims Glycogen synthase kinase 3 (GSK-3) signalling is implicated in the growth of the heart during development and in response to stress. However, its precise role remains unclear. We set out to characterize developmental growth and response to chronic isoproterenol (ISO) stress in knockin (KI) mice lacking the critical N-terminal serines, 21 of GSK-3α and 9 of GSK-3β respectively, required for inactivation by upstream kinases. Methods and results Between 5 and 15 weeks, KI mice grew more rapidly, but normalized heart weight and contractile performance were similar to wild-type (WT) mice. Isolated hearts of both genotypes responded comparably to acute ISO infusion with increases in heart rate and contractility. In WT mice, chronic subcutaneous ISO infusion over 14 days resulted in cardiac hypertrophy, interstitial fibrosis, and impaired contractility, accompanied by foetal gene reactivation. These effects were all significantly attenuated in KI mice. Indeed, ISO-treated KI hearts demonstrated reversible physiological remodelling traits with increased stroke volume and a preserved contractile response to acute adrenergic stimulation. Furthermore, simultaneous pharmacological inhibition of GSK-3 in KI mice treated with chronic subcutaneous ISO recapitulated the adverse remodelling phenotype seen in WT hearts. Conclusion Expression of inactivation-resistant GSK-3α/β does not affect eutrophic myocardial growth but protects against pathological hypertrophy induced by chronic adrenergic stimulation, maintaining cardiac function and attenuating interstitial fibrosis. Accordingly, strategies to prevent phosphorylation of Ser-21/9, and consequent inactivation of GSK-3α/β, may enable a sustained cardiac response to chronic β-agonist stimulation while preventing pathological remodelling