Search

Alzheimer's disease (AD) pathology is frequently observed as a comorbidity in people with dementia with Lewy bodies (DLB). Here, we evaluated the in vivo distribution of tau burden and its influence on the clinical phenotype of DLB. Tau deposition was quantified using [18F]-AV1451 positron emission tomography in people with DLB (n = 10), AD (n = 27), and healthy controls (n = 14). A subset of patients with Lewy body diseases (n = 4) also underwent [11C]-PK11195 positron emission tomography to estimate microglial activation. [18F]-AV1451 BPND was lower in DLB than AD across widespread regions. The medial temporal lobe [18F]-AV1451 BPND distinguished people with DLB from AD (AUC = 0.87), and negatively correlated with Addenbrooke's Cognitive Examination-Revised and Mini-Mental State Examination. There was a high degree of colocalization between [18F]-AV1451 and [11C]-PK11195 binding (p < 0.001). Our findings of minimal tau burden in DLB confirm previous studies. Nevertheless, the associations of [18F]-AV1451 binding with cognitive impairment suggest that tau may interact synergistically with other pathologic processes to aggravate disease severity in DLB., Highlights • We evaluated [18F]-AV1451 uptake in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). • There is minimal tau deposition in DLB compared to healthy controls. • Tau imaging may be useful for differential diagnosis of DLB and AD. • Tau deposition was correlated with cognitive impairment in DLB.

Drugs that increase noradrenaline levels can improve cognition in Parkinson’s disease, but identifying which patients will benefit the most remains a challenge. O’Callaghan et al. show that drug response depends on the integrity of the locus coeruleus, a finding that could inform treatment and clinical trial patient selection., Cognitive decline is a common feature of Parkinson’s disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition deficits. Restoring noradrenaline levels using the noradrenergic reuptake inhibitor atomoxetine can improve response inhibition in some patients with Parkinson’s disease, but there is considerable heterogeneity in treatment response. Accurately predicting the patients who would benefit from therapies targeting this neurotransmitter system remains a critical goal, in order to design the necessary clinical trials with stratified patient selection to establish the therapeutic potential of atomoxetine. Here, we test the hypothesis that integrity of the noradrenergic locus coeruleus explains the variation in improvement of response inhibition following atomoxetine. In a double-blind placebo-controlled randomized crossover design, 19 patients with Parkinson’s disease completed an acute psychopharmacological challenge with 40 mg of oral atomoxetine or placebo. A stop-signal task was used to measure response inhibition, with stop-signal reaction times obtained through hierarchical Bayesian estimation of an ex-Gaussian race model. Twenty-six control subjects completed the same task without undergoing the drug manipulation. In a separate session, patients and controls underwent ultra-high field 7 T imaging of the locus coeruleus using a neuromelanin-sensitive magnetization transfer sequence. The principal result was that atomoxetine improved stop-signal reaction times in those patients with lower locus coeruleus integrity. This was in the context of a general impairment in response inhibition, as patients on placebo had longer stop-signal reaction times compared to controls. We also found that the caudal portion of the locus coeruleus showed the largest neuromelanin signal decrease in the patients compared to controls. Our results highlight a link between the integrity of the noradrenergic locus coeruleus and response inhibition in patients with Parkinson’s disease. Furthermore, they demonstrate the importance of baseline noradrenergic state in determining the response to atomoxetine. We suggest that locus coeruleus neuromelanin imaging offers a marker of noradrenergic capacity that could be used to stratify patients in trials of noradrenergic therapy and to ultimately inform personalized treatment approaches.

© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., Introduction: Apathy adversely affects prognosis and survival of patients with frontotemporal dementia (FTD). We test whether apathy develops in presymptomatic genetic FTD, and is associated with cognitive decline and brain atrophy. Methods: Presymptomatic carriers of MAPT, GRN or C9orf72 mutations (N = 304), and relatives without mutations (N = 296) underwent clinical assessments and MRI at baseline, and annually for 2 years. Longitudinal changes in apathy, cognition, gray matter volumes, and their relationships were analyzed with latent growth curve modeling. Results: Apathy severity increased over time in presymptomatic carriers, but not in non-carriers. In presymptomatic carriers, baseline apathy predicted cognitive decline over two years, but not vice versa. Apathy progression was associated with baseline low gray matter volume in frontal and cingulate regions. Discussion: Apathy is an early marker of FTD-related changes and predicts a subsequent subclinical deterioration of cognition before dementia onset. Apathy may be a modifiable factor in those at risk of FTD., This work is co‐funded by the UK Medical Research Council (MR/M023664/1), the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, a Canadian Institutes of Health Research operating grant and the Bluefield Project, as well as a JPND grant “GENFI‐prox” (by DLR/BMBF to MS, joined with JDR, JvS, MO, BB and CG). MM is supported by the Cambridge Trust & Sidney Sussex College Scholarship. PSJ is supported by the Cambridge Centre for Parkinson Plus. KAT is supported by the British Academy Postdoctoral Fellowship (KAT: PF160048) and Guarantors of Brain (KAT: 101149). TR is supported by the Cambridge Centre for Parkinson Plus and Cambridge Biomedical Resource Centre. RAK is supported by Medical Research Council (RAK: SUAG/047/G101400). JBR reports grants from the NIHR Cambridge Biomedical research centre, Wellcome Trust (103838), and Medical Research Council (SUAG051/G101400; MR/T033371/1); personal fees from Asceneuron, WAVE, Astex, and Biogen; and grants from Janssen, AZ Medimmune, and Eli Lilly, outside the submitted work. JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). MB is supported by a Fellowship award from the Alzheimer's Society, UK (AS‐JF‐19a‐004‐517), and by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK.

BACKGROUND: Synaptic loss is a prominent and early feature of many neurodegenerative diseases. OBJECTIVES: We tested the hypothesis that synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) (Richardson's syndrome) and amyloid-negative corticobasal syndrome (CBS). METHODS: Forty-four participants (15 CBS, 14 PSP, and 15 age-/sex-/education-matched controls) underwent PET with the radioligand [11 C]UCB-J, which binds to synaptic vesicle glycoprotein 2A, a marker of synaptic density; participants also had 3 Tesla MRI and clinical and neuropsychological assessment. RESULTS: Nine CBS patients had negative amyloid biomarkers determined by [11 C]PiB PET and hence were deemed likely to have corticobasal degeneration (CBD). Patients with PSP-Richardson's syndrome and amyloid-negative CBS were impaired in executive, memory, and visuospatial tasks. [11 C]UCB-J binding was reduced across frontal, temporal, parietal, and occipital lobes, cingulate, hippocampus, insula, amygdala, and subcortical structures in both PSP and CBD patients compared to controls (P < 0.01), with median reductions up to 50%, consistent with postmortem data. Reductions of 20% to 30% were widespread even in areas of the brain with minimal atrophy. There was a negative correlation between global [11 C]UCB-J binding and the PSP and CBD rating scales (R = -0.61, P < 0.002; R = -0.72, P < 0.001, respectively) and a positive correlation with the revised Addenbrooke's Cognitive Examination (R = 0.52; P = 0.01). CONCLUSIONS: We confirm severe synaptic loss in PSP and CBD in proportion to disease severity, providing critical insight into the pathophysiology of primary degenerative tauopathies. [11 C]UCB-J may facilitate treatment strategies for disease-modification, synaptic maintenance, or restoration. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

See Piguet (doi:10.1093/brain/awaa119) for a scientific commentary on this article. Murley et al. report the results of a transdiagnostic study of clinical phenotype and brain atrophy in frontotemporal lobar degeneration syndromes, showing that these syndromes exist on a multidimensional spectrum, rather than as discrete entities., 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. We included patients with logopenic PPA and those who met criteria for PPA but not a specific subtype. To date, 49 patients have a neuropathological diagnosis. A principal component analysis identified symptom dimensions that broadly recapitulated the core features of the main clinical syndromes. However, the subject-specific scores on these dimensions showed considerable overlap across the diagnostic groups. Sixty-two per cent of participants had phenotypic features that met the diagnostic criteria for more than one syndrome. Behavioural disturbance was prevalent in all groups. Forty-four per cent of patients with corticobasal syndrome had progressive supranuclear palsy-like features and 30% of patients with progressive supranuclear palsy had corticobasal syndrome-like features. Many patients with progressive supranuclear palsy and corticobasal syndrome had language impairments consistent with non-fluent variant PPA while patients with behavioural variant frontotemporal dementia often had semantic impairments. Using multivariate source-based morphometry on a subset of patients (n = 133), we identified patterns of covarying brain atrophy that were represented across the diagnostic groups. Canonical correlation analysis of clinical and imaging components found three key brain-behaviour relationships, with a continuous spectrum across the cohort rather than discrete diagnostic entities. In the 46 patients with follow-up (mean 3.6 years) syndromic overlap increased with time. Together, these results show that syndromes associated with frontotemporal lobar degeneration do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders while deficits in behaviour, movement and language domains are not confined to specific diagnostic groups. It is important to recognize individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. We suggest that a transdiagnostic approach to the spectrum of frontotemporal lobar degeneration syndromes provides a useful framework with which to understand disease aetiology, progression, and heterogeneity and to target future treatments to a higher proportion of patients.

Synaptic loss is an early feature of neurodegenerative disease models, and is often severe inpost mortemclinical studies, including frontotemporal dementia. Positron emission tomography (PET) imaging with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synapsesin vivo. This study used [11C]UCB-J PET in people with behavioural variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity. We performed a cross-sectional observational study of bvFTD,versushealthy controls, in which participants underwent neurological examination, neuropsychological assessment, magnetic resonance imaging (MRI) and [11C]UCB-J PET. Patients were recruited from the Cambridge Centre for Frontotemporal Dementia at the University of Cambridge, and healthy volunteers from the UK National Institute for Health Research Join Dementia Research register. Eleven people with a clinical diagnosis of probable bvFTD and 25 age- and sex-matched healthy controls were included. All participants underwent dynamic [11C]UCB-J PET imaging, structural MRI and a neuropsychological battery, including the Addenbrooke’s cognitive examination (ACE-R), and INECO frontal screening (IFS). General linear models were used to compare [11C]UCB-J binding potential maps between groups, and correlate synaptic density with cognitive performance and clinical features in patients. Group-comparison and correlation analyses were also performed using partial-volume corrected [11C]UCB-J binding potential from regions of interest (ROIs). Patients with bvFTD showed severe synaptic loss compared to controls. In particular, [11C]UCB-J binding was significantly reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex and medial temporal lobe. Synaptic loss in the left frontal and cingulate regions correlated significantly with cognitive impairments as assessed with ACE-R and IFS. Results from ROI-based analyses mirrored the voxel-wise results. In keeping with preclinical models, and human post mortem data, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to disease severity. [11C]UCB-J PET could support translational studies and experimental medicines strategies for new disease-modifying treatments for neurodegeneration.

Background: Neurodegeneration in the locus coeruleus (LC) contributes to neuropsychiatric symptoms in both Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Spatial precision of LC imaging is improved with ultrahigh field 7 T magnetic resonance imaging. Objectives: This study aimed to characterize the spatial patterns of LC pathological change in PD and PSP and the transdiagnostic relationship between LC signals and neuropsychiatric symptoms. Methods: Twenty-five people with idiopathic PD, 14 people with probable PSP-Richardson's syndrome, and 24 age-matched healthy controls were recruited. Participants underwent clinical assessments and high-resolution (0.08 mm3 ) 7 T-magnetization-transfer imaging to measure LC integrity in vivo. Spatial patterns of LC change were obtained using subregional mean contrast ratios and significant LC clusters; we further correlated the LC contrast with measures of apathy and cognition, using both mixed-effect models and voxelwise analyses. Results: PSP and PD groups showed significant LC degeneration in the caudal subregion relative to controls. Mixed-effect models revealed a significant interaction between disease-group and apathy-related correlations with LC degeneration (? = 0.46, SE [standard error] = 0.17, F(1, 35) = 7.46, P = 0.01), driven by a strong correlation in PSP (? = -0.58, SE = 0.21, t(35) = -2.76, P = 0.009). Across both disease groups, voxelwise analyses indicated that lower LC integrity was associated with worse cognition and higher apathy scores. Conclusions: The relationship between LC and nonmotor symptoms highlights a role for noradrenergic dysfunction across both PD and PSP, confirming the potential for noradrenergic therapeutic strategies to address transdiagnostic cognitive and behavioral features in neurodegenerative disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterised by neuro-glial tau pathology. A new staging system for PSP pathology at post-mortem has been described and validated. We used a data-driven approach to test whether post-mortem pathological staging in PSP can be reproduced in vivo with 18F-flortaucipir PET. Methods:N = 42 patients with probable PSP and N = 39 controls underwent 18F-flortaucipir PET. Conditional inference tree analyses on regional binding potential values identified absent/present pathology thresholds to define in vivo staging. Following the staging system for PSP pathology, the combination of absent/present values across all regions was evaluated to assign each participant to in vivo stages. Analysis of variance was applied to analyse differences among means of disease severity between stages. In vivo staging was compared with post-mortem staging in N = 9 patients who also had post-mortem confirmation of the diagnosis and stage. Results: Stage assignment was estimable in 41 patients: N = 10 patients were classified in stage I/II, N = 26 in stage III/IV, N = 5 in stage V/VI, while N = 1 was not classifiable. An explorative sub-staging identified N = 2 patients in stage I, N = 8 in stage II, N = 9 in stage III, N = 17 in stage IV and N = 5 in stage V. However, the nominal 18F-flortaucipir derived stage was not associated with clinical severity and was not indicative of pathology staging at post-mortem. Conclusion:18F-flortaucipir PET in vivo does not correspond to neuropathological staging in PSP. This analytic approach, seeking to mirror in vivo the neuropathology staging with PET-to-autopsy correlational analyses might enable in vivo staging with next-generation PET tracers for tau, but further evidence and comparison with post-mortem data are needed.

Highlights • We investigated network dynamics in the tauopathy progressive supranuclear palsy • Abnormal temporal properties of large-scale networks are related to phenotype • Progressive supranuclear palsy paradoxically increases frontoparietal state time • Reductions in neural signal complexity relate to altered network dynamics • Dynamic network and topological changes occur distally to primary sites of atrophy, The clinical syndromes of Progressive Supranuclear Palsy (PSP) may be mediated by abnormal temporal dynamics of brain networks, due to the impact of atrophy, synapse loss and neurotransmitter deficits. We tested the hypothesis that alterations in signal complexity in neural networks influence short-latency state transitions. Ninety-four participants with PSP and 64 healthy controls were recruited from two independent cohorts. All participants underwent clinical and neuropsychological testing and resting-state functional MRI. Network dynamics were assessed using hidden Markov models and neural signal complexity measured in terms of multiscale entropy. In both cohorts, PSP increased the proportion of time in networks associated with higher cognitive functions. This effect correlated with clinical severity as measured by the PSP-rating-scale, and with reduced neural signal complexity. Regional atrophy influenced abnormal brain-state occupancy, but abnormal network topology and dynamics were not restricted to areas of atrophy. Our findings show that the pathology of PSP causes clinically relevant changes in neural temporal dynamics, leading to a greater proportion of time in inefficient brain-states.

Parkinson’s disease and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals, and have been linked with worse prognosis and lack of improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus noradrenergic system. Here we test the hypothesis that loss of structural integrity of the locus coeruleus explains response inhibition deficits in progressive supranuclear palsy and Parkinson’s disease. This cross-sectional observational study recruited 24 people with idiopathic Parkinson’s disease, 14 with PSP-Richardson’s syndrome, and 24 age- and sex-matched controls. All participants undertook a stop-signal task and ultrahigh field 7T-magnetic transfer weighted imaging of the locus coeruleus. Hierarchical Bayesian estimation of the parameters of ‘race models’ of go-versus stop-decisions was used to quantify the cognitive processes of response inhibition. We tested the multivariate relationship between locus coeruleus integrity and model parameters using partial least squares. Both disorders impaired response inhibition at the group level. Progressive supranuclear palsy caused a distinct pattern of abnormalities in inhibitory control, relative to Parkinson’s disease and healthy controls, with a paradoxically reduced threshold for go responses, but longer non-decision times, and more lapses of attention. The variation in response inhibition correlated with variation in the integrity of the locus coeruleus, across participants in both clinical groups. Structural imaging of the locus coeruleus, coupled with behavioural modelling in parkinsonian disorders, confirms that locus coeruleus integrity is associated with response inhibition and its degeneration contributes to neurobehavioural changes. The noradrenergic system is therefore a promising target to treat impulsivity in these conditions. The optimisation of noradrenergic treatment is likely to benefit from stratification according to locus coeruleus integrity.

Predicting tissue outcome early after stroke is an important goal. MRI >3 h accurately predicts infarction but is insensitive to selective neuronal loss (SNL). Previous studies suggest that chronic-stage 11 C-flumazenil PET (FMZ-PET) is a validated marker of SNL in rats, while early-stage FMZ-PET may predict infarction. Whether early FMZ-PET also predicts SNL is unknown. Following 45-min distal MCA occlusion, adult rats underwent FMZ-PET at 1 h and 48 h post-reperfusion to map distribution volume (VT), which reflects GABA-A receptor binding. NeuN immunohistochemistry was performed at Day 14. In each rat, VT and %NeuN loss were determined in 44 ROIs spanning the hemisphere. NeuN revealed isolated SNL and cortical infarction in five and one rats, respectively. In the SNL subgroup, VT-1 h was mildly reduced and only weakly predicted SNL, while VT-48 h was significantly increased and predicted SNL both individually ( p T, the stronger the SNL. Similar correlations were found in the rat with infarction. Our findings suggest GABA-A receptors are still present on injured neurons at the 48 h timepoint, and the increased 48 h VT observed here is consistent with earlier rat studies showing early GABA-A receptor upregulation. That FMZ binding at 48 h was predictive of SNL may have clinical implications.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuroglial tau pathology. A new staging system for PSP pathology postmortem has been described and validated. We used a data-driven approach to test whether postmortem pathologic staging in PSP can be reproduced in vivo with

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 (behavioural 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. Metabolite concentrations were corrected for age, sex, and partial volume then compared with cognitive and behavioural measures using canonical correlation analysis. Metabolite concentrations varied significantly by brain region and diagnosis (region x metabolite x diagnosis interaction F(64)=1.73, p

Highlights • Dendritic complexity and presynaptic density are reduced in the 4R-tauopathies of PSP and CBD. • The reduction in ODI and UCB-J binding is coupled across the cortical mantle as well as subcortically. • The relationship between ODI and UCB-J binding is not attributed to atrophy. • ODI may be a useful biomarker of synaptic pathology in neurodegenerative diseases., Understanding the cellular underpinnings of neurodegeneration remains a challenge; loss of synapses and dendritic arborization are characteristic and can be quantified in vivo, with [11C]UCB-J PET and MRI-based Orientation Dispersion Imaging (ODI), respectively. We aimed to assess how both measures are correlated, in 4R-tauopathies of progressive supranuclear palsy – Richardson's Syndrome (PSP-RS; n = 22) and amyloid-negative (determined by [11C]PiB PET) Corticobasal Syndrome (Cortiobasal degeneration, CBD; n =14), as neurodegenerative disease models, in this proof-of-concept study. Compared to controls (n = 27), PSP-RS and CBD patients had widespread reductions in cortical ODI, and [11C]UCB-J non-displaceable binding potential (BPND) in excess of atrophy. In PSP-RS and CBD separately, regional cortical ODI was significantly associated with [11C]UCB-J BPND in disease-associated regions (p < 0.05, FDR corrected). Our findings indicate that reductions in synaptic density and dendritic complexity in PSP-RS and CBD are more severe and extensive than atrophy. Furthermore, both measures are tightly coupled in vivo, furthering our understanding of the pathophysiology of neurodegeneration, and applicable to studies of early neurodegeneration with a safe and widely available MRI platform.

BackgroundVulnerability of the substantia nigra dopaminergic neurons in Parkinson’s disease is associated with ferric overload, leading to neurodegeneration with cognitive and motor decline. Here, we quantify iron and neuromelanin-related markers in vivo using ultra-high field 7-Tesla MRI, and examine the clinical correlates of these imaging assessments.MethodsTwenty-five people with mild-to-moderate Parkinson’s disease and twenty-six healthy controls underwent high-resolution imaging at 7-Tesla with a T2*-weighted sequence (measuring susceptibility-χ and R2*, sensitive to iron) and a magnetization transfer-weighted sequence (MT-w, sensitive to neuromelanin). From an independent control group (N=29), we created study-specific regions-of-interest for five neuromelanin- and/or iron-rich subregions within the substantia nigra. Mean R2*, susceptibility-χ and their ratio, as well as the MT-w contrast-to-noise ratio (MT-CNR) were extracted from these regions and compared between groups. We then tested the relationships between these imaging metrics and clinical severity.ResultsPeople with Parkinson’s disease showed a significant ~50% reduction in MT-CNR compared to healthy controls. They also showed a 1.2-fold increase in ferric iron loading (elevation of the ratio from 0.19±0.058ms/ppm to 0.22±0.059ms/ppm) in an area of the substantia nigra identified as having both high neuromelanin and susceptibility MRI signal in healthy controls. In this region, the ferric-to-ferrous iron loading was associated with disease duration (β=0.0072, pFDR=0.048) and cognitive impairment (β=−0.0115, pFDR=0.048).ConclusionsT2*-weighted and MT-weighted high-resolution 7T imaging markers identified neurochemical consequences of Parkinson’s disease, in overlapping but not-identical regions. These changes correlated with non-motor symptoms.

ObjectiveTo measure cortical metabolite deficits in vivo in syndromes associated with frontotemporal lobar degeneration, in relation to cognitive and behavioral change.MethodsSixty patients were recruited 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 using 3T semi-laser magnetic resonance spectroscopy. Metabolite concentrations were corrected for age, sex, and partial volume. We related corrected metabolite concentrations to cognitive and behavioral measures using canonical correlation analysis.ResultsMetabolite concentrations varied significantly by brain region and diagnosis (region x metabolite x diagnosis interaction F(64)=1.73, pConclusionMagnetic resonance spectroscopy confirms behaviourally relevant metabolite deficits including glutamate, in syndromes associated with frontotemporal lobar degeneration. Magnetic resonance spectroscopy may be a useful index of neurodegeneration, and highlight candidates for pharmacological treatment.

Understanding the cellular underpinnings of neurodegeneration remains a challenge; loss of synapses and dendritic arborisation are characteristic and can be quantified in vivo, with [11C]UCB-J PET and MRI-based Orientation Dispersion Imaging (ODI), respectively. We aimed to assess how both measures are correlated, in 4R-tauopathies of Progressive Supranuclear Palsy (PSP-RS; n = 22) and amyloid-negative (determined by [11C]PiB PET) Corticobasal Degeneration (CBD; n =14), as neurodegenerative disease models, in this proof-of-concept study. Compared to controls (n = 27), PSP-RS and CBD patients had widespread reductions in cortical ODI, and [11C]UCB-J non-displaceable binding potential (BPND) in excess of atrophy. In PSP-RS and CBD separately, regional cortical ODI was significantly associated with [11C]UCB-J BPND in disease-associated regions (p < 0.05, FDR corrected). Our findings indicate that reductions in synaptic density and dendritic complexity in PSP-RS and CBD are more severe and extensive than atrophy. Furthermore, both measures are tightly coupled in vivo, furthering our understanding of the pathophysiology of neurodegeneration, and applicable to studies of early neurodegeneration with a safe and widely available MRI platform.

Murley et al. use ultra-high field (7T) magnetic resonance spectroscopy to measure in vivo glutamate and GABA in frontotemporal lobar degeneration syndromes, and show that deficits in these neurotransmitters are associated with behavioural 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. Reductions in the neurotransmitters glutamate and GABA correlate with impulsive behaviour in several neuropsychiatric diseases and there is post-mortem evidence of their deficit in FTLD. Here, we tested the hypothesis that prefrontal glutamate and GABA levels are reduced by FTLD in vivo, and that their deficit is associated with impaired response inhibition. Thirty-three participants with a syndrome associated with FTLD (15 patients with behavioural variant frontotemporal dementia and 18 with progressive supranuclear palsy, including both Richardson’s syndrome and progressive supranuclear palsy-frontal subtypes) and 20 healthy control subjects were included. Participants undertook ultra-high field (7 T) magnetic resonance spectroscopy and a stop-signal task of response inhibition. We measured glutamate and GABA levels using semi-LASER magnetic resonance spectroscopy in the right inferior frontal gyrus, because of its strong association with response inhibition, and in the primary visual cortex, as a control region. The stop-signal reaction time was calculated using an ex-Gaussian Bayesian model. Participants with frontotemporal dementia and progressive supranuclear palsy had impaired response inhibition, with longer stop-signal reaction times compared with controls. GABA concentration was reduced in patients versus controls in the right inferior frontal gyrus, but not the occipital lobe. There was no group-wise difference in partial volume corrected glutamate concentration between patients and controls. Both GABA and glutamate concentrations in the inferior frontal gyrus correlated inversely with stop-signal reaction time, indicating greater impulsivity in proportion to the loss of each neurotransmitter. We conclude that the glutamatergic and GABAergic deficits in the frontal lobe are potential targets for symptomatic drug treatment of frontotemporal dementia and progressive supranuclear palsy.

Neuroinflammation occurs in frontotemporal dementia, however its timing relative to protein aggregation and neuronal loss is unknown. Using positron emission tomography and magnetic resonance imaging to quantify these processes in a pre‐symptomatic carrier of the 10 + 16 MAPT mutation, we show microglial activation in frontotemporal regions, despite a lack of protein aggregation or atrophy in these areas. The distribution of microglial activation better discriminated the carrier from controls than did protein aggregation at this pre‐symptomatic disease stage. Our findings suggest an early role for microglial activation in frontotemporal dementia. Longitudinal studies are needed to explore the causality of this pathophysiological association.

INTRODUCTIONWe report in vivo patterns of neuroinflammation and abnormal protein aggregation in seven cases of familial frontotemporal dementia with mutations in MAPT, GRN and C9orf72 genes.METHODSUsing positron emission tomography (PET), we explored the association of the distribution of activated microglia, as measured by the radioligand [11C]PK11195, and the regional distribution of tau- or TDP-43 pathology, indexed using the radioligand [18F]AV-1451. The familial FTD PET data were compared to healthy controls.RESULTSFamilial FTD patients across all mutation groups showed increased [11C]PK11195 binding predominantly in frontotemporal regions, with additional regions showing abnormalities in individuals. Patients with MAPT mutations had a consistent distribution of [18F]AV-1451 binding across the brain, with heterogeneous distributions among carriers of GRN and C9orf72 mutations.DISCUSSIONThis case series suggests a consistent role for neuroinflammation in the pathophysiology of familial FTD, warranting further consideration of immunomodulatory therapies for disease modification and prevention.

Objective: We examined the relationship between tau pathology and neuroinflammation using [11 C]PK11195 and [18 F]AV-1451 PET in seventeen patients with progressive supranuclear palsy Richardson's syndrome (PSP). We tested the hypothesis that neuroinflammation and tau protein aggregation co-localize macroscopically, and correlate with clinical severity. Methods: Non-displaceable binding potential (BPND ) for each ligand was quantified in 83 regions of interest (ROIs). The [11 C]PK11195 and [18 F]AV-1451 BPND values were correlated across all regions. The spatial distributions of [11 C]PK11195 and [18 F]AV-1451 binding were determined by principal component analyses (PCAs), and the loading of each spatial component compared against the patients' clinical severity (using the PSP-rating-scale). Results: Regional [11 C]PK11195 and [18 F]AV-1451 binding were positively correlated (R=0.577, p

Bevan-Jones, Cope et al. report that neuroinflammation co-localizes with protein aggregation in all major types of frontotemporal dementia, both in vivo with positron emission tomography, and at post mortem. In vivo neuroinflammation patterns are disease-specific and can accurately classify patients into groups., The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the localization of tau and TDP-43 pathology, and to the heterogeneity of clinical disease. We used PET in vivo with (i) 11C-PK-11195, a marker of activated microglia and a proxy index of neuroinflammation; and (ii) 18F-AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and TDP-43-related disease, and which is used as a surrogate marker of non-amyloid-β protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant, 11 with the semantic variant and 10 with the non-fluent variant), 28 of whom underwent both 18F-AV-1451 and 11C-PK-11195 PET, and matched control subjects (14 for 18F-AV-1451 and 15 for 11C-PK-11195). We used a univariate region of interest analysis, a paired correlation analysis of the regional relationship between binding distributions of the two ligands, a principal component analysis of the spatial distributions of binding, and a multivariate analysis of the distribution of binding that explicitly controls for individual differences in ligand affinity for TDP-43 and different tau isoforms. We found significant group-wise differences in 11C-PK-11195 binding between each patient group and controls in frontotemporal regions, in both a regions-of-interest analysis and in the comparison of principal spatial components of binding. 18F-AV-1451 binding was increased in semantic variant primary progressive aphasia compared to controls in the temporal regions, and both semantic variant primary progressive aphasia and behavioural variant frontotemporal dementia differed from controls in the expression of principal spatial components of binding, across temporal and frontotemporal cortex, respectively. There was a strong positive correlation between 11C-PK-11195 and 18F-AV-1451 uptake in all disease groups, across widespread cortical regions. We confirmed this association with post-mortem quantification in 12 brains, demonstrating strong associations between the regional densities of microglia and neuropathology in FTLD-TDP (A), FTLD-TDP (C), and FTLD-Pick's. This was driven by amoeboid (activated) microglia, with no change in the density of ramified (sessile) microglia. The multivariate distribution of 11C-PK-11195 binding related better to clinical heterogeneity than did 18F-AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate classification of participants. These in vivo findings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia.

Objective Widespread metabolic changes are seen in neurodegenerative disease and could be used as biomarkers for diagnosis and disease monitoring. They may also reveal disease mechanisms that could be a target for therapy. In this study we looked for blood-based biomarkers in syndromes associated with frontotemporal lobar degeneration. Methods Plasma metabolomic profiles were measured from 134 patients with a syndrome associated with frontotemporal lobar degeneration (behavioural variant frontotemporal dementia n = 30, non fluent variant primary progressive aphasia n = 26, progressive supranuclear palsy n = 45, corticobasal syndrome n = 33) and 32 healthy controls. Results Forty-nine of 842 metabolites were significantly altered in frontotemporal lobar degeneration syndromes (after false-discovery rate correction for multiple comparisons). These were distributed across a wide range of metabolic pathways including amino acids, energy and carbohydrate, cofactor and vitamin, lipid and nucleotide pathways. The metabolomic profile supported classification between frontotemporal lobar degeneration syndromes and controls with high accuracy (88.1–96.6%) while classification accuracy was lower between the frontotemporal lobar degeneration syndromes (72.1–83.3%). One metabolic profile, comprising a range of different pathways, was consistently identified as a feature of each disease versus controls: the degree to which a patient expressed this metabolomic profile was associated with their subsequent survival (hazard ratio 0.74 [0.59–0.93], p = 0.0018). Conclusions The metabolic changes in FTLD are promising diagnostic and prognostic biomarkers. Further work is required to replicate these findings, examine longitudinal change, and test their utility in differentiating between FTLD syndromes that are pathologically distinct but phenotypically similar.

AimsStudies of thalamic structure and function in Progressive Supranuclear Palsy (PSP) suggest it may play a role in key aspects of the clinical syndrome. This study examined thalamic changes across PSP phenotypes investigating (i) thalamic atrophy (ii) thalamic functional connectivity and (iii) the relationship between thalamic structural and functional connectivity changes with clinical severity.MethodsParticipants92 participants with PSP [63 PSP-Richardson's Syndrome (RS), 24 PSP-cortical, 5 PSP-subcortical] and 104 age-matched controls were recruited from the Cambridge Centre for Parkinson's Plus Disorders cohort. Clinical assessments and imaging were conducted within 1 year of diagnosis.Structural AnalysisThalamic volumes (TVs) were obtained using FreeSurfer. Bayesian multiple regression (brms, R) was used to model (i) mean TVs (ii) group differences in mean TVs (iii) relationships between Z-standardised clinical scores and TVs with age, gender, and total grey matter as covariates.Functional AnalysisVoxel-wise seed-based functional connectivity of the thalamus used the Functional Magnetic Resonance Imaging Expert Analysis Tool (FEAT) in FMRIB's Software Library (FSL). Inter-group differences and relationships between clinical scores and functional connectivity for each group were assessed using a general linear model with age and gender as covariates.ResultsStructural AnalysisTVs for all PSP subgroups were smaller than controls. No differences between PSP subgroups were detected. There was evidence for a relationship between TVs for the entire PSP group and Revised Addenbrooke's Cognitive Examination (ACER) scores [ß = 0.28, 95% credible interval (CI) = 0.04–0.53]. Subgroup analysis showed evidence for a relationship between ACER scores and TVs in PSP-RS [ß = 0.33, 95% CI = 0.09–0.57] and PSP-cortical [ß = 0.46, 95% CI = 0.12–0.83] phenotypes. A negative influence of TVs on total PSP rating scale scores was found for the PSP cohort a whole [ß = −0.51, 95% CI = −1.00 – −0.02].Functional AnalysisPSP patients as a group showed decreased thalamic functional connectivity in higher cortical regions. Subgroup analysis revealed decreased connectivity in those areas compared to controls but in distinct distributions and magnitude. Increased thalamic connectivity with the middle temporal gyrus correlated with ACER scores for PSP patients as a group and in the PSP-cortical subtype.ConclusionThalamic volume loss is a prominent aspect of PSP and is associated with a wide network of changes in functional connectivity that may be distinct between PSP subtypes. Changes in thalamic structure and function predict clinical severity, particularly in PSP-RS and PSP-cortical subtypes.

Synaptic loss is prominent in several human neurodegenerative diseases. We tested the hypothesis that synaptic density is reduced by the primary tauopathies of progressive supranuclear palsy (PSP) and cor- ticobasal syndrome (CBS). Thirty-three participants (10 CBS, 10 PSP, and thirteen age-/sex-/education- matched controls) underwent clinical and neuropsychological assessment, 3T-magnetic resonance imaging, and positron emission tomography with the radioligand [11C]UCB-J which targets the Synaptic Vesicle Glycoprotein 2A (SV2A). Eight CBS patients had negative β-amyloid biomarker. As expected, PSP and CBS groups were impaired in executive, memory and visuospatial tasks. [11C]UCB-J binding was reduced across frontal, temporal, parietal, and occipital lobes, cingulate, hippocampus, insula, amygdala and subcortical structures in both PSP and CBS patients compared to controls (pnda26@cam.ac.uk

Modern ischaemic stroke management involves intravenous thrombolysis followed by mechanical thrombectomy, which allows markedly higher rates of recanalization and penumbral salvage than thrombolysis alone. However