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Background/Objective: The corticobasal syndrome (CBS) is a complex asymmetric movement disorder, with cognitive impairment. Although commonly associated with the primary 4‐repeat‐tauopathy of corticobasal degeneration, clinicopathological correlation is poor, and a significant proportion is due to Alzheimer's disease (AD). Synaptic loss is a pathological feature of many clinical and preclinical tauopathies. We therefore measured the degree of synaptic loss in patients with CBS and tested whether synaptic loss differed according to β‐amyloid status. Methods: Twenty‐five people with CBS, and 32 age‐/sex‐/education‐matched healthy controls participated. Regional synaptic density was estimated by [11C]UCB‐J non‐displaceable binding potential (BPND), AD‐tau pathology by [18F]AV‐1451 BPND, and gray matter volume by T1‐weighted magnetic resonance imaging. Participants with CBS had β‐amyloid imaging with 11C‐labeled Pittsburgh Compound‐B ([11C]PiB) positron emission tomography. Symptom severity was assessed with the progressive supranuclear palsy‐rating‐scale, the cortical basal ganglia functional scale, and the revised Addenbrooke's Cognitive Examination. Regional differences in BPND and gray matter volume between groups were assessed by ANOVA. Results: Compared to controls, patients with CBS had higher [18F]AV‐1451 uptake, gray matter volume loss, and reduced synaptic density. Synaptic loss was more severe and widespread in the β‐amyloid negative group. Asymmetry of synaptic loss was in line with the clinically most affected side. Discussion: Distinct patterns of [11C]UCB‐J and [18F]AV‐1451 binding and gray matter volume loss, indicate differences in the pathogenic mechanisms of CBS according to whether it is associated with the presence of Alzheimer's disease or not. This highlights the potential for different therapeutic strategies in CBSs. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: The APOE ε4 allele is the primary genetic risk factor for the sporadic type of Alzheimer's disease (AD). However, the mechanisms by which APOE ε4 is associated with neurodegeneration are still poorly understood. Here, we applied the NODDI to characterise the effects of APOE ε4 and its interactions with age and education on cortical microstructure in cognitively normal individuals. Method: Data from 1954 participants were included from the PREVENT‐Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non‐carriers, 757 APOE ε4 carriers). T1 MRIs were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index (ODI) maps from diffusion MRI. Primary analyses were focused on the (a) main effects of APOE ε4, and the (b) interactions of APOE ε4 with age and education on lobar and vertex‐wise ODI and implemented using Permutation Analysis of Linear Models. Result: APOE ε4 carriers and non‐carriers did not differ in terms of lobar ODI. However, there were APOE ε4 × age interactions in the temporo‐parietal and frontal lobes (TFCE p FWE < 0.05), indicating steeper age‐dependent ODI changes in APOE ε4 (Figure 1). Lobar analyses revealed decreased temporal ODI in APOE ε4 carriers after age = 60 (Figure 2). There was a three‐way interaction of APOE ε4 x age x education; steeper age‐related ODI declines among APOE ε4 carriers with lower years of education (Figure 3, TFCE p FWE < 0.05). There were no significant main effects or interactions of APOE ε4 on cortical thickness. Conclusion: We found novel evidence that APOE ε4 worsened age‐related ODI decreases in brain regions typically associated with atrophy patterns of AD. This finding also suggests that APOE ε4 may hasten the onset age of dementia by accelerating age‐dependent reductions in cortical ODI, although additional studies are needed to verify this hypothesis. These findings were independent of cortical thickness. While conclusions are limited due to the cross‐sectional design, our findings imply that APOE ε4 related changes in ODI may precede macroscopically visible changes in cortical atrophy and may be a more sensitive marker of incipient AD. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence for early and extensive synaptic loss in frontotemporal lobar degeneration syndromes from in vivo and post‐mortem studies. We proposed that synaptic loss would affect behaviour, in relation to changes in functional connectivity. Method: We recruited 29 participants with progressive supranuclear palsy, 16 participants with amyloid‐negative corticobasal syndrome, 8 participants with behavioural variant frontotemporal dementia and 24 similarly‐aged healthy volunteers. All participants underwent resting‐state functional 3T MRI and positron emission tomography with [11C]UCB‐J, that binds synaptic vesicle 2A. We compared the connectivity metrics of nodal weighted degree and voxelwise regional homogeneity with [11C]UCB‐J non‐displaceable binding potential (BPND), in associative and commonality analyses. We then used independent component analysis to extract [11C]UCB‐J BPND signal variance across participants, followed by derivation of participant‐specific scores of functional spatial covariance with the [11C]UCB‐J components. We applied model selection to assess whether connectivity scores would improve prediction of and moderate the effect of synaptic loss on clinical severity. Result: Reduced [11C]UCB‐J BPND was associated with reduced connectivity, with synaptic density predicting both measures of connectivity over and above grey matter volume (Figure 1). The anatomical distribution of synaptic loss partially overlapped in PSP, bvFTD and CBS, but there were also disease‐specific effects (Figure 2). The effect of synaptic loss on functional connectivity was expressed local to the regions of severe synaptic loss, and in remote regions. Moreover, functional connectivity explained additional variance and moderated the relationship between synaptic density and clinical severity (Figure 3). Conclusion: In vivo synaptic loss is associated with reduced connectivity, and changes in behaviour, with implications for modelling disease pathogenesis and translational studies. [ABSTRACT FROM AUTHOR]

Background: Novel, validated imaging biomarkers for assessing disease severity and progression in dementia with Lewy Bodies (DLB) are needed as standard neuroimaging changes such as atrophy are not pronounced. Both multi‐modal MR and PET offer opportunities, for example cortical microstructure and dendritic imaging can be assessed using advanced MR diffusion weighted imaging (DWI) methods such as neurite orientation dispersion and density imaging (NODDI) and PET with UCB‐J can assess synaptic density. We applied these and other markers to people with DLB and controls. Method: In linked studies, people with probable DLB and similarly aged controls (n = 10‐30 per group depending on study) underwent multimodal 3T‐MRI (including structural, multi‐shell DWI and arterial spin labelling imaging) and PET imaging with AV1451 (for assessment of tau), PiB (for amyloid status) and [11C]UCB‐J PET/MR. For MR, T1‐MRI and DWI datasets were processed using FreeSurfer 7.2 and FSL 6.0.4 respectively with whole‐brain ODI derived from the Microstructure Diffusion Toolbox. The [11C]UCB‐J and [18F]AV1451 binding potentials (BPND) were assessed using a simplified reference tissue model (reference centrum semiovale for UCBJ and cerebellum for AV1451). Group differences in ODI, UCB‐J and AV1451 BPND were examined and correlated with structural changes and clinical and cognitive variables (ACE‐R score). Result: Compared to controls, people with DLB showed significantly thinner neocortex (T = ‐2.8, p = 0.01) in temporo‐parietal regions but more widespread reductions in cortical microstructure (ODI, T = ‐3.9, p < 0.001)(Figure 1). Within the DLB group, hippocampal ODI was positively correlated with cognitive performance (robust linear regression: p < 0.001)(Figure 2). Reduced synaptic density (UCB‐J BPND) was found for the DLB group in posterior regions (p<0.05, FWE corrected)(Figure 3), with a trend for greater reductions in those who were amyloid positive. ACE‐R scores significantly correlated with synaptic density (p<0.05, FWE corrected). There were no significant differences in AV1451 binding between DLB and controls. Conclusion: Extensive reductions in ODI and reduced synaptic density, both associated with cognitive impairment and occurring in regions without significant atrophy or tau deposition, suggests that NODDI and synaptic PET imaging are promising biomarkers for DLB which merit further investigation, including in longitudinal studies. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is an important pathogenic mechanism in frontotemporal dementia (FTD) and related disorders. Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, and as proportionate to symptom severity and rate of progression. However, data on inflammation blood markers of inflammation and their relationship with central inflammation are limited. Here we assess inflammatory patterns of 41 serum cytokines from patients with FTD and related conditions, and their association with regional microglial activation (TSPO PET). Method: Blood samples were obtained from 29 healthy controls, and 214 patients with a clinical diagnosis of behavioural variant FTD (bvFTD = 52), primary progressive aphasia (PPA = 51), progressive supranuclear palsy (PSP = 58) and corticobasal syndrome (CBS = 53). Serum assays used the MesoScale Discovery V‐Plex‐Human Cytokine 36 plex panel plus five additional cytokine assays. A Principal Component Analysis (PCA) across all participants was used to reduce dimensionality of cytokine data. A sub‐group of patients (bvFTD = 10, PPA = 17, PSP = 17) underwent PET imaging with [11C]PK11195 PET, as index of microglial activation. Kruskal‐Wallis and pairwise t‐tests were performed on the resulting components to compare each patient cohort to controls. [11C]PK11195 non‐displaceable binding potential (BPND) was calculated in 83 regions of interest (ROIs) across the whole brain. Spearman correlations tested associations between cytokine components and regional [11C]PK11195 BPND. Result: Sixteen cytokines were undetectable in >50% of participants and thus excluded. The first component identified by the PCA on the remaining 25 cytokines (explaining 19.7%) was strongly loaded by pro‐inflammatory cytokines (Figure 1, left). Kruskal–Wallis one‐way analyses of variance on detected significant differences across the groups (χ2(4) = 11.0, p = 0.027), and the pairwise t‐tests identified significant differences between each patient cohort and controls (Figure 1, right). Spearman correlations identified regional positive associations between individual cytokine‐component scores and microglial activation in frontal and brainstem regions across the whole group (R≥0.25), and syndrome‐specific regional patterns (Figure 2). Conclusion: This data‐driven approach identified a pro‐inflammatory profile across FTD and related conditions, which is positively associated with higher levels of microglial activation in syndrome‐related key brain regions. Blood‐based tests could greatly increase the scalability and access to neuroinflammatory assessment in dementia and experimental medicine studies. [ABSTRACT FROM AUTHOR]

There is a pressing need to understand the factors that predict prognosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), with high heterogeneity over the poor average survival. We test the hypothesis that the magnitude and distribution of connectivity changes in PSP and CBS predict the rate of progression and survival time, using datasets from the Cambridge Centre for Parkinson‐plus and the UK National PSP Research Network (PROSPECT‐MR). Resting‐state functional MRI images were available from 146 participants with PSP, 82 participants with CBS, and 90 healthy controls. Large‐scale networks were identified through independent component analyses, with correlations taken between component time series. Independent component analysis was also used to select between‐network connectivity components to compare with baseline clinical severity, longitudinal rate of change in severity, and survival. Transdiagnostic survival predictors were identified using partial least squares regression for Cox models, with connectivity compared to patients' demographics, structural imaging, and clinical scores using five‐fold cross‐validation. In PSP and CBS, between‐network connectivity components were identified that differed from controls, were associated with disease severity, and were related to survival and rate of change in clinical severity. A transdiagnostic component predicted survival beyond demographic and motion metrics but with lower accuracy than an optimal model that included the clinical and structural imaging measures. Cortical atrophy enhanced the connectivity changes that were most predictive of survival. Between‐network connectivity is associated with variability in prognosis in PSP and CBS but does not improve predictive accuracy beyond clinical and structural imaging metrics. [ABSTRACT FROM AUTHOR]

Background: Synaptic loss is characteristic of many neurodegenerative diseases; it occurs early and is strongly related to functional deficits. Objective: In this longitudinal observational study, we determine the rate at which synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and we test the relationship with disease progression. Methods: Our cross‐sectional cohort included 32 participants with probable PSP and 16 with probable CBD (all amyloid‐negative corticobasal syndrome), recruited from tertiary care centers in the United Kingdom, and 33 sex‐ and age‐matched healthy control subjects. Synaptic density was estimated by positron emission tomography imaging with the radioligand [11C]UCB‐J that binds synaptic vesicle 2A. Clinical severity and cognition were assessed by the PSP Rating Scale and the Addenbrooke's cognitive examination. Regional [11C]UCB‐J nondisplaceable binding potential was estimated in Hammersmith Atlas regions of interest. Twenty‐two participants with PSP/CBD had a follow‐up [11C]UCB‐J positron emission tomography scan after 1 year. We calculated the annualized change in [11C]UCB‐J nondisplaceable binding potential and correlated this with the change in clinical severity. Results: We found significant annual synaptic loss within the frontal lobe (−3.5%, P = 0.03) and the right caudate (−3.9%, P = 0.046). The degree of longitudinal synaptic loss within the frontal lobe correlated with the rate of change in the PSP Rating Scale (R = 0.47, P = 0.03) and cognition (Addenbrooke's Cognitive Examination–Revised, R = −0.62, P = 0.003). Conclusions: We provide in vivo evidence for rapid progressive synaptic loss, correlating with clinical progression in primary tauopathies. Synaptic loss may be an important therapeutic target and outcome variable for early‐phase clinical trials of disease‐modifying treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Introduction: We tested whether changes in functional networks predict cognitive decline and conversion from the presymptomatic prodrome to symptomatic disease in familial frontotemporal dementia (FTD). Methods: For hypothesis generation, 36 participants with behavioral variant FTD (bvFTD) and 34 controls were recruited from one site. For hypothesis testing, we studied 198 symptomatic FTD mutation carriers, 341 presymptomatic mutation carriers, and 329 family members without mutations. We compared functional network dynamics between groups, with clinical severity and with longitudinal clinical progression. Results: We identified a characteristic pattern of dynamic network changes in FTD, which correlated with neuropsychological impairment. Among presymptomatic mutation carriers, this pattern of network dynamics was found to a greater extent in those who subsequently converted to the symptomatic phase. Baseline network dynamic changes predicted future cognitive decline in symptomatic participants and older presymptomatic participants. Discussion: Dynamic network abnormalities in FTD predict cognitive decline and symptomatic conversion. Highlights: We investigated brain network predictors of dementia symptom onsetFrontotemporal dementia results in characteristic dynamic network patternsAlterations in network dynamics are associated with neuropsychological impairmentNetwork dynamic changes predict symptomatic conversion in presymptomatic carriersNetwork dynamic changes are associated with longitudinal cognitive decline [ABSTRACT FROM AUTHOR]

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 [11C]UCB‐J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity. Methods: Eleven participants with clinically probable bvFTD and 25 age‐ and sex‐matched healthy controls were included. Participants underwent dynamic [11C]UCB‐J PET, structural magnetic resonance imaging, and a neuropsychological battery, including the revised Addenbrooke Cognitive Examination, and INECO frontal screening. General linear models compared [11C]UCB‐J binding potential maps and gray matter volume between groups, and assessed associations between synaptic density and clinical severity in patients. Analyses were also performed using partial volume corrected [11C]UCB‐J binding potential from regions of interest (ROIs). Results: Patients with bvFTD showed severe synaptic loss compared to controls. [11C]UCB‐J binding was 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 frontal and cingulate regions correlated significantly with cognitive impairments. Synaptic loss was more severe than atrophy. Results from ROI‐based analyses mirrored the voxelwise results. Interpretation: In accordance with preclinical models, and human postmortem evidence, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to severity. [11C]UCB‐J PET could support translational studies and experimental medicine strategies for new disease‐modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142–154 [ABSTRACT FROM AUTHOR]

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 (β = 0.46, SE [standard error] = 0.17, F(1, 35) = 7.46, P = 0.01), driven by a strong correlation in PSP (β = −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 [ABSTRACT FROM AUTHOR]

Synaptic loss is an early and clinically relevant feature of many neurodegenerative diseases. Here we assess three adults at risk of frontotemporal dementia from C9orf72 mutation, using [11C]UCB‐J PET to quantify synaptic density in comparison with 19 healthy controls and one symptomatic patient with behavioural variant frontotemporal dementia. The three pre‐symptomatic C9orf72 carriers showed reduced synaptic density in the thalamus compared to controls, and there was an additional extensive synaptic loss in frontotemporal regions of the symptomatic patient. [11C]UCB‐J PET may facilitate early, pre‐symptomatic assessment, monitoring of disease progression and evaluation of new preventive treatment strategies for frontotemporal dementia. [ABSTRACT FROM AUTHOR]

Accurate identification of brain function is necessary to understand neurocognitive aging, and thereby promote health and well‐being. Many studies of neurocognitive aging have investigated brain function with the blood‐oxygen level‐dependent (BOLD) signal measured by functional magnetic resonance imaging. However, the BOLD signal is a composite of neural and vascular signals, which are differentially affected by aging. It is, therefore, essential to distinguish the age effects on vascular versus neural function. The BOLD signal variability at rest (known as resting state fluctuation amplitude, RSFA), is a safe, scalable, and robust means to calibrate vascular responsivity, as an alternative to breath‐holding and hypercapnia. However, the use of RSFA for normalization of BOLD imaging assumes that age differences in RSFA reflecting only vascular factors, rather than age‐related differences in neural function (activity) or neuronal loss (atrophy). Previous studies indicate that two vascular factors, cardiovascular health (CVH) and cerebrovascular function, are insufficient when used alone to fully explain age‐related differences in RSFA. It remains possible that their joint consideration is required to fully capture age differences in RSFA. We tested the hypothesis that RSFA no longer varies with age after adjusting for a combination of cardiovascular and cerebrovascular measures. We also tested the hypothesis that RSFA variation with age is not associated with atrophy. We used data from the population‐based, lifespan Cam‐CAN cohort. After controlling for cardiovascular and cerebrovascular estimates alone, the residual variance in RSFA across individuals was significantly associated with age. However, when controlling for both cardiovascular and cerebrovascular estimates, the variance in RSFA was no longer associated with age. Grey matter volumes did not explain age differences in RSFA, after controlling for CVH. The results were consistent between voxel‐level analysis and independent component analysis. Our findings indicate that cardiovascular and cerebrovascular signals are together sufficient predictors of age differences in RSFA. We suggest that RSFA can be used to separate vascular from neuronal factors, to characterize neurocognitive aging. We discuss the implications and make recommendations for the use of RSFA in the research of aging. Impact Statement: The use of resting state fluctuation amplitudes (RSFA) for normalization of BOLD imaging assumes that age differences in RSFA reflect only vascular factors, rather than age‐related differences in neural function or neuronal loss. In this multimodal and multivariate study of 250 population‐based adults (18–88 years of age), we found that cardiovascular and cerebrovascular signals together sufficiently captured the age differences in RSFA. Our findings establish RSFA as an important marker that can be used to separate vascular signals from neuronal signals in BOLD‐fMRI, allowing the development of better models of ageing and age‐related disorders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD). Methods: We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data‐driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. Results: There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure‐function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non‐carriers, and increased with proximity to the expected onset of disease. Discussion: Our findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance. [ABSTRACT FROM AUTHOR]

Objective: We examined the relationship between tau pathology and neuroinflammation using [11C]PK11195 and [18F]AV‐1451 PET in 17 patients with progressive supranuclear palsy (PSP) Richardson's syndrome. We tested the hypothesis that neuroinflammation and tau protein aggregation colocalize macroscopically, and correlate with clinical severity. Methods: Nondisplaceable binding potential (BPND) for each ligand was quantified in 83 regions of interest (ROIs). The [11C]PK11195 and [18F]AV‐1451 BPND values were correlated across all regions. The spatial distributions of [11C]PK11195 and [18F]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 [11C]PK11195 and [18F]AV‐1451 binding were positively correlated (R = 0.577, p < 0.0001). The PCA identified 4 components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions. Positive associations between [11C]PK11195 and [18F]AV‐1451 components' loadings were found in both subcortical (R = 0.769, p < 0.0001) and cortical regions (R = 0.836, p < 0.0001). There were positive correlations between clinical severity and both subcortical tau pathology (R = 0.667, p = 0.003) and neuroinflammation (R = 0.788, p < 0.001). Interpretation: We show that tau pathology and neuroinflammation colocalize in PSP, and that individual differences in subcortical tau pathology and neuroinflammation are linked to clinical severity. Although longitudinal studies are needed to determine causal associations between these molecular pathologies, we suggest that the combination of tau‐ and immune‐oriented strategies may be useful for effective disease‐modifying treatments in PSP. ANN NEUROL 2020;88:1194–1204 [ABSTRACT FROM AUTHOR]

Background: Apathy is a common neuropsychiatric feature of both Parkinson’s disease and progressive supranuclear palsy (PSP) (Aarsland, et al., 2001). Early neuropathology in the locus coeruleus (LC) and consequent noradrenergic deficiency are proposed to be key contributors to the pathogenesis of apathy (Passamonti et al., 2018). Here we test the hypothesis that in vivo LC integrity measured by ultra‐high field 7T‐MRI is predictive of apathy in Parkinson’s disease and PSP. Method: Sixty‐three participants aged 50‐80 years were recruited: 25 people with idiopathic Parkinson’s disease, 14 patients with PSP Richardson’s syndrome and 24 age‐ and sex‐matched healthy controls (HC). Patients underwent clinical assessments for apathy, impulsivity, global cognition, motor severity, mood and sleep (Figure 2A&B). The LC was measured in vivo using a sensitive magnetisation transfer (MT) weighted sequence with ultra‐high 7T‐MRI (0.1mm3 voxels). The contrast‐to‐noise ratio of an atlas‐based signal was used to estimate the LC structural integrity (Ye et al., 2021). The LC integrity was correlated with clinical assessments. To estimate the spatial extent of the correlation within LC, voxelwise analyses used FSL randomise for localising the group differences and the clinical correlations. Result: Reduced LC integrity was observed along the rostrocaudal axis for both PD and PSP patients, most prominently in the caudal subregion (Figure 1A‐D). This was confirmed by significant voxelwise comparisons between the patient groups and controls (HC>PD, right caudal LC, 37 voxels; HC>PSP, bilateral caudal LC, 206 voxels; FWE‐corrected p<0.05), Figures 1E&F. Patients with PSP and PD showed similar levels of LC degeneration relative to controls, but this was more spatially widespread in PSP. The variability of LC integrity in both disease groups was associated with ACER, MoCA and apathy (Figure 2C&D). Distinctive spatial patterns were identified for the correlations, with the caudal LC consistently associated with cognitive impairment and apathy. Conclusion: Reduced LC integrity was confirmed in both PD and PSP using in vivo 7T‐MRI. LC degeneration, particularly in the caudal subregion, was associated with apathy and cognitive impairment. Our results suggest, noradrenergic therapies may be beneficial in targeting cognitive and behavioural features of Parkinson’s disease and PSP. [ABSTRACT FROM AUTHOR]

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 [11C]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 [11C]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. [11C]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 [11C]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. [11C]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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Post‐mortem clinical studies and animal models described severe synaptic loss as an early feature of neurodegenerative disease, including frontotemporal dementia. Recently, PET radiotracers that bind to synaptic vesicle glycoprotein 2A have been developed and proven to enable in vivo quantification of synaptic loss in people with neurodegenerative diseases. This study used [11C]UCB‐J PET to quantify synaptic loss in people with behavioural variant frontotemporal dementia (bvFTD). Method: We recruited 10 people with a clinical diagnosis of bvFTD and 24 age‐ and sex‐matched healthy controls. Participants underwent dynamic [11C]UCB‐J PET‐MR, and a neuropsychological assessment, including the Addenbrooke's cognitive examination (ACE‐R) as a global measure of cognitive performance, and the INECO frontal screening. Synaptic density was estimated using [11C]UCB‐J non‐displaceable binding potential (BPND) at voxel level and in whole‐brain regions of interest. General linear models were used to compare [11C]UCB‐J binding voxel‐wise between groups, and correlate synaptic density with cognitive performance in bvFTD cohort. These analyses were also performed using regional [11C]UCB‐J binding potentials, with and without partial‐volume correction. Regional correlations were performed with both frequentist and Bayesian approaches. Result: People with bvFTD showed severe synaptic loss compared to controls at individual level and as a group. [11C]UCB‐J binding was significantly reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insula cortex and medial temporal lobe (5.1 ≤ t ≤ 9.3, p < 0.05 FWE at voxel level, Figure 1A). Results from ROI‐based analyses mirrored the voxel‐wise results, with and without partial‐volume correction. Synaptic loss in the left frontal and cingulate regions significantly correlated with cognitive impairments as assessed with ACE‐R and INECO (r > 0.8, p<0.001 at voxel level, p<0.05 FWE at cluster level, Figure 1B). Correlations were confirmed by regional‐based analyses, with both frequentist and Bayesian approaches (Figure 1C). Conclusion: Different analytic approaches converged showing a significant and widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to disease severity. [11C]UCB‐J PET could therefore be a useful supporting tool for translational studies and experimental medicines strategies for new disease‐modifying treatments in this condition. [ABSTRACT FROM AUTHOR]

Background: Recent studies have suggested that melatonin-a hormone produced by the pineal gland under circadian control-contributes to PD-related sleep dysfunction. We hypothesized that degenerative changes to the neural structures controlling pineal function (especially the suprachiasmatic nuclei of the anterior hypothalamus) may be responsible for reduced melatonin output in these patients. We compared hypothalamic volumes in PD patients with matched controls and determined whether volume loss correlated with reduced melatonin output in the PD group.Methods: A total of 12 PD patients and 12 matched controls underwent magnetic resonance imaging to determine hypothalamic volume. In addition, PD patients underwent 24-hour blood sampling in a controlled environment to determine serum melatonin concentrations using enzyme-linked immunosorbent assays.Results: PD patients had significantly reduced hypothalamic gray matter volume when compared with matched controls. Melatonin levels were significantly associated with hypothalamic gray matter volume and disease severity in PD patients.Conclusion: Melatonin levels are associated with hypothalamic gray matter volume loss and disease severity in PD patients. This provides anatomical and physiological support for an intrinsic sleep and circadian phenotype in PD. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objectives Recovery of independent ambulation after stroke is a major goal. However, which rehabilitation regimen best benefits each individual is unknown and decisions are currently made on a subjective basis. Predictors of response to specific therapies would guide the type of therapy most appropriate for each patient. Although lesion topography is a strong predictor of upper limb response, walking involves more distributed functions. Earlier studies that assessed the cortico-spinal tract (CST) were negative, suggesting other structures may be important. Experimental Design: The relationship between lesion topography and response of walking speed to standard rehabilitation was assessed in 50 adult-onset patients using both volumetric measurement of CST lesion load and voxel-based lesion-symptom mapping (VLSM) to assess non-CST structures. Two functional mobility scales, the functional ambulation category (FAC) and the modified rivermead mobility index (MRMI) were also administered. Performance measures were obtained both at entry into the study (3-42 days post-stroke) and at the end of a 6-week course of therapy. Baseline score, age, time since stroke onset and white matter hyperintensities score were included as nuisance covariates in regression models. Principal Observations: CST damage independently predicted response to therapy for FAC and MRMI, but not for walk speed. However, using VLSM the latter was predicted by damage to the putamen, insula, external capsule and neighbouring white matter. Conclusions Walk speed response to rehabilitation was affected by damage involving the putamen and neighbouring structures but not the CST, while the latter had modest but significant impact on everyday functions of general mobility and gait. Hum Brain Mapp 37:689-703, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia is clinically and neuropathologically heterogeneous, but atrophy, neuroinflammation, and executive dysfunction occur in each of the principal variants. Across the clinical spectrum of frontotemporal dementia, we assessed the predictive value of in vivo neuroimaging measures of grey‐matter volume (from structural MRI) and microglial activation (from [11C]PK11195 PET) on the rate of future executive decline. We hypothesised a detrimental effect of inflammation and atrophy severity on executive dysfunction progression. Method: Thirty patients with frontotemporal dementia underwent a baseline multi‐modal imaging assessment, including [11C]PK11195 PET to index microglial activation and structural MRI for atrophy, as part of the Neuroimaging of Inflammation in Memory and Related Other Disorders (NIMROD) study. Cognitive impairments were assessed at baseline and serially for up to 5 years with the revised Addenbrooke's Cognitive Examination (ACE‐R). Regional grey‐matter volumes and [11C]PK11195 binding potentials were averaged in four regions of interest: left and right frontal and temporal lobes. Linear mixed models were applied to the longitudinal ACE‐R attention/executive sub‐score. Regional CSF‐corrected PET values and TIV‐corrected grey‐matter volumes were included in linear mixed models as predictors, with age and education as covariates. Specifically, negative associations of atrophy and inflammation with annual rate of executive decline were tested. Result: Patients showed a mean 3.3‐point loss per year on the ACE‐R attention/executive sub‐score (p<0.001, Figure 1). Faster decline in ACE‐R was associated with reduced baseline grey‐matter volume of the left frontal lobe (beta=1.000, SE=0.285, p=0.000789, p‐FDR= 0.00316; Figure 2) and increased inflammation in frontal regions bilaterally (Left: beta=‐0.722, SE=0.251, p=0.00528, p‐FDR=0.0105, Figure 2; Right: Estimate=‐0.623, SE=0.256, p=0.0175, p‐FDR=0.0233). These associations remain significant when including both left frontal grey‐matter volume and [11C]PK11195 binding as predictors in the same model, and after controlling for baseline attention/executive scores. In these regions, grey‐matter volumes and inflammation levels were negatively correlated (left: r=‐0.414, p<0.001; right: r=‐0.374, p<0.001). Conclusion: Imaging markers for atrophy and microglial activation provide useful and independent information to evaluate and stratify patients with frontotemporal dementia. This may improve cohort selection in clinical trials and highlights the potential for immunomodulatory treatment strategies in frontotemporal dementia. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is implicated in the pathogenesis of neurodegenerative disorders including dementia with Lewy bodies (DLB), but its relationship with disease progression, including cognitive decline, is less well understood. We investigated the predictive value of microglial activation, assessed in vivo using positron emission tomography (PET) imaging with [11C]PK11195, on the rate of annual cognitive decline in patients with DLB. We hypothesised a detrimental effect of inflammation on cognition over time. Method: Nineteen patients with DLB underwent baseline assessment, including [11C]PK11195 PET and cognitive tests from the Neuroimaging of Inflammation in Memory and Related Other Disorders (NIMROD) study. Cognitive performance was then assessed at an average of 1.1‐year intervals (standard deviation (SD) ± 0.03 years) up to 3.4 years (average ± SD = 3.20 ± 0.16) using the revised Addenbrooke's Cognitive Examination (ACE‐R) and Cambridge Neuropsychological Test Automated Battery (CANTAB). Regional [11C]PK11195 binding potential values were included in a principal component analysis (PCA). Linear mixed effects models were applied to the longitudinal ACE‐R scores. Individual component scores were included in analysis of interaction with time to test for associations between [11C]PK11195 uptake at baseline and longitudinal cognitive performance scores. Age and sex were included as covariates in the models. Result: Patients showed a mean 8.8‐point loss per year on the ACE‐R total score (p<0.001) (Figure 1, left panel). The PCA identified five components, explaining >80% of variance. Annual rate of change in the ACE‐R total score (estimate=‐2.90, p=0.0226) (Figure 1, right panel), memory (estimate=‐1.14, p=0.004) and attention/executive function (estimate=‐0.80, p=0.022) sub‐scores was negatively associated with increased microglial activation in component #4, which was mainly loaded onto the hippocampus, amygdala and pallidum but also parahippocampal cortex and the pre‐subgenual frontal area. Conclusion: Higher levels of neuroinflammation in medial temporal regions and pallidum predict faster cognitive decline in patients with DLB, particularly in the domains of memory and attention/executive function. Our results encourage the application of [11C]PK11195 PET in DLB to inform prognosis, and to improve patient stratification for clinical trials. [ABSTRACT FROM AUTHOR]

Background: Progressive Supranuclear Palsy (PSP) is associated with tau pathology and neurodegeneration, particularly in basal ganglia, diencephalon, and brainstem. Recently, neuroinflammation has been recognized as another key aspect in the pathophysiology of PSP. Understanding whether these three pathological features predict the clinical progression is crucial to develop new prognostic measures. Here, we studied how baseline assessments of in vivo tau pathology (measured by [18F]AV‐1451 PET), neuroinflammation ([11C]PK11195 PET), and atrophy (structural MRI) predicted longitudinal clinical changes in n=17 patients with PSP‐Richardson's syndrome. Method: All patients underwent a baseline multi‐modal assessment with [18F]AV‐1451 PET, [11C]PK11195 PET, and structural MRI. They were clinically assessed up to 4 years, with the PSP rating scale. Regional PET binding potentials and grey‐matter volumes across all brain regions were summarised by method‐specific Principal Component Analyses (PCAs). A linear mixed model was applied to the longitudinal PSP rating scale scores to estimate the rate of annual decline in each participant. We regressed the individuals' estimated rate of clinical progression on neuroimaging components, to identify the prognostic value of PET and MRI markers in different clusters of regions, with age and time between scan and the first clinical assessment as covariates. Result: PCAs identified four components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions, and seven components of grey‐matter volumes. Patients showed an average increase of 6.15 points (p<0.0001) per year on the PSP rating scale. PCA‐derived components reflecting tau burden (r=0.639, p=0.010) and neuroinflammation (r=0.596, p=0.019) in PSP‐related subcortical areas were linked to the annual rate of change of disease severity. These pathology markers components were associated with atrophy of the same regions (tau: r=‐0.626, p=0.007; neuroinflammation: r=‐0.584, p=0.014) but atrophy did not correlate with clinical progression (r=‐0.474, p=0.074). Conclusion: In vivo PET markers of both tau pathology and neuroinflammation in subcortical regions predicted clinical progression in PSP patients. Our results encourage the application of [18F]AV‐1451 and [11C]PK11195 PET in PSP as stratification measures that inform prognosis, to develop new targeting disease‐modifying therapies and empower clinical trials. [ABSTRACT FROM AUTHOR]

Background: In frontotemporal dementia (FTD), apathy is reported to negatively impact the prognosis and survival of patients. The study of genetic FTD in its pre‐symptomatic period permits the investigation of markers in the early stages of disease progression. Therefore, in pre‐symptomatic gene carriers in the multicentre Genetic FTD Initiative (GENFI), we examined longitudinal apathy changes in association with cognitive decline over time, and baseline measures of atrophy. Method: Six hundred participants from Data Freeze 4 (2019) were included: 304 pre‐symptomatic mutation carriers, and 296 family members without mutations. Clinical assessment and a structural MRI scan were undertaken at baseline, and annually for at least 2‐years. Latent Growth Curve modelling (LGCM) was used to assess: 1) longitudinal changes in apathy, as measured by the apathy subscale of the Revised Cambridge Behavioural Inventory; 2) the relationship with longitudinal changes in executive function; 3) the association with baseline regional grey matter volumes. The time to the expected year of symptom onset was included as a covariate. Result: Univariate LGCM identified a significant linear increase in apathy scores for pre‐symptomatic carriers (estimate= 0.51, se=0.18, z scores= 2.88, p=0.004), but not in non‐carriers (estimate= 0.08, se=0.08, z scores=1.04, p=0.30). An equality constrained comparison suggested a significant group difference in the progression of apathy (i.e. the slope) ((∆ χ2=10.14; p=0.0015). Pre‐symptomatic carriers also had a significant decline in executive functions (est=‐0.07, se=0.03, z scores=‐2.49, p=0.017), which was predicted by baseline apathy (standard estimate=‐0.40, p=0.008). In pre‐symptomatic carriers only, the annual rate of change in apathy was significantly associated with brain volume in frontal lobe (standard estimate=‐0.47, p=0.008) and cingulate cortex (standard estimate=‐0.29, p=0.05) at the baseline. Conclusion: Apathy progresses significantly in pre‐symptomatic FTD and predicts a sub‐clinical deterioration of executive performance in gene carriers. Apathy changes over 2 years are associated with volume in the frontal lobe and cingulate gyrus measured at the baseline. We suggest that apathy may be a modifiable factor to protect function and cognition in those with, or at risk of, frontotemporal dementia. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is part of the pathophysiology of Alzheimer's disease (AD), in addition to amyloid‐β plaques and tau neurofibrillary tangles. PET markers of microglial activation have indicated inflammation of temporo‐parietal regions, in proportion to disease severity. Here we test the prognostic value of [11C]PK11195 PET on longitudinal clinical decline in AD, alone and in combination with MRI and tau ([18F]AV‐1451) PET imaging. Method: Twenty‐six patients with Alzheimer's dementia or amyloid‐positive Mild Cognitive Impairment, and 29 controls underwent multi‐modal assessment with [11C]PK11195 PET, [18F]AV‐1451 PET, structural MRI, and annual cognitively assessment with the Revised Addenbrooke's Cognitive Examination. Regional PET binding potentials and grey‐matter volumes from fifteen bilateral temporo‐parietal region were summarised by method‐specific Principal Component Analyses (PCAs). The rate of longitudinal cognitive decline was estimated using a Latent Growth Curve Model. The predictive value of PET and MRI on cognitive decline was tested with modality‐specific regression models, and a multi‐modality regression model. Result: PCA on each PET ligand consistently identified one component in anterior temporal regions, and another in posterior temporo‐parietal regions, while for MRI, a single component was identified across all regions. Worse annual rate of cognitive decline correlated with higher [11C]PK11195 in the anterior temporal component (r = −0.47, p = 0.002), and in posterior temporo‐parietal regions (r = −0.39, p = 0.012). An optimal multi‐modality model was identified by stepwise regression and Bayesian selection, that included the anterior [11C]PK11195 component and both [18F]AV‐1451 components as predictors of cognitive decline (R2 = 0.418; p = 0.001), but not their interaction and not the baseline MRI. Conclusion: These results suggest that in addition to tau pathology, microglial activation in the anterior temporal lobe plays a key role in predicting future cognitive decline in patients with AD. The results support therapeutic strategies targeting tau and microglial activation as disease‐modifying therapy against AD. [ABSTRACT FROM AUTHOR]

Background: Progressive supranuclear palsy (PSP) and behavioural variant frontotemporal dementia (bvFTD) are clinical syndromes associated with frontotemporal lobar degeneration (FTLD). Although distinct diseases, they have in common cognitive and behavioural changes, including personality, motivation and executive function. This phenotypic overlap between bvFTD and PSP is reflected in the MDS‐2017 criteria for the PSP‐F subtype (Höglinger et al., 2017), and frequent parkinsonism seen in bvFTD (Rowe, 2019). This study uses ultra‐high field MRI to identify the atrophy patterns in bvFTD and PSP, complementing neurochemical insights from spectroscopy (Murley, 2020). Method: 23 Healthy controls, 23 people with probable PSP, and 16 people with bvFTD underwent structural imaging with MP2RAGE sequence (0.7mm isotropic resolution) at ultra‐high field (7T) on a MAGNETOM Siemens TERRA scanner. Clinical and cognitive assessment was undertaken contemporary with imaging. Grey and white matter volumes were compared between groups using independent two‐sample t‐tests, including age and total intracranial volume as covariates of no interest. Significant effects were identified using cluster‐level statistics (p<0.05, family‐wise error corrected for multiple comparisons) above a height threshold of p<0.001 (uncorrected). Result: Compared to controls, both patients with PSP and bvFTD show significant atrophy of the cingulate gyrus, frontal gyri, and the supplementary motor cortex with the parietal and especially occipital lobe being spared (p <0.05, FWE). Patients with PSP show additional white matter atrophy of the brainstem and basal ganglia (p <0.05, FWE). Compared to PSP, patients with bvFTD show more grey matter atrophy in the inferior frontal gyrus, inferior temporal gyrus, temporal pole, as well as the right insula. Patients with PSP show more white matter atrophy of the basal ganglia, brain stem, and superior cerebellum compared to those with bvFTD (p<0.001, uncorrected). Conclusion: This is the first voxel‐based morphometry study comparing bvFTD and PSP at ultra‐high field, with higher resolution imaging than previous studies at 1.5T or 3.T. Although both classified as syndromes associated with FTLD, patients with bvFTD and PSP show both specific and complementary patterns of atrophy compared to those of healthy controls and each other. [ABSTRACT FROM AUTHOR]

Loss of control over hedonically motivated actions is a defining component of impulse control disorders, such as drug dependence and the proposed 'food addiction' model of obesity. Devolution from goal-directed to compulsively maintained behaviors is partially attributed to abnormalities in the orbitofrontal cortex, an area critical in reward valuation. In the current study, overlapping reductions in orbitofrontal gray matter volume relating to body mass index were seen in healthy control and cocaine-dependent individuals, as well as in relation to duration of cocaine abuse, providing support for a shared neuropathology between the two conditions potentially related to dysfunctional reward-seeking behavior. [ABSTRACT FROM AUTHOR]

Background: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) change speech and language as well as motor function. Here, we used the new Mini Linguistic State Examination (MLSE), a brief, yet comprehensive language assessment tool, to investigate structural correlates of language impairment in PSP and CBS, alongside patients with the nonfluent variant of primary progressive aphasia (nfvPPA). Method: Twenty‐eight patients (PSP N=8, CBS N=10 and nfvPPA N=10) and 24 aged‐matched controls completed the MLSE, the Addenbrooke's Cognitive Examination III, and 3T PRISMA structural MRI. T1‐weighted images were processed using Freesurfer 6.0. The groups were compared using an ANCOVA of cortical thickness including age, gender and MLSE total score as covariates. Result: PSP and CBS patients' MLSE total scores were significantly (p<0.001) impaired compared to controls but better (p<0.05) than nfvPPA. For the MLSE subscores, compared to controls, PSP impaired motor speech (p=0.003), while CBS impaired phonology, semantics, and syntax (p<0.05). There was a positive correlation between cortical thickness with MLSE total score in the left inferior frontal gyrus pars triangularis, middle temporal gyrus, and supramarginal gyrus (p<0.001 unc). Conclusion: The MLSE screening tool identifies speech and language deficits in PSP and CBS. Impairments were associated with atrophy in key regions of left hemisphere frontotemporal language networks. Future work will identify multisite scalability of the MLSE and its imaging correlates. [ABSTRACT FROM AUTHOR]