Drawing from name in semantic dementia reveals graded object knowledge representations in anterior temporal lobe.

Semantic dementia (SD) is characterized by progressive impairment in conceptual knowledge due to anterior temporal lobe (ATL) neurodegeneration. Extended neuropsychological assessments can quantitatively demonstrate the semantic impairment, but this graded loss of knowledge can also be readily observed in the qualitative observation of patients' recall of single concepts. Here, we present the results of a simple task of object drawing-from-name, by patients with SD (N = 19), who have isolated atrophy of the ATL bilaterally. Both cross-sectionally and longitudinally, patient drawings demonstrated a pattern of degradation in which rare and distinctive features (such as the hump on a camel) were lost earliest in disease course, and there was an increase in the intrusion of prototypical features (such as the typical small ears of most mammals on an elephant) with more advanced disease. Crucially, patient drawings showed a continuum of conceptual knowledge loss rather than a binary 'present' or 'absent' state. Overall, we demonstrate that qualitative evaluation of line drawings of animals and objects provides fascinating insights into the transmodal semantic deficit in SD. Our results are consistent with a distributed-plus-hub model of semantic memory. The graded nature of the deficit in semantic performance observed in our subset of longitudinally observed patients suggests that the temporal lobe binds feature-based semantic attributes in its central convergence zone.

Parkinson's disease impairs cortical sensori-motor decision-making cascades.

The transformation from perception to action requires a set of neuronal decisions about the nature of the percept, identification and selection of response options and execution of the appropriate motor response. The unfolding of such decisions is mediated by distributed representations of the decision variables-evidence and intentions-that are represented through oscillatory activity across the cortex. Here we combine magneto-electroencephalography and linear ballistic accumulator models of decision-making to reveal the impact of Parkinson's disease during the selection and execution of action. We used a visuomotor task in which we independently manipulated uncertainty in sensory and action domains. A generative accumulator model was optimized to single-trial neurophysiological correlates of human behaviour, mapping the cortical oscillatory signatures of decision-making, and relating these to separate processes accumulating sensory evidence and selecting a motor action. We confirmed the role of widespread beta oscillatory activity in shaping the feed-forward cascade of evidence accumulation from resolution of sensory inputs to selection of appropriate responses. By contrasting the spatiotemporal dynamics of evidence accumulation in age-matched healthy controls and people with Parkinson's disease, we identified disruption of the beta-mediated cascade of evidence accumulation as the hallmark of atypical decision-making in Parkinson's disease. In frontal cortical regions, there was inefficient processing and transfer of perceptual information. Our findings emphasize the intimate connection between abnormal visuomotor function and pathological oscillatory activity in neurodegenerative disease. We propose that disruption of the oscillatory mechanisms governing fast and precise information exchanges between the sensory and motor systems contributes to behavioural changes in people with Parkinson's disease.

Immediate neural impact and incomplete compensation after semantic hub disconnection.

The human brain extracts meaning using an extensive neural system for semantic knowledge. Whether broadly distributed systems depend on or can compensate after losing a highly interconnected hub is controversial. We report intracranial recordings from two patients during a speech prediction task, obtained minutes before and after neurosurgical treatment requiring disconnection of the left anterior temporal lobe (ATL), a candidate semantic knowledge hub. Informed by modern diaschisis and predictive coding frameworks, we tested hypotheses ranging from solely neural network disruption to complete compensation by the indirectly affected language-related and speech-processing sites. Immediately after ATL disconnection, we observed neurophysiological alterations in the recorded frontal and auditory sites, providing direct evidence for the importance of the ATL as a semantic hub. We also obtained evidence for rapid, albeit incomplete, attempts at neural network compensation, with neural impact largely in the forms stipulated by the predictive coding framework, in specificity, and the modern diaschisis framework, more generally. The overall results validate these frameworks and reveal an immediate impact and capability of the human brain to adjust after losing a brain hub.

Temporal lobe perceptual predictions for speech are instantiated in motor cortex and reconciled by inferior frontal cortex.

Humans use predictions to improve speech perception, especially in noisy environments. Here we use 7-T functional MRI (fMRI) to decode brain representations of written phonological predictions and degraded speech signals in healthy humans and people with selective frontal neurodegeneration (non-fluent variant primary progressive aphasia [nfvPPA]). Multivariate analyses of item-specific patterns of neural activation indicate dissimilar representations of verified and violated predictions in left inferior frontal gyrus, suggestive of processing by distinct neural populations. In contrast, precentral gyrus represents a combination of phonological information and weighted prediction error. In the presence of intact temporal cortex, frontal neurodegeneration results in inflexible predictions. This manifests neurally as a failure to suppress incorrect predictions in anterior superior temporal gyrus and reduced stability of phonological representations in precentral gyrus. We propose a tripartite speech perception network in which inferior frontal gyrus supports prediction reconciliation in echoic memory, and precentral gyrus invokes a motor model to instantiate and refine perceptual predictions for speech.

Microglial activation in the frontal cortex predicts cognitive decline in frontotemporal dementia.

Frontotemporal dementia is clinically and neuropathologically heterogeneous, but neuroinflammation, atrophy and cognitive impairment occur in all of its principal syndromes. Across the clinical spectrum of frontotemporal dementia, we assess the predictive value of in vivo neuroimaging measures of microglial activation and grey-matter volume on the rate of future cognitive decline. We hypothesized that inflammation is detrimental to cognitive performance, in addition to the effect of atrophy. Thirty patients with a clinical diagnosis of frontotemporal dementia underwent a baseline multimodal imaging assessment, including [11C]PK11195 PET to index microglial activation and structural MRI to quantify grey-matter volume. Ten people had behavioural variant frontotemporal dementia, 10 had the semantic variant of primary progressive aphasia and 10 had the non-fluent agrammatic variant of primary progressive aphasia. Cognition was assessed at baseline and longitudinally with the revised Addenbrooke's Cognitive Examination, at an average of 7-month intervals (for an average of ∼2 years, up to ∼5 years). Regional [11C]PK11195 binding potential and grey-matter volume were determined, and these were averaged within four hypothesis-driven regions of interest: bilateral frontal and temporal lobes. Linear mixed-effect models were applied to the longitudinal cognitive test scores, with [11C]PK11195 binding potentials and grey-matter volumes as predictors of cognitive performance, with age, education and baseline cognitive performance as covariates. Faster cognitive decline was associated with reduced baseline grey-matter volume and increased microglial activation in frontal regions, bilaterally. In frontal regions, microglial activation and grey-matter volume were negatively correlated, but provided independent information, with inflammation the stronger predictor of the rate of cognitive decline. When clinical diagnosis was included as a factor in the models, a significant predictive effect was found for [11C]PK11195 BPND in the left frontal lobe (-0.70, P = 0.01), but not for grey-matter volumes (P > 0.05), suggesting that inflammation severity in this region relates to cognitive decline regardless of clinical variant. The main results were validated by two-step prediction frequentist and Bayesian estimation of correlations, showing significant associations between the estimated rate of cognitive change (slope) and baseline microglial activation in the frontal lobe. These findings support preclinical models in which neuroinflammation (by microglial activation) accelerates the neurodegenerative disease trajectory. We highlight the potential for immunomodulatory treatment strategies in frontotemporal dementia, in which measures of microglial activation may also improve stratification for clinical trials.

Neurophysiological consequences of synapse loss in progressive supranuclear palsy.

Synaptic loss occurs early in many neurodegenerative diseases and contributes to cognitive impairment even in the absence of gross atrophy. Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. We advocate that biophysical models of neurophysiology offer both a bridge from preclinical to clinical models of pathology and quantitative assays for experimental medicine. Such biophysical models can also disclose hidden neuronal dynamics generating neurophysiological observations such as EEG and magnetoencephalography. Here, we augment a biophysically informed mesoscale model of human cortical function by inclusion of synaptic density estimates as captured by 11C-UCB-J PET, and provide insights into how regional synapse loss affects neurophysiology. We use the primary tauopathy of progressive supranuclear palsy (Richardson's syndrome) as an exemplar condition, with high clinicopathological correlations. Progressive supranuclear palsy causes a marked change in cortical neurophysiology in the presence of mild cortical atrophy and is associated with a decline in cognitive functions associated with the frontal lobe. Using parametric empirical Bayesian inversion of a conductance-based canonical microcircuit model of magnetoencephalography data, we show that the inclusion of regional synaptic density-as a subject-specific prior on laminar-specific neuronal populations-markedly increases model evidence. Specifically, model comparison suggests that a reduction in synaptic density in inferior frontal cortex affects superficial and granular layer glutamatergic excitation. This predicted individual differences in behaviour, demonstrating the link between synaptic loss, neurophysiology and cognitive deficits. The method we demonstrate is not restricted to progressive supranuclear palsy or the effects of synaptic loss: such pathology-enriched dynamic causal models can be used to assess the mechanisms of other neurological disorders, with diverse non-invasive measures of pathology, and is suitable to test the effects of experimental pharmacology.

Synaptic Loss in Frontotemporal Dementia Revealed by [11 C]UCB-J Positron Emission Tomography.

OBJECTIVE: Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [11 C]UCB-J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity. METHODS: Eleven participants with clinically probable bvFTD and 25 age- and sex-matched healthy controls were included. Participants underwent dynamic [11 C]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 [11 C]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 [11 C]UCB-J binding potential from regions of interest (ROIs). RESULTS: Patients with bvFTD showed severe synaptic loss compared to controls. [11 C]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. [11 C]UCB-J PET could support translational studies and experimental medicine strategies for new disease-modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142-154.

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

There is a pressing need to accelerate therapeutic strategies against the syndromes caused by frontotemporal lobar degeneration, including symptomatic treatments. One approach is for experimental medicine, coupling neurophysiological studies of the mechanisms of disease with pharmacological interventions aimed at restoring neurochemical deficits. Here we consider the role of glutamatergic deficits and their potential as targets for treatment. We performed a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study in 20 people with symptomatic frontotemporal lobar degeneration (10 behavioural variant frontotemporal dementia, 10 progressive supranuclear palsy) and 19 healthy age- and gender-matched controls. Both magnetoencephalography sessions recorded a roving auditory oddball paradigm: on placebo or following 10 mg memantine, an uncompetitive NMDA-receptor antagonist. Ultra-high-field magnetic resonance spectroscopy confirmed lower concentrations of GABA in the right inferior frontal gyrus of people with frontotemporal lobar degeneration. While memantine showed a subtle effect on early-auditory processing in patients, there was no significant main effect of memantine on the magnitude of the mismatch negativity (MMN) response in the right frontotemporal cortex in patients or controls. However, the change in the right auditory cortex MMN response to memantine (vs. placebo) in patients correlated with individuals' prefrontal GABA concentration. There was no moderating effect of glutamate concentration or cortical atrophy. This proof-of-concept study demonstrates the potential for baseline dependency in the pharmacological restoration of neurotransmitter deficits to influence cognitive neurophysiology in neurodegenerative disease. With changes to multiple neurotransmitters in frontotemporal lobar degeneration, we suggest that individuals' balance of excitation and inhibition may determine drug efficacy, with implications for drug selection and patient stratification in future clinical trials.

Causal Evidence for the Multiple Demand Network in Change Detection: Auditory Mismatch Magnetoencephalography across Focal Neurodegenerative Diseases.

The multiple demand (MD) system is a network of fronto-parietal brain regions active during the organization and control of diverse cognitive operations. It has been argued that this activation may be a nonspecific signal of task difficulty. However, here we provide convergent evidence for a causal role for the MD network in the "simple task" of automatic auditory change detection, through the impairment of top-down control mechanisms. We employ independent structure-function mapping, dynamic causal modeling (DCM), and frequency-resolved functional connectivity analyses of MRI and magnetoencephalography (MEG) from 75 mixed-sex human patients across four neurodegenerative syndromes [behavioral variant fronto-temporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), posterior cortical atrophy (PCA), and Alzheimer's disease mild cognitive impairment with positive amyloid imaging (ADMCI)] and 48 age-matched controls. We show that atrophy of any MD node is sufficient to impair auditory neurophysiological response to change in frequency, location, intensity, continuity, or duration. There was no similar association with atrophy of the cingulo-opercular, salience or language networks, or with global atrophy. MD regions displayed increased functional but decreased effective connectivity as a function of neurodegeneration, suggesting partially effective compensation. Overall, we show that damage to any of the nodes of the MD network is sufficient to impair top-down control of sensation, providing a common mechanism for impaired change detection across dementia syndromes.SIGNIFICANCE STATEMENT Previous evidence for fronto-parietal networks controlling perception is largely associative and may be confounded by task difficulty. Here, we use a preattentive measure of automatic auditory change detection [mismatch negativity (MMN) magnetoencephalography (MEG)] to show that neurodegeneration in any frontal or parietal multiple demand (MD) node impairs primary auditory cortex (A1) neurophysiological response to change through top-down mechanisms. This explains why the impaired ability to respond to change is a core feature across dementias, and other conditions driven by brain network dysfunction, such as schizophrenia. It validates theoretical frameworks in which neurodegenerating networks upregulate connectivity as partially effective compensation. The significance extends beyond network science and dementia, in its construct validation of dynamic causal modeling (DCM), and human confirmation of frequency-resolved analyses of animal neurodegeneration models.

Synaptic density in carriers of C9orf72 mutations: a [11 C]UCB-J PET study.

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 [11 C]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. [11 C]UCB-J PET may facilitate early, pre-symptomatic assessment, monitoring of disease progression and evaluation of new preventive treatment strategies for frontotemporal dementia.

GABAergic cortical network physiology in frontotemporal lobar degeneration.

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients' GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials.

Cortical Complexity Analyses and Their Cognitive Correlate in Alzheimer's Disease and Frontotemporal Dementia.

BACKGROUND: The changes of cortical structure in Alzheimer's disease (AD) and frontotemporal dementia (FTD) are usually described in terms of atrophy. However, neurodegenerative diseases may also affect the complexity of cortical shape, such as the fractal dimension of the brain surface. OBJECTIVE: In this study, we aimed at assessing the regional patterns of cortical thickness and fractal dimension changes in a cross-sectional cohort of patients with AD and FTD. METHODS: Thirty-two people with symptomatic AD-pathology (clinically probable AD, n = 18, and amyloid-positive mild cognitive impairment, n = 14), 24 with FTD and 28 healthy controls underwent high-resolution 3T structural brain MRI. Using surface-based morphometry, we created vertex-wise cortical thickness and fractal dimension maps for group comparisons and correlations with cognitive measures in AD and FTD. RESULTS: In addition to the well-established pattern of cortical thinning encompassing temporoparietal regions in AD and frontotemporal areas in FTD, we observed reductions of fractal dimension encompassing cingulate areas and insula for both conditions, but specifically involving orbitofrontal cortex and paracentral gyrus for FTD (FDR p < 0.05). Correlational analyses between fractal dimension and cognition showed that these regions were particularly vulnerable with regards to memory and language impairment, especially in FTD. CONCLUSION: While the present study demonstrates globally similar patterns of fractal dimension changes in AD and FTD, we observed distinct cortical complexity correlates of cognitive domains impairment. Further studies are required to assess cortical complexity measures at earlier disease stages (e.g., in prodromal/asymptomatic carriers of FTD-related gene mutations) and determine whether fractal dimension represents a sensitive imaging marker for prevention and diagnostic strategies.

Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum.

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-ß 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.

Anterior temporal lobe is necessary for efficient lateralised processing of spoken word identity.

In the healthy human brain, the processing of language is strongly lateralised, usually to the left hemisphere, while the processing of complex non-linguistic sounds recruits brain regions bilaterally. Here we asked whether the anterior temporal lobes, strongly implicated in semantic processing, are critical to this special treatment of spoken words. Nine patients with semantic dementia (SD) and fourteen age-matched controls underwent magnetoencephalography and structural MRI. Voxel based morphometry demonstrated the stereotypical pattern of SD: severe grey matter loss restricted to the anterior temporal lobes, with the left side more affected. During magnetoencephalography, participants listened to word sets in which identity and meaning were ambiguous until word completion, for example PLAYED versus PLATE. Whereas left-hemispheric responses were similar across groups, patients demonstrated increased right hemisphere activity 174-294 msec after stimulus disambiguation. Source reconstructions confirmed recruitment of right-sided analogues of language regions in SD: atrophy of anterior temporal lobes was associated with increased activity in right temporal pole, middle temporal gyrus, inferior frontal gyrus and supramarginal gyrus. Overall, the results indicate that anterior temporal lobes are necessary for normal and efficient lateralised processing of word identity by the language network.

GABA-ergic Dynamics in Human Frontotemporal Networks Confirmed by Pharmaco-Magnetoencephalography.

To bridge the gap between preclinical cellular models of disease and in vivo imaging of human cognitive network dynamics, there is a pressing need for informative biophysical models. Here we assess dynamic causal models (DCM) of cortical network responses, as generative models of magnetoencephalographic observations during an auditory oddball roving paradigm in healthy adults. This paradigm induces robust perturbations that permeate frontotemporal networks, including an evoked 'mismatch negativity' response and transiently induced oscillations. Here, we probe GABAergic influences in the networks using double-blind placebo-controlled randomized-crossover administration of the GABA reuptake inhibitor, tiagabine (oral, 10 mg) in healthy older adults. We demonstrate the facility of conductance-based neural mass mean-field models, incorporating local synaptic connectivity, to investigate laminar-specific and GABAergic mechanisms of the auditory response. The neuronal model accurately recapitulated the observed magnetoencephalographic data. Using parametric empirical Bayes for optimal model inversion across both drug sessions, we identify the effect of tiagabine on GABAergic modulation of deep pyramidal and interneuronal cell populations. We found a transition of the main GABAergic drug effects from auditory cortex in standard trials to prefrontal cortex in deviant trials. The successful integration of pharmaco- magnetoencephalography with dynamic causal models of frontotemporal networks provides a potential platform on which to evaluate the effects of disease and pharmacological interventions.SIGNIFICANCE STATEMENT Understanding human brain function and developing new treatments require good models of brain function. We tested a detailed generative model of cortical microcircuits that accurately reproduced human magnetoencephalography, to quantify network dynamics and connectivity in frontotemporal cortex. This approach identified the effect of a test drug (GABA-reuptake inhibitor, tiagabine) on neuronal function (GABA-ergic dynamics), opening the way for psychopharmacological studies in health and disease with the mechanistic precision afforded by generative models of the brain.

In vivo evidence for pre-symptomatic neuroinflammation in a MAPT mutation carrier.

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.

[18F]AV-1451 binding is increased in frontotemporal dementia due to C9orf72 expansion.

The PET ligand [18F]AV-1451 was developed to bind tau pathology in Alzheimer's disease, but increased binding has been shown in both genetic tauopathies and in semantic dementia, a disease strongly associated with TDP-43 pathology. Here we assessed [18F]AV-1451 binding in behavioral variant frontotemporal dementia due to a hexanucleotide repeat expansion in C9orf72, characterized by TDP-43 pathology. We show that the C9orf72 mutation increases binding in frontotemporal cortex, with a distinctive distribution of binding compared with healthy controls.

Neurophysiological signatures of Alzheimer's disease and frontotemporal lobar degeneration: pathology versus phenotype.

The disruption of brain networks is characteristic of neurodegenerative dementias. However, it is controversial whether changes in connectivity reflect only the functional anatomy of disease, with selective vulnerability of brain networks, or the specific neurophysiological consequences of different neuropathologies within brain networks. We proposed that the oscillatory dynamics of cortical circuits reflect the tuning of local neural interactions, such that different pathologies are selective in their impact on the frequency spectrum of oscillations, whereas clinical syndromes reflect the anatomical distribution of pathology and physiological change. To test this hypothesis, we used magnetoencephalography from five patient groups, representing dissociated pathological subtypes and distributions across frontal, parietal and temporal lobes: amnestic Alzheimer's disease, posterior cortical atrophy, and three syndromes associated with frontotemporal lobar degeneration. We measured effective connectivity with graph theory-based measures of local efficiency, using partial directed coherence between sensors. As expected, each disease caused large-scale changes of neurophysiological brain networks, with reductions in local efficiency compared to controls. Critically however, the frequency range of altered connectivity was consistent across clinical syndromes that shared a likely underlying pathology, whilst the localization of changes differed between clinical syndromes. Multivariate pattern analysis of the frequency-specific topographies of local efficiency separated the disorders from each other and from controls (accuracy 62% to 100%, according to the groups' differences in likely pathology and clinical syndrome). The data indicate that magnetoencephalography has the potential to reveal specific changes in neurophysiology resulting from neurodegenerative disease. Our findings confirm that while clinical syndromes have characteristic anatomical patterns of abnormal connectivity that may be identified with other methods like structural brain imaging, the different mechanisms of neurodegeneration also cause characteristic spectral signatures of physiological coupling that are not accessible with structural imaging nor confounded by the neurovascular signalling of functional MRI. We suggest that these spectral characteristics of altered connectivity are the result of differential disruption of neuronal microstructure and synaptic physiology by Alzheimer's disease versus frontotemporal lobar degeneration.