Genetic topography and cortical cell loss in Huntington's disease link development and neurodegeneration.

Cortical cell loss is a core feature of Huntington's disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate these using cell-specific post-mortem data. Eighty premanifest participants on average 15 years from disease onset and 71 controls were included. Using volumetric and diffusion MRI we extracted HD-specific whole brain maps where lower grey matter volume and higher grey matter mean diffusivity, relative to controls, were used as proxies of cortical cell loss. These maps were combined with gene expression data from the Allen Human Brain Atlas (AHBA) to investigate the biological processes relating genetic topography and cortical cell loss. Cortical cell loss was positively correlated with the expression of developmental genes (i.e. higher expression correlated with greater atrophy and increased diffusivity) and negatively correlated with the expression of synaptic and metabolic genes that have been implicated in neurodegeneration. These findings were consistent for diffusion MRI and volumetric HD-specific brain maps. As wild-type huntingtin is known to play a role in neurodevelopment, we explored the association between wild-type huntingtin (HTT) expression and developmental gene expression across the AHBA. Co-expression network analyses in 134 human brains free of neurodegenerative disorders were also performed. HTT expression was correlated with the expression of genes involved in neurodevelopment while co-expression network analyses also revealed that HTT expression was associated with developmental biological processes. Expression weighted cell-type enrichment (EWCE) analyses were used to explore which specific cell types were associated with HD cortical cell loss and these associations were validated using cell specific single nucleus RNAseq (snRNAseq) data from post-mortem HD brains. The developmental transcriptomic profile of cortical cell loss in preHD was enriched in astrocytes and endothelial cells, while the neurodegenerative transcriptomic profile was enriched for neuronal and microglial cells. Astrocyte-specific genes differentially expressed in HD post-mortem brains relative to controls using snRNAseq were enriched in the developmental transcriptomic profile, while neuronal and microglial-specific genes were enriched in the neurodegenerative transcriptomic profile. Our findings suggest that cortical cell loss in preHD may arise from dual pathological processes, emerging as a consequence of neurodevelopmental changes, at the beginning of life, followed by neurodegeneration in adulthood, targeting areas with reduced expression of synaptic and metabolic genes. These events result in age-related cell death across multiple brain cell types.

Quantitative MRI maps of human neocortex explored using cell type-specific gene expression analysis.

Quantitative magnetic resonance imaging (qMRI) allows extraction of reproducible and robust parameter maps. However, the connection to underlying biological substrates remains murky, especially in the complex, densely packed cortex. We investigated associations in human neocortex between qMRI parameters and neocortical cell types by comparing the spatial distribution of the qMRI parameters longitudinal relaxation rate (${R_{1}}$), effective transverse relaxation rate (${R_{2}}^{\ast }$), and magnetization transfer saturation (MTsat) to gene expression from the Allen Human Brain Atlas, then combining this with lists of genes enriched in specific cell types found in the human brain. As qMRI parameters are magnetic field strength-dependent, the analysis was performed on MRI data at 3T and 7T. All qMRI parameters significantly covaried with genes enriched in GABA- and glutamatergic neurons, i.e. they were associated with cytoarchitecture. The qMRI parameters also significantly covaried with the distribution of genes enriched in astrocytes (${R_{2}}^{\ast }$ at 3T, ${R_{1}}$ at 7T), endothelial cells (${R_{1}}$ and MTsat at 3T), microglia (${R_{1}}$ and MTsat at 3T, ${R_{1}}$ at 7T), and oligodendrocytes and oligodendrocyte precursor cells (${R_{1}}$ at 7T). These results advance the potential use of qMRI parameters as biomarkers for specific cell types.

Visual dysfunction is a better predictor than retinal thickness for dementia in Parkinson's disease.

BACKGROUND: Dementia is a common and devastating symptom of Parkinson's disease (PD). Visual function and retinal structure are both emerging as potentially predictive for dementia in Parkinson's but lack longitudinal evidence. METHODS: We prospectively examined higher order vision (skew tolerance and biological motion) and retinal thickness (spectral domain optical coherence tomography) in 100 people with PD and 29 controls, with longitudinal cognitive assessments at baseline, 18 months and 36 months. We examined whether visual and retinal baseline measures predicted longitudinal cognitive scores using linear mixed effects models and whether they predicted onset of dementia, death and frailty using time-to-outcome methods. RESULTS: Patients with PD with poorer baseline visual performance scored lower on a composite cognitive score (ß=0.178, SE=0.05, p=0.0005) and showed greater decreases in cognition over time (ß=0.024, SE=0.001, p=0.013). Poorer visual performance also predicted greater probability of dementia (χ² (1)=5.2, p=0.022) and poor outcomes (χ² (1) =10.0, p=0.002). Baseline retinal thickness of the ganglion cell-inner plexiform layer did not predict cognitive scores or change in cognition with time in PD (ß=-0.013, SE=0.080, p=0.87; ß=0.024, SE=0.001, p=0.12). CONCLUSIONS: In our deeply phenotyped longitudinal cohort, visual dysfunction predicted dementia and poor outcomes in PD. Conversely, retinal thickness had less power to predict dementia. This supports mechanistic models for Parkinson's dementia progression with onset in cortical structures and shows potential for visual tests to enable stratification for clinical trials.

Structural and Functional Imaging Correlates of Visual Hallucinations in Parkinson's Disease.

PURPOSE OF REVIEW: To review recent structural and functional MRI studies of visual hallucinations in Parkinson's disease. RECENT FINDINGS: Previously, neuroimaging had shown inconsistent findings in patients with Parkinson's hallucinations, especially in studies examining grey matter volume. However, recent advances in structural and functional MRI techniques allow better estimates of structural connections, as well as the direction of connectivity in functional MRI. These provide more sensitive measures of changes in structural connectivity and allow models of the changes in directional functional connectivity to be tested. We identified 27 relevant studies and found that grey matter imaging continues to show heterogeneous findings in Parkinson's patients with visual hallucinations. Newer approaches in diffusion imaging and functional MRI are consistent with emerging models of Parkinson's hallucinations, suggesting shifts in attentional networks. In particular, reduced bottom-up, incoming sensory information, and over-weighting of top-down signals appear to be important drivers of visual hallucinations in Parkinson's disease.

Neurofilament light-associated connectivity in young-adult Huntington's disease is related to neuronal genes.

Upregulation of functional network connectivity in the presence of structural degeneration is seen in the premanifest stages of Huntington's disease (preHD) 10-15 years from clinical diagnosis. However, whether widespread network connectivity changes are seen in gene carriers much further from onset has yet to be explored. We characterized functional network connectivity throughout the brain and related it to a measure of disease pathology burden (CSF neurofilament light, NfL) and measures of structural connectivity in asymptomatic gene carriers, on average 24 years from onset. We related these measurements to estimates of cortical and subcortical gene expression. We found no overall differences in functional (or structural) connectivity anywhere in the brain comparing control and preHD participants. However, increased functional connectivity, particularly between posterior cortical areas, correlated with increasing CSF NfL level in preHD participants. Using the Allen Human Brain Atlas and expression-weighted cell-type enrichment analysis, we demonstrated that this functional connectivity upregulation occurred in cortical regions associated with regional expression of genes specific to neuronal cells. This relationship was validated using single-nucleus RNAseq data from post-mortem Huntington's disease and control brains showing enrichment of neuronal-specific genes that are differentially expressed in Huntington's disease. Functional brain networks in asymptomatic preHD gene carriers very far from disease onset show evidence of upregulated connectivity correlating with increased disease burden. These changes occur among brain areas that show regional expression of genes specific to neuronal GABAergic and glutamatergic cells.

Longitudinal thalamic white and grey matter changes associated with visual hallucinations in Parkinson's disease.

OBJECTIVE: Visual hallucinations are common in Parkinson's disease (PD) and associated with worse outcomes. Large-scale network imbalance is seen in PD-associated hallucinations, but mechanisms remain unclear. As the thalamus is critical in controlling cortical networks, structural thalamic changes could underlie network dysfunction in PD hallucinations. METHODS: We used whole-brain fixel-based analysis and cortical thickness measures to examine longitudinal white and grey matter changes in 76 patients with PD (15 hallucinators, 61 non-hallucinators) and 26 controls at baseline, and after 18 months. We compared white matter and cortical thickness, adjusting for age, gender, time-between-scans and intracranial volume. To assess thalamic changes, we extracted volumes for 50 thalamic subnuclei (25 each hemisphere) and mean fibre cross-section (FC) for white matter tracts originating in each subnucleus and examined longitudinal change in PD-hallucinators versus non-hallucinators. RESULTS: PD hallucinators showed white matter changes within the corpus callosum at baseline and extensive posterior tract involvement over time. Less extensive cortical thickness changes were only seen after follow-up. White matter connections from the right medial mediodorsal magnocellular thalamic nucleus showed reduced FC in PD hallucinators at baseline followed by volume reductions longitudinally. After follow-up, almost all thalamic subnuclei showed tract losses in PD hallucinators compared with non-hallucinators. INTERPRETATION: PD hallucinators show white matter loss particularly in posterior connections and in thalamic nuclei, over time with relatively preserved cortical thickness. The right medial mediodorsal thalamic nucleus shows both connectivity and volume loss in PD hallucinations. Our findings provide mechanistic insights into the drivers of network imbalance in PD hallucinations and potential therapeutic targets.

Regional brain iron and gene expression provide insights into neurodegeneration in Parkinson's disease.

The mechanisms responsible for the selective vulnerability of specific neuronal populations in Parkinson's disease are poorly understood. Oxidative stress secondary to brain iron accumulation is one postulated mechanism. We measured iron deposition in 180 cortical regions of 96 patients with Parkinson's disease and 35 control subjects using quantitative susceptibility mapping. We estimated the expression of 15 745 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. Using partial least squares regression, we then identified the profile of gene transcription in the healthy brain that underlies increased cortical iron in patients with Parkinson's disease relative to controls. Applying gene ontological tools, we investigated the biological processes and cell types associated with this transcriptomic profile and identified the sets of genes with spatial expression profiles in control brains that correlated significantly with the spatial pattern of cortical iron deposition in Parkinson's disease. Gene ontological analyses revealed that these genes were enriched for biological processes relating to heavy metal detoxification, synaptic function and nervous system development and were predominantly expressed in astrocytes and glutamatergic neurons. Furthermore, we demonstrated that the genes differentially expressed in Parkinson's disease are associated with the pattern of cortical expression identified in this study. Our findings provide mechanistic insights into regional selective vulnerabilities in Parkinson's disease, particularly the processes involving iron accumulation.

Visual Dysfunction Predicts Cognitive Impairment and White Matter Degeneration in Parkinson's Disease.

BACKGROUND: Visual dysfunction predicts dementia in Parkinson's disease (PD), but whether this translates to structural change is not known. The objectives of this study were to identify longitudinal white matter changes in patients with Parkinson's disease and low visual function and also in those who developed mild cognitive impairment. METHODS: We used fixel-based analysis to examine longitudinal white matter change in PD. Diffusion MRI and clinical assessments were performed in 77 patients at baseline (22 low visual function/55 intact vision and 13 PD-mild cognitive impairment/51 normal cognition) and 25 controls and again after 18 months. We compared microstructural changes in fiber density, macrostructural changes in fiber bundle cross-section and combined fiber density and cross-section, across white matter, adjusting for age, sex, and intracranial volume. RESULTS: Patients with PD and visual dysfunction showed worse cognitive performance at follow-up and were more likely to develop mild cognitive impairment compared with those with normal vision (P = 0.008). Parkinson's with poor visual function showed diffuse microstructural and macrostructural changes at baseline, whereas those with mild cognitive impairment showed fewer baseline changes. At follow-up, Parkinson's with low visual function showed widespread macrostructural changes, involving the fronto-occipital fasciculi, external capsules, and middle cerebellar peduncles bilaterally. No longitudinal change was seen in those with mild cognitive impairment at baseline or converters, even when the 2 groups were combined. CONCLUSION: Parkinson's patients with poor visual function show increased white matter damage over time, providing further evidence for visual function as a marker of imminent cognitive decline. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Differences in network controllability and regional gene expression underlie hallucinations in Parkinson's disease.

Visual hallucinations are common in Parkinson's disease and are associated with poorer prognosis. Imaging studies show white matter loss and functional connectivity changes with Parkinson's visual hallucinations, but the biological factors underlying selective vulnerability of affected parts of the brain network are unknown. Recent models for Parkinson's disease hallucinations suggest they arise due to a shift in the relative effects of different networks. Understanding how structural connectivity affects the interplay between networks will provide important mechanistic insights. To address this, we investigated the structural connectivity changes that accompany visual hallucinations in Parkinson's disease and the organizational and gene expression characteristics of the preferentially affected areas of the network. We performed diffusion-weighted imaging in 100 patients with Parkinson's disease (81 without hallucinations, 19 with visual hallucinations) and 34 healthy age-matched controls. We used network-based statistics to identify changes in structural connectivity in Parkinson's disease patients with hallucinations and performed an analysis of controllability, an emerging technique that allows quantification of the influence a brain region has across the rest of the network. Using these techniques, we identified a subnetwork of reduced connectivity in Parkinson's disease hallucinations. We then used the Allen Institute for Brain Sciences human transcriptome atlas to identify regional gene expression patterns associated with affected areas of the network. Within this network, Parkinson's disease patients with hallucinations showed reduced controllability (less influence over other brain regions), than Parkinson's disease patients without hallucinations and controls. This subnetwork appears to be critical for overall brain integration, as even in controls, nodes with high controllability were more likely to be within the subnetwork. Gene expression analysis of gene modules related to the affected subnetwork revealed that down-weighted genes were most significantly enriched in genes related to mRNA and chromosome metabolic processes (with enrichment in oligodendrocytes) and upweighted genes to protein localization (with enrichment in neuronal cells). Our findings provide insights into how hallucinations are generated, with breakdown of a key structural subnetwork that exerts control across distributed brain regions. Expression of genes related to mRNA metabolism and membrane localization may be implicated, providing potential therapeutic targets.

Atrial Fibrillation: An Underestimated Cause of Ischemic Monocular Visual Loss?

INTRODUCTION: Atrial fibrillation (AF) is a major cause of ischemic stroke and Transient Ischemic Attack (TIA) and investigation for paroxysmal AF is recommended following an embolic brain event. In contrast, retinal ischemic monocular blindness is traditionally considered most linked to carotid artery disease (CAS) and investigating for AF is less vigilant. We aimed to determine the prevalence of AF in patients with ischemic monocular blindness. METHODS: Consecutive records of all patients presenting to a daily TIA clinic with transient or permanent ischemic monocular blindness were reviewed, January 2014-October 2016. RESULTS: Of 400 patients, 224 (56.0%) were male, mean age 64.5 years (SD 15.1). A total of 263 (66%) presented with transient and 137 (34%) with permanent ischemic monocular blindness. ECG was performed in 364 patients (91%) but only 211 (52%) had further cardiac monitoring. The vast majority (97.3%) had carotid imaging. Thirty-six patients (9%) were found to have AF while 53 (14%) had ipsilateral CAS. Median ABCD2 score was 1 in AF and non-AF groups. Only 55% of known AF patients were anticoagulated at presentation, despite all having CHADVASC2 score greater than or equal to 1. Patients with AF had more hypertension (P = .004), previous TIA (P = .002), previous stroke (P = .044) and ischemic heart disease (P = .022) with no difference in age (P = .791), diabetes (P = .563), smoking (P = .460) nor hypercholesterolaemia (P = .083). CONCLUSIONS: A total of 9% of patients with ischemic monocular blindness had AF. This is an underestimate, as only 53% of patients had prolonged cardiac monitoring. Known AF was suboptimally managed with only 55% receiving anticoagulation despite being eligible.

Undertreatment of Vascular Risk Factors in Patients with Monocular Ischaemic Visual Loss.

BACKGROUND AND PURPOSE: Ischaemic visual loss is often considered a lower risk factor than other transient ischaemic attacks (TIA). We aimed to determine the recurrence risk, prevalence and management of vascular risk factors in these patients. METHODS: The study took place in the University College Hospital London daily TIA clinic, main referral centre for North-Central London and Moorfields Eye Hospital. Consecutive records for patients with transient (< 24 h) or permanent (> 24 h) ischaemic visual loss were reviewed during the period January 2014-October 2016. Patients diagnosed with temporal arteritis were excluded. RESULTS: Of 400 patients, 224 (56%) were male with mean age 64.5 years (SD 15.1); 263 patients (65.8%) presented with transient and 137 patients (34.2%) with permanent ischaemic visual loss; 51.3% had hypertension (HTN), 35.3% hypercholesterolaemia, 14.5% diabetes, 11.8% ischaemic ocular events, 10.0% ischaemic heart disease, 7.3% atrial fibrillation (AF), 6.3% TIA, 5.3% stroke, and 12.3% were smokers. Median vascular risk factors were 2 (range 1-6), but 122 (30.5%) had ≥3. Those with diabetes (p < 0.001), HTN (p = 0.008), previous myocardial infarction (p = 0.005), or ≥3 vascular risk factors (p = 0.012) were more likely to present with permanent visual loss, while patients with history of transient events, TIA (p = 0.002), or ocular (p = 0.002) presented with transient visual loss. Ninety-day recurrence was 10.5%; this was higher in patients with ≥3 risk factors (hazard ratio 1.42, 95% CI 0.95-2.11, p = 0.111). Patients with past TIA were more likely to be on secondary prevention than those with ocular ischaemia; 60.0 vs. 34.1% received antiplatelets and 76.0 vs. 43.9% statins. At presentation, only 55.2% (16 patients) with known AF were anticoagulated, despite all of them having CHADSVASC ≥1. CONCLUSIONS: Approximately one-third of patients with ocular ischaemia had ≥3 vascular risk factors with recurrences higher in these patients. Yet only half of those with previous ischaemic ocular events were on antiplatelets or statins. These patients should be investigated and treated as aggressively as other forms of TIA or stroke.

Glial fibrillary acidic protein antibody-positive meningoencephalomyelitis.

Glial fibrillary acidic protein antibody-positive meningoencephalomyelitis is a newly described, possibly under-recognised, severe inflammatory condition of the nervous system. The clinical presentation is variable but most commonly is a combination of meningitis, encephalitis and myelitis; other manifestations may include seizures, psychiatric symptoms and tremor. There is a significant association with malignancies, often occult, and with other autoimmune conditions. Although the disease responds well to corticosteroids acutely, it typically relapses when these are tapered, and so patients need long-term immunosuppression. We report a young man presenting with subacute meningoencephalitis and subsequent myelitis, and discuss the typical presentation and management of this severe but treatable condition.

CD8+ encephalitis: a severe but treatable HIV-related acute encephalopathy.

Rapidly progressive encephalopathy in an HIV-positive patient presents a major diagnostic and management challenge. CD8+ encephalitis is a severe but treatable form of HIV-related acute encephalopathy, characterised by diffuse perivascular and intraparenchymal CD8+ lymphocytic infiltration. It can occur in patients who are apparently stable on antiretroviral treatment and probably results from viral escape into the central nervous system. Treatment, including high-dose corticosteroids, can give an excellent neurological outcome, even in people with severe encephalopathy and a very poor initial neurological status. We report a woman with CD8+ encephalitis, with a normal CD4 count and undetectable serum viral load, who made a good recovery despite the severity of her presentation.

Neuroimaging and fluid biomarkers in Parkinson's disease in an era of targeted interventions.

A major challenge in Parkinson's disease is the variability in symptoms and rates of progression, underpinned by heterogeneity of pathological processes. Biomarkers are urgently needed for accurate diagnosis, patient stratification, monitoring disease progression and precise treatment. These were previously lacking, but recently, novel imaging and fluid biomarkers have been developed. Here, we consider new imaging approaches showing sensitivity to brain tissue composition, and examine novel fluid biomarkers showing specificity for pathological processes, including seed amplification assays and extracellular vesicles. We reflect on these biomarkers in the context of new biological staging systems, and on emerging techniques currently in development.

Neuroimaging and plasma evidence of early white matter loss in Parkinson's disease with poor outcomes.

Parkinson's disease is a common and debilitating neurodegenerative disorder, with over half of patients progressing to postural instability, dementia or death within 10 years of diagnosis. However, the onset and rate of progression to poor outcomes is highly variable, underpinned by heterogeneity in underlying pathological processes. Quantitative and sensitive measures predicting poor outcomes will be critical for targeted treatment, but most studies to date have been limited to a single modality or assessed patients with established cognitive impairment. Here, we used multimodal neuroimaging and plasma measures in 98 patients with Parkinson's disease and 28 age-matched controls followed up over 3 years. We examined: grey matter (cortical thickness and subcortical volume), white matter (fibre cross-section, a measure of macrostructure; and fibre density, a measure of microstructure) at whole-brain and tract level; structural and functional connectivity; and plasma levels of neurofilament light chain and phosphorylated tau 181. We evaluated relationships with subsequent poor outcomes, defined as development of mild cognitive impairment, dementia, frailty or death at any time during follow-up, in people with Parkinson's disease. We show that extensive white matter macrostructural changes are already evident at baseline assessment in people with Parkinson's disease who progress to poor outcomes (n = 31): with up to 19% reduction in fibre cross-section in multiple tracts, and a subnetwork of reduced structural connectivity strength, particularly involving connections between right frontoparietal and left frontal, right frontoparietal and left parietal and right temporo-occipital and left parietal modules. In contrast, grey matter volumes and functional connectivity were preserved in people with Parkinson's disease with poor outcomes. Neurofilament light chain, but not phosphorylated tau 181 levels were increased in people with Parkinson's disease with poor outcomes, and correlated with white matter loss. These findings suggest that imaging sensitive to white matter macrostructure and plasma neurofilament light chain may be useful early markers of poor outcomes in Parkinson's disease. As new targeted treatments for neurodegenerative disease are emerging, these measures show important potential to aid patient selection for treatment and improve stratification for clinical trials.

Changes in both top-down and bottom-up effective connectivity drive visual hallucinations in Parkinson's disease.

Visual hallucinations are common in Parkinson's disease and are associated with a poorer quality of life and a higher risk of dementia. An important and influential model that is widely accepted as an explanation for the mechanism of visual hallucinations in Parkinson's disease and other Lewy body diseases is that these arise due to aberrant hierarchical processing, with impaired bottom-up integration of sensory information and overweighting of top-down perceptual priors within the visual system. This hypothesis has been driven by behavioural data and supported indirectly by observations derived from regional activation and correlational measures using neuroimaging. However, until now, there was no evidence from neuroimaging for differences in causal influences between brain regions measured in patients with Parkinson's hallucinations. This is in part because previous resting-state studies focused on functional connectivity, which is inherently undirected in nature and cannot test hypotheses about the directionality of connectivity. Spectral dynamic causal modelling is a Bayesian framework that allows the inference of effective connectivity-defined as the directed (causal) influence that one region exerts on another region-from resting-state functional MRI data. In the current study, we utilize spectral dynamic causal modelling to estimate effective connectivity within the resting-state visual network in our cohort of 15 Parkinson's disease visual hallucinators and 75 Parkinson's disease non-visual hallucinators. We find that visual hallucinators display decreased bottom-up effective connectivity from the lateral geniculate nucleus to primary visual cortex and increased top-down effective connectivity from the left prefrontal cortex to primary visual cortex and the medial thalamus, as compared with non-visual hallucinators. Importantly, we find that the pattern of effective connectivity is predictive of the presence of visual hallucinations and associated with their severity within the hallucinating group. This is the first study to provide evidence, using resting-state effective connectivity, to support a model of aberrant hierarchical predictive processing as the mechanism for visual hallucinations in Parkinson's disease.

Changes in dynamic transitions between integrated and segregated states underlie visual hallucinations in Parkinson's disease.

Hallucinations are a core feature of psychosis and common in Parkinson's. Their transient, unexpected nature suggests a change in dynamic brain states, but underlying causes are unknown. Here, we examine temporal dynamics and underlying structural connectivity in Parkinson's-hallucinations using a combination of functional and structural MRI, network control theory, neurotransmitter density and genetic analyses. We show that Parkinson's-hallucinators spent more time in a predominantly Segregated functional state with fewer between-state transitions. The transition from integrated-to-segregated state had lower energy cost in Parkinson's-hallucinators; and was therefore potentially preferable. The regional energy needed for this transition was correlated with regional neurotransmitter density and gene expression for serotoninergic, GABAergic, noradrenergic and cholinergic, but not dopaminergic, receptors. We show how the combination of neurochemistry and brain structure jointly shape functional brain dynamics leading to hallucinations and highlight potential therapeutic targets by linking these changes to neurotransmitter systems involved in early sensory and complex visual processing.

Organisational and neuromodulatory underpinnings of structural-functional connectivity decoupling in patients with Parkinson's disease.

Parkinson's dementia is characterised by changes in perception and thought, and preceded by visual dysfunction, making this a useful surrogate for dementia risk. Structural and functional connectivity changes are seen in humans with Parkinson's disease, but the organisational principles are not known. We used resting-state fMRI and diffusion-weighted imaging to examine changes in structural-functional connectivity coupling in patients with Parkinson's disease, and those at risk of dementia. We identified two organisational gradients to structural-functional connectivity decoupling: anterior-to-posterior and unimodal-to-transmodal, with stronger structural-functional connectivity coupling in anterior, unimodal areas and weakened towards posterior, transmodal regions. Next, we related spatial patterns of decoupling to expression of neurotransmitter receptors. We found that dopaminergic and serotonergic transmission relates to decoupling in Parkinson's overall, but instead, serotonergic, cholinergic and noradrenergic transmission relates to decoupling in patients with visual dysfunction. Our findings provide a framework to explain the specific disorders of consciousness in Parkinson's dementia, and the neurotransmitter systems that underlie these.