Presynaptic Dopaminergic Imaging Characterizes Patients with REM Sleep Behavior Disorder Due to Synucleinopathy.

OBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024;95:1178-1192.

Subthalamic nucleus shows opposite functional connectivity pattern in Huntington's and Parkinson's disease.

Huntington's and Parkinson's disease are two movement disorders representing mainly opposite states of the basal ganglia inhibitory function. Despite being an integral part of the cortico-subcortico-cortical circuitry, the subthalamic nucleus function has been studied at the level of detail required to isolate its signal only through invasive studies in Huntington's and Parkinson's disease. Here, we tested whether the subthalamic nucleus exhibited opposite functional signatures in early Huntington's and Parkinson's disease. We included both movement disorders in the same whole-brain imaging study, and leveraged ultra-high-field 7T MRI to achieve the very fine resolution needed to investigate the smallest of the basal ganglia nuclei. Eleven of the 12 Huntington's disease carriers were recruited at a premanifest stage, while 16 of the 18 Parkinson's disease patients only exhibited unilateral motor symptoms (15 were at Stage I of Hoehn and Yahr off medication). Our group comparison interaction analyses, including 24 healthy controls, revealed a differential effect of Huntington's and Parkinson's disease on the functional connectivity at rest of the subthalamic nucleus within the sensorimotor network, i.e. an opposite effect compared with their respective age-matched healthy control groups. This differential impact in the subthalamic nucleus included an area precisely corresponding to the deep brain stimulation 'sweet spot'-the area with maximum overall efficacy-in Parkinson's disease. Importantly, the severity of deviation away from controls' resting-state values in the subthalamic nucleus was associated with the severity of motor and cognitive symptoms in both diseases, despite functional connectivity going in opposite directions in each disorder. We also observed an altered, opposite impact of Huntington's and Parkinson's disease on functional connectivity within the sensorimotor cortex, once again with relevant associations with clinical symptoms. The high resolution offered by the 7T scanner has thus made it possible to explore the complex interplay between the disease effects and their contribution on the subthalamic nucleus, and sensorimotor cortex. Taken altogether, these findings reveal for the first time non-invasively in humans a differential, clinically meaningful impact of the pathophysiological process of these two movement disorders on the overall sensorimotor functional connection of the subthalamic nucleus and sensorimotor cortex.

Network connectivity and structural correlates of survival in progressive supranuclear palsy and corticobasal syndrome.

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.

Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials.

The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based end point selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA) and related disorders, to compare candidate clinical trial end points. In this multicentre UK study, participants were assessed with serial questionnaires, motor examination, neuropsychiatric and MRI assessments at baseline, 6 and 12 months. Participants were classified by diagnosis at baseline and study end, into Richardson syndrome, PSP-subcortical (PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (PSP-frontal, PSP-speech and language and PSP-CBS subtypes), MSA-parkinsonism, MSA-cerebellar, CBS with and without evidence of Alzheimer's disease pathology and indeterminate syndromes. We calculated annual rate of change, with linear mixed modelling and sample sizes for clinical trials of disease-modifying agents, according to group and assessment type. Two hundred forty-three people were recruited [117 PSP, 68 CBS, 42 MSA and 16 indeterminate; 138 (56.8%) male; age at recruitment 68.7 ± 8.61 years]. One hundred and fifty-nine completed the 6-month assessment (82 PSP, 27 CBS, 40 MSA and 10 indeterminate) and 153 completed the 12-month assessment (80 PSP, 29 CBS, 35 MSA and nine indeterminate). Questionnaire, motor examination, neuropsychiatric and neuroimaging measures declined in all groups, with differences in longitudinal change between groups. Neuroimaging metrics would enable lower sample sizes to achieve equivalent power for clinical trials than cognitive and functional measures, often achieving N < 100 required for 1-year two-arm trials (with 80% power to detect 50% slowing). However, optimal outcome measures were disease-specific. In conclusion, phenotypic variance within PSP, CBS and MSA is a major challenge to clinical trial design. Our findings provide an evidence base for selection of clinical trial end points, from potential functional, cognitive, clinical or neuroimaging measures of disease progression.

Reward insensitivity is associated with dopaminergic deficit in rapid eye movement sleep behaviour disorder.

Idiopathic rapid eye movement sleep behaviour disorder (iRBD) has now been established as an important marker of the prodromal stage of Parkinson's disease and related synucleinopathies. However, although dopamine transporter single photon emission computed tomography (SPECT) has been used to demonstrate the presence of nigro-striatal deficit in iRBD, quantifiable correlates of this are currently lacking. Sensitivity to rewarding stimuli is reduced in some people with Parkinson's disease, potentially contributing to aspects of the neuropsychiatric phenotype in these individuals. Furthermore, a role for dopaminergic degeneration is suggested by the fact that reward insensitivity can be improved by dopaminergic medications. Patients with iRBD present a unique opportunity to study the relationship between reward sensitivity and early dopaminergic deficit in the unmedicated state. Here, we investigate whether a non-invasive, objective measure of reward sensitivity might be a marker of dopaminergic status in prodromal Parkinson's disease by comparing with SPECT/CT measurement of dopaminergic loss in the basal ganglia. Striatal dopaminergic deficits in iRBD are associated with progression to Parkinsonian disorders. Therefore, identification of a clinically measurable correlate of this degenerative process might provide a basis for the development of novel risk stratification tools. Using a recently developed incentivized eye-tracking task, we quantified reward sensitivity in a cohort of 41 patients with iRBD and compared this with data from 40 patients with Parkinson's disease and 41 healthy controls. Patients with iRBD also underwent neuroimaging with dopamine transporter SPECT/CT. Overall, reward sensitivity, indexed by pupillary response to monetary incentives, was reduced in iRBD cases compared with controls and was not significantly different to that in patients with Parkinson's disease. However, in iRBD patients with normal dopamine transporter SPECT/CT imaging, reward sensitivity was not significantly different from healthy controls. Across all iRBD cases, a positive association was observed between reward sensitivity and dopaminergic SPECT/CT signal in the putamen. These findings demonstrate a direct relationship between dopaminergic deficit and reward sensitivity in patients with iRBD and suggest that measurement of pupillary responses could be of value in models of risk stratification and disease progression in these individuals.

Genetics of validated Parkinson's disease subtypes in the Oxford Discovery and Tracking Parkinson's cohorts.

OBJECTIVES: To explore the genetics of four Parkinson's disease (PD) subtypes that have been previously described in two large cohorts of patients with recently diagnosed PD. These subtypes came from a data-driven cluster analysis of phenotypic variables. METHODS: We looked at the frequency of genetic mutations in glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 against our subtypes. Then we calculated Genetic Risk Scores (GRS) for PD, multiple system atrophy, progressive supranuclear palsy, Lewy body dementia, and Alzheimer's disease. These GRSs were regressed against the probability of belonging to a subtype in the two independent cohorts and we calculated q-values as an adjustment for multiple testing across four subtypes. We also carried out a Genome-Wide Association Study (GWAS) of belonging to a subtype. RESULTS: A severe disease subtype had the highest rates of patients carrying GBA mutations while the mild disease subtype had the lowest rates (p=0.009). Using the GRS, we found a severe disease subtype had a reduced genetic risk of PD (p=0.004 and q=0.015). In our GWAS no individual variants met genome wide significance (<5×10e-8) although four variants require further follow-up, meeting a threshold of <1×10e-6. CONCLUSIONS: We have found that four previously defined PD subtypes have different genetic determinants which will help to inform future studies looking at underlying disease mechanisms and pathogenesis in these different subtypes of disease.

Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging.

A key aim in epidemiological neuroscience is identification of markers to assess brain health and monitor therapeutic interventions. Quantitative susceptibility mapping (QSM) is an emerging magnetic resonance imaging technique that measures tissue magnetic susceptibility and has been shown to detect pathological changes in tissue iron, myelin and calcification. We present an open resource of QSM-based imaging measures of multiple brain structures in 35,273 individuals from the UK Biobank prospective epidemiological study. We identify statistically significant associations of 251 phenotypes with magnetic susceptibility that include body iron, disease, diet and alcohol consumption. Genome-wide associations relate magnetic susceptibility to 76 replicating clusters of genetic variants with biological functions involving iron, calcium, myelin and extracellular matrix. These patterns of associations include relationships that are unique to QSM, in particular being complementary to T2* signal decay time measures. These new imaging phenotypes are being integrated into the core UK Biobank measures provided to researchers worldwide, creating the potential to discover new, non-invasive markers of brain health.

Altered network stability in progressive supranuclear palsy.

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

Longitudinal Changes in Parkinson's Disease Symptoms with and Without Rapid Eye Movement Sleep Behavior Disorder: The Oxford Discovery Cohort Study.

BACKGROUND: Parkinson's disease (PD) comorbid with rapid eye movement sleep behavior disorder (RBD) may show more severe motor and nonmotor symptoms, suggesting a distinct PD subtype. OBJECTIVE: The aim of this study was to investigate the impact of RBD on the longitudinal change of motor and nonmotor symptoms in patients with PD. METHODS: Patients with early PD (diagnosed within 3.5 years) recruited from 2010 to 2019 were followed every 18 months in the Oxford Parkinson's Disease Centre Discovery cohort. At each visit, we used standard questionnaires and measurements to assess demographic features and motor and nonmotor symptoms (including RBD, daytime sleepiness, mood, autonomic symptoms, cognition, and olfaction). Data were analyzed with linear mixed effects and Cox regression models. Possible RBD (pRBD) was longitudinally determined according to RBD Screening Questionnaire scores. RESULTS: A total of 923 patients were recruited (mean age: 67.1 ± 9.59 years; 35.9% female), and 788 had follow-up assessment(s) (mean: 4.8 ± 1.98 years, range: 1.3-8.3). Among them, 33.3% were identified as pRBD (PD + pRBD). Patients with PD + pRBD had more severe baseline symptoms and showed faster progression on Movement Disorder Society-Unified Parkinson's Disease Rating Scale parts I and III, Purdue Pegboard test, and Beck Depression Inventory scores. Moreover, PD + pRBD was associated with an increased level of risk for mild cognitive impairment (hazard ratio [HR] = 1.36, 95% confidence interval [CI]: 1.01-1.83), freezing of gait (HR = 1.42, 95% CI: 1.10-1.86), and frequent falling (HR = 1.62, 95% CI: 1.02-2.60). CONCLUSIONS: Patients with PD + pRBD progress faster on motor, mood, and cognitive symptoms, confirming a more aggressive PD subtype that can be identified at baseline and has major clinical implications. © 2021 International Parkinson and Movement Disorder Society.

International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson's Disease.

BACKGROUND: Brain structure abnormalities throughout the course of Parkinson's disease have yet to be fully elucidated. OBJECTIVE: Using a multicenter approach and harmonized analysis methods, we aimed to shed light on Parkinson's disease stage-specific profiles of pathology, as suggested by in vivo neuroimaging. METHODS: Individual brain MRI and clinical data from 2357 Parkinson's disease patients and 1182 healthy controls were collected from 19 sources. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effects models. Patients grouped according to Hoehn and Yahr stage were compared with age- and sex-matched controls. Within the patient sample, we investigated associations with Montreal Cognitive Assessment score. RESULTS: Overall, patients showed a thinner cortex in 38 of 68 regions compared with controls (dmax  = -0.20, dmin  = -0.09). The bilateral putamen (dleft  = -0.14, dright  = -0.14) and left amygdala (d = -0.13) were smaller in patients, whereas the left thalamus was larger (d = 0.13). Analysis of staging demonstrated an initial presentation of thinner occipital, parietal, and temporal cortices, extending toward rostrally located cortical regions with increased disease severity. From stage 2 and onward, the bilateral putamen and amygdala were consistently smaller with larger differences denoting each increment. Poorer cognition was associated with widespread cortical thinning and lower volumes of core limbic structures. CONCLUSIONS: Our findings offer robust and novel imaging signatures that are generally incremental across but in certain regions specific to disease stages. Our findings highlight the importance of adequately powered multicenter collaborations. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Olfactory Testing in Parkinson Disease and REM Behavior Disorder: A Machine Learning Approach.

OBJECTIVE: We sought to identify an abbreviated test of impaired olfaction amenable for use in busy clinical environments in prodromal (isolated REM sleep behavior disorder [iRBD]) and manifest Parkinson disease (PD). METHODS: Eight hundred ninety individuals with PD and 313 controls in the Discovery cohort study underwent Sniffin' Stick odor identification assessment. Random forests were initially trained to distinguish individuals with poor (functional anosmia/hyposmia) and good (normosmia/super-smeller) smell ability using all 16 Sniffin' Sticks. Models were retrained using the top 3 sticks ranked by order of predictor importance. One randomly selected 3-stick model was tested in a second independent PD dataset (n = 452) and in 2 iRBD datasets (Discovery n = 241, Marburg n = 37) before being compared to previously described abbreviated Sniffin' Stick combinations. RESULTS: In differentiating poor from good smell ability, the overall area under the curve (AUC) value associated with the top 3 sticks (anise/licorice/banana) was 0.95 in the Development dataset (sensitivity 90%, specificity 92%, positive predictive value 92%, negative predictive value 90%). Internal and external validation confirmed AUCs ≥0.90. The combination of the 3-stick model determined poor smell, and an RBD screening questionnaire score of ≥5 separated those with iRBD from controls with a sensitivity, specificity, positive predictive value, and negative predictive value of 65%, 100%, 100%, and 30%. CONCLUSIONS: Our 3-Sniffin'-Stick model holds potential utility as a brief screening test in the stratification of individuals with PD and iRBD according to olfactory dysfunction. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a 3-Sniffin'-Stick model distinguishes individuals with poor and good smell ability and can be used to screen for individuals with iRBD.

Comparing Programming Sessions of Vim-DBS.

Background: Essential Tremor (ET) is a progressive neurological disorder characterized by postural and kinetic tremor most commonly affecting the hands and arms. Medically intractable ET can be treated by deep brain stimulation (DBS) of the ventral intermediate nucleus of thalamus (VIM). We investigated whether the location of the effective contact (most tremor suppression with at least side effects) in VIM-DBS for ET changes over time, indicating a distinct mechanism of loss of efficacy that goes beyond progression of tremor severity, or a mere reduction of DBS efficacy. Methods: We performed programming sessions in 10 patients who underwent bilateral vim-DBS surgery between 2009 and 2017 at our department. In addition to the intraoperative (T1) and first clinical programming session (T2) a third programming session (T3) was performed to assess the effect- and side effect threshold (minimum voltage at which a tremor suppression or side effects occurred). Additionally, we compared the choice of the effective contact between T1 and T2 which might be affected by a surgical induced "brain shift." Discussion: Over a time span of about 4 years VIM-DBS in ET showed continuous efficacy in tremor suppression during stim-ON compared to stim-OFF. Compared to immediate postoperative programming sessions in ET-patients with DBS, long-term evaluation showed no relevant change in the choice of contact with respect to side effects and efficacy. In the majority of the cases the active contact at T2 did not correspond to the most effective intraoperative stimulation site T1, which might be explained by a brain-shift due to cerebral spinal fluid loss after neurosurgical procedure.

A nudge towards better lumbar puncture practice.

BACKGROUND: Despite a body of evidence demonstrating reduced incidence of post-lumbar puncture headache associated with pencil-point (vs bevelled-edge) needles, their use remains variable in the UK. METHODS: A multimodal longitudinal intervention was performed over a 12-month period at a tertiary neurology referral centre. In addition to simulation training using pencil-point needles and an electronic documentation pro forma, a change in the default needles presented in clinical environments was performed. RESULTS: Prior to the intervention, pencil-point needle usage was minimal. Documentation significantly improved throughout the intervention period. Simulation training interventions only resulted in transient, moderate improvements in pencil-point needle usage. However, changing the default produced a marked increase in use that was sustained. No significant changes in operator success rate were found. CONCLUSIONS: In the context of wider literature on the power of default options in driving behavioural choices, changing defaults may be an effective, inexpensive and acceptable intervention to improve lumbar puncture practice.

Cohort profile: the Oxford Parkinson's Disease Centre Discovery Cohort MRI substudy (OPDC-MRI).

PURPOSE: The Oxford Parkinson's Disease Centre (OPDC) Discovery Cohort MRI substudy (OPDC-MRI) collects high-quality multimodal brain MRI together with deep longitudinal clinical phenotyping in patients with Parkinson's, at-risk individuals and healthy elderly participants. The primary aim is to detect pathological changes in brain structure and function, and develop, together with the clinical data, biomarkers to stratify, predict and chart progression in early-stage Parkinson's and at-risk individuals. PARTICIPANTS: Participants are recruited from the OPDC Discovery Cohort, a prospective, longitudinal study. Baseline MRI data are currently available for 290 participants: 119 patients with early idiopathic Parkinson's, 15 Parkinson's patients with pathogenic mutations of the leucine-rich repeat kinase 2 or glucocerebrosidase (GBA) genes, 68 healthy controls and 87 individuals at risk of Parkinson's (asymptomatic carriers of GBA mutation and patients with idiopathic rapid eye movement sleep behaviour disorder-RBD). FINDINGS TO DATE: Differences in brain structure in early Parkinson's were found to be subtle, with small changes in the shape of the globus pallidus and evidence of alterations in microstructural integrity in the prefrontal cortex that correlated with performance on executive function tests. Brain function, as assayed with resting fMRI yielded more substantial differences, with basal ganglia connectivity reduced in early Parkinson'sand RBD. Imaging of the substantia nigra with the more recent adoption of sequences sensitive to iron and neuromelanin content shows promising results in identifying early signs of Parkinsonian disease. FUTURE PLANS: Ongoing studies include the integration of multimodal MRI measures to improve discrimination power. Follow-up clinical data are now accumulating and will allow us to correlate baseline imaging measures to clinical disease progression. Follow-up MRI scanning started in 2015 and is currently ongoing, providing the opportunity for future longitudinal imaging analyses with parallel clinical phenotyping.

Cortical aging - new insights with multiparametric quantitative MRI.

Understanding the microstructural changes related to physiological aging of the cerebral cortex is pivotal to differentiate healthy aging from neurodegenerative processes. The aim of this study was to investigate the age-related global changes of cortical microstructure and regional patterns using multiparametric quantitative MRI (qMRI) in healthy subjects with a wide age range. 40 healthy participants (age range: 2nd to 8th decade) underwent high-resolution qMRI including T1, PD as well as T2, T2* and T2' mapping at 3 Tesla. Cortical reconstruction was performed with the FreeSurfer toolbox, followed by tests for correlations between qMRI parameters and age. Cortical T1 values were negatively correlated with age (p=0.007) and there was a widespread age-related decrease of cortical T1 involving the frontal and the parietotemporal cortex, while T2 was correlated positively with age, both in frontoparietal areas and globally (p=0.004). Cortical T2' values showed the most widespread associations across the cortex and strongest correlation with age (r= -0.724, p=0.0001). PD and T2* did not correlate with age. Multiparametric qMRI allows to characterize cortical aging, unveiling parameter-specific patterns. Quantitative T2' mapping seems to be a promising imaging biomarker of cortical age-related changes, suggesting that global cortical iron deposition is a prominent process in healthy aging.

Signal variance-based collateral index in DSC perfusion: A novel method to assess leptomeningeal collateralization in acute ischaemic stroke.

As a determinant of the progression rate of the ischaemic process in acute large-vessel stroke, the degree of collateralization is a strong predictor of the clinical outcome after reperfusion therapy and may influence clinical decision-making. Therefore, the assessment of leptomeningeal collateralization is of major importance. The purpose of this study was to develop and evaluate a quantitative and observer-independent method for assessing leptomeningeal collateralization in acute large-vessel stroke based on signal variance characteristics in T2*-weighted dynamic susceptibility contrast (DSC) perfusion-weighted MR imaging (PWI). Voxels representing leptomeningeal collateral vessels were extracted according to the magnitude of signal variance in the PWI raw data time series in 55 patients with proximal large-artery occlusion and an intra-individual collateral vessel index (CVIPWI) was calculated. CVIPWI correlated significantly with the initial ischaemic core volume (rho = -0.459, p = 0.0001) and the PWI/DWI mismatch ratio (rho = 0.494, p = 0.0001) as an indicator of the amount of salvageable tissue. Furthermore, CVIPWI was significantly negatively correlated with NIHSS and mRS at discharge (rho = -0.341, p = 0.015 and rho = -0.305, p = 0.023). In multivariate logistic regression, CVIPWI was an independent predictor of favourable functional outcome (mRS 0-2) (OR = 16.39, 95% CI 1.42-188.7, p = 0.025). CVIPWI provides useful rater-independent information on the leptomeningeal collateral supply in acute stroke.

Nigrosome 1 imaging in REM sleep behavior disorder and its association with dopaminergic decline.

OBJECTIVES: Rapid eye movement sleep behavior disorder (RBD) patients have a high risk of developing a Parkinsonian disorder, offering an opportunity for neuroprotective intervention. Predicting near-term conversion, however, remains a challenge. Dopamine transporter imaging, while informative, is expensive and not widely available. Here, we investigate the utility of susceptibility-weighted MRI (SWI) to detect abnormalities of the substantia nigra in RBD, and explore their association with striatal dopaminergic deficits. METHODS: SWI of the substantia nigra was performed in 46 RBD patients, 27 Parkinson's patients, and 32 control subjects. Dorsal nigral hyperintensity (DNH) was scored by two blinded raters, and separately quantified using a semiautomated process. Forty-two RBD patients were also imaged with 123 I-ioflupane single-photon emission computed tomography (DaT SPECT/CT). RESULTS: Consensus visual DNH classification was possible in 87% of participants. 27.5% of RBD patients had lost DNH, compared with 7.7% of control subjects and 96% of Parkinson's patients. RBD patients lacking DNH had significantly lower putamen dopaminergic SPECT/CT activity compared to RBD patients with DNH present (specific uptake ratios 1.89 vs. 2.33, P = 0.002). The mean quantified DNH signal intensity declined in a stepwise pattern, with RBD patients having lower intensity than controls (0.837 vs. 0.877, P = 0.01) but higher than PD patients (0.837 vs. 0.765, P < 0.001). INTERPRETATION: Over one quarter of RBD patients have abnormal substantia nigra SWI reminiscent of Parkinson's, which is associated with a greater dopaminergic deficit. This modality may help enrich neuroprotective trials with early converters.

Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome.

Importance: Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied. Objective: To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD. Design, Setting, Participants: This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer disease (CBS-AD), and CBS-non-AD. Data were analyzed from February 1, through May 1, 2019. Main Outcomes and Measures: Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures. Results: A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 [58.1%] male; mean [SD] age at recruitment, 68.3 [8.7] years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve [AUC], 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS-non-AD group (AUC, 0.80-0.87; P < .05). Serum NF-L levels distinguished PD from all PSP and CBS cases combined (AUC, 0.80; P < .05). Conclusions and Relevance: These findings suggest that studies focusing on the PSP-RS subtype are likely to miss a large number of patients with underlying PSP tau pathology. Analysis of cerebrospinal fluid defined a distinct CBS-AD subtype. The PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis.

Cortical quantitative MRI parameters are related to the cognitive status in patients with relapsing-remitting multiple sclerosis.

OBJECTIVES: We aimed to assess cortical damage in patients with relapsing-remitting multiple sclerosis (RRMS)/clinically isolated syndrome (CIS) with a multiparametric, surface-based quantitative MRI (qMRI) approach and to evaluate the correlation of imaging-derived parameters with cognitive scores, hypothesizing that qMRI parameters are correlated with cognitive abilities. METHODS: Multiparametric qMRI-data (T1, T2 and T2* relaxation times and proton density (PD)) were obtained from 34 patients/24 matched healthy control subjects. Cortical qMRI values were analyzed on the reconstructed cortical surface with Freesurfer. We tested for group differences of cortical microstructural parameters between the healthy and patient collectives and for partial Pearson correlations of qMRI parameters with cognitive scores, correcting for age. RESULTS: Cortical T2-/T2*-/PD values and four cognitive parameters differed between groups (p ≤ 0.046). These cognitive scores, reflecting information processing speed, verbal memory, visuospatial abilities, and attention, were correlated with cortical T2 (p ≤ 0.02) and T2* (p ≤ 0.03). Cortical changes appeared heterogeneous across the cortex and their distribution differed between the parameters. Vertex-wise correlation of T2 with neuropsychological parameters revealed specific patterns of cortical damage being related to distinct cognitive deficits. CONCLUSIONS: Microstructural changes are distributed heterogeneously across the cortex in RRMS/CIS. QMRI has the potential to provide surrogate parameters for the assessment of cognitive impairment in these patients for clinical studies. The characteristics of cognitive impairment in RRMS might depend on the distribution of cortical changes. KEY POINTS: • The goal of the presented study was to investigate cortical changes in RRMS/CIS and their relation to the cognitive status, using multiparametric quantitative MRI. • Cortical T2, T2*, and PD increases observed in patients appeared heterogeneous across the cortex and their distribution differed between the parameters. • Vertex-wise correlation of T2 with neuropsychological scores revealed specific patterns of cortical changes being related to distinct cognitive deficits.

Predicting motor, cognitive & functional impairment in Parkinson's.

OBJECTIVE: We recently demonstrated that 998 features derived from a simple 7-minute smartphone test could distinguish between controls, people with Parkinson's and people with idiopathic Rapid Eye Movement sleep behavior disorder, with mean sensitivity/specificity values of 84.6-91.9%. Here, we investigate whether the same smartphone features can be used to predict future clinically relevant outcomes in early Parkinson's. METHODS: A total of 237 participants with Parkinson's (mean (SD) disease duration 3.5 (2.2) years) in the Oxford Discovery cohort performed smartphone tests in clinic and at home. Each test assessed voice, balance, gait, reaction time, dexterity, rest, and postural tremor. In addition, standard motor, cognitive and functional assessments and questionnaires were administered in clinic. Machine learning algorithms were trained to predict the onset of clinical outcomes provided at the next 18-month follow-up visit using baseline smartphone recordings alone. The accuracy of model predictions was assessed using 10-fold and subject-wise cross validation schemes. RESULTS: Baseline smartphone tests predicted the new onset of falls, freezing, postural instability, cognitive impairment, and functional impairment at 18 months. For all outcome predictions AUC values were greater than 0.90 for 10-fold cross validation using all smartphone features. Using only the 30 most salient features, AUC values greater than 0.75 were obtained. INTERPRETATION: We demonstrate the ability to predict key future clinical outcomes using a simple smartphone test. This work has the potential to introduce individualized predictions to routine care, helping to target interventions to those most likely to benefit, with the aim of improving their outcome.