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Supplementary data is available online at https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awad105/7091433#supplementary-data . Accepted manuscripts are PDF versions of the author’s final manuscript, as accepted for publication by the journal but prior to copyediting or typesetting. They can be cited using the author(s), article title, journal title, year of online publication, and DOI. They will be replaced by the final typeset articles, which may therefore contain changes. The DOI will remain the same throughout. Copyright © The Author(s) 2023. 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. The Progressive Supranuclear Palsy–Corticobasal Syndrome–Multiple System Atrophy (PROSPECT-M-UK) study is supported by grants for PROSPECT, cerebrospinal fluid biomarker measurements, and PROSPECT magnetic resonance imaging and Sara Koe Fellowship grants from the PSP Association UK, CBD Solutions, the MSA Trust, the Wellcome Trust (103838; 220258); the NIHR Cambridge Biomedical Research Centre and Cambridge Brain Bank (BRC 1215-20014; NIHR203312: The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care); Cambridge Centre for Parkinson-Plus; Medical Research Council (SUAG/092 116768); and the NIHR UCLH Biomedical Research Centre. Queen Square Brain Bank is supported by the Reta Lila Weston Institute for Neurological Studies and the MRC. The fluid biomarker measurements were supported in part by the UK Dementia Research Institute at UCL and a multiuser equipment grant from Wellcome Trust. The Cambridge Brain Bank is part of the Cambridge Human research Tissue Bank funded by the Biomedical Research Council. The Oxford Brain Bank is supported by the MRC, Brains for Dementia Research (Alzheimer’s Society and Alzheimer’s Research UK), and the NIHR Oxford Biomedical Research Centre. In addition, this study was supported by the Medical Research Council (MRC 548211) (Dr Jabbari); the Association of British Neurologists Clinical Research Training Fellowships (Dr Holland, Dr Goh and Dr Chelban); the MSA Trust (Dr Chelban, Dr Goh); Guarantors of Brain (Dr Chelban); CBD Solutions (Dr Revesz, and Dr Morris); the NIHR Oxford Health Clinical Research Facility (Dr Klein); the NIHR Queen Square Biomedical Research Centre based at UCLH (Dr Revesz and Dr Jaunmuktane) a Wallenberg Academy fellowship (Dr Zetterberg); the Monument Trust Discovery Award from Parkinson’s UK (Dr Hu). Dr Bocchetta is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). Dr Bocchetta’s work was also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. Professor Rohrer is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). Professor Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), European Union Joint Program for Neurodegenerative Disorders (JPND2021-00694), and the UK Dementia Research Institute at UCL. Professor Roncaroli’s work is supported by The Manchester Brain Bank, which is part of BDR, jointly funded by Alzheimer’s Society and Alzheimer’s Research UK. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission, under a Creative Commons Attribution 4.0 International License.

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 behavioral 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 10mg memantine, an uncompetitive NMDA-receptor antagonist. Ultrahigh-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 right frontotemporal cortex in patients, or controls. However, the change in 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 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., Cambridge Centre for Parkinson-Plus; a Cambridge Trust Vice-Chancellor’s Award and Fitzwilliam College Scholarship; the Association of British Neurologists – Patrick Berthoud Charitable Trust (RG99368);and the NIHR Cambridge Clinical Research Facility.

Funder: NIHR Cambridge Clinical Research Facility and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014), 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., Cambridge Centre for Parkinson-Plus; a Cambridge Trust Vice-Chancellor’s Award and Fitzwilliam College Scholarship; the Association of British Neurologists – Patrick Berthoud Charitable Trust (RG99368); NIHR Cambridge Clinical Research Facility

Introduction: Prediagnostic features of Parkinson’s Disease are well described but prediagnostic Progressive Supranuclear Palsy (PSP) is less understood. The diagnosis of PSP is delayed by an average of three years after symptom onset. Understanding the changes that occur in the prediagnostic period will aid earlier diagnosis, clarify the natural history, and may aid the design of early disease-modifying therapy trials. We set out to identify motor and cognitive markers of prediagnostic PSP, with Parkinson’s disease as a comparator condition, in a large prospective cohort. Methods: Baseline UK Biobank data from 502,504 individuals were collected between 2006 and 2010. Subsequent PSP and Parkinson’s disease cases were identified from primary and secondary care electronic health records’ diagnostic coding data and death registry, with 5,404 matched controls. Results: 176 PSP cases (time to diagnosis 7.8±2.8 years) and 2,526 Parkinson’s disease cases (time to diagnosis 7.8±2.9 years) were identified. At baseline, those later diagnosed with PSP had slower reaction times, weaker hand grip, lower fluid intelligence, prospective memory, self-rated health scores and digit recall than controls. Reaction times were correlated with time to diagnosis. The PSP group had higher mortality than both Parkinson’s disease and control groups. Conclusions: Motor slowing, cognitive dysfunction, and postural instability are clinical diagnostic features of PSP that are typically symptomatic three years before diagnosis. Objective markers of these features were evident on average 7.8 years before diagnosis. Our findings suggest the existence of a long prediagnostic phase in PSP, with subtle changes in motor and cognitive function.

INTRODUCTION: Prediagnostic features of Parkinson's Disease are well described but prediagnostic Progressive Supranuclear Palsy (PSP) is less understood. The diagnosis of PSP is delayed by an average of three years after symptom onset. Understanding the changes that occur in the prediagnostic period will aid earlier diagnosis, clarify the natural history, and may aid the design of early disease-modifying therapy trials. We set out to identify motor and cognitive markers of prediagnostic PSP, with Parkinson's disease as a comparator condition, in a large prospective cohort. METHODS: Baseline UK Biobank data from 502,504 individuals were collected between 2006 and 2010. Subsequent PSP and Parkinson's disease cases were identified from primary and secondary care electronic health records' diagnostic coding data and death registry, with 5404 matched controls. RESULTS: 176 PSP cases (time to diagnosis 7.8 ± 2.8 years) and 2526 Parkinson's disease cases (time to diagnosis 7.8 ± 2.9 years) were identified. At baseline, those later diagnosed with PSP had slower reaction times, weaker hand grip, lower fluid intelligence, prospective memory, self-rated health scores and digit recall than controls. Reaction times were correlated with time to diagnosis. The PSP group had higher mortality than both Parkinson's disease and control groups. CONCLUSIONS: Motor slowing, cognitive dysfunction, and postural instability are clinical diagnostic features of PSP that are typically symptomatic three years before diagnosis. Objective markers of these features were evident on average 7.8 years before diagnosis. Our findings suggest the existence of a long prediagnostic phase in PSP, with subtle changes in motor and cognitive function.

Progressive supranuclear palsy causes diverse clinical presentations, including classical Richardson’s syndrome and several variant phenotypes. Clinical trials of disease-modifying therapies have recently been completed, with more planned for the next 2 years. However, many people with progressive supranuclear palsy do not meet eligibility criteria for these clinical trials. Understanding clinical progression with different phenotypes would improve trial design and enhance the accuracy of risk–benefit and cost–benefit assessments of new treatments for progressive supranuclear palsy. We set out to determine rates of motor and cognitive progression of possible, probable and definite progressive supranuclear palsy, with different phenotypes, from a representative cohort in a regional UK healthcare service. Longitudinal clinical data from people with Richardson’s syndrome and variant phenotypes were analysed using linear mixed-modelling, using both the full and modified versions of the Progressive Supranuclear Palsy Rating Scale, Mini-Mental State Examination and the revised Addenbrooke’s Cognitive Examination. Subgroup analyses considered patients meeting recent Phase II trial entry criteria and patients with neuropathological confirmation. Two hundred and twenty-seven patients [male = 59%, mean age (±standard deviation), 71.8 (±7.0) years] were followed for a mean 21.6 (±15.6) months. One hundred and seventy-four (77%) had Richardson’s syndrome at the outset, 25 had cortical variant presentations (13%, frontal, corticobasal, speech and language variants) and 28 had subcortical variant presentations (14%, parkinsonism, postural instability and gait freezing variants). Across all participants, annual progression in Richardson’s syndrome was faster than variant phenotypes on the Mini-Mental State Examination (−1.8 versus −0.9/year, P = 0.005) and revised Addenbrooke’s Cognitive Examination (−5.3 versus −3.0/year, P = 0.01) but not the Progressive Supranuclear Palsy Rating Scale (9.0 versus 7.1/year, P = 0.2) nor the modified Progressive Supranuclear Palsy Rating Scale (2.7 versus 2.3/year, P = 0.4). However, for those with more than 1 years’ follow-up, a significant difference was observed between Richardson’s syndrome and variant phenotypes in Progressive Supranuclear Palsy Rating Scale (8.7 versus 6.3/year, P = 0.04). Survival was longer in variant phenotypes than Richardson’s syndrome [7.3 (±3.9) versus 5.6 (±2.0) years, P = 0.02]. Pathologically confirmed cases (n = 49) supported these findings. Patients meeting basic trial-eligibility criteria (n = 129) progressed faster on the Progressive Supranuclear Palsy Rating Scale than trial-not-eligible patients (10.1 versus 6.1/year, P = 0.001). In conclusion, phenotypes other than Richardson’s syndrome show slower progression and longer survival. Trial criteria do not select representative progressive supranuclear palsy cases. This has implications for trial design, and application of trial results to clinically more diverse patient populations., Street et al. show that progression and survival with progressive supranuclear palsy vary according to people’s symptoms and clinical trial eligibility. Common clinical trial criteria exclude many patients. Their exclusion may limit the relevance of clinical trials and affect the relative risks and benefits of future treatments for many people., Graphical Abstract Graphical Abstract

The incidence, diagnostic landscape, and workload impact of CNS inflammatory diseases other than multiple sclerosis (MS) (CIDOMS) in a tertiary setting is unknown. We describe a retrospective case series of 64 patients identified over a 2-year period (2009–2010) at the Wessex Neurological Centre in the United Kingdom, accounting for 4% of all patients seen at the center. As expected, neurosarcoidosis and neuromyelitis optica (NMO) were the most common diagnoses reached (14% each); other diagnoses singly accounted for