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Purpose of Review: The most common four neurodegenerative atypical parkinsonian disorders (APDs) are progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB). Their formal diagnostic criteria often require subspecialty experience to implement as designed and all require excluding competing diagnoses without clearly specifying how to do that. Validated diagnostic criteria are not available at all for many of the other common APDs, including normal pressure hydrocephalus (NPH), vascular parkinsonism (VP), or drug-induced parkinsonism (DIP). APDs also include conditions of structural, genetic, vascular, toxic/metabolic, infectious, and autoimmune origin. Their differential diagnosis can be challenging early in the course, if the presentation is atypical, or if a rare or non-neurodegenerative condition is present. This review equips community general neurologists to make an early provisional diagnosis before, or in place of, referral to a tertiary center. Early diagnosis would allay diagnostic uncertainty, allow prompt symptomatic management, provide disease-specific information and support resources, avoid further pointless testing and treatments, and create the possibility of trial referral., Recent Findings: We address 64 APDs using one over-arching flow diagram and a series of detailed tables. Most instances of APDs can be diagnosed with a careful history and neurological exam, along with a non-contrast brain MRI. Additional diagnostic tests are rarely needed but are delineated where applicable. Our diagnostic algorithm encourages referral to a tertiary center whenever the general neurologist feels it would be in the patient's best interest. Our algorithm emphasizes that the diagnosis of APDs is an iterative process, refined with the appearance of new diagnostic features, availability of new technology, and advances in scientific understanding of the disorders. Clinicians' proposals for all diagnostic tests for the APDs, including repeat visits, should be discussed with patients and their families to ensure that the potential information to be gained aligns with their larger clinical goals., Summary: We designed this differential diagnostic algorithm for the APDs to enhance general neurologists' diagnostic skills and confidence and to help them address the less common or more ambiguous cases., Competing Interests: M.K. Bruno: no relevant conflict of interest. She does have research funding from Michael J. Fox Foundation; R. Dhall: no relevant conflict of interest. He has received financial support from the following within the last year: Amneal pharmaceuticals, Sage Therapeutics, Neuroderm, Cerevel Therapeutics, Neurocrine, Neuraly, Alexion, Sun Pharma, Praxis Precision Medicines, Parkinson's Foundation, Aeon Biopharma, Abbvie, Pharma Two B, NIH Parent Grant #UL1TR003107 TRI Pilot Grant “Research Benefitting Rural Populations”. Dr. Dhall has received consulting revenues from Mitsubishi Tanabe Pharma America and Best Doctors. Dr. Dhall reports stock ownership (all at <$10,000) in medically related fields for Armata Pharmaceuticals, Compass Pathways, Biogen Idec, Atea Pharmaceuticals, Gilead Sciences, Imara, Inc, and SQZ Biotech; L.S. Honig: consulted for Biogen Eisai, Genentech/Roche, Medscape, and Prevail/Lilly. L.S. Honig has received research funding from Abbvie, Acumen, Alector, Biogen, Bristol-Myer Squibb, Cognition, Eisai, Genentech/Roche, Janssen/Johnson & Johnson, Eli Lilly, Transposon, UCB, and Vaccinex; Z. Mari: no relevant conflict of interest. He is immediate past Chair of the Movement Disorder Society's Telemedicine Study Group, Director of the Cleveland Clinic Lou Ruvo Center for Brain Health Parkinson's Foundation Center of Excellence, Chair of Parkinson Study Group's Motor Features WG, Associate Editor of Parkinsonism & Related Disorders, president-elect for the Clark County Medical Society, which he also is a Trustee; Z. Mari serves on the IAPRD's Congress Site Selection Committee and Website Committee, and the PPMI's Wearable Devices Task Force. Z. Mari has been recipient of institutional grant support from the NIH, PF, MJFF, Biogen, Eli Lilly, AbbVie, Cerevel, and Praxis Precision Medicines; is cofounder and CMO of Neuraly, Inc, and Z NeuroSciences LLC; is shareholder of D&D PharmaTech, NeuroReserve, Neunos Inc, and Sensory Cloud; and has received honoraria for consulting and advisory board service from GB Sciences, GKC, Bial, Supernus, AbbVie, ACADIA, Sunovion. N.R. McFarland: received research support from the NIH-NINDS, Michael J. Fox Foundation, and Parkinson Foundation. He receives royalties from UpToDate and serves on advisory committee for ONO Pharmaceutical. L. Montaser-Kouhsari received consultant fees from Darmyian, Trinity Life Sciences, Guidepoint, and Techspert, has received research support from the NIH (NINDS), and has received Talk honorarium from Cleveland Clinic. A.M. Wills: no relevant conflict of interest. She does have consulting agreements with Genentech, Amylyx, and Ono pharmaceuticals and have research funding from the NIH, Parkinson's Foundation, and CurePSP. L.I. Golbe: consults for AI Therapeutics, Amylyx, Apellis, Aprinoia, Ferrer, IQVIA, Mitochon, Mitsubishi Tanabe, P3Lab, Roche, Switch, UCB and Woolsey. He serves on advisory boards for Amylyx, CurePSP, Roche, Rossy Centre and Springer. He receives royalties from Rutgers University Press, licensing fees from Rutgers University and travel expenses from CurePSP. The rest of the authors report no relevant conflicts of interest. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Up to 10 % of Parkinson's disease (PD) populations carry a genetic risk variant, which may not only increase one's chance of developing PD but also affect disease presentation and progression. We hypothesize motor impairment in genetic carriers of PD correlate to different patterns of microstructural changes over time., Design/methods: Data were accessed from the Parkinson's Progression Markers Initiative (PPMI) project. Connectometry analyses were performed for GBA1+ PD, LRRK2+ PD, and sporadic PD correlating white matter structural changes, as measured by quantitative anisotropy (QA), with motor impairment, as measured by MDS-UPDRS III., Results: There was a negative correlation between QA and MDS-UPDRS III in all 3 cohorts at 48 months. In GBA1+ PD (n = 12), the white matter tracts identified were cortical and subcortical, while in the LRRK2+ PD (n = 18) and sporadic PD (n = 45) cohorts white tracts identified were primarily subcortical and within the brainstem., Conclusions: Our findings highlight the association between motor symptom progrerssion and structural connectivity in individuals with GBA1+ PD, LRRK2+ PD, and sporadic PD. Due to the small sample size, larger studies are needed in the future to confirm the findings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: Expedient diagnosis of incipient dementia is often hindered by time constraints in primary care visits, shortage of dementia specialists, and extended waitlists for comprehensive neuropsychological evaluations., Methods: We developed the Rapid Access Memory Program (RAMP) to improve access of neuropsychological services for older adults presenting to our institutional primary care clinics with concerns of cognitive decline. RAMP provides abbreviated neurocognitive assessment, same-day patient feedback, expedited reporting to referring providers, and is financially self-supported. Here, we describe development of RAMP and clinical outcomes from the first 3 years., Results: Of 160 patients seen, dementia was diagnosed in 30% and Mild Cognitive Impairment in 50%; Alzheimer's disease was the most common suspected etiology. New psychiatric diagnosis was made in about one-third (n = 54). Most frequent recommendations involved medication adjustments (initiating cholinesterase inhibitors, deprescribing anticholinergics), safety (driving, decision-making), and specialist referrals. Additionally, 27 (17%) subsequently enrolled in local research., Conclusions: Results support feasibility and utility of RAMP for connecting older adults in primary care with neuropsychological services., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer's disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)-parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners., (© 2024. The Author(s).)

Background: Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that lead to involuntary postures or repetitive movements. Genetic mutations are being increasingly recognized as a cause of dystonia. Deep brain stimulation (DBS) is one of the limited treatment options available. However, there are varying reports on its efficacy in genetic dystonias. This systematic review of the characteristics of genetic dystonias treated with DBS and their outcomes aims to aid in the evaluation of eligibility for such treatment., Methods: We performed a PUBMED search of all papers related to genetic dystonias and DBS up until April 2022. In addition to performing a systematic review, we also performed a meta-analysis to assess the role of the mutation on DBS response. We included cases that had a confirmed genetic mutation and DBS along with pre-and post-operative BFMDRS., Results: Ninety-one reports met our inclusion criteria and from them, 235 cases were analyzed. Based on our analysis DYT-TOR1A dystonia had the best evidence for DBS response and Rapid-Onset Dystonia Parkinsonism was among the least responsive to DBS., Conclusion: While our report supports the role of genetics in DBS selection and response, it is limited by the rarity of the individual genetic conditions, the reliance on case reports and case series, and the limited ability to obtain genetic testing on a large scale in real-time as opposed to retrospectively as in many cases., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest relevant to this work., (Copyright © 2023. Published by Elsevier B.V.)

Background: Post-stroke movement disorders (PSMD) encompass a wide array of presentations, which vary in mode of onset, phenomenology, response to treatment, and natural history. There are no evidence-based guidelines on the diagnosis and treatment of PSMD., Objectives: To survey current opinions and practices on the diagnosis and treatment of PSMD., Methods: A survey was developed by the PSMD Study Group, commissioned by the International Parkinson's and Movement Disorders Society (MDS). The survey, distributed to all members, yielded a total of 529 responses, 395 (74.7%) of which came from clinicians with experience with PSMD., Results: Parkinsonism (68%), hemiballismus/hemichorea (61%), tremor (58%), and dystonia (54%) were by far the most commonly endorsed presentation of PSMD, although this varied by region. Basal ganglia stroke (76% of responders), symptoms contralateral to stroke (75%), and a temporal relationship (59%) were considered important factors for the diagnosis of PSMD. Oral medication use depended on the phenomenology of the PSMD. Almost 50% of respondents considered deep brain stimulation and ablative surgeries as options for treatment. The lack of guidelines for the diagnosis and treatment was considered the most important gap to address., Conclusions: Regionally varying opinions and practices on PSMD highlight gaps in (and mistranslation of) epidemiologic and therapeutic knowledge. Multicenter registries and prospective community-based studies are needed for the creation of evidence-based guidelines to inform the diagnosis and treatment of patients with PSMD., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Decrements in verbal fluency following deep brain stimulation (DBS) in people with Parkinson's disease (PwP) are common. As such, verbal fluency tasks are used in assessing DBS candidacy and target selection. However, the correspondence between testing performance and the patient's perception of communication abilities is not well-established., Methods: The Communication Participation Item Bank (CPIB) was administered to 85 PwP during pre-DBS neuropsychological evaluations. Central tendencies for CPIB responses and correlations between CPIB total scores, clinical and demographic factors, and language-based tasks were examined., Results: Most PwP indicated some degree of communication interference on the CPIB. Worse scores on semantic fluency and greater motor impairment were associated with more communication interference., Conclusions: Our findings suggest an incomplete correspondence between commonly used language-based tests and patient-reported outcomes of communication abilities. The need for a functional communication instrument that reflects the different aspects of communication abilities in functional contexts is emphasized., (© 2023 International Parkinson and Movement Disorder Society.)

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Cognitive deficits within the first years of Parkinson's disease (PD) diagnosis are commonly reported, and progression to dementia greatly impacts independence. Identifying measures sensitive to early changes is critical for trials of symptomatic therapies and neuroprotection., Methods: A sample of 253 newly diagnosed PD patients and 134 Health Controls (HC) completed a brief cognitive battery annually over a 5-year period through the Parkinson's Progression Markers Initiative (PPMI). The battery included standardized measures of memory, visuospatial functions, processing speed, working memory, and verbal fluency. Inclusion criterion for HCs was performance above a cutoff for possible Mild Cognitive Impairment (pMCI) on cognitive screening (MoCA ⩾ 27) The PD sample was therefore divided to match HCs on baseline cognitive testing (PD-normal n = 169; PD-pMCI n = 84). The multivariate approach to repeated measures examined rates of change between groups on cognitive measures., Results: An interaction indicating slightly greater decline over time in PD-normal relative to HCs was observed on a measure of working memory: letter-number sequencing. Differential rates of change were not observed on any other measures. Motor symptoms on the dominant right upper extremity accounted for performance differences on a test with writing demands (Symbol-Digit Modality Test). PD-pMCI performed worse than PD-normal on all cognitive measures at baseline, but did not decline faster., Discussion: Working memory appears to decline slightly faster in early PD compared to HCs, while other domains remain similar. Within PD, faster decline was not associated with lower baseline cognition. These findings have implications for clinical trial outcome selection and study design., (Copyright © 1964–2023 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co-pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co-pathologies in DLB and their cross-sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease-specific and disease-nonspecific biomarkers and how co-pathologies can impact these biomarkers. We propose a framework for integrating multi-modal biomarker fingerprints and step-wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co-pathologies., (© 2022 the Alzheimer's Association.)

Background: Complex visual hallucinations (VH) are a common complication of Parkinson's disease (PD). Recent studies have demonstrated relevance of face pareidolia to VH in PD and Lewy body dementia (LBD)., Objective: This study examined utility of the 20-item Noise Pareidolia Task (NPT-20) in assessing visuoperceptual disturbances associated with VH in PD., Methods: Retrospective chart review included 46 consecutive PD patients who completed NPT-20 during clinical neuropsychological evaluation., Results: About half the sample (43%) reported VH. PD with VH made significantly more false-positive pareidolia errors on the NPT-20 ( p  < 0.0001). A cut-off of 2 errors yielded 40% sensitivity, 100% specificity to VH; cut-off of 1 yielded 75% sensitivity, 81% specificity. NPT-20 was not associated with any other clinical or demographic factor. Across groups, NPT-20 evinced moderate correlations with visuospatial functioning and visual memory., Conclusions: Current findings support utility of the NPT-20 for evaluating visuoperceptual disturbances associated with VH in PD., (© 2022 International Parkinson and Movement Disorder Society.)

Poststroke movement disorders (PSMDs) are a common cause of secondary movement disorders. Although prior studies have highlighted the clinical spectrum and phenomenology of PSMDs, there are many knowledge gaps worth addressing. Some of the most important include lack of clinical definitions, variable stroke symptom latencies, and lack of biomarkers for vulnerability for or resilience against developing PSMDs. Collectively, the association between stroke localization and phenomenology is less than 30%, and the long-term clinical prognosis and treatment responses are highly variable. After summarizing the accumulated evidence regarding the phenomenology, pathophysiology, neuroimaging, and treatment of PSMDs, highlighting the many gaps and controversies including diagnostic challenges, we propose a roadmap for future research to fill these gaps and resolve the related controversies. More research is warranted concerning the phenomenology, classification, diagnostic criteria, and pathophysiology of PSMDs. Further, there is an urgent need for treatment guidelines for the management of PSMDs. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Background: The reliability of the Progressive Supranuclear Palsy Rating Scale (PSPRS) using teleneurology has not been assessed., Objectives: To test whether removing items inadequately assessed by video would impact measurement of PSP severity and progression., Methods: We performed secondary analyses of two data sets: the phase 2/3 trial of Davunetide in PSP and a large single-center cohort. We examined two modifications of the PSPRS: (1) removing neck rigidity, limb rigidity, and postural stability (25 items; mPSPRS-25) and (2) also removing three ocular motor items and limb dystonia (21 items; mPSPRS-21). Proportional agreement relative to the possible total scores was measured using the intraclass correlation coefficient, compared to the original PSPRS baseline values and change over 6 and 12 months. We examined the ability of both scales to predict survival in the single-center cohort using proportional hazards models., Results: The mPSPRS-25 showed excellent agreement (0.99; P < 0.001) with the original PSPRS at baseline, 0.98 (P < 0.001) agreement in measuring change over 6 months, and 0.98 (P < 0.001) over 12 months. The mPSPRS-21 showed agreement of 0.94 (P < 0.001) with the original PSPRS at baseline, 0.92 (P < 0.001) at 6 months, and 0.95 (P < 0.001) at 12 months. Baseline and 6-month change in both modified scales were highly predictive of survival in the single-center cohort., Conclusions: Modified versions of the PSPRS which can be administered remotely show excellent agreement with the original scale and predict survival in PSP. The mPSPRS-21 should facilitate clinical care and research in PSP via teleneurology. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer's or Parkinson's disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials., (© 2022. The Author(s).)

Background: This investigation examined whether aspects of attention and executive functioning differed between Parkinson's Disease (PD) patients with freezing of gait (FOG) based on responsiveness to dopamine. We also explored association of cognition with FOG severity and gait metrics., Methods: Fifty-four individuals with PD completed the study protocol: 17 without freezing (PDC), 23 with dopa-responsive FOG (RFOG), and 14 with dopa-unresponsive (URFOG). Standardized neuropsychological tests assessed attention (focused and sustained), psychomotor speed, and set-switching (time and errors). FOG severity was measured using the new FOG Questionnaire (nFOG-Q). Metrics from timed up and go (TUG) tasks were obtained while "on" and "off" dopamine, with and without dual cognitive tasks., Results: After controlling for clinical and demographic factors, analysis of covariance revealed a significant between-group difference for set-switching errors; planned contrasts revealed increased set-switching errors in URFOG relative to RFOG and PD control groups. Groups were not different in other cognitive domains. FOG severity was modestly associated with set-switching errors in RFOG but not URFOG. TUG performances while "on" were associated with set-switching errors in PD controls, and with focused attention in RFOG., Conclusion: PD patients with dopa-unresponsive FOG are more prone to set-switching errors than those who respond to treatment. Furthermore, executive function appears relevant to FOG severity only in patients who show dopamine response. Together, these findings suggest disruption of a common dopamine-mediated pathway for FOG and ability to monitor rules while alternating cognitive processes. Consideration of dopa-response could be useful in characterizing cohorts and treating FOG in PD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To evaluate whether orthostatic hypotension (OH) or supine hypertension (SH) is associated with brain atrophy and white matter hyperintensities (WMH), we analyzed clinical and radiologic data from a large multicenter consortium of patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB)., Methods: Supine and orthostatic blood pressure (BP) and structural MRI data were extracted from patients with PD and DLB evaluated at 8 tertiary-referral centers in the United States, Canada, Italy, and Japan. OH was defined as a systolic/diastolic BP fall ≥20/10 mm Hg within 3 minutes of standing from the supine position (severe ≥30/15 mm Hg) and SH as a BP ≥140/90 mm Hg with normal sitting BP. Diagnosis-, age-, sex-, and disease duration-adjusted differences in global and regional cerebral atrophy and WMH were appraised with validated semiquantitative rating scales., Results: A total of 384 patients (310 with PD, 74 with DLB) met eligibility criteria, of whom 44.3% (n = 170) had OH, including 24.7% (n = 42) with severe OH and 41.7% (n = 71) with SH. OH was associated with global brain atrophy ( p = 0.004) and regional atrophy involving the anterior-temporal ( p = 0.001) and mediotemporal ( p = 0.001) regions, greater in severe vs nonsevere OH ( p = 0.001). The WMH burden was similar in those with and without OH ( p = 0.49). SH was not associated with brain atrophy ( p = 0.59) or WMH ( p = 0.72)., Conclusions: OH, but not SH, was associated with cerebral atrophy in Lewy body disorders, with prominent temporal region involvement. Neither OH nor SH was associated with WMH., (© 2021 American Academy of Neurology.)

Performance in verbal fluency tasks are widely used as a marker of cognitive impairment in Parkinson disease. However, the anatomical substrate of its impairment remains undetermined. Based on the dual-stream language model, we hypothesized cortical input to the subcortical circuitry would be a crucial determinant of fluency. We performed a retrospective study using individual whole-brain structural connectomes derived from 135 individuals with PD and assessed the relationship between white matter integrity and verbal fluency tasks. Controlling for multiple factors, including dysarthria, we observed higher integrity of dorsal stream-caudate connectivity was associated with better letter fluency. This preliminary study indicates the possible dissociation between dorsal and ventral stream connectivity and letter fluency in PD. In addition, it suggests a non-motor role of the frontostriatal fibers in letter fluency., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; the most common phenotype of corticobasal degeneration) are tauopathies with a relentless course, usually starting in the mid-60s and leading to death after an average of 7 years. There is as yet no specific or disease-modifying treatment. Clinical deficits in PSP are numerous, involve the entire neuraxis, and present as several discrete phenotypes. They center on rigidity, bradykinesia, postural instability, gait freezing, supranuclear ocular motor impairment, dysarthria, dysphagia, incontinence, sleep disorders, frontal cognitive dysfunction, and a variety of behavioral changes. CBS presents with prominent and usually asymmetric dystonia, apraxia, myoclonus, pyramidal signs, and cortical sensory loss. The symptoms and deficits of PSP and CBS are amenable to a variety of treatment strategies but most physicians, including many neurologists, are reluctant to care for patients with these conditions because of unfamiliarity with their multiplicity of interacting symptoms and deficits. CurePSP, the organization devoted to support, research, and education for PSP and CBS, created its CurePSP Centers of Care network in North America in 2017 to improve patient access to clinical expertise and develop collaborations. The directors of the 25 centers have created this consensus document outlining best practices in the management of PSP and CBS. They formed a writing committee for each of 12 sub-topics. A 4-member Steering Committee collated and edited the contributions. The result was returned to the entire cohort of authors for further comments, which were considered for incorporation by the Steering Committee. The authors hope that this publication will serve as a convenient guide for all clinicians caring for patients with PSP and CBS and that it will improve care for patients with these devastating but manageable disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bluett, Pantelyat, Litvan, Ali, Apetauerova, Bega, Bloom, Bower, Boxer, Dale, Dhall, Duquette, Fernandez, Fleisher, Grossman, Howell, Kerwin, Leegwater-Kim, Lepage, Ljubenkov, Mancini, McFarland, Moretti, Myrick, Patel, Plummer, Rodriguez-Porcel, Rojas, Sidiropoulos, Sklerov, Sokol, Tuite, VandeVrede, Wilhelm, Wills, Xie and Golbe.)

Objective: We sought to evaluate demographic, clinical, and habits/occupational variables between phenotypic extremes in Parkinson's disease (PD)., Methods: Databases from nine movement disorders centers across seven countries were retrospectively searched for subjects meeting criteria for very slowly progressive, benign, PD (bPD) and rapidly progressive, malignant, PD (mPD). bPD was defined as Hoehn and Yahr (H&Y) stage ≤ 3, normal cognitive function, and Schwab and England (S&E) score ≥ 70 after ≥ 20 years of PD (≥ 10 years if older than 60 at PD onset); mPD as H&Y > 3, S&E score < 70, and cognitive impairment within 10 years from PD onset. We performed between-group analysis of demographic, habits/occupational, and clinical features at baseline and follow-up and unsupervised data-driven analysis of the clinical homogeneity of bPD and mPD., Results: At onset, bPD subjects (n = 210) were younger, had a single limb affected, lower severity and greater asymmetry of symptoms, and lower prevalence of depression than mPD (n = 155). bPD was associated with active smoking and physical activity, mPD with agricultural occupation. At follow-up, mPD showed higher prevalence of depression, hallucinations, dysautonomia, and REM behaviour disorder. Interestingly, the odds of mPD were significantly reduced by the presence of dyskinesia and wearing-off. Data-driven analysis confirmed the independent clustering of bPD and mPD, with age at onset emerging as a critical discriminant between the two groups (< 46-year-old vs. > 68-year-old)., Conclusions: Phenotypic PD extremes showed distinct demographic, clinical, and habits/occupational factors. Motor complications may be conceived as markers of therapeutic success given their attenuating effects on the odds of mPD.

Background: Movement disorders are frequent features of prionopathies. However, their prevalence and onset remain poorly described., Methods: We performed a systematic review of case reports and case series of pathologically- and genetically confirmed prionopathies. Timing of symptom and movement disorder onset were documented. Continuous variables were compared between two groups using the Wilcoxon rank sum test and between multiple groups using Kruskal-Wallis test. Categorical variables were compared using Fisher's exact test., Results: A total of 324 cases were included in this analysis. Movement disorders were a common feature at the onset of symptoms in most prionopathies. Gait ataxia was present in more than half of cases in all types of prionopathies. The prevalence of limb ataxia (20%) and myoclonus (24%) was lower in Gerstmann-Sträussler-Scheinker disease compared to other prionopathies (p ≤ 0.004). Myoclonus was common but often a later feature in sporadic Creutzfeldt-Jakob disease (2 months before death). Chorea was uncommon but disproportionately prevalent in variant Creutzfeldt-Jakob disease (30% of cases; p < 0.001). In genetic Creutzfeldt-Jakob disease, E200K PRNP carriers exhibited gait and limb ataxia more often when compared to other mutation carriers., Discussion: Movement disorders are differentially present in the course of the various prionopathies. The movement phenomenology and appearance are associated with the type of prion disease and the PRNP genotype and likely reflect the underlying pattern of neurodegeneration. Reliance on myoclonus as a diagnostic feature of sporadic Creutzfeldt-Jakob disease may delay its recognition given its relatively late appearance in the disease course., Competing Interests: Funding: None. Conflicts of Interest: The authors report no conflicts of interest. Ethics Statement: Not applicable for this category of article., (© 2019 Rodriguez-Porcel et al.)

Objective: Review the effect of orthostatic hypotension (OH) and rapid-eye-movement sleep behavioural disorder (RBD) on survival, cognitive impairment and postural stability, and discuss pathogenic mechanisms involved in the association of these two common non-motor features with relevant clinical outcomes in α-synucleinopathies., Methods: We searched PubMed (January 2007-February 2019) for human studies of OH and RBD evaluating cognitive impairment, postural instability, and survival in Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and pure autonomic failure (PAF). Included studies were analysed for design, key results and limitations as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines., Results: OH and RBD showed a positive association with cognitive impairment in PD and DLB, conflicting association in PAF, and no association in MSA. OH was correlated with incident falls and postural instability in PD and DLB but not in MSA. The association between RBD and postural instability was inconclusive; positive in five studies, negative in seven. OH, but not RBD, correlated with reduced survival in PD, DLB and MSA. The combination of OH and RBD was associated with cognitive impairment and more rapid progression of postural instability., Conclusions: OH and RBD yielded individual and combined negative effects on disability in α-synucleinopathies, reflecting a 'malignant' phenotype of PD with early cognitive impairment and postural instability. Underlying mechanisms may include involvement of selected brainstem cholinergic and noradrenergic nuclei., Competing Interests: Competing interests: AP received speaker honoraria from BioMarin Pharmaceutical, Chiesi Pharmaceuticals, Nutricia Pharmaceuticals, UCB Pharma and Zambon Pharmaceuticals. He received travel grants from AbbVie Pharmaceuticals, BioMarin Pharmaceutical, Nutricia Pharmaceuticals, Zambon Pharmaceuticals and the Italian movement disorder society. AR received speaker honoraria from AbbVie and Chiesi Pharmaceuticals and travel grants from Medtronic, Lusofarmaco and UCB Pharma. JAT has no financial conflicts to disclose. JAV has no financial conflicts to disclose. LM has no financial conflicts to disclose. MZ received speaker honoraria from AbbVie, Medtronic, Zambon and UCB Pharma and received travel grants from AbbVie. MR has no financial conflicts to disclose. FR-P has no financial conflicts to disclose. BB has no financial conflicts to disclose. MCR has no financial conflicts to disclose. CR received speaker honoraria from Zambon and UCB Pharma and received travel grants from Zambon, UCB Pharma, Medtronic and Chiesi Pharmaceuticals. DV-E has no financial conflicts to disclose. JRM has received research support from Axovant. She is also an editorial board member for NEJM Journal Watch Neurology. Leonardo Lopiano received honoraria for lecturing and travel grants from Medtronic, UCB Pharma, and AbbVie. RC received speaker honoraria from General Electric, AbbVie, UCB Pharma, Zambon. He received consulting fees from General Electric and Zambon and grant support from Ministry of Health (MINSAL). MM receives salary support from the Department of Medicine at Sunnybrook Health Sciences Centre and the University of Toronto, as well as the Sunnybrook Research Institute. He has received grants/research Support from: Parkinson Canada, Canadian Institutes of Health Research, Teva, Early Researcher Award - Ministry of Economic Development and Innovation, C5R, Weston Brain Institute, Ontario Brain Institute, Sunnybrook AFP Innovation Fund, Novartis, Washington University, Roche, Alzheimer’s Drug Discovery Foundation (ADDF), Brain Canada, Heart and Stroke Foundation Centre for Stroke Recovery. He has received consulting Fees from UCB, Ionis, Novartis, and Arkuda Therapeutics, as well as royalties from Henry Stewart Talks Ltd. Alberto Espay has received grant support from the NIH, Great Lakes Neurotechnologies and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, Adamas, Acadia, Acorda, Neuroderm, TEVA, Impax, Sunovion, Lundbeck, Osmotica Pharmaceutical and USWorldMeds; publishing royalties from Lippincott Williams and honoraria from Abbvie, UCB, USWorldMeds, Lundbeck, Acadia, Sunovion, the American Academy of Neurology and the Movement Disorders Society. AP received grant support from Ministry of Health (MINSAL) and Ministry of Education, Research and University (MIUR), from CARIPLO Foundation; personal compensation as a consultant/scientific advisory board member for Avanir, Lundbeck, Eli-Lilly, Neuraxpharma, Biogen, GE Health. AM is supported by NIH (KL2 TR001426) and has received speaker honoraria from CSL Behring, Cynapsus Therapeutics, Lundbeck, AbbVie, and Abbott. He has received grant support from Lundbeck and Abbott., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Abnormal movements are a relatively uncommon complication of strokes. Besides the known correlation between stroke location and certain movement disorders, there remain uncertainties about the collective effects of age and stroke mechanism on phenomenology, onset latency, and outcome of abnormal movements., Materials and Methods: We systematically reviewed all published cases and case series with adequate clinical-imaging correlations. A total of 284 cases were analyzed to evaluate the distribution of different movement disorders and their association with important cofactors., Results: Posterolateral thalamus was the most common region affected (22.5%) and dystonia the most commonly reported movement disorder (23.2%). The most common disorders were parkinsonism (17.4%) and chorea (17.4%) after ischemic strokes and dystonia (45.5%) and tremor (19.7%) after hemorrhagic strokes. Strokes in the caudate and putamen were complicated by dystonia in one third of the cases; strokes in the globus pallidus were followed by parkinsonism in nearly 40%. Chorea was the earliest poststroke movement disorder, appearing within hours, whereas dystonia and tremor manifested several months after stroke. Hemorrhagic strokes were responsible for most delayed-onset movement disorders (>6 months) and were particularly overrepresented among younger individuals affected by dystonia., Conclusions: This evidence-mapping portrait of poststroke movement disorders will require validation or correction based on a prospective epidemiologic study. We hypothesize that selective network vulnerability and resilience may explain the differences observed in movement phenomenology and outcomes after stroke., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: The motor subscale of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) has limited applicability for the assessment of motor fluctuations in the home setting., Methods: To assess whether a self-administered, tablet-based application can reliably quantify differences in motor performance using two-target finger tapping and forearm pronation-supination tasks in the ON (maximal dopaminergic medication efficacy) and OFF (reemergence of parkinsonian deficits) medication states, we recruited 11 Parkinson disease (PD) patients (age, 60.6 ± 9.0 years; disease duration, 12.8 ± 4.1 years) and 11 healthy age-matched controls (age, 62.5 ± 10.5 years). The total number of taps, tap interval, tap duration, and tap accuracy were algorithmically calculated by the application, using the more affected side in patients and the dominant hand in healthy controls., Results: Compared to the OFF state, PD patients showed a higher number of taps (84.2 ± 20.3 vs. 54.9 ± 26.9 taps; p = 0.0036) and a shorter tap interval (375.3 ± 97.2 vs. 708.2 ± 412.8 ms; p = 0.0146) but poorer tap accuracy (2,008.4 ± 995.7 vs. 1,111.8 ± 901.3 pixels; p = 0.0055) for the two-target task in the ON state, unaffected by the magnitude of coexistent dyskinesia. Overall, test-retest reliability was high ( r >0.75) and the discriminatory ability between OFF and ON states was good (0.60 ≤ AUC ≤ 0.82). The correlations between tapping data and MDS-UPDRS-III scores were only moderate (-0.55 to 0.55)., Conclusions: A self-administered, tablet-based application can reliably distinguish between OFF and ON states in fluctuating PD patients and may be sensitive to additional motor phenomena, such as accuracy, not captured by the MDS-UPDRS-III., Competing Interests: B.D.W. is supported by the NIH (T32GM063483-14). G.M. is the founder and CEO of Apptomics, Inc. A.K.D. is supported by the NIH as a co-investigator (1R01HL125016-01) and as a collaborator (R21 AI118228). He has also been serving as a statistician in 4 CPRIT grants (PP110156, PP140211, PP150031, and PP130083), Coldwell (co-investigator), and MSA Coalition (collaborator) and as a principal investigator in a TTUHSC ELP mini seed grant. He is a director of biostatistics and epidemiology consulting laboratory at the TTUHSC ELP. S.P. is a full-time employee at TEVA Pharmaceuticals and co-chair of the Task Force on Technology for the International Parkinson and Movement Disorder Society. S.K., J.R.L.C., and E.S. have nothing to disclose. A.P.D. has served as a consultant for Merz Pharma, US WorldMeds, and Auspex Pharmaceuticals and has received honoraria from UCB. F.R.-P., J.V., L.L., I.T., and A.S. have nothing to disclose. A.J.E. is the chair of the Task Force on Technology for the International Parkinson and Movement Disorder Society, is supported by the NIH, and has received grant support from Cleveland Medical Devices Inc./Great Lakes NeuroTechnologies, the Davis Phinney Foundation, and the Michael J. Fox Foundation; personal compensation as a consultant/scientific advisory board member for Solvay, Abbott, Chelsea Therapeutics, TEVA, Impax, Merz, Lundbeck, and Eli Lilly; honoraria from TEVA, UCB, the American Academy of Neurology, and the Movement Disorder Society; and publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer. He has no financial interests in, nor has received compensation from, iMotor or Apptomics, Inc., (Copyright © 2018 by S. Karger AG, Basel.)

Idiopathic normal pressure hydrocephalus (NPH) remains both oversuspected on clinical grounds and underconfirmed when based on immediate and sustained response to cerebrospinal fluid diversion. Poor long-term postshunt benefits and findings of neurodegenerative pathology in most patients with adequate follow-up suggest that hydrocephalic disorders appearing in late adulthood may often result from initially unapparent parenchymal abnormalities. We critically review the NPH literature, highlighting the near universal lack of blinding and controls, absence of specific clinical, imaging, or pathological features, and ongoing dependence for diagnostic confirmation on variable cutoffs of gait response to bedside fluid-drainage testing. We also summarize our long-term institutional experience, in which postshunt benefits in patients with initial diagnosis of idiopathic NPH persist in only 32% of patients at 36 months, with known revised diagnosis in over 25% (Alzheimer's disease, dementia with Lewy bodies, and progressive supranuclear palsy). We postulate that previously reported NPH cases with "dual" pathology (ie, developing a "second" disorder) more likely represent ventriculomegalic presentations of selected neurodegenerative disorders in which benefits from shunting may be short-lived, with a consequently unfavorable risk-benefit ratio. Ann Neurol 2017;82:503-513., (© 2017 American Neurological Association.)

Background: Disruption of the frontal lobes and its associated networks are a common consequence of neurodegenerative disorders. Given the wide range of cognitive, behavioral and motor processes in which the frontal lobes are involved, there can be a great variety of manifestations depending on the pathology distribution. The most common are the behavioral variant of frontotemporal dementia (bvFTD) and the frontal variant of Alzheimer's disease (fvAD), which are particularly challenging to disentangle. Recognizing fvAD from bvFTD-related pathologies is a diagnostic challenge and a critical need in the management and counseling of these patients., Case Presentation: Here we present three pathology-proven cases of Alzheimer's disease initially misdiagnosed as bvFTD and discuss the distinctive or less overlapping historical, examination, and laboratory findings of fvAD and bvFTD, deriving analogies for mnemonic endurance from the Wizard of Oz worldview., Conclusion: The Yellow Brick Road to diagnosing these disorders may be served by the metaphor of fvAD as the irritable, paranoid, and tremulous Scarecrow and bvFTD the heartless, ritualistic, and rigid Tin Man. An Oz-inspired creative license may help the clinician recognize the differential disease progression, caregiver burden, and treatment response of fvAD compared with bvFTD.

Given the wide range of manifestations of parkinsonism and its mimics, the diagnosis may remain elusive or be misattributed in some patients. Dopamine transporter (DAT) single photon emission computed tomography (SPECT) (DaTscan), an imaging technique that probes the integrity of the presynaptic nigrostriatal system, can be useful in the evaluation of clinically complex parkinsonian disorders in the appropriate context and when adequately interpreted. Pearls and pitfalls in the use of DaTscan for the differential diagnosis of parkinsonisms are reviewed using a case-based format. While the DaTscan is no replacement for a careful neurological examination in ascertaining the likelihood of Parkinson disease or other parkinsonisms in most clinical scenarios, it can be useful in the assessment of disorders where an abducting resting tremor, a prominent postural tremor, or incongruent features are not sufficiently clear on exam to distinguish neurodegenerative parkinsonism from dystonia, drug-induced parkinsonism and functional (psychogenic) parkinsonism, respectively.

Immune reconstitution inflammatory syndrome (IRIS) refers to the presence of paradoxical clinical deterioration attributable to immune system recovery during highly active antiretroviral therapy (HAART). We present an immunocompetent patient with multifocal leukoencephalopathy on HAART, with central nervous system (CNS) IRIS pathology of unknown infectious etiology. CNS IRIS pathology should be suspected in patients on longstanding HAART without immune reconstitution, presenting with unexplained leukoencephalopathy.

Tumors or chronic inflammatory lesions of the occipital condyle may cause occipital pain associated with an ipsilateral hypoglossal nerve injury (occipital condyle syndrome). We describe a young woman with recurrent otitis media and occipital condyle syndrome associated with a limited form of Wegener's disease.

Serotonin (5-HT) plays a key role in early brain development, and manipulation of 5-HT levels during this period can have lasting neurobiological and behavioral consequences. It is unclear how perinatal exposure to drugs, such as selective serotonin reuptake inhibitors (SSRIs), impacts cortical neural network function and what mechanism(s) may elicit the disruption of normal neuronal connections/interactions. In this article, we report on cortical wiring organization after pre- and postnatal exposure to the SSRI citalopram. We show that manipulation of 5-HT during early development in both in vitro and in vivo models disturbs characteristic chemoarchitectural and electrophysiological brain features, including changes in raphe and callosal connections, sensory processing, and myelin sheath formation. Also, drug-exposed rat pups exhibit neophobia and disrupted juvenile play behavior. These findings indicate that 5-HT homeostasis is required for proper brain maturation and that fetal/infant exposure to SSRIs should be examined in humans, particularly those with developmental dysfunction, such as autism.

We have demonstrated that neonatal exposure to selective serotonin reuptake inhibitors has lasting effects on behavior and serotonergic neurons in Long Evans rats. Hyperserotoninemia and altered sensory processing are reported in autistic spectrum disorders (ASD). We hypothesized that early life exposure to SSRIs alters sensory processing, disrupts responses to novelty, and impairs social interactions in a manner similar to that observed in ASD. Male and female Long-Evans rat pups were administered citalopram, buproprion, fluoxetine, or saline from postnatal day (P) 8-21. Rats were tested for response to a novel tone before weaning (P25). Later, rats were tested 2× for response to a novel object (P39), and to a novel conspecific (P78, P101). In addition, rats were assessed for juvenile play behaviors (P32-P34) and later, we assessed sexual response to an estrus female in male rats (P153-184). Antidepressant exposure increased freezing after tone, diminished novel object exploration, and reduced conspecific interaction up to 3× compared to saline exposed rats. Juvenile play was profoundly reduced in antidepressant-exposed males when compared to saline exposed groups. Exposure to the SSRIs, but not bupropion disrupted male sexual behaviors. Moreover, specific male responses to female proceptive behaviors were disrupted in SSRI, but not bupropion exposed rats. We conclude that neonatal exposure to antidepressants in rats results in sensory and social abnormalities that parallel many of those reported in ASD., (Copyright © 2011 Wiley-Liss, Inc.)