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Introduction Cognitive impairment is common in Parkinson's Disease, but the impact of predictive factors on incidence and rate of cognitive decline is incompletely understood. We aimed to determine the effects of sex and APOE allele status on cognitive performance in patients with Parkinson's Disease (PD). Material and methods We conducted a retrospective analysis of 325 clinically diagnosed PD patients who underwent one or more cognitive screenings with a Mini-Mental Status Examination (MMSE) or Mattis Dementia Rating Scale (DRS-2). We used proportional odds regression models to estimate odds ratios for higher versus lower cognitive scores in association with age, sex, education, disease duration, and APOE allele status. Results Higher cognitive scores were independently associated with female sex on the MMSE (OR 2.43; 95% CI 1.14, 5.14) and DRS-2 total (OR 4.14; 95% CI 2.01, 8.53). APOE e4 dose was associated with lower DRS-2 totals (OR 0.42; 95% CI 0.22, 0.81), but there was no evidence of association with MMSE. Higher education level was also associated with higher scores on the MMSE (OR 1.22; 95% CI 1.07, 1.38) and DRS-2 total (OR 1.31; 95% CI 1.15, 1.50). Disease duration was not associated with cognitive performance on any measure when adjusting for age. Conclusion Male sex and APOE e4, along with age and lower education level, were associated with poorer cognitive performance among a population of predominantly non-demented PD patients.

Introduction We examined the temporal sequence of the core features in probable dementia with Lewy bodies (DLB). Methods In 488 patients with probable DLB, the onset of each core feature and time to diagnosis was determined for men and women, and a pathologic subgroup (n = 209). Results REM sleep behavior disorder (RBD) developed before the other core features in men and women. Men were more likely to have RBD and were diagnosed with probable DLB earlier than women. Visual hallucinations developed after the other core features in men, but in women, they appeared earlier and concurrently with fluctuations and parkinsonism. Women were older and more cognitively impaired at first visit, were less likely to have RBD, more likely to be diagnosed with probable DLB later than men, and more likely to have neocortical tangles. Discussion An earlier latency to probable DLB was associated with men, RBD, and Lewy body disease without neocortical tangles.

Introduction Accumulation of polyglutamine (polyQ) ataxin-3 (ATXN3) contributes to the pathobiology of spinocerebellar ataxia type 3 (SCA3). Recently, we showed that polyQ ATXN3 is elevated in the plasma and cerebrospinal fluid (CSF) of SCA3 patients, and has the potential to serve as a biological marker for this disease [1]. Based on these findings, we investigated whether polyQ ATXN3 can also be detected in urine samples from SCA3 patients. Methods We analyzed urine samples from 30 SCA3 subjects (including one pre-symptomatic subject), 35 subjects with other forms of ataxia, and 37 healthy controls. To quantify polyQ ATXN3 protein levels, we used our previously developed immunoassay. Results PolyQ ATXN3 can be detected in the urine of SCA3 patients, but not in urine samples from healthy controls or other forms of ataxia. There was a significant statistical association between polyQ ATXN3 levels in urine samples and those in plasma. Further, the levels of polyQ ATXN3 urine associated with an earlier age of SCA3 disease onset. Conclusion As clinical trials for SCA3 advance, urine polyQ ATXN3 protein has potential to be a useful, non-invasive and inexpensive biomarker for SCA3.

Background Colony-stimulating factor-1 receptor (CSF1R)-related leukoencephalopathy is a rapidly progressive neurodegenerative disease for which there is currently no cure. Hematopoietic stem cell transplantation (HSCT) has been proposed as a disease-modifying treatment. Objective The objective of this study was to determine the effect of HSCT on disease progression. Methods We collected all available clinical data from a cohort of 7 patients with CSF1R-related leukoencephalopathy who underwent HSCT at our institutions. Clinical data included detailed neurological examination by a board-certified neurologist, serial cognitive screens, formal neuropsychological evaluations, and serial brain magnetic resonance imaging (MRI). Results Our patients had an average disease duration of 27.6 months at the time of transplant, and we have 87 months of total posttransplant follow-up time (median, 11; range, 2-27). One patient died in the periprocedural period. The remaining patients showed a variable response to treatment, with 6 of 7 patients trending toward stabilization on motor examination, cognitive scores, and/or MRI abnormalities, especially with white matter lesion burden. Conclusions This is the largest series of patients with CSF1R-related leukoencephalopathy receiving HSCT. We conclude that HSCT can stabilize the disease in some patients. Variability in patient responsiveness suggests that measures of disease heterogeneity and severity need to be considered when evaluating a patient's candidacy for transplant. HSCT appears to be the first disease-modifying therapy for CSF1R-related leukoencephalopathy. This milestone may serve as a foothold toward better understanding the disease's pathomechanism, thus providing new opportunities for better disease-specific therapies. © 2021 International Parkinson and Movement Disorder Society.

Background: With increasing demand for neurologists, nontraditional health care delivery mechanisms have been developed to leverage this limited resource. Introduction: Telemedicine has emerged as ...

The global prevalence of dementia is expected to triple by the year 2050. This impending health care crisis has led to new heights of public awareness and general concern regarding cognitive impairment. Subsequently, clinicians are seeing more and more people presenting with cognitive concerns. It is important that clinicians meet these concerns with a strategy promoting accurate diagnoses. We have diagramed and described a practical approach to cognitive impairment. Through an algorithmic approach, we determine the presence and severity of cognitive impairment, systematically evaluate domains of function, and use this information to determine the next steps in evaluation. We also discuss how to proceed when cognitive impairment is associated with motor abnormalities or rapid progression.

Many patients who have Alzheimer disease (AD) present initially with mild cognitive impairment (MCI). This chapter reviews the clinical features of MCI and AD, the clinical evaluation of patients with these entities, and the approaches to management. MCI is defined by cognitive decline that is more than expected by aging alone but does not meet criteria for dementia because the person has the ability to perform activities of daily living. MCI is considered to be a prodrome to dementia, especially AD, given the increased risk of progression to dementia. MCI, which probably represents the earliest stages of dementia in many patients, requires clinical follow-up and is expected to become an important intervention point in future clinical trials of novel preventive therapies.

Parkinsonism is usually designated a movement disorder. However, cognitive impairment comprises a major part of many parkinsonian syndromes, and inversely correlates with quality of life. Parkinsonian features are largely attributed to subcortical dopaminergic dysfunction, although other brain regions and neurotransmitters also contribute. This is illustrated by phenotypic differences among different parkinsonian syndromes. Slowed processing speed and executive dysfunction are generally expected in parkinsonian patients, but additional cognitive features can suggest specific pathological substrates, e.g. apraxia in corticobasal degeneration. Similarly, motor symptoms generally include combinations of bradykinesia, rigidity, rest tremor, and postural instability, although nuanced differences and associated clinical features often help differentiate between parkinsonian syndromes. Human gait requires complex synchronisation at every level of the nervous system, yet occurs with minimal conscious effort on behalf of the walker. Deviations from the normal gait pattern can result from otherwise unnoticeable insults to the body, both intrinsic and extrinsic to the nervous system. Gait is almost always abnormal in parkinsonism, ranging from subtle arm swing asymmetry to discrete episodes of gait freezing. Moreover, one's cognitive state can directly affect one's quality of gait. The notion that a gait profile could in fact be a disease-specific biomarker is an area of great research interest. This review focuses on the manifestations of, and correlations between, cognitive and gait impairment in common parkinsonian conditions, and provides guidance for a clinical approach to assessing them.

ObjectiveTo evaluate the pattern and severity of autonomic dysfunction in autopsy-confirmed progressive supranuclear palsy (PSP) compared to α-synuclein pathology.MethodsAutopsy-confirmed cases of 14 patients with PSP, 18 with multiple system atrophy (MSA), and 24 with Lewy body disease (LBD) with antemortem autonomic testing were reviewed retrospectively. All patients underwent comprehensive clinical evaluations by a movement disorder specialist, formal autonomic testing, and postmortem examinations at Mayo Clinic.ResultsThe absence of orthostatic hypotension (OH) was the strongest autonomic parameter that distinguished PSP from α-synucleinopathies (0% vs 69%, p < 0.0001). Tests of adrenergic failure, which distinguish neurogenic OH, also differentiated PSP from other groups. These included the pressure recovery time (p = 0.0008), adrenergic impairment score (p = 0.001), and magnitude of change of systolic (p = 0.0002) and diastolic (p = 0.0001) blood pressures (BPs) during upright tilt. In addition, REM sleep behavior disorder was seen less frequently (p = 0.006) in PSP (33%) compared to MSA (87%) and LBD (90%). Antemortem clinical diagnostic accuracy for these phenotypically variable disorders was 57% for PSP and 83% for α-synucleinopathies.ConclusionOur results suggest that the cardiovascular adrenergic system, which sustains BP during standing, is relatively unaffected, if not spared, in PSP. These findings increase our understanding of the clinical signature of PSP and have the potential to improve diagnostic accuracy in atypical parkinsonisms by distinguishing PSP from the α-synucleinopathies.

Background Multiple system atrophy (MSA) presents with various combinations of autonomic dysfunction, parkinsonism, and cerebellar ataxia. Although clinical diagnostic criteria have been widely used, the sensitivity and specificity are suboptimal. This study aims to provide evidence supporting the revision of the current diagnostic criteria for MSA. Methods Medical records of 171 patients with autopsy-confirmed MSA in the Mayo Clinic brain bank were reviewed with regard to their clinical features and diagnoses. Pathologic features, including concomitant pathologies (i.e., Alzheimer-related and Lewy-related pathologies), were also assessed. Results The cohort included 133 MSA-parkinsonian type, 36 MSA-cerebellar type, and 2 unclassified MSA patients who did not show significant motor symptoms. Twenty-three patients (13%) were not clinically diagnosed with MSA, but instead with progressive supranuclear palsy, Parkinson's disease (PD), PD with dementia (PDD), or dementia with Lewy bodies (DLB). Three patients with PDD and DLB also had concomitant Lewy body pathology. Six patients had late-onset MSA, with an age of onset greater than 75 years. Erectile dysfunction was frequent in male patients (60/63; 95%) in all age ranges. REM sleep behavior disorder (RBD) was present in 82 patients (48%) and was the initial symptom in 13 patients. Cognitive impairment was present in 60 patients (35%), but was an initial symptom in only two patients. Conclusions Our findings support the conclusion that late-onset presentation should not exclude MSA. The findings of this large autopsy-based cohort provides valuable insights for improving clinical criteria for MSA.

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

Aim. To evaluate five illustrative cases and perform a literature review to identify and describe a working approach to adult-onset white matter diseases (WMD). State of the art. Inherited WMD are a group of disorders often seen in childhood. In adulthood, progressive WMDs are rare, apart from the common nonspecific causes of hypertension and other cerebrovascular diseases. The pattern of WMDs on neuroimaging can be an important clue to the final diagnosis. Due to the adoption of a combined clinical-imaging-laboratory approach, WMD is becoming better recognised, in addition to the rapidly evolving field of genomics in this area. Clinical implications. While paediatric WMDs have a well-defined and literature-based clinical-laboratory approach to diagnosis, adult-onset WMDs remain an important, pathologically diverse, radiographic phenotype, with different and distinct neuropathologies among the various subtypes of WMD. Adult-onset WMDs comprise a wide collection of both acquired and inherited aetiologies. While severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neurological complications are emerging, we are as yet unaware of it causing WMD outside of post-anoxic changes. It is important to recognise WMD as a potentially undefined acquired or genetic syndrome, even when extensive full genome testing reveals variants of unknown significance. Future directions. We propose a combined clinical-imaging-laboratory approach to WMD and continued exploration of acquired and genetic factors. Adult-onset WMD, even given this approach, can be challenging because hypertension is often comorbid. Therefore, we propose that undiagnosed patients with WMD be entered into multicentre National Organisation for Rare Diseases registries to help researchers worldwide make new discoveries that will hopefully translate into future cures.

To help address the scarcity of studies on the genetics of Parkinson's disease (PD) in Latin America, we screened 426 Ecuadorians with PD and 80 Colombians (PD = 55, Control = 26) for mutations within several PD-related genes. Among Colombians, we identified several variants within PARKIN and PINK1 genes.

Introduction. In this edition, Szymuś et al. conducted a systematic review revealing sexual dysfunction to be more prevalent in patients with Huntington’s Disease compared to controls. Clinical reflections. Sexual dysfunction in HD (SDHD) is common and significantly affects patient quality of life. Commonly used HD rating scales and treatment guidelines do not explicitly address SDHD, and research studies are limited by size and methodology. Clinical implications. It is important that validated sexual dysfunction screening tools be utilised in clinical and research settings.

Background Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by a combination of dysautonomia, parkinsonism, and cerebellar ataxia. Other disorders can mimic MSA, but it is unknown whether cerebrovascular pathology, so-called “vascular parkinsonism,” can mimic MSA. This study aimed to determine the clinicopathological features and red flags for vascular parkinsonism masquerading as MSA. Methods Using a brain bank database, we screened 270 patients with an antemortem diagnosis of MSA, who did not have pathologic evidence of MSA, but rather cerebrovascular pathology, including leukoencephalopathy, lacunar infarcts, and microinfarcts. Histologic sections from the neocortex, basal ganglia, thalamus, brainstem, and cerebellum were reviewed. Medical records were reviewed to characterize the clinical features. The probability of a clinical diagnosis of MSA was assigned retrospectively, guided by current consensus criteria. Results Four patients had cerebrovascular pathology without neurodegenerative processes. Chronic ischemic changes in periventricular white matter, subcortical leukoencephalopathy, lacunar infarcts, or microinfarcts were detected in basal ganglia of all patients. Cerebrovascular pathology that might contribute to autonomic failure was not identified. Clinically, two patients were diagnosed with possible MSA-parkinsonism, one with probable MSA-parkinsonism, and one with possible MSA-cerebellar type; however, they also had one or more non-supporting features of MSA (e.g., onset >75-years of age, dementia), vascular risk factors, and other etiologies (e.g., autonomic neuropathy) that could cause autonomic failure. Conclusions When combined with cerebrovascular risk factors and comorbidities, cerebrovascular pathology may masquerade as MSA. The important lesson from this study is that the diagnosis of MSA requires exclusion of other causes, including cerebrovascular disease.

We aimed to replicate a recent study that found a high frequency of the GBA p.K198E mutant in Colombian patients with PD. We identified the p.K198E substitution at a lower frequency in our cohort of Colombians with PD (2.1%), and this was not significantly different than controls (1.7%, P = 0.86) emphasizing the need for larger genetic studies in Latin America.

We present a case in which a movement disorder neurologist developed two different hyperkinetic movements due to corticospinal tract hyperexcitability, which resolved completely with surgical removal of an epidural spinal canal tumor. The first-hand description of these movements creates a unique opportunity for enhanced insight into these complex movement phenomena.

Introduction: In the current edition, Szejko and colleagues describe a subset of patients with Gilles de la Tourette syndrome (GTS) who had dystonic tics (DTs), which occurred more frequently in those with a greater number of tics and likely contribute to impairment. Clinical Reflections: DTs manifest as an abnormal posture that may be difficult to distinguish from other movements, such as dystonia and other tic types. Electromyography is an invaluable tool that can aid clinicians in making this important distinction. Clinical Implications: Accurately diagnosing these movements can significantly impact treatment decisions and contribute to more homogenous research populations.

Introduction The significant symptom overlap between progressive supranuclear palsy (PSP) and other parkinsonian neurodegenerative diseases frequently results in misdiagnosis. However, neuroimaging can be used to quantify disease-related morphological changes and specific markers. The cerebral peduncle angle (CPA) has been shown to differentiate clinically diagnosed PSP from other parkinsonian diseases but this result has yet to be confirmed in autopsy-proven disease. Methods Magnetic resonance imaging (MRI) scans were obtained for 168 patients representing 69 medical facilities. Following randomization, the images were divided into two groups (Type 1 and Type 2) based upon midbrain morphological differences. Two readers were blinded and independently measured the CPA of 146 patients with autopsy-proven progressive supranuclear palsy (PSP; n = 54), corticobasal degeneration (n = 16), multiple system atrophy (MSA; n = 11) and Lewy body disease (n = 65). Results Applying two separate measurement techniques revealed no statistically significant differences in CPA measurements among any study groups regardless of classification measurement approach. The interobserver agreement showed significant differences in measurements using the Type 2 approach. Conclusion Measuring the CPA on MRI is not a reliable way of differentiating among patients with PSP, corticobasal degeneration, MSA, or Lewy body disease.

PURPOSE Patients presenting with pain, numbness, or paresthesias frequently have normal electrodiagnostic studies. Supranormal sensory nerve action potential amplitudes may be a potential biomarker of sensory nerve hyperexcitability. METHODS A retrospective chart review of 400 consecutive patients with normal electromyography reports between July and November 2016 was performed. Patients were divided into tertiles based on the degree of sensory nerve action potential amplitudes above lower limits of normal ( 3×). Patient demographics and sensory symptom quality were assessed. Multivariate analysis assessed for an association between sensory symptoms and sensory nerve action potential amplitudes, age, or gender. RESULTS After controlling for age and gender, subjects in the 2-3× and >3× normal tertiles had a higher association with multifocal symptoms, whereas those in the >3× normal tertile had a lower association with distal symptoms compared with the

We read the recent article by Barthel et al.1 regarding laser shoes and alleviating freezing of gait (FOG) in Parkinson disease and were gratified that they reproduced the results we demonstrated years ago, with an adjustable, mounted laser on a rolling walker.2 Having the lasers attached to shoes to provide a continuous visual cue to attenuate FOG was prudent, for visual cues that require activation on demand for FOG require dual-tasking, which is undermined by parkinsonism.3 As visual cueing for reduction of FOG is likely underutilized, articles about it in high-profile journals, such as Neurology ® and Neurology Today ,4 are most welcome. However, a comment made in the Neurology Today article4 merits rebuttal; namely, that visual cueing for FOG “habituates.” This has not been our experience.

Advances in the treatment and prevention of disease have contributed to an aging global population. Subsequently, there is an increasing prevalence of age‑related conditions, such as dementia. There are currently no disease‑modifying therapies commercially available, and there is a growing emphasis on strategies to prevent dementia. We have reviewed the relevant literature pertaining to dementia risk and putative prevention factors. We present our findings by summarizing the pertinent items that may play a role in prevention and conclude our recommendations at this time.

Restless legs syndrome (RLS) and nocturnal leg cramps (NLCs) are common disorders affecting 7.0% and 24.1% of the population in some European countries, respectively. Patients suffering from RLS experience uncomfortable nocturnal sensations in the legs with the urge to move that dissipates while moving. NLC is characterized by abrupt muscle contraction, most often in the gastrocnemius or foot muscles, which occurs at night and may result in significant sleep disturbances. The diagnosis of these disorders has presented a challenge to health care providers because of symptom overlap with other sensory and motor disturbances with nocturnal predominance. Treatment options and approaches are lacking, partially because of our currently incomplete understanding of the pathophysiological mechanisms underlying these conditions. We reviewed the medical literature to provide a comprehensive assessment of RLS and NLC with a focus on improved diagnostic accuracy and treatment approaches.

Spinocerebellar ataxia 15 (SCA15) is a clinically heterogeneous movement disorder characterized by the adult onset of slowly progressive cerebellar ataxia. ITPR1 is the SCA15 causative gene. However, despite numerous reports of genetically-confirmed SCA15, phenotypic uncertainty persists. We reviewed the phenotypes of 60 patients for whom SCA15 was confirmed by the presence of a genetic deletion involving ITPR1. The most prevalent symptoms were gait ataxia (88.3%), dysarthria (75.0%), nystagmus (73.3%), and limb ataxia (71.7%). We also present a novel SCA15 phenotype in a woman with an ITPR1 variant found to have hydrocephalus that improved with ventriculoperitoneal shunting. This is the first reported case of hydrocephalus associated with SCA15. In this review, we analyzed previously reported SCA15 phenotypes and present a novel SCA15 phenotype. We also address important considerations for evaluating patients with complex hereditary movement disorders.

We appreciate the response by Hines et al.1 to our skepticism that their video NeuroImage was accurately interpreted, either clinically or neurophysiologically. However, we do not find support for their conclusion that their case represents a unique form of spinal myoclonus.

Neurons in many brain regions release endocannabinoids from their dendrites that act as retrograde signals to transiently suppress neurotransmitter release from presynaptic terminals. Little is known, however, about the physiological mechanisms of short-term endocannabinoid-mediated plasticity under physiological conditions. Here we investigate calcium-dependent endocannabinoid release from cartwheel cells (CWCs) of the mouse dorsal cochlear nucleus (DCN) in the auditory brainstem that provide feedforward inhibition onto DCN principal neurons. We report that sustained action potential firing by CWCs evokes endocannabinoid release in response to submicromolar elevation of dendritic calcium that transiently suppresses their parallel fiber (PF) inputs by >70%. Basal spontaneous CWC firing rates are insufficient to evoke tonic suppression of PF synapses. However, elevating CWC firing rates by stimulating PFs triggers the release of endocannabinoids and heterosynaptic suppression of PF inputs. Spike-evoked suppression by endocannabinoids selectively suppresses excitatory synapses, but glycinergic/GABAergic inputs onto CWCs are not affected. Our findings demonstrate a mechanism of transient plasticity mediated by endocannabinoids that heterosynaptically suppresses subsets of excitatory presynaptic inputs to CWCs that regulates feedforward inhibition of DCN principal neurons and may influence the output of the DCN.

The Pemberton maneuver is a tool that may be utilized during the physical examination to demonstrate the presence of latent pressure in the thoracic inlet [1]. The maneuver is achieved by having the patient elevate both arms until they touch the sides of the face. A positive sign is marked by the presence of facial congestion and cyanosis, as well as respiratory distress after approximately one minute [2]. The sign is most commonly present in patients with substernal goiters where the goiter “corks off” the thoracic inlet [3]. We describe a 67-year-old Caucasian male with a positive Pemberton’s sign due to compression of the thoracic inlet by enlarged mediastinal nodes. The sign was amplified by the presence of a restrictive cardiomyopathy and constrictive pericarditis due to amyloidosis. We propose that a positive Pemberton’s sign should not be used exclusively to evaluate the probability of a substernal goiter, but rather to assess the potential for vascular compression due to pathological changes in the anatomical environment of the thoracic inlet.