An Autopsy Series of Seven Cases of VPS13A Disease (Chorea-Acanthocytosis).

BACKGROUND: Vacuolar protein sorting 13 homolog A (VPS13A) disease, historically known as chorea-acanthocytosis, is a rare neurodegenerative disorder caused by biallelic mutations in VPS13A, usually resulting in reduced or absent levels of its protein product, VPS13A. VPS13A localizes to contact sites between subcellular organelles, consistent with its recently identified role in lipid transfer between membranes. Mutations are associated with neuronal loss in the striatum, most prominently in the caudate nucleus, and associated marked astrogliosis. There are no other known disease-specific cellular changes (eg, protein aggregation), but autopsy reports to date have been limited, often lacking genetic or biochemical diagnostic confirmation. OBJECTIVE: The goal of this study was to characterize neuropathological findings in the brains of seven patients with VPS13A disease (chorea-acanthocytosis). METHODS: In this study, we collected brain tissues and clinical data from seven cases of VPS13A for neuropathological analysis. The clinical diagnosis was confirmed by the presence of VPS13A mutations and/or immunoblot showing the loss or reduction of VPS13A protein. Tissues underwent routine, special, and immunohistochemical staining focused on neurodegeneration. Electron microscopy was performed in one case. RESULTS: Gross examination showed severe striatal atrophy. Microscopically, there was neuronal loss and astrogliosis in affected regions. Luxol fast blue staining showed variable lipid accumulation with diverse morphology, which was further characterized by electron microscopy. In some cases, rare degenerating p62- and ubiquitin-positive cells were present in affected regions. Calcifications were present in four cases, being extensive in one. CONCLUSIONS: We present the largest autopsy series of biochemically and genetically confirmed VPS13A disease and identify novel histopathological findings implicating abnormal lipid accumulation. © 2023 International Parkinson and Movement Disorder Society.

Sphingolipid and Phospholipid Levels Are Altered in Human Brain in Chorea-Acanthocytosis.

BACKGROUND: Chorea-acanthocytosis (ChAc) is associated with mutations of VPS13A, which encodes for chorein, a protein implicated in lipid transport at intracellular membrane contact sites. OBJECTIVES: The goal of this study was to establish the lipidomic profile of patients with ChAc. METHODS: We analyzed 593 lipid species in the caudate nucleus (CN), putamen, and dorsolateral prefrontal cortex (DLPFC) from postmortem tissues of four patients with ChAc and six patients without ChAc. RESULTS: We found increased levels of bis(monoacylglycerol)phosphate, sulfatide, lysophosphatidylserine, and phosphatidylcholine ether in the CN and putamen, but not in the DLPFC, of patients with ChAc. Phosphatidylserine and monoacylglycerol were increased in the CN and N-acyl phosphatidylserine in the putamen. N-acyl serine was decreased in the CN and DLPFC, whereas lysophosphatidylinositol was decreased in the DLPFC. CONCLUSIONS: We present the first evidence of altered sphingolipid and phospholipid levels in the brains of patients with ChAc. Our observations are congruent with recent findings in cellular and animal models, and implicate defects of lipid processing in VPS13A disease pathophysiology. © 2023 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Essential Tremor accentuates the pattern of tremor-band coherence between upper-limb muscles.

Although Essential Tremor is one of the most common movement disorders, current treatment options are relatively limited. Peripheral tremor suppression methods have shown potential, but we do not currently know which muscles are most responsible for patients' tremor, making it difficult to optimize suppression methods. The purpose of this study was to quantify the relationships between the tremorogenic activity in muscles throughout the upper limb. Muscle activity was recorded from the 15 major superficial upper-limb muscles in 24 subjects with Essential Tremor while they held various postures or made upper-limb movements. We calculated the coherence in the tremor band (4-12 Hz) between the activity of all muscle pairs and the time-varying phase difference between sufficiently coherent muscle pairs. Overall, the observed pattern somewhat mirrored functional relationships: agonistic muscle pairs were most coherent and in phase, whereas antagonist and unrelated muscle pairs exhibited less coherence and were either consistently in phase, consistently antiphase, consistently out of phase (unrelated pairs only), or else inconsistent. Patients exhibited significantly more coherence than control subjects (p<0.001) in the vast majority of muscle pairs (95 out of 105). Furthermore, differences between patients and controls were most pronounced among agonists; thus, the coherence pattern existing in control subjects was accentuated in patients with ET. We conclude that tremor-band activity is broadly distributed among the muscles of the upper limb, challenging efforts to determine which muscles are most responsible for a patient's tremor.

Role of supplementary motor area in cervical dystonia and sensory tricks.

Sensory trick is a characteristic feature of cervical dystonia (CD), where a light touch on the area adjacent to the dystonia temporarily improves symptoms. Clinical benefit from sensory tricks can be observed before tactile contact is made or even by imagination. The supplementary motor area (SMA) may dynamically interact with the sensorimotor network and other brain regions during sensory tricks in patients with CD. In this study, we examined the functional connectivity of the SMA at rest and during sensory trick performance and imagination in CD patients compared to healthy controls using functional magnetic resonance imaging. The functional connectivity between the SMA and left intraparietal sulcus (IPS) region was lower in CD patients at rest and it increased with sensory trick imagination and performance. SMA-right cerebellum connectivity also increased with sensory trick imagination in CD patients, while it decreased in healthy controls. In CD patients, SMA connectivity increased in the brain regions involved in sensorimotor integration during sensory trick performance and imagination. Our study results showed a crucial role of SMA in sensorimotor processing during sensory trick performance and imagination and suggest the IPS as a novel potential therapeutic target for brain modulation.

Distribution of tremorogenic activity among the major superficial muscles of the upper limb in persons with Essential tremor.

OBJECTIVE: Peripheral tremor suppression has the potential to reduce tremor, but we do not currently know where best to intervene. The purpose of this study was to characterize the distribution of tremorogenic activity among upper-limb muscles. METHODS: Surface electromyography was recorded from the 15 major superficial muscles of the upper limb while 25 patients with Essential Tremor performed postural and kinetic tasks. We defined tremorogenic activity as power in the tremor band (4-8 Hz) and determined the distribution of this power among muscles. RESULTS: The distribution varied considerably between patients (mean r = 0.58), but on average, the greatest power was found in the anterior deltoid and extensor carpi ulnaris muscles. Other muscles with high power included the extensor carpi radialis, pectoralis major, lateral deltoid, and brachialis muscles. This distribution was similar (mean r ≥ 0.88) for postural and kinetic tremor, various limb configurations, repetitions, and patient characteristics (sex, tremor severity, age of onset, and duration). CONCLUSIONS: We identified a rough pattern in which muscles opposing gravity appeared to have the highest tremor-band power; we hypothesize that the distribution of tremorogenic muscle activity depends in part on the distribution of voluntary activity required by the task. SIGNIFICANCE: Understanding which muscles exhibit the most tremorogenic activity is one of the steps in the pursuit of optimizing peripheral tremor suppression.

Distribution of tremor among the major degrees of freedom of the upper limb in subjects with Essential Tremor.

OBJECTIVE: Although Essential Tremor is one of the most common movement disorders, we do not currently know which muscles are most responsible for tremor. Determining this requires multiple steps, one of which is characterizing the distribution of tremor among the degrees of freedom (DOF) of the upper limb. METHODS: Upper-limb motion was recorded while 22 subjects with ET performed postural and kinetic tasks involving a variety of limb configurations. We calculated the mean distribution of tremor among the seven DOF from the shoulder to the wrist, as well as the effect of limb configuration, repetition, and subject characteristics (sex, tremor onset, duration, and severity) on the distribution. RESULTS: On average, kinetic tremor was greatest in forearm pronation-supination and wrist flexion-extension, intermediate in shoulder internal-external rotation and wrist radial-ulnar deviation and then shoulder flexion-extension and elbow flexion-extension, and least in shoulder abduction-adduction. The average distribution of postural tremor was similar except for forearm pronation-supination, which played a smaller role than in kinetic tremor. Limb configuration and subject characteristics did significantly affect tremor, but practically only in forearm pronation-supination and wrist flexion-extension. There were no significant differences between repetitions, indicating that the distribution was consistent over the duration of the experiment. CONCLUSIONS: This paper presents a thorough characterization of tremor distribution from the shoulder to the wrist. SIGNIFICANCE: Understanding which DOF exhibit the most tremor may lead to more targeted peripheral tremor suppression.

Modulation of Resting Connectivity Between the Mesial Frontal Cortex and Basal Ganglia.

Background: The mesial prefrontal cortex, cingulate cortex, and the ventral striatum are key nodes of the human mesial fronto-striatal circuit involved in decision-making and executive function and pathological disorders. Here we ask whether deep wide-field repetitive transcranial magnetic stimulation (rTMS) targeting the mesial prefrontal cortex (MPFC) influences resting state functional connectivity. Methods: In Study 1, we examined functional connectivity using resting state multi-echo and independent components analysis in 154 healthy subjects to characterize default connectivity in the MPFC and mid-cingulate cortex (MCC). In Study 2, we used inhibitory, 1 Hz deep rTMS with the H7-coil targeting MPFC and dorsal anterior cingulate (dACC) in a separate group of 20 healthy volunteers and examined pre- and post-TMS functional connectivity using seed-based and independent components analysis. Results: In Study 1, we show that MPFC and MCC have distinct patterns of functional connectivity with MPFC-ventral striatum showing negative, whereas MCC-ventral striatum showing positive functional connectivity. Low-frequency rTMS decreased functional connectivity of MPFC and dACC with the ventral striatum. We further showed enhanced connectivity between MCC and ventral striatum. Conclusions: These findings emphasize how deep inhibitory rTMS using the H7-coil can influence underlying network functional connectivity by decreasing connectivity of the targeted MPFC regions, thus potentially enhancing response inhibition and decreasing drug-cue reactivity processes relevant to addictions. The unexpected finding of enhanced default connectivity between MCC and ventral striatum may be related to the decreased influence and connectivity between the MPFC and MCC. These findings are highly relevant to the treatment of disorders relying on the mesio-prefrontal-cingulo-striatal circuit.

Low specificity of voltage-gated calcium channel antibodies in Lambert-Eaton myasthenic syndrome: a call for caution.

As testing for neuronal antibodies become more readily available, the spectrum of conditions potentially associated with these autoantibodies has been widening. Voltage-gated calcium channel antibodies (VGCC-Ab) are no exception to this trend. The significance of an elevated VGCC-Ab titer beyond its original clinicopathological correlate, Lambert-Eaton myasthenic syndrome (LEMS) remains undetermined. We sought to determine the diagnostic significance of an elevated serum VGCC-Ab titer in a large single-center cohort of 100 patients. The majority of patients (58%) with elevated VGCC-Ab levels lacked an inflammatory or autoimmune etiology of their neurologic diagnosis. Only six cases (6%) of LEMS and two cases (2%) of SCLC (without LEMS) were identified. No significant differences in antibody titers were seen between the autoimmune and non-autoimmune groups. These findings support the notions that: (a) elevated VGCC-Ab titers without clinical correlation must be interpreted with caution, and (b) the clinical and electrodiagnostic criteria for LEMS should remain the mainstay in the diagnosis of LEMS.

A Practical Primer on Prion Pathology.

Prion diseases comprise a group of transmissible degenerative encephalopathies resulting from propagation of a misfolded cellular protein of uncertain function. As is generally the case with rare diseases, lack of institutional experience compromises individual familiarity with the varying, and apparently protean, manifestations of prion diseases, both clinically and pathologically. Coupled with the documented transmissibility of these diseases both within and between species, the Centers for Disease Control and Prevention (CDC) has established the National Prion Disease Pathology Surveillance Center to both aid with diagnosis of prion disease and to survey the United States for evidence of zoonotic transmission. We have assembled this primer with the hope that our accumulated experience will enable the neuropathological community to help the CDC "save lives and protect people."

Pedunculopontine Nucleus Cholinergic Deficiency in Cervical Dystonia.

BACKGROUND: The etiology of cervical dystonia is unknown. Cholinergic abnormalities have been identified in dystonia animal models and human imaging studies. Some animal models have cholinergic neuronal loss in the striatum and increased acetylcholinesterase activity in the pedunculopontine nucleus. OBJECTIVES: The objective of this study was to determine the presence of cholinergic abnormalities in the putamen and pedunculopontine nucleus in cervical dystonia human brain donors. METHODS: Formalin-fixed brain tissues were obtained from 8 cervical dystonia and 7 age-matched control brains (controls). Pedunculopontine nucleus was available in only 6 cervical dystonia and 5 controls. Neurodegeneration was evaluated pathologically in the putamen, pedunculopontine nucleus, and other regions. Cholinergic neurons were detected using choline acetyltransferase immunohistochemistry in the putamen and pedunculopontine nucleus. Putaminal cholinergic neurons were quantified. A total of 6 cervical dystonia patients and 6 age-matched healthy controls underwent diffusion tensor imaging to determine if there were white matter microstructural abnormalities around the pedunculopontine nucleus. RESULTS: Decreased or absent choline acetyltransferase staining was identified in all 6 pedunculopontine nucleus samples in cervical dystonia. In contrast, strong choline acetyltransferase staining was present in 4 of 5 pedunculopontine nucleus controls. There were no differences in pedunculopontine nucleus diffusion tensor imaging between cervical dystonia and healthy controls. There was no difference in numbers of putaminal cholinergic neurons between cervical dystonia and controls. CONCLUSIONS: Our findings suggest that pedunculopontine nucleus choline acetyltransferase deficiency represents a functional cholinergic deficit in cervical dystonia. Structural lesions and confounding neurodegenerative processes were excluded by absence of neuronal loss, gliosis, diffusion tensor imaging abnormalities, and beta-amyloid, tau, and alpha-synuclein pathologies. © 2018 International Parkinson and Movement Disorder Society.

Triaging Patients with Multiple Sclerosis in the Emergency Department: Room for Improvement.

BACKGROUND: Patients with multiple sclerosis (MS) present to the emergency department (ED) for various reasons. Although true relapse is rarely the underlying culprit, ED visits commonly result in new magnetic resonance imaging (MRI) and neurology admissions. We studied ED visits in patients with MS and evaluated decision making regarding diagnostic/therapeutic interventions and visit outcomes. We identified potential areas for improvement and used the data to propose a triaging algorithm for patients with MS in the ED. METHODS: We reviewed the medical records from 176 ED visits for patients with MS in 2014. RESULTS: Ninety-seven visits in 75 patients were MS related (66.6% female; mean ± SD age, 52.6 ± 13.8 years; mean ± SD disease duration, 18.5 ± 10.5 years). Thirty-three visits were for new neurologic symptoms (category 1), 29 for worsening preexisting symptoms (category 2), and 35 for MS-related complications (category 3). Eighty-nine visits (91.8%) resulted in hospital admission (42.7% to neurology). Only 39% of ordered MRIs showed radiographic activity. New relapses were determined in 27.8% of the visits and were more prevalent in category 1 compared with category 2 (P = .003); however, the two categories had similar rates of ordered MRIs and neurology admissions. CONCLUSIONS: New relapse is a rare cause of ED visits in MS. Unnecessary MRIs and neurology admissions can be avoided by developing a triaging system for patients with MS based on symptom stratification.

Positron emission tomography imaging in a case of E200K mutation-related spongiform encephalopathy with non-diagnostic magnetic resonance imaging and cerebrospinal fluid testing.

OBJECTIVE: Creutzfeldt-Jakob disease is a rapidly progressive spongiform encephalopathy. The E200K mutation is found in a majority of genetically transmitted Creutzfeldt-Jakob disease cases. METHODS: We describe the case and associated neuroimaging of an E200K-129M gene-mutation-related fatal spongiform encephalopathy with resultant clinical insomnia and thalamic changes. RESULTS: A 46-year-old Caucasian male presented with, who was well until 2 months prior to admission, a rapidly progressive dementia followed by a change in personality with auditory and visual hallucinations. His wife noted progressively worsening jerking and other limb movements and that he kept his eyes open overnight and was "awake" at all hours. Magnetic resonance imaging, electroencephalogram and initial cerebrospinal fluid analysis were essentially non-diagnostic. Positron emission topography revealed severe bilateral thalamic hypometabolism. Posthumous cerebrospinal fluid analysis revealed abnormal PrP 27-30 protein. Autopsy confirmed prion disease and presence of the E200K-129M mutation. CONCLUSION: This report highlights that positron emission topography imaging may help diagnose E200K-129M mutation-related spongiform encephalopathy. In cases of non-diagnostic magnetic resonance imaging, electroencephalogram and cerebrospinal fluid studies, early positron emission topography may help in the workup of rapidly progressive dementia.

Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Correlation of Histopathology and MRI in Prion Disease.

Creutzfeldt-Jakob disease (CJD) and other prion diseases are rapidly progressive spongiform encephalopathies that are invariably fatal. Clinical features and magnetic resonance imaging, electroencephalogram, and cerebrospinal fluid abnormalities may suggest prion disease, but a definitive diagnosis can only be made by means of neuropathologic examination. Fluorodeoxyglucose positron emission tomography (FDG-PET) is not routinely used to evaluate patients with suspected prion disease. This study includes 11 cases of definite prion disease in which FDG-PET scans were obtained. There were 8 sporadic CJD cases, 2 genetic CJD cases, and 1 fatal familial insomnia case. Automated FDG-PET analysis revealed parietal region hypometabolism in all cases. Surprisingly, limbic and mesolimbic hypermetabolism were also present in the majority of cases. When FDG-PET hypometabolism was compared with neuropathologic changes (neuronal loss, astrocytosis, spongiosis), hypometabolism was predictive of neuropathology in 80.6% of cortical regions versus 17.6% of subcortical regions. The odds of neuropathologic changes were 2.1 times higher in cortical regions than subcortical regions (P=0.0265). A similar discordance between cortical and subcortical regions was observed between FDG-PET hypometabolism and magnetic resonance imaging diffusion weighted imaging hyperintensity. This study shows that there may be a relationship between FDG-PET hypometabolism and neuropathology in cortical regions in prion disease but it is unlikely to be helpful for diagnosis.

Clinical utility of seropositive voltage-gated potassium channel-complex antibody.

BACKGROUND: Antibodies against voltage-gated potassium channel (VGKC)-complex are implicated in the pathogenesis of acquired neuromyotonia, limbic encephalitis, faciobrachial dystonic seizure, and Morvan syndrome. Outside these entities, the clinical value of VGKC-complex antibodies remains unclear. METHODS: We conducted a single-center review of patients positive for VGKC-complex antibodies over an 8-year period. RESULTS: Among 114 patients positive for VGKC-complex antibody, 11 (9.6%) carrying the diagnosis of limbic encephalitis (n = 9) or neuromyotonia (n = 2) constituted the classic group, and the remaining 103 cases of various neurologic and non-neurologic disorders comprised the nonclassic group. The median titer for the classic group was higher than the nonclassic group (p < 0.0001). A total of 90.9% of the patients in the classic and 21.4% in the nonclassic group possessed high (>0.25 nM) VGKC-complex antibody levels (p < 0.0001). A total of 75.0% of the patients in the high-level group had definite or probable autoimmune basis, while nonautoimmune disorders were seen in 75.6% of patients from the low-level group (p < 0.0001). A total of 26.3% of patients were found with active or remote solid organ or hematologic malignancy, but no antibody titer difference was observed among subgroups of absent, active, or remote malignancy. Compared to age-matched US national census, rates of active cancer in our cohort were higher in patients older than 45 years. CONCLUSIONS: High VGKC-complex antibody titers are more likely found in patients with classically associated syndromes and other autoimmune conditions. Low-level VGKC-complex antibodies can be detected in nonspecific and mostly nonautoimmune disorders. The presence of VGKC-complex antibody, rather than its level, may serve as a marker of malignancy.

Clinical experience of seropositive ganglionic acetylcholine receptor antibody in a tertiary neurology referral center.

INTRODUCTION: Antibody against the acetylcholine receptor of autonomic ganglia (gAChR-Ab) is implicated in the pathogenesis of autoimmune autonomic ganglionopathy (AAG) and several other disorders. METHODS: This study was a retrospective evaluation of 95 patients positive for gAChR-Ab. RESULTS: Twenty-one (22%) patients had AAG, with a greater median gAChR-Ab level (0.21 nmol/L) and higher percentage (57%) of antibody levels >0.20 nmol/L when compared with the remaining 74 patients without autonomic manifestations (non-AAG group, 0.10 nmol/L and 15%, respectively). Only 2 new cases of malignancy were diagnosed after gAChR-Ab detection. The non-AAG group was associated with high frequencies of neurological and non-neurological autoimmunity, but also included 23 (31%) patients with mostly degenerative disorders. CONCLUSION: Detection of gAChR-Ab, especially at a higher level, is helpful for the diagnosis of AAG in patients with corresponding autonomic symptoms. However, its value is limited for predicting cancer risk and for diagnosis and management of patients without autonomic symptoms.