Cerebellar Pathology Research Articles

Neuroimaging and neuropathological characteristics of cerebellar injury in extremely low birth weight infants

ObjectiveTo determine the morphological characteristics and pathogenic factors of cerebellar injury in extremely low birth weight infants (ELBWI). Subjects and methodsNeuroimaging examination was performed on 17 eligible surviving ELBWI. Their MR images were assessed and classified its pattern of cerebellar injuries. Brain pathology was examined on 15 patients, who isolated this neuroimaging subjects. The trend of brain pathologies was revealed. ResultsFour types of morphological pattern were recognized: (i) the absence of major portions in the cerebellum (6/17 cases); (ii) focal cerebellar tissue loss (2/17); (iii) unilateral cerebellar atrophy/hypoplasia (3/17); (iv) small cerebellum with entrapped fourth ventricle (6/17). In cerebellar pathology, the most common findings were focal or widespread cerebellar subarachnoid hemorrhage (12/15) and olivocerebellar degeneration (12/15). In addition, one-third of the cases indicated remote cerebellar parenchymal hemorrhage. ConclusionIn MRI-defined lesions, the absence of major portions or focal tissue loss was associated with cerebellar parenchymal hemorrhage and/or hemorrhagic infarction, that is destructive lesion. On the other hand, small cerebellum or unilateral atrophy/hypoplasia, that is impaired development, may be related to the cerebellar neuron loss due to hemosiderin deposits in the surface of the cerebellum. The cerebellar injury in ELBWI is probably caused by not only environmental factors such as hemorrhage, hypoxia-ischemia, or other deleterious effect, but also immaturity of the rapidly growing cerebellum in particular gestational age.

Rapid, label-free identification of cerebellar structures using multiphoton microscopy.

The cerebellum is the prominent laminar structure of the mammalian brain that has been implicated in various psychiatric and neurological diseases. Although clinical brain imaging techniques have provided precise anatomic images of cerebellar structures, a definitive diagnosis still requires adequate resolution to identify individual layers in cerebellar cortex, the extent of tumor, even requires the histological tissue examination during surgical procedures. In this study, multiphoton microscopy (MPM), based on second harmonic generation (SHG) and two-photon excited fluorescence (TPEF), was perform on the rat cerebellar structures and pathology with the combination of image analysis methods. Results show that MPM can reveal the cerebellar vermis, hemispheres, medulla, and ventricle, as well as axon bundles, Purkinje cells, capillaries, and the pia mater of the cerebellum. Together with custom-developed image processing algorithms, MPM could further differentiate between the gray and white matter, as well as evaluate the Purkinje cell layer, identify the cerebellar tumor boundary, and distinguish between the tumor core and peritumor regions. Our results establish a direct visualization and rapid assessment approach for the cerebellar structures, as well as suggest the feasibility of in vivo multiphoton microendoscopes and fiberscopes as clinical tools for neuropathological diagnoses.

An Ultra-High Field Study of Cerebellar Pathology in Early Relapsing-Remitting Multiple Sclerosis Using MP2RAGE.

The aim of this study was to study focal cerebellar pathology in early stages of multiple sclerosis (MS) using ultra-high-field magnetization-prepared 2 inversion-contrast rapid gradient-echo (7T MP2RAGE). Twenty early-stage relapsing-remitting MS patients underwent an MP2RAGE acquisition at 7 T magnetic resonance imaging (MRI) (images acquired at 2 different resolutions: 0.58 × 0.58 × 0.58 mm, 7T_0.58, and 0.75 × 0.75 × 0.90 mm, 7T_0.75) and 3 T MRI (1.0 × 1.0 × 1.2 mm, 3T_1.0). Total cerebellar lesion load and volume and mean cerebellar lesion volume were compared across images using a Wilcoxon signed-rank test. Mean T1 relaxation times in lesions and normal-appearing tissue as well as contrast-to-noise ratio (CNR) measurements were also compared using a Wilcoxon signed-rank test. A multivariate analysis was applied to assess the contribution of MRI metrics to clinical performance in MS patients. Both 7T_0.58 and 7T_0.75 MP2RAGE showed significantly higher lesion load compared with 3T_1.0 MP2RAGE (P < 0.001). Plaques that were judged as leukocortical in 7T_0.75 and 3T_1.0 MP2RAGEs were instead identified as WM lesions in 7T_0.58 MP2RAGE. Cortical lesion CNR was significantly higher in MP2RAGEs at 7 T than at 3 T. Total lesion load as well as total and mean lesion volume obtained at both 7 T and 3 T MP2RAGE significantly predicted attention (P < 0.05, adjusted R = 0.5), verbal fluency (P < 0.01, adjusted R = 0.6), and motor performance (P = 0.01, adjusted R = 0.7). This study demonstrates the value of 7 T MP2RAGE to study the cerebellum in early MS patients. 7T_0.58 MP2RAGE provides a more accurate anatomical description of white and gray matter pathology compared with 7T_0.75 and 3T_1.0 MP2RAGE, likely due to the improved spatial resolution, lower partial volume effects, and higher CNR.

Cerebellar Pathology in Early Onset and Late Onset Essential Tremor (S17.006)

Cerebellar Pathology in Early Onset and Late Onset Essential Tremor (S17.006)

Editorial: The Cerebellum: Not Just an Anatomical Structure

In human, the cerebellum occupies about ten percent of the total skull. It contains numerous cells one of which is the Purkinje cell. Traditionally, the cerebellum is made up of four important types of neuronal cells namely Golgi cells, granules cells, Purkinje cells, and; stellate cells (basket cells). However, with the rapid advances in medical sciences, it is now known that the cerebellum contains many other cells, these includes; candelabrum cells, Lugaro cells, and unipolar brush cells. The fact that these neuronal cells are usually not cited in the standard basic expression of the microscopic anatomy of the cerebellum, or even in standard anatomy, physiology, or histology literatures, indicate that our knowledge of the existence of these cells is fractional (1). Recent microscopic study by Tang et al. (2016) (2) has shown that the cerebellum contains the significant number of neuronal cells and synapses compared with any other structure within the central nervous system. The functions of these wide arrays of neurons are determined by a set of biological stimulus (i.e. excitatory or inhibitory inputs). According to Heshmat (2016) (3), excitatory inputs are generated by many mossy fibers which developed from the pontine nuclei and climbing fibers originating from the inferior olivary nucleus. On the other hand, large inhibitory inputs arise from the Purkinje cells situated in the cerebellar cortex. Observations made from the neurobiology of the cerebellum showed that there is need for integration between excitatory and inhibitory inputs so as to develop the output signal required for the functional integrity of the cerebellum. The inhibitory input from a single cerebellar nucleus is usually opposed by depolarizing potentials in the recipient cerebellar nuclei cells due to spontaneous depolarization activity in the presence of such an inhibitory input (3). Evidences from cognitive studies further suggest that cerebellar pathology may be associated with alterations mainly in mental function, instead of motor processes. These pools of evidences continue to attract a sizeable number of researches into the neuroanatomy, neurobiology and neurobehavioral role of the cerebellum and the theories associated with its functions

Synaptic pathology in the cerebellar dentate nucleus in chronic multiple sclerosis.

In multiple sclerosis, cerebellar symptoms are associated with clinical impairment and an increased likelihood of progressive course. Cortical atrophy and synaptic dysfunction play a prominent role in cerebellar pathology and although the dentate nucleus is a predilection site for lesion development, structural synaptic changes in this region remain largely unexplored. Moreover, the mechanisms leading to synaptic dysfunction have not yet been investigated at an ultrastructural level in multiple sclerosis. Here, we report on synaptic changes of dentate nuclei in post-mortem cerebella of 16 multiple sclerosis patients and eight controls at the histological level as well as an electron microscopy evaluation of afferent synapses of the cerebellar dentate and pontine nuclei of one multiple sclerosis patient and one control. We found a significant reduction of afferent dentate synapses in multiple sclerosis, irrespective of the presence of demyelination, and a close relationship between glial processes and dentate synapses. Ultrastructurally, we show autophagosomes containing degradation products of synaptic vesicles within dendrites, residual bodies within intact-appearing axons and free postsynaptic densities opposed to astrocytic appendages. Our study demonstrates loss of dentate afferent synapses and provides, for the first time, ultrastructural evidence pointing towards neuron-autonomous and neuroglia-mediated mechanisms of synaptic degradation in chronic multiple sclerosis.

Dexmedetomidine protects against glucocorticoid induced progenitor cell apoptosis in neonatal mouse cerebellum

Objectives: Glucocorticoids (GCs) are used to improve respiratory mechanics in preterm infants despite clinical evidence linking neonatal GC therapy to cerebellar pathology. In developing mouse cerebellum, the GC dexamethasone (DEX) causes rapid GC-induced neural progenitor cell apoptosis (GINA). Focusing on pharmacological neuroprotection strategies, we investigated whether dexmedetomidine (DMT) protects against GINA.Methods: Neonatal mice were pretreated with DMT prior to DEX challenge. Additionally, we tested clonidine and yohimbine in vivo to determine mechanism of DMT neuroprotection. For in vitro studies, cerebellar neural progenitor cells were pretreated with DMT before DEX challenge.Results: In vivo, DMT attenuated GINA at 1 μg/kg and above, p < 0.0001. Clonidine significantly attenuated GINA, p < 0.0001, while yohimbine reversed DMT neuroprotection, p < 0.0001, suggesting DMT neuroprotection is likely mediated via adrenergic signaling. In vitro, DMT neuroprotection was achieved at 10 μM and above, p < 0.001, indicating DMT rescue is cell autonomous.Conclusions: DMT affords dose-dependent neuroprotection from GINA at clinically relevant doses, an effect that is cell autonomous and likely mediated by α2 adrenergic receptor agonism. DMT co-administration with GCs may be an effective strategy to protect the neonatal brain from GINA while retaining the beneficial effects of GCs on respiratory mechanics.

Jules Dejerine, André-Thomas and the pathology of the cerebellum

Jules Dejerine, André-Thomas and the pathology of the cerebellum

Role of altered cerebello-thalamo-cortical network in the neurobiology of essential tremor

Essential tremor (ET) is the most common movement disorder among adults. Although ET has been recognized as a mono-symptomatic benign illness, reports of non-motor symptoms and non-tremor motor symptoms have increased its clinical heterogeneity. The neural correlates of ET are not clearly understood. The aim of this study was to understand the neurobiology of ET using resting state fMRI. Resting state functional MR images of 30 patients with ET and 30 age- and gender-matched healthy controls were obtained. The functional connectivity of the two groups was compared using whole-brain seed-to-voxel-based analysis. The ET group had decreased connectivity of several cortical regions especially of the primary motor cortex and the primary somatosensory cortex with several right cerebellar lobules compared to the controls. The thalamus on both hemispheres had increased connectivity with multiple posterior cerebellar lobules and vermis. Connectivity of several right cerebellar seeds with the cortical and thalamic seeds had significant correlation with an overall score of Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) as well as the subscores for head tremor and limb tremor. Seed-to-voxel resting state connectivity analysis revealed significant alterations in the cerebello-thalamo-cortical network in patients with ET. These alterations correlated with the overall FTM scores as well as the subscores for limb tremor and head tremor in patients with ET. These results further support the previous evidence of cerebellar pathology in ET.

Cerebellar and Striatal Pathologies in Mouse Models of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic component. To date, several hundred different genetic mutations have been identified to play a role in its aetiology. The heterogeneity of genetic abnormalities combined with the different brain regions where aberrations are found makes the search for causative mechanisms a daunting task. Even within a limited number of brain regions, a myriad of different neural circuit dysfunctions may lead to ASD. Here, we review mouse models that incorporate mutations of ASD risk genes causing pathologies in the cerebellum and striatum and highlight the vulnerability of related circuit dysfunctions within these brain regions in ASD pathophysiology.

Progression of alpha-synuclein pathology in multiple system atrophy of the cerebellar type.

The aim of this study was to identify early foci of α-synuclein (α-syn pathology) accumulation, subsequent progression and neurodegeneration in multiple system atrophy of the cerebellar type (MSA-C). We analysed 70-μm-thick sections of 10 cases with MSA-C and 24 normal controls. MSA-C cases with the lowest burden of pathology showed α-syn glial cytoplasmic inclusions (GCIs) in the cerebellum as well as in medullary and pontine cerebellar projections. Cerebellar pathology was highly selective and severely involved subcortical white matter, whereas deep white matter and granular layer were only mildly affected and the molecular layer was spared. Loss of Purkinje cells increased with disease duration and was associated with neuronal and axonal abnormalities. Neocortex, basal ganglia and spinal cord became consecutively involved with the increasing burden of α-syn pathology, followed by hippocampus, amygdala, and, finally, the visual cortex. GCIs were associated with myelinated axons, and the severity of GCIs correlated with demyelination. Our findings indicate that cerebellar subcortical white matter and cerebellar brainstem projections are likely the earliest foci of α-syn pathology in MSA-C, followed by involvement of more widespread regions of the central nervous system and neurodegeneration with disease progression.

T-Cells Underlie Some but Not All of the Cerebellar Pathology in a Neonatal Rat Model of Congenital Lymphocytic Choriomeningitis Virus Infection.

Lymphocytic choriomeningitis virus (LCMV) infection during pregnancy injures the human fetal brain. Neonatal rats inoculated with LCMV are an excellent model of congenital LCMV infection because they develop cerebellar injuries similar to those in humans. To evaluate the role of T-lymphocytes in LCMV-induced cerebellar pathology, congenitally athymic rats, deficient in T-lymphocytes were compared with euthymic rats. Peak viral titers and cellular targets of infection were similar, but viral clearance from astrocytes was impaired in the athymic rats. Cytokines and chemokines rose to higher levels and for a greater duration in the euthymic rats than in their athymic counterparts. The euthymic rats developed an intense lymphocytic infiltration, accompanied by destructive lesions of the cerebellum and a neuronal migration defect because of T-cell-mediated alteration of Bergmann glia. These pathologic changes were absent in the athymic rats but were restored by adoptive transfer of lymphocytes. Athymic rats were not free of pathologic effects, however, as the virus induced cerebellar hypoplasia. Thus, T-lymphocytes play key roles in LCMV clearance, cytokine/chemokine responses, and pathogenesis of destructive lesions and neuronal migration disturbances but not all pathology is T-lymphocyte-dependent. Cerebellar hypoplasia from LCMV occurs even in the absence of T-lymphocytes and is likely due to the viral infection itself.

Memory deficits, gait ataxia and neuronal loss in the hippocampus and cerebellum in mice that are heterozygous for Pur-alpha

Pur-alpha is a highly conserved sequence-specific DNA and RNA binding protein with established roles in DNA replication, RNA translation, cell cycle regulation, and maintenance of neuronal differentiation. Prior studies have shown that mice lacking Pur-alpha (−/−) display decreased neurogenesis and impaired neuronal differentiation. We sought to examine for the first time, the behavioral phenotype and brain histopathology of mice that are heterozygous (+/−) for Pur-alpha. Standardized behavioral phenotyping revealed a decreased escape response to touch, limb and abdominal hypotonia, and gait abnormalities in heterozygous Pur-alpha (+/−) mice, compared to wild-type (+/+) littermates. Footprint pattern analyses showed wider-based steps, increased missteps and more outwardly rotated hindpaws in heterozygous Pur-alpha (+/−) mice, suggestive of cerebellar pathology. The Barnes maze and novel object location testing revealed significant memory deficits in heterozygous Pur-alpha mice, suggestive of hippocampal pathology. Quantitative immunohistochemical assays of the vermal region of the cerebellum and CA1-3 regions of the hippocampus revealed reduced numbers of neurons in general, as well as reduced numbers of Pur-alpha+-immunopositive neurons and dendrites in heterozygous Pur-alpha mice, compared to wild-type littermates. Past studies have implicated mutations in Pur-alpha in several diseases of brain development and neurodegeneration. When combined with these new findings, the Pur-alpha heterozygous knockout mice may provide an animal model to study mechanisms of and treatments for Pur-alpha-related cognitive deficiencies and neuropathology.

AβPP/PS1 Transgenic Mice Show Sex Differences in the Cerebellum Associated with Aging.

Cerebellar pathology has been related to presenilin 1 mutations in certain pedigrees of familial Alzheimer's disease. However, cerebellum tissue has not been intensively analyzed in transgenic models of mutant presenilins. Furthermore, the effect of the sex of the mice was not systematically analyzed, despite the fact that important gender differences in the evolution of the disease in the human population have been described. We analyzed whether the progression of amyloidosis in a double transgenic mouse, AβPP/PS1, is susceptible to aging and differentially affects males and females. The accumulation of amyloid in the cerebellum differentially affects males and females of the AβPP/PS1 transgenic line, which was found to be ten-fold higher in 15-month-old females. Amyloid-β accumulation was more evident in the molecular layer of the cerebellum, but glia reaction was only observed in the granular layer of the older mice. The sex divergence was also observed in other neuronal, survival, and autophagic markers. The cerebellum plays an important role in the evolution of the pathology in this transgenic mouse model. Sex differences could be crucial for a complete understanding of this disease. We propose that the human population could be studied in this way. Sex-specific treatment strategies in human populations could show a differential response to the therapeutic approach.

Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice.

Loss-of-function mutations in the gene encoding the postsynaptic scaffolding protein SHANK2 are a highly penetrant cause of autism spectrum disorders (ASD) involving cerebellum-related motor problems. Recent studies have implicated cerebellar pathology in the aetiology of ASD. Here we evaluate the possibility that cerebellar Purkinje cells (PCs) represent a critical locus of ASD-like pathophysiology in mice lacking Shank2. Absence of Shank2 impairs both PC intrinsic plasticity and induction of long-term potentiation at the parallel fibre to PC synapse. Moreover, inhibitory input onto PCs is significantly enhanced, most prominently in the posterior lobe where simple spike (SS) regularity is most affected. Using PC-specific Shank2 knockouts, we replicate alterations of SS regularity in vivo and establish cerebellar dependence of ASD-like behavioural phenotypes in motor learning and social interaction. These data highlight the importance of Shank2 for PC function, and support a model by which cerebellar pathology is prominent in certain forms of ASD.

Cerebello-cortical networks in orthostatic tremor.

This scientific commentary refers to ‘Orthostatic tremor: a cerebellar pathology?’ by Gallea et al. (doi:10.1093/brain/aww140). There is no tremor as clinically uncontroversial as orthostatic tremor with its unique symptom of shaking in the legs and trunk at a pathognomonic frequency of 13–20 Hz. It is present only during standing and absent while sitting, but rare patients can trigger orthostatic tremor with isometric contraction of limb muscles. The presenting complaint of the patient is a feeling of unsteadiness in the standing position, despite an unremarkable neurological examination. Later in the disease, a quarter of patients have sudden falls. The tremor is hardly visible unless the patient presents with subharmonics but it is regularly palpable and can be auscultated with a normal stethoscope (helicopter sign). The diagnosis is confirmed with EMG from at least one leg muscle (Deuschl et al. , 1998). The cause of orthostatic tremor is unknown. Rare symptomatic causes have been proposed in patients with cerebellar atrophy or lesions in the pons or midbrain together with orthostatic tremor (Vetrugno et al. , 2013). An autoimmune aetiology has also been proposed because of concomitant Graves’ disease, stiff person syndrome or simply because immunoglobulins were helpful in selected patients (Hassan et al. , 2016). In this issue of Brain , Gallea and co-workers present anatomical and functional connectivity data suggesting that orthostatic tremor may be a cerebellar pathology (Gallea et al. , 2016). Metabolic imaging studies of orthostatic tremor have shown intact serotonergic and dopaminergic pathways (Trocello et al. , 2008) and further biochemical analyses have been fruitless. A few peculiar observations are associated with this condition. The first is that all muscles of the body tremble at the main tremor frequency and only during stance. While for other tremors the coherence between different muscles changes over time, …

Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency

The cerebellar pathologies in peroxisomal diseases underscore that these organelles are required for the normal development and maintenance of the cerebellum, but the mechanisms have not been resolved.Here we investigated the origins of the early-onset coordination impairment in a mouse model with neural selective deficiency of multifunctional protein-2, the central enzyme of peroxisomal β-oxidation. At the age of 4weeks, Nestin-Mfp2−/− mice showed impaired motor learning on the accelerating rotarod and underperformed on the balance beam test. The gross morphology of the cerebellum and Purkinje cell arborization were normal. However, electrophysiology revealed a reduced Purkinje cell firing rate, a decreased excitability and an increased membrane capacitance. The distribution of climbing and parallel fiber synapses on Purkinje cells was immature and was accompanied by an increased spine length. Despite normal myelination, Purkinje cell axon degeneration was evident from the occurrence of axonal swellings containing accumulated organelles. In conclusion, the electrical activity, axonal integrity and wiring of Purkinje cells are exquisitely dependent on intact peroxisomal β-oxidation in neural cells.

Cerebellar contribution to higher and lower order rule learning and cognitive flexibility in mice

Cognitive flexibility has traditionally been considered a frontal lobe function. However, converging evidence suggests involvement of a larger brain circuit which includes the cerebellum. Reciprocal pathways connecting the cerebellum to the prefrontal cortex provide a biological substrate through which the cerebellum may modulate higher cognitive functions, and it has been observed that cognitive inflexibility and cerebellar pathology co-occur in psychiatric disorders (e.g., autism, schizophrenia, addiction). However, the degree to which the cerebellum contributes to distinct forms of cognitive flexibility and rule learning is unknown. We tested lurcher↔wildtype aggregation chimeras which lose 0–100% of cerebellar Purkinje cells during development on a touchscreen-mediated attentional set-shifting task to assess the contribution of the cerebellum to higher and lower order rule learning and cognitive flexibility. Purkinje cells, the sole output of the cerebellar cortex, ranged from 0 to 108,390 in tested mice. Reversal learning and extradimensional set-shifting were impaired in mice with⩾95% Purkinje cell loss. Cognitive deficits were unrelated to motor deficits in ataxic mice. Acquisition of a simple visual discrimination and an attentional-set were unrelated to Purkinje cells. A positive relationship was observed between Purkinje cells and errors when exemplars from a novel, non-relevant dimension were introduced. Collectively, these data suggest that the cerebellum contributes to higher order cognitive flexibility, lower order cognitive flexibility, and attention to novel stimuli, but not the acquisition of higher and lower order rules. These data indicate that the cerebellar pathology observed in psychiatric disorders may underlie deficits involving cognitive flexibility and attention to novel stimuli.

Psychosis and mega cisterna magna: Case report

Introduction Mega cisterna magna is a developmental variation of the posterior fossa characterized by the enlargement of the cisterna magna, morphologically intact vermis and cerebellar hemispheres [1]. Cerebellar structures, especially the vermis, are considered to be associated with the pathophysiology of psychiatric disorders such as schizophrenia [2]. We present a case of psychosis with in a patient with ‘mega-cisterna magna'. Case A 21-year-old male with a three-day history of psychotic symptoms presented with disinhibited behavior, delusions of persecution and grandeur and labil affect. He neglected personal hygiene and grooming activities. He had dropped out of school a few weeks ago and functioned poorly. The patient admitted to the service. The patient's problems have regressed after 4mg Pimozid treatment. Neurological examination and EEG were normal. CT and MRI scans disclosed ‘mega-cisterna magna'. Conclusion This report presents a case of cerebellar lesions presenting with neuropsychiatric symptomatology. As in this case, cerebellar pathologies such as mega cisterna magna that could have a role in development psychotic symptoms should be paid attention.

Clinicopathological Correlates in a PRNP P102L Mutation Carrier with Rapidly Progressing Parkinsonism-dystonia.

Parkinsonism-dystonia is rare in carriers of PRNP P102L mutation. Severity and distribution of prion protein (PrP) deposition may influence the clinical presentation. We present such clinic-pathological correlation in a 56-year-old male with a PRNP P102L mutation associated with a phenotype characterized by rapidly progressing parkinsonism-dystonia. The patient was studied clinically (videotaped exams, brain MRIs); molecular genetically (gene sequence analysis); and neuropathologically (histology, immunohistochemistry) during his 7-month disease course. The patient had parkinsonism, apraxia, aphasia, and dystonia, which progressed rapidly. Molecular genetic analysis revealed PRNP P102L mutation carrier status. Brain MRIs revealed progressive global volume loss and T2/FLAIR hyperintensity in neocortex and basal ganglia. Postmortem examination showed neuronal loss, gliosis, spongiform changes, and PrP deposition in the striatum. PrP immunohistochemistry revealed widespread severe PrP deposition in the thalamus and cerebellar cortex. Based on the neuropathological and molecular-genetic analysis, the rapidly progressing parkinsonism-dystonia correlated with nigrostriatal, thalamic, and cerebellar pathology.