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Ataxia and impaired motor learning are both fundamental features in diseases affecting the cerebellum. However, it remains unclarified whether motor learning is impaired only when ataxia clearly manifests, nor it is known whether the progression of ataxia, the speed of which often varies among patients with the same disease, can be monitored by examining motor learning. We evaluated motor learning and ataxia at intervals of several months in 40 patients with degenerative conditions [i.e., multiple system atrophy (MSA), Machado–Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3), SCA6, and SCA31]. Motor learning was quantified as the adaptability index (AI) in the prism adaptation task and ataxia was scored using the Scale for the Assessment and Rating of Ataxia (SARA). We found that AI decreased most markedly in both MSA-C and MSA-P, moderately in MJD, and mildly in SCA6 and SCA31. Overall, the AI decrease occurred more rapidly than the SARA score increase. Interestingly, AIs remained normal in purely parkinsonian MSA-P patients (n = 4), but they dropped into the ataxia range when these patients started to show ataxia. The decrease in AI during follow-up (dAI/dt) was significant in patients with SARA scores < 10.5 compared with patients with SARA scores ≥ 10.5, indicating that AI is particularly useful for diagnosing the earlier phase of cerebellar degeneration. We conclude that AI is a useful marker for progressions of cerebellar diseases, and that evaluating the motor learning of patients can be particularly valuable for detecting cerebellar impairment, which is often masked by parkinsonisms and other signs. [ABSTRACT FROM AUTHOR]

Degenerative effects of nerve tissues are often accompanied by changes in vascularization. In this regard, knowledge about hereditary cerebellar degeneration is limited. In this study, we compared the vascularity of the individual cerebellar components of 3-month-old wild-type mice (n = 8) and Purkinje cell degeneration (pcd) mutant mice, which represent a model of hereditary cerebellar degeneration (n = 8). Systematic random samples of tissue sections were processed, and laminin was immunostained to visualize microvessels. A computer-assisted stereology system was used to quantify microvessel parameters including total number, total length, and associated densities in cerebellar layers. Our results in pcd mice revealed a 45% (p < 0.01) reduction in the total volume of the cerebellum, a 28% (p < 0.05) reduction in the total number of vessels and a lower total length, approaching 50% (p < 0.001), compared to the control mice. In pcd mutants, cerebellar degeneration is accompanied by significant reduction in the microvascular network that is proportional to the cerebellar volume reduction therefore does not change density of in the cerebellar gray matter of pcd mice. [ABSTRACT FROM AUTHOR]

Copyright of Neurologie Pro Praxi is the property of SOLEN sro and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The cerebellum is recognized to play a critical role in the automatic and implicit process by which movement errors are used to keep the sensorimotor system precisely calibrated. However, its role in other learning processes frequently engaged during sensorimotor adaptation tasks remains unclear. In the present study, we tested the performance of individuals with cerebellar degeneration on a variant of a visuomotor adaptation task in which learning requires the use of strategic re-aiming, a process that can nullify movement errors in a rapid and volitional manner. Our design allowed us to assess two components of this learning process, the discovery of an appropriate strategy and the recall of a learned strategy. Participants were exposed to a 60° visuomotor rotation twice, with the initial exposure block assessing strategy discovery and the re-exposure block assessing strategy recall. Compared to age-matched controls, individuals with cerebellar degeneration were slower to derive an appropriate aiming strategy in the initial Discovery block but exhibited similar recall of the aiming strategy during the Recall block. This dissociation underscores the multi-faceted contributions of the cerebellum to sensorimotor learning, highlighting one way in which this subcortical structure facilitates volitional action selection. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological disorders are rare in children, with paraneoplastic cerebellar degeneration (PCD) considered highly atypical. We describe a 13-yearold girl with progressive neurobehavioral regression, cerebellar ataxia, and intractable epilepsy presenting in super-refractory status epilepticus. After an extensive evaluation, her clinical picture was suggestive of probable autoimmune encephalitis (AE). Further diagnostic testing revealed a molecularly undefined neural-restricted autoantibody in both serum and CSF, raising suspicion over an adrenal mass previously considered incidental. Surgical resection led to a robust clinical improvement, and pathology revealed a benign ganglioneuroma. This report widens the spectrum of paraneoplastic manifestations of ganglioneuroma, reviews the diagnostic approach to antibody-negative pediatric AE, and raises important clinical considerations regarding benign and incidentally found tumors in the setting of a suspected paraneoplastic neurologic syndrome. [ABSTRACT FROM AUTHOR]

To investigate physical activity levels of individuals with ataxia and correlate fitness to ataxia severity. An observational study An outpatient ataxia clinic in a large, tertiary, urban hospital in the US. Individuals with cerebellar ataxia (N=42). Not applicable. Participants were classified as sedentary or physically active using the International Physical Activity Questionnaire-Short Form (IPAQ-SF). Maximal oxygen consumption (V̇ o 2 max) as an indicator of fitness level was measured, and ataxia severity was determined by the Scale for the Assessment and Rating of Ataxia (SARA). Mixed effect models were used to correlate ataxia severity to fitness levels. Most participants (28 out of 42) lived sedentary lifestyles, and these individuals had poor fitness levels (only 67.3% of their predicted measure). The main barriers to physical activity included lack of energy, lack of time, and fear of falling. There were no differences in age, sex, disease type, disease duration, ataxia severity, fatigue level, and medication use between sedentary and active groups. Measures of V̇ o 2 max, maximal work, maximal heart rate, and anerobic threshold demonstrated statistically significant differences between groups whereas maximal respiratory rate and expired ventilation/carbon dioxide production were similar between groups. When adjusting for age, sex, functional mobility status, and disease duration, ataxia severity was inversely correlated with fitness level in the sedentary group. There was no relationship between ataxia severity and fitness level in the 14 individuals who were physically active. Lower fitness levels were associated with more ataxia symptoms in the sedentary group. This relationship was not seen in individuals who were more active. Given the poor health outcomes associated with low fitness, physical activity should be encouraged in this population. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological disorders are rare in children, with paraneoplastic cerebellar degeneration (PCD) considered highly atypical. We describe a 13-year-old girl with progressive neurobehavioral regression, cerebellar ataxia, and intractable epilepsy presenting in super-refractory status epilepticus. After an extensive evaluation, her clinical picture was suggestive of probable autoimmune encephalitis (AE). Further diagnostic testing revealed a molecularly undefined neural-restricted autoantibody in both serum and CSF, raising suspicion over an adrenal mass previously considered incidental. Surgical resection led to a robust clinical improvement, and pathology revealed a benign ganglioneuroma. This report widens the spectrum of paraneoplastic manifestations of ganglioneuroma, reviews the diagnostic approach to antibody-negative pediatric AE, and raises important clinical considerations regarding benign and incidentally found tumors in the setting of a suspected paraneoplastic neurologic syndrome.

Paraneoplastic neurological syndrome (PNS) is rarely associated with malignant pleural mesothelioma (MPM). We report the first case of sarcomatoid mesothelioma in a 63-year-old female diagnosed with cerebellar degeneration in January 2018. Systemic examination showed right pleura thickening. The pleural biopsy of the mass revealed a sarcomatoid MPM cT3N0M0. In February 2018, anti-Ma2 antibody positivity indicated PNS complicated with MPM. First, cisplatin (75 mg/m2) + pemetrexed (500 mg/m2) chemotherapy was given. For PNS, steroid pulse therapy and high-dose immunoglobulin therapy were administered. MPM may cause anti-Ma2 antibody-related PNS. Early diagnosis and starting anticancer treatment and immunotherapy are critical.

Abstract Introduction Subacute cerebellar ataxia combined with cerebrospinal fluid (CSF) pleocytosis is the result of an immune response that can occur due to viral infections, paraneoplastic diseases or autoimmune-mediated mechanisms. In the following we present the first description of a patient with anti-Homer-3 antibodies in serum and CSF who has been diagnosed with paraneoplastic subacute cerebellar degeneration due to a papillary adenocarcinoma of the breast. Case presentation A 58-year-old female was admitted to our clinical department because of increasing gait and visual disturbances starting nine months ago. The neurological examination revealed a downbeat nystagmus, oscillopsia, a severe standing and gait ataxia and a slight dysarthria. Cranial MRI showed no pathological findings. Examination of CSF showed a lymphocytic pleocytosis of 11 cells/µl and an intrathecal IgG synthesis of 26%. Initially, standard serological testing in serum and CSF did not indicate any autoimmune or paraneoplastic aetiology. However, an antigen-specific indirect immunofluorescence test (IIFT) revealed the presence of anti-Homer-3 antibodies (IgG) with a serum titer of 1: 32,000 and a titer of 1: 100 in CSF. Subsequent histological examination of a right axillary lymph node mass showed papillary adenocarcinoma cells. Breast MRI detected multiple bilateral lesions as a diffuse tumour manifestation indicative of adenocarcinoma of the breast. Treatment with high-dose methylprednisolone followed by five plasmaphereses and treatment with 4-aminopyridine resulted in a moderate decrease of the downbeat nystagmus and she was able to move independently with a wheeled walker after 3 weeks. The patient was subsequently treated with chemotherapy (epirubicin, cyclophosphamide) and two series of immunoglobulins (5 × 30 g each). This resulted in a moderate improvement of the cerebellar symptoms with a decrease of ataxia and disappearance of the downbeat nystagmus. Conclusion The presented case of anti-Homer-3 antibody-associated cerebellar degeneration is the first that is clearly associated with the detection of a tumour. Interestingly, the Homer-3 protein interaction partner metabotropic glutamate receptor subtype 1A (mGluR1A) is predominantly expressed in Purkinje cells where its function is essential for motor coordination and motor learning. Based on our findings, in subacute cerebellar degeneration, we recommend considering serological testing for anti-Homer-3 antibodies in serum and cerebrospinal fluid together with tumor screening.

Sporadic, adult-onset cerebellar ataxia is a disease with multiple etiologies. In addition to cortical cerebellar atrophy (CCA), which is often used for the pathological diagnosis, other terms such as idiopathic late-onset cerebellar ataxia (ILOCA) and sporadic adult-onset ataxia of unknown etiology (SAOA) have been used to refer to this disorder. These names describe key features of the disease, including degeneration limited to the cerebellar cortex (with or without secondary involvement of inferior olivary nuclei), a slowly progressive ataxia, and absence of a clear etiology, such as multiple system atrophy, as well as paraneoplastic, autoimmune, infectious and inherited ataxias. In this Point of View article, we describe two patients with sporadic, adult-onset ataxia with rapidly progressive disease course in addition to extracerebellar symptoms resembling prion disease, including the reevaluation of one patient who was previously reported. Pathological findings are mostly consistent with CCA, but also have degenerative changes in the thalamus. Whole genome sequencing in two patients with rapidly progressive CCA did not reveal any pathogenic variants associated with cerebellar ataxia. Although the underlying etiology behind rapidly progressive CCA is unknown, we suggest that the unique combination of clinical and pathological features of CAA with a short disease course defines a new disease entity, rapidly progressive cerebellar cortical and thalamic degeneration. This viewpoint article draws attention to this rare sporadic cerebellar ataxia with the hope that highlighting clinical and pathologic findings in a typical case will lead to improved recognition and research. [ABSTRACT FROM AUTHOR]

Introduction: Subacute cerebellar ataxia combined with cerebrospinal fluid (CSF) pleocytosis is the result of an immune response that can occur due to viral infections, paraneoplastic diseases or autoimmune-mediated mechanisms. In the following we present the first description of a patient with anti-Homer-3 antibodies in serum and CSF who has been diagnosed with paraneoplastic subacute cerebellar degeneration due to a papillary adenocarcinoma of the breast. Case presentation: A 58-year-old female was admitted to our clinical department because of increasing gait and visual disturbances starting nine months ago. The neurological examination revealed a downbeat nystagmus, oscillopsia, a severe standing and gait ataxia and a slight dysarthria. Cranial MRI showed no pathological findings. Examination of CSF showed a lymphocytic pleocytosis of 11 cells/µl and an intrathecal IgG synthesis of 26%. Initially, standard serological testing in serum and CSF did not indicate any autoimmune or paraneoplastic aetiology. However, an antigen-specific indirect immunofluorescence test (IIFT) revealed the presence of anti-Homer-3 antibodies (IgG) with a serum titer of 1: 32,000 and a titer of 1: 100 in CSF. Subsequent histological examination of a right axillary lymph node mass showed papillary adenocarcinoma cells. Breast MRI detected multiple bilateral lesions as a diffuse tumour manifestation indicative of adenocarcinoma of the breast. Treatment with high-dose methylprednisolone followed by five plasmaphereses and treatment with 4-aminopyridine resulted in a moderate decrease of the downbeat nystagmus and she was able to move independently with a wheeled walker after 3 weeks. The patient was subsequently treated with chemotherapy (epirubicin, cyclophosphamide) and two series of immunoglobulins (5 × 30 g each). This resulted in a moderate improvement of the cerebellar symptoms with a decrease of ataxia and disappearance of the downbeat nystagmus. Conclusion: The presented case of anti-Homer-3 antibody-associated cerebellar degeneration is the first that is clearly associated with the detection of a tumour. Interestingly, the Homer-3 protein interaction partner metabotropic glutamate receptor subtype 1A (mGluR1A) is predominantly expressed in Purkinje cells where its function is essential for motor coordination and motor learning. Based on our findings, in subacute cerebellar degeneration, we recommend considering serological testing for anti-Homer-3 antibodies in serum and cerebrospinal fluid together with tumor screening. [ABSTRACT FROM AUTHOR]

Alcohol use, while commonly associated with liver damage, also has significant neurologic implications, which often mimic hepatic encephalopathy and complicate diagnosis and management. Alcohol mediates its acute central nervous system effects by altering neurotransmitter balance, notably between gamma-aminobutyric acid and glutamate. Its chronic neurotoxicity, compounded by thiamine deficiency, results in chronic neurologic complications. Clinically, alcohol-related neurologic disorders present a spectrum from acute intoxication and withdrawal to chronic conditions like Korsakoff syndrome, dementia, cerebellar degeneration, and peripheral neuropathy. This review underscores differentiating these conditions from hepatic encephalopathy and highlights the importance of history-taking and physical examination in clinical practice., Competing Interests: Disclosure All authors have no commercial or financial conflicts of interest to disclose. There are no funding sources to disclose for this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Paraneoplastic neurological syndrome (PNS) represents a rare group of central nervous system disorders that are unrelated to direct tumor invasion or metastasis but may be triggered by an immune system reaction to a neoplasm or malignant tumor. In many patients, PNS is diagnosed before identifying the primary cancer. In such instances, positron emission tomography/computed tomography scan can assess individuals with suspected PNS enabling the detection of hidden malignancies. We share an interesting image of paraneoplastic cerebellar degeneration in a case of invasive ductal carcinoma breast. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the benefit of vestibular rehabilitation therapy (VRT) in the management of patients with idiopathic cerebellar ataxia with bilateral vestibulopathy (iCABV). BACKGROUND: iCABV is a hindbrain degenerative disorder with impairment of both central and peripheral vestibular pathways. There is combined failure of four compensatory eye movement systems including the vestibulo-ocular reflex (VOR), optokinetic reflex, smooth pursuit and the visually enhanced vestibulo-ocular reflex (VVOR). Phenotypic presentation includes postural and gait instability, oscillopsia and dizziness with active head movement. The benefit of VRT in iCABV patients has not been established. METHODS: A retrospective review was performed on a cohort of twelve patients diagnosed with iCABV in a multidisciplinary neuro-otology clinic. All participated in VRT and completed their suggested course of VRT. The following clinical measures were assessed before starting and after finishing VRT: 1) Dizziness Handicap Inventory (DHI), 2) Activities-Specific Balance Confidence (ABC) Scale, 3) Catastrophization scale, 4) Positive Affective Negative Affective Score (PANAS), 5) Dynamic Gait Index (DGI) and 6) Modified Clinical Test of Sensory Interaction in Balance (mCTSIB). The number of falls historically was recorded in addition to gait speed (ft./sec). RESULTS: Following VRT, patients were found to have improved balance on mCTSIB (condition 4 : 7 vs 18 seconds, P = 0.04) and a better postural stability with a reduced number of falls (p = 0.01). No statistically significant improvement was seen in the DHI, ABC, Catastrophization scale, DGI, PANAS and gait speed (p > 0.05). CONCLUSIONS: iCABV patients who underwent VRT were found to have a better postural stability and reduced risk of falls. VRT was not found to significantly improve patients' overall subjective perception of their symptoms or their psychological status. [ABSTRACT FROM AUTHOR]

Copyright of Neurologie Pro Praxi is the property of SOLEN sro and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cerebellar involvement in language processing has received considerable attention in the neuroimaging and neuropsychology literatures. Building off the motor control literature, one account of this involvement centers on the idea of internal models. In the context of language, this hypothesis suggests that the cerebellum is essential for building semantic models that, in concert with the cerebral cortex, help anticipate or predict linguistic input. To date, supportive evidence has primarily come from neuroimaging studies showing that cerebellar activation increases in contexts in which semantic predictions are generated and violated. Taking a neuropsychological approach, we put the internal model hypothesis to the test, asking if individuals with cerebellar degeneration ( n = 14) show reduced sensitivity to semantic prediction. Using a sentence verification task, we compare reaction time to sentences that vary in terms of cloze probability. We also evaluated a more constrained variant of the prediction hypothesis, asking if the cerebellum facilitates the generation of semantic predictions when the content of a sentence refers to a dynamic rather than static mental transformation. The results failed to support either hypothesis: Compared to matched control participants ( n = 17), individuals with cerebellar degeneration showed a similar reduction in reaction time for sentences with high cloze probability and no selective impairment in predictions involving dynamic transformations. These results challenge current theorizing about the role of the cerebellum in language processing, pointing to a misalignment between neuroimaging and neuropsychology research on this topic., Competing Interests: Competing Interests: The authors have included a competing interest section at back of article. Richard B. Ivry is a co-founder with equity in Magnetic Tides, Inc. The other authors declare no competing interests exist., (© 2022 Massachusetts Institute of Technology.)

• Paraneoplastic cerebellar degeneration (PCD) symptoms include ataxia and nystagmus. • Holmes tremor is a large amplitude, 3–4 Hz tremor associated with PCD. • PCD associated with non-Hodgkin's lymphoma has rarely been reported. • Malignancy workup and repeat biopsy is recommended if suspicion for PCD is high. • Treating the underlying malignancy is the most likely to improve PCD symptoms. [ABSTRACT FROM AUTHOR]

Human motor learning is governed by a suite of interacting mechanisms each one of which modifies behavior in distinct ways and rely on different neural circuits. In recent years, much attention has been given to one type of motor learning, called motor adaptation. Here, the field has generally focused on the interactions of three mechanisms: sensory prediction error SPE-driven, explicit (strategy-based), and reinforcement learning. Studies of these mechanisms have largely treated them as modular, aiming to model how the outputs of each are combined in the production of overt behavior. However, when examined closely the results of some studies also suggest the existence of additional interactions between the sub-components of each learning mechanism. In this perspective, we propose that these sub-component interactions represent a critical means through which different motor learning mechanisms are combined to produce movement; understanding such interactions is critical to advancing our knowledge of how humans learn new behaviors. We review current literature studying interactions between SPE-driven, explicit, and reinforcement mechanisms of motor learning. We then present evidence of sub-component interactions between SPE-driven and reinforcement learning as well as between SPE-driven and explicit learning from studies of people with cerebellar degeneration. Finally, we discuss the implications of interactions between learning mechanism sub-components for future research in human motor learning.

Human motor learning is governed by a suite of interacting mechanisms each one of which modifies behavior in distinct ways and rely on different neural circuits. In recent years, much attention has been given to one type of motor learning, called motor adaptation. Here, the field has generally focused on the interactions of three mechanisms: sensory prediction error SPE-driven, explicit (strategy-based), and reinforcement learning. Studies of these mechanisms have largely treated them as modular, aiming to model how the outputs of each are combined in the production of overt behavior. However, when examined closely the results of some studies also suggest the existence of additional interactions between the sub-components of each learning mechanism. In this perspective, we propose that these sub-component interactions represent a critical means through which different motor learning mechanisms are combined to produce movement; understanding such interactions is critical to advancing our knowledge of how humans learn new behaviors. We review current literature studying interactions between SPE-driven, explicit, and reinforcement mechanisms of motor learning. We then present evidence of sub-component interactions between SPE-driven and reinforcement learning as well as between SPE-driven and explicit learning from studies of people with cerebellar degeneration. Finally, we discuss the implications of interactions between learning mechanism sub-components for future research in human motor learning. [ABSTRACT FROM AUTHOR]

Proper functioning of the cerebellum is crucial to motor balance and coordination in adult mammals. Purkinje cells (PCs), the sole output neurons of the cerebellar cortex, play essential roles in cerebellar motor function. Tripartite motif-containing protein 32 (TRIM32) is an E3 ubiquitin ligase that is involved in balance activities of neurogenesis in the subventricular zone of the mammalian brain and in the development of many nervous system diseases, such as Alzheimer's disease, autism spectrum disorder, attention deficit hyperactivity disorder. However, the role of TRIM32 in cerebellar motor function has never been examined. In this study we found that motor balance and coordination of mid-aged TRIM32 deficient mice were poorer than those of wild-type littermates. Immunohistochemical staining was performed to assess cerebella morphology and TRIM32 expression in PCs. Golgi staining showed that the extent of dendritic arborization and dendritic spine density of PCs were decreased in the absence of TRIM32. The loss of TRIM32 was also associated with a decrease in the number of synapses between parallel fibers and PCs, and in synapses between climbing fibers and PCs. In addition, deficiency of TRIM32 decreased Type I inositol 1,4,5-trisphosphate 5-phosphatase (INPP5A) levels in cerebellum. Overall, this study is the first to elucidate a role of TRIM32 in cerebellar motor function and a possible mechanism, thereby highlighting the importance of TRIM32 in the cerebellum.

A brain stem/cerebellar neural integrator enables stable eccentric gaze. Cerebellar loss-of-function can cause an inability to maintain gaze eccentrically (gaze-evoked nystagmus). Moreover, after returning gaze to straight ahead, the eyes may drift toward the prior eye position (rebound nystagmus). Typically, gaze-evoked nystagmus decays during continuously held eccentric gaze. We hypothesized this adaptive behavior to be prerequisite for rebound nystagmus and thus predicted a correlation between the velocity decay of gaze-evoked nystagmus and the initial velocity of rebound nystagmus. Using video-oculography, eye position was measured in 11 patients with cerebellar degeneration at nine horizontal gaze angles (15° nasal to 25° temporal) before (baseline), during, and after attempted eccentric gaze at ± 30° for 20 s. We determined the decrease of slow-phase velocity at eccentric gaze and the slow-phase velocity of the subsequent rebound nystagmus relative to the baseline. During sustained eccentric gaze, eye drift velocity of gaze-evoked nystagmus decreased by 2.40 ± 1.47°/s. Thereafter, a uniform change of initial eye drift velocity relative to the baseline (2.40 ± 1.35°/s) occurred at all gaze eccentricities. The velocity decrease during eccentric gaze and the subsequent uniform change of eye drift were highly correlated (R2 = 0.80, p < 0.001, slope = 1.09). Rebound nystagmus can be explained as gaze-evoked nystagmus relative to a set point (position with least eye drift) away from straight-ahead eye position. To improve detection at the bedside, we suggest testing rebound nystagmus not at straight-ahead eye position but at an eccentric position opposite of prior eccentric gaze (e.g., 10°), ideally using quantitative video-oculography to facilitate diagnosis of cerebellar loss-of-function. [ABSTRACT FROM AUTHOR]

Proper functioning of the cerebellum is crucial to motor balance and coordination in adult mammals. Purkinje cells (PCs), the sole output neurons of the cerebellar cortex, play essential roles in cerebellar motor function. Tripartite motif-containing protein 32 (TRIM32) is an E3 ubiquitin ligase that is involved in balance activities of neurogenesis in the subventricular zone of the mammalian brain and in the development of many nervous system diseases, such as Alzheimer's disease, autism spectrum disorder, attention deficit hyperactivity disorder. However, the role of TRIM32 in cerebellar motor function has never been examined. In this study we found that motor balance and coordination of mid-aged TRIM32 deficient mice were poorer than those of wild-type littermates. Immunohistochemical staining was performed to assess cerebella morphology and TRIM32 expression in PCs. Golgi staining showed that the extent of dendritic arborization and dendritic spine density of PCs were decreased in the absence of TRIM32. The loss of TRIM32 was also associated with a decrease in the number of synapses between parallel fibers and PCs, and in synapses between climbing fibers and PCs. In addition, deficiency of TRIM32 decreased Type I inositol 1,4,5-trisphosphate 5-phosphatase (INPP5A) levels in cerebellum. Overall, this study is the first to elucidate a role of TRIM32 in cerebellar motor function and a possible mechanism, thereby highlighting the importance of TRIM32 in the cerebellum. [ABSTRACT FROM AUTHOR]

Background: Cerebellar cortical degeneration (CCD) is the premature death of cerebellar neurons of heterogeneous etiology that is uncommonly observed as neurological complication of certain neoplasia. Case Description: Here, we report an 8-month-old male domestic cat with altered consciousness, symmetric ataxia, hypermetric gait, vertical positional nystagmus, mydriasis, strabismus, intention tremor of the head, and increased patellar reflexes. Neuroanatomical diagnosis suggested a multifocal brain dysfunction (cerebellar and cerebral). The cat tested seropositive for feline leukemia virus. Cerebrospinal fluid analysis indicated mononuclear and neutrophilic pleocytosis. Contrast computed tomography imaging revealed multiple hypodense heterogeneous areas in both cerebral hemispheres, mild ventriculomegaly at the level of the caudal fossa, and a circular sharply marginated, homogeneously hyperdense mass occupying the right cerebellar hemisphere. Postmortem study indicated a 1,1 × 1,3 x 1,2 cm mass in the right cerebellar hemisphere close to the vermis. Histopathological analysis showed diffuse and severe Purkinje cell loss with a decrease in granular cell density and moderate gliosis compatible with CCD. Further, numerous neoplastic lymphoid cells were observed in the infiltrated mass, consistent with a diagnosis of central nervous system (CNS) lymphoma. Immunohistochemistry showed CD20 expression, indicative of a B cell immunophenotype. In humans, CCD is reported as a rare paraneoplastic syndrome in patients with Hodgkin lymphoma. CNS lymphoma and/or FeLV infection were both considered as possible cause of CCD in this case. Conclusion: This is the first described case of possible paraneoplastic cerebellar cortical degeneration associated with CNS lymphoma and/or FeLV infection in a domestic cat.

Phenytoin is a commonly used antiepileptic drug for various types of seizure disorders except for absent seizures. Long-term dose-dependent neurological side effects of phenytoin therapy include cerebellar atrophy, cerebral atrophy, and brain stem atrophy. Skull hyperostosis, gum hypertrophy, and megaloblastic anemia are other known effects of long-term therapy. We present four cases depicting clinical and neuroimaging findings of phenytoin-induced toxicity. [ABSTRACT FROM AUTHOR]

Introduction: Paraneoplastic cerebellar degeneration (PCD) is a rare set of neurological disorders arising from tumor-associated autoimmunity against antigens within the cerebellum. Anti-Purkinje cell cytoplasmic antibody 1 (PCA-1), or anti-Yo, is the most commonly linked antibody and is classically associated with breast and ovarian cancers. Methods: Medical records of patients at our institution who developed PCA-1 associated PCD were reviewed. Clinical information, including cancer history, cancer-directed treatment, and serum and CSF titers of PCA-1 antibody were extracted. Cases: We report a series of cases of PCA-1 associated PCD in patients with known breast or ovarian cancer diagnosis not receiving immunotherapy. These cases highlight aspects of PCA-1 paraneoplastic syndrome such as triggering by cytotoxic chemotherapy or surgery, the possibility of tumor recurrence and the association with development of a second cancer. Discussion: Diagnosis of the syndrome requires neurological workup with lumbar puncture (LP) with cerebrospinal fluids (CSF) studies, serum and CSF paraneoplastic antibody panel, and neuroimaging. Inpatient admission for prompt workup and initiation of treatment is recommended. Treatment most commonly includes immunosuppression with corticosteroids, plasmapheresis, and/or intravenous immune globulin (IVIG); however, we postulate that other immune modulating treatments may warrant consideration. Conclusion: These cases highlight the need for early recognition of the syndrome in patients receiving nonimmune based chemotherapy, for prompt workup and treatment. [ABSTRACT FROM AUTHOR]

While cerebellar ataxia (CA) is a neurodegenerative disease known for motor impairment, changes in mood have also been reported. A full account of neuropsychiatric symptomology in CA may guide improvements in treatment regimes, measure the presence and severity of sub-clinical neuropsychiatric disturbance symptomology in CA, and compare patient versus informant symptom recognition. Neuropsychiatric phenomena were gathered from CA patients with genetic and unknown etiologies and their informants (e.g., spouse or parent). Information was obtained from in-person interviews and the Center for Epidemiologic Studies Depression Scale. Responses were converted to the Neuropsychiatric Inventory-Questionnaire (NPI-Q) scores by consensus ratings. Patient NPI-Q scores were evaluated for symptom prevalence and severity relative to those obtained from healthy controls. Patient-informant NPI-Q score disagreements were evaluated. In this cohort, 95% of patients presented with at least one neuropsychiatric symptom and 51% of patients with three or more symptoms. The most common symptoms were anxiety, depression, nighttime behaviors (e.g., interrupted sleep), irritability, disinhibition, abnormal appetite, and agitation. The prevalence of these neuropsychiatric symptoms was uniform across patients with genetic versus unknown etiologies. Patient and informant symptom report disagreements reflected that patients noted sleep impairment and depression, while informants noted irritability and agitation. Neuropsychiatric disturbance is highly prevalent in patients with CA and contributes to the phenomenology of CA, regardless of etiology. Clinicians should monitor psychiatric health in their CA patients, considering that supplemental information from informants can help gauge the impact on family members and caregivers. [ABSTRACT FROM AUTHOR]

Genetic variants in TMEM106B are a major risk factor for several neurodegenerative diseases including frontotemporal degeneration, limbic‐predominant age‐related TDP‐43 encephalopathy, Parkinson's disease, late‐onset‐Alzheimer's disease and constitute a genetic determinant of differential aging. TMEM106B encodes an integral lysosomal membrane protein but its precise physiological function in the central nervous system remains enigmatic. Presently, we aimed to increase understanding of TMEM106B contribution to general brain function and aging. We analyzed an aged cohort of Tmem106b knockout‐, heterozygote and wild‐type mice in a behavioral test battery including assessments of motor function as well as, social, emotional and cognitive function. Aged Tmem106b knockout (KO) mice displayed diverse behavioral deficits including motor impairment, gait defects and reduced startle reactivity. In contrast, no prominent deficits were observed in social, emotional or cognitive behaviors. Histologically, we observed late‐onset loss of Purkinje cells followed by reactive gliosis in the cerebellum, which likely contributed to progressive decline in motor function and gait defects in particular. Reactive gliosis was not restricted to the cerebellum but observed in different areas of the brain including the brain stem and parts of the cerebral cortex. Surviving Purkinje cells showed vacuolated lysosomes in the axon initial segment, implicating TMEM106B‐dependent lysosomal trafficking defects as the underlying cause of axonal and more general neuronal dysfunction contributing to behavioral impairments. Our experiments help to elucidate how TMEM106B affects spatial neuronal homeostasis and exemplifies a critical role of TMEM106B in neuronal cells for survival. [ABSTRACT FROM AUTHOR]