Kufor-Rakeb syndrome-associated psychosis: a novel loss-of-function ATP13A2 variant and response to antipsychotic therapy.

Biallelic (autosomal recessive) pathogenic variants in ATP13A2 cause a form of juvenile-onset parkinsonism, termed Kufor-Rakeb syndrome. In addition to motor symptoms, a variety of other neurological and psychiatric symptoms may occur in affected individuals, including supranuclear gaze palsy and cognitive decline. Although psychotic symptoms are often reported, response to antipsychotic therapy is not well described in previous case reports/series. As such, we describe treatment response in an individual with Kufor-Rakeb syndrome-associated psychosis. His disease was caused by a homozygous novel loss-of-function ATP13A2 variant (NM_022089.4, c.1970_1975del) that was characterized in this study. Our patient exhibited a good response to quetiapine monotherapy, which he has so far tolerated well. We also reviewed the literature and summarized all previous descriptions of antipsychotic treatment response. Although its use has infrequently been described in Kufor-Rakeb syndrome, quetiapine is commonly used in other degenerative parkinsonian disorders, given its lower propensity to cause extrapyramidal symptoms. As such, quetiapine should be considered in the treatment of Kufor-Rakeb syndrome-associated psychosis when antipsychotic therapy is deemed necessary.

Microstructural Abnormalities of the Dentatorubrothalamic Tract in Cervical Dystonia.

BACKGROUND: The dentatorubrothalamic tract (DRTT) remains understudied in idiopathic cervical dystonia (CD), despite evidence that the pathway is relevant in the pathophysiology of the disorder. OBJECTIVE: The aim of this study was to examine the DRTT in patients with CD using diffusion tensor imaging (DTI)-based tractography. METHODS: Magnetic resonance imaging scans from 67 participants were collected to calculate diffusion tractography metrics using a binary tractography-based DRTT template. Fractional anisotropy and diffusivity measures of left and right DRTT were computed and compared between 32 subjects with CD and 35 age-matched healthy volunteers. RESULTS: Fractional anisotropy of right DRTT and mean and axial diffusivity of left DRTT were significantly reduced in patients with CD. Similar abnormalities were observed in patients with focal CD and patients with CD without tremor. DTI metrics did not correlate with disease duration or severity. CONCLUSIONS: Significant reductions in DTI measures suggest microstructural abnormalities within the DRTT in CD, characterized by a tractography pattern consistent with decreased axonal integrity. © 2021 International Parkinson and Movement Disorder Society.

Common and unique connectivity at the interface of motor, neuropsychiatric, and cognitive symptoms in Parkinson's disease: A commonality analysis.

Parkinson's disease (PD) is characterized by overlapping motor, neuropsychiatric, and cognitive symptoms. Worse performance in one domain is associated with worse performance in the other domains. Commonality analysis (CA) is a method of variance partitioning in multiple regression, used to separate the specific and common influence of collinear predictors. We apply, for the first time, CA to the functional connectome to investigate the unique and common neural connectivity underlying the interface of the symptom domains in 74 non-demented PD subjects. Edges were modeled as a function of global motor, cognitive, and neuropsychiatric scores. CA was performed, yielding measures of the unique and common contribution of the symptom domains. Bootstrap confidence intervals were used to determine the precision of the estimates and to directly compare each commonality coefficient. The overall model identified a network with the caudate nucleus as a hub. Neuropsychiatric impairment accounted for connectivity in the caudate-dorsal anterior cingulate and caudate-right dorsolateral prefrontal-right inferior parietal circuits, while caudate-medial prefrontal connectivity reflected a unique effect of both neuropsychiatric and cognitive impairment. Caudate-precuneus connectivity was explained by both unique and shared influence of neuropsychiatric and cognitive symptoms. Lastly, posterior cortical connectivity reflected an interplay of the unique and common effects of each symptom domain. We show that CA can determine the amount of variance in the connectome that is unique and shared amongst motor, neuropsychiatric, and cognitive symptoms in PD, thereby improving our ability to interpret the data while gaining novel insight into networks at the interface of these symptom domains.

Zfp423/ZNF423 regulates cell cycle progression, the mode of cell division and the DNA-damage response in Purkinje neuron progenitors.

The Zfp423/ZNF423 gene encodes a 30-zinc-finger transcription factor involved in key developmental pathways. Although null Zfp423 mutants develop cerebellar malformations, the underlying mechanism remains unknown. ZNF423 mutations are associated with Joubert Syndrome, a ciliopathy causing cerebellar vermis hypoplasia and ataxia. ZNF423 participates in the DNA-damage response (DDR), raising questions regarding its role as a regulator of neural progenitor cell cycle progression in cerebellar development. To characterize in vivo the function of ZFP423 in neurogenesis, we analyzed allelic murine mutants in which distinct functional domains are deleted. One deletion impairs mitotic spindle orientation, leading to premature cell cycle exit and Purkinje cell (PC) progenitor pool deletion. The other deletion impairs PC differentiation. In both mutants, cell cycle progression is remarkably delayed and DDR markers are upregulated in cerebellar ventricular zone progenitors. Our in vivo evidence sheds light on the domain-specific roles played by ZFP423 in different aspects of PC progenitor development, and at the same time strengthens the emerging notion that an impaired DDR may be a key factor in the pathogenesis of JS and other ciliopathies.

The impact of traumatic brain injury on cognitive and neuropsychiatric symptoms of Parkinson's disease.

The objective was to determine whether a history of traumatic brain injury (TBI) was associated with Parkinson's Disease (PD) and specific cognitive, motor, and neuropsychiatric symptoms. A cross-sectional cohort study of 120 participants aged 60-85 years old (48 females) were recruited (69 PD and 51 healthy controls). Assessments included demographic information, neuropsychological tests, a motor evaluation, neuropsychiatric questionnaires, and the Brain Injury Screening Questionnaire. A history of TBI or number of TBIs was not significantly related to an increased risk of developing PD or poorer motor scores on the United Parkinson Disease Rating Scale part 3. There was a significant negative correlation between number of TBI's and mean z-scores of global cognition (rs(69) = -0.338, p = 0.004), executive function (rs(69) = -0.251, p = 0.038), memory (rs(69) = -0.262, p = 0.029), and language (rs(69) = -0.245, p = 0.042), and a significant positive correlation on the Beck Depression Inventory II (rs(69) = 0.285, p = 0.018) and the Patient Health Questionnaire-9 (PHQ-9) (rs(69) = 0.326, p = 0.006) in the PD group only. In conclusion, a history of TBI was negatively associated with cognition and positively associated with depressive symptoms in patients with PD, but not with motor symptoms.

Network basis of the dysexecutive and posterior cortical cognitive profiles in Parkinson's disease.

BACKGROUND: The dual syndrome hypothesis of cognitive impairment in PD suggests that two cognitive profiles exist with distinct pathological mechanisms and a differential risk for further cognitive decline. How these profiles relate to network dysfunction has never been explicitly characterized. OBJECTIVE: First, to assess intranetwork functional connectivity while considering global connectivity, and second, to relate network connectivity with measures of the dysexecutive and posterior cortical profiles. METHODS: Eighty-two subjects with idiopathic PD and 37 age-matched controls underwent resting-state functional MRI and comprehensive neuropsychological assessment. Intranetwork and global connectivity was compared between groups. Measures of the dysexecutive and posterior cortical profiles were related to network connectivity while considering demographic and disease-related covariates. RESULTS: PD subjects show decreased connectivity within several cortical networks. However, only the sensorimotor network displayed a loss of connectivity independent of the observed decreased global connectivity. The dysexecutive factor was independently related to increased motor severity, less education, and decreased connectivity in the sensorimotor network. The posterior cortical factor was related to increased age, less education, decreased connectivity in the central executive network, as well as increased connectivity in the temporal network. CONCLUSIONS: Our results provide evidence supporting a network-specific process of degeneration in the sensorimotor network which contributes to the dysexecutive cognitive profile. In contrast, connectivity of the temporal and central executive network is related to the posterior cortical profile, representing a distinct network signature of this syndrome. © 2019 International Parkinson and Movement Disorder Society.

Feasibility and Relevance of Antipsychotic Safety Monitoring in Children With Tourette Syndrome: A Prospective Longitudinal Study.

PURPOSE/BACKGROUND: Antipsychotics are efficacious for tics and are increasingly prescribed to children with behavioral disorders. Antipsychotics have important adverse effects, and systematic monitoring of drug safety is infrequently performed. The objectives of this study were to determine the feasibility of antipsychotic safety monitoring in children with Tourette Syndrome using a defined protocol and to evaluate the risk of adverse effects with chronic use. METHODS/PROCEDURES: A prospective longitudinal study of children prescribed antipsychotics was performed. Children were monitored for extrapyramidal, metabolic, and hormonal adverse effects using the Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotic Medications guidelines. This included the measurement of height, weight, waist circumference, the Extrapyramidal Symptom Rating Scale, and laboratory tests of lipids, glucose, insulin, and prolactin at prespecified time points. FINDINGS/RESULTS: Fifty-seven children who started on risperidone or aripiprazole were monitored for a mean of 10 months 3 days. Significant increases in body mass index (BMI) and waist circumference percentiles occurred with time. There was a significant time by drug interaction, with children on aripiprazole having smaller changes in BMI initially, followed by a faster rate of increase than with risperidone. There was a significant difference between Extrapyramidal Symptom Rating Scale scores on versus before starting antipsychotics and significant increases in insulin and prolactin. Change from a healthy to overweight or obese BMI percentile occurred in 26%. Extrapyramidal symptoms occurred in 35%. Medication was discontinued because of metabolic effects in 19%, and extrapyramidal symptoms in 7%. IMPLICATIONS/CONCLUSIONS: Monitoring of antipsychotic safety in children is feasible and recommended to inform treatment decisions.

Neurologic complications of metronidazole.

Metronidazole (Flagyl®) is an antimicrobial agent commonly used in clinical practice. Although it is generally well tolerated with minimal side effects, there are a host of still under-recognized neurologic complications of metronidazole treatment. The following review is aimed at summarizing current literature pertaining to metronidazole-induced neurotoxicity including clinical syndromes, neuroradiological findings, prognosis and proposed pathophysiology. Recognition of the neurotoxic effects of metronidazole is critical as prompt discontinuation is generally associated with full clinical recovery and radiological resolution. Complications neurologiques du métronidazole. Le métronidazole (Flagyl®) est un agent antimicrobien utilisé couramment en pratique clinique. Bien qu'il soit généralement bien toléré et que ses effets secondaires soient minimes, il existe une myriade de complications neurologiques du traitement par le métronidazole qui ne sont pas toujours reconnues. Le but de cette revue constitue un sommaire de la littérature actuelle concernant la neurotoxicité induite par le métronidazole dont les syndromes cliniques, les constatations neuroradiologiques, le pronostic et l'hypothèse physiopathologique expliquant cette neurotoxicité. Il est important d'identifier ces effets neurotoxiques du métronidazole étant donné que l'arret immédiat du traitement est généralement associé à une guérison clinique complète et à la disparition des signes radiologiques.

Cerebellar Brain Inhibition Is Associated With the Severity of Cervical Dystonia.

PURPOSE: Cerebellar connectivity is thought to be abnormal in cervical dystonia (CD) and other dystonia subtypes, based on evidence from imaging studies and animal work. The authors investigated whether transcranial magnetic stimulation-induced cerebellar brain inhibition (CBI), a measure of cerebellar efficiency at inhibiting motor outflow, is abnormal in patients with CD and/or is associated with clinical features of CD. Because of methodological heterogeneity in CBI reporting, the authors deployed additional controls to reduce potential sources of variability in this study. METHODS: Cerebellar brain inhibition was applied in 20 CD patients and 14 healthy control subjects. Cerebellar brain inhibition consisted of a cerebellar conditioning stimulus delivered at four different interstimulus intervals (ISIs) before a test stimulus delivered to hand muscle representation in the motor cortex. The average ratio of conditioned to unconditioned motor evoked potential was computed for each ISI. Cervical dystonia clinical severity was measured using the Toronto Western Spasmodic Torticollis Rating Scale. Control experiments involved neuronavigated transcranial magnetic stimulation, neck postural control in patients, and careful screening for noncerebellar pathway inhibition via cervicomedullary evoked potentials. RESULTS: There was no difference between CBI measured in healthy control subjects and CD patients at any of the four ISIs; however, CBI efficiency was significantly correlated with worsening CD clinical severity at the 5 ms ISI. CONCLUSIONS: Cerebellar brain inhibition is a variable measure in both healthy control subjects and CD patients; much of this variability may be attributed to experimental methodology. Yet, CD severity is significantly associated with reduced CBI at the 5 ms ISI, suggestive of cerebello-thalamo-cortical tract dysfunction in this disorder.

Case Report: Biallelic Loss of Function ATM due to Pathogenic Synonymous and Novel Deep Intronic Variant c.1803-270T > G Identified by Genome Sequencing in a Child With Ataxia-Telangiectasia.

Ataxia-telangiectasia (AT) is a complex neurodegenerative disease with an increased risk for bone marrow failure and malignancy. AT is caused by biallelic loss of function variants in ATM, which encodes a phosphatidylinositol 3-kinase that responds to DNA damage. Herein, we report a child with progressive ataxia, chorea, and genome instability, highly suggestive of AT. The clinical ataxia gene panel identified a maternal heterozygous synonymous variant (NM_000051.3: c.2250G > A), previously described to result in exon 14 skipping. Subsequently, trio genome sequencing led to the identification of a novel deep intronic variant [NG_009830.1(NM_000051.3): c.1803-270T > G] inherited from the father. Transcript analyses revealed that c.1803-270T > G results in aberrant inclusion of 56 base pairs of intron 11. In silico tests predicted a premature stop codon as a consequence, suggesting non-functional ATM; and DNA repair analyses confirmed functional loss of ATM. Our findings highlight the power of genome sequencing, considering deep intronic variants in undiagnosed rare disease patients.

Patterned Purkinje cell loss in the ataxic sticky mouse.

The ataxic sticky (sti/sti) mouse is a spontaneous autosomal recessive mutant resulting from a disruption in the editing domain of the alanyl-tRNA synthetase (Aars) gene. The sticky phenotype is characterized by a small body size, a characteristic unkempt coat and neurological manifestations including marked tremor and ataxia starting at 6 weeks of age. The present study was undertaken to examine the spatiotemporal features of Purkinje cell degeneration in the sticky mouse. Purkinje cell loss was found to be both progressive and patterned, with vermal lobules VI, IX and X, crus 1 of the hemisphere, and the flocculus and paraflocculus being differentially resistant to degeneration. The pattern of Purkinje cell degeneration in sticky is not random - in general, the sphingosine kinase 1a-immunonegative Purkinje cell subset is preferentially susceptible to early cell death. In addition, zebrin II/aldolase C expression in the sticky cerebellum is profoundly downregulated, whereas the heat-shock protein 25 is both ectopically expressed in some scattered Purkinje cells and downregulated in other Purkinje cells in which it is normally expressed constitutively. Compared with many mouse mutants with patterned Purkinje cell death, in which successive stripes of cell loss are very clear, Purkinje cell loss in sticky shows a less clear-cut pattern between different Purkinje cell subtypes, with the result that preferential survival is less dramatic. This may represent a secondary consequence of the downregulation of zebrin II expression.

Myoclonus and cerebellar ataxia associated with COVID-19: a case report and systematic review.

BACKGROUND: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic in December 2019, neurological manifestations have been recognized as potential complications. Relatively rare movement disorders associated with COVID-19 are increasingly reported in case reports or case series. Here, we present a case and systematic review of myoclonus and cerebellar ataxia associated with COVID-19. METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline using the PubMed and Ovid MEDLINE databases, from November 1, 2019 to December 6, 2020. RESULTS: 51 cases of myoclonus or ataxia associated with COVID-19, including our case, were identified from 32 publications. The mean age was 59.6 years, ranging from 26 to 88 years, and 21.6% were female. Myoclonus was multifocal or generalized and had an acute onset, usually within 1 month of COVID-19 symptoms. Myoclonus occurred in isolation (46.7%), or with ataxia (40.0%) or cognitive changes (30.0%). Most cases improved within 2 months, and treatment included anti-epileptic medications or immunotherapy. Ataxia had an acute onset, usually within 1 month of COVID-19 symptoms, but could be an initial symptom. Concurrent neurological symptoms included cognitive changes (45.5%), myoclonus (36.4%), or a Miller Fisher syndrome variant (21.2%). Most cases improved within 2 months, either spontaneously or with immunotherapy. CONCLUSIONS: This systematic review highlights myoclonus and ataxia as rare and treatable post-infectious or para-infectious, immune-mediated phenomena associated with COVID-19. The natural history is unknown and future investigation is needed to further characterize these movement disorders and COVID-19.

Action fluency identifies different sex, age, global cognition, executive function and brain activation profile in non-demented patients with Parkinson's disease.

Patients with Parkinson's disease (PD) have difficulties processing action words, which could be related to early cognitive decline. The action fluency test can be used to quickly and easily assess the processing of action words in PD. The goal of this study was to characterize how the action fluency test relates to personal characteristics, disease factors, cognition, and neural activity in PD. Forty-eight participants with PD (34 male, 14 female) and 35 control participants (16 male, 19 female) completed functional neuroimaging using a set-shifting task and a neuropsychological assessment including the action fluency test. PD participants with a score one standard deviation below the norm or lower on the action fluency test were identified. All PD participants with poor performance (PD-P, n = 15) were male. They were compared to male PD participants with scores within the normal range (PD-N, n = 19) and male healthy controls (HC, n = 16). PD-P were older, had lower global cognition scores, lower executive functions scores, and decreased activity in fronto-temporal regions compared with PD-N. There was no difference between the two PD groups in terms of the duration of the disease, dose of dopaminergic medication, and severity of motor symptoms. PD-N were younger than HC, but there was no other significant difference between these groups. The action fluency test identified a subgroup of PD patients with distinct sex, age, global cognition, executive functions, and brain activity characteristics. Implications for the evaluation of cognition are discussed.

Patterns of brain activity during a set-shifting task linked to mild behavioral impairment in Parkinson's disease.

Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergence of sustained neuropsychiatric symptoms, as an at-risk state for incident cognitive decline and dementia. Prior studies have reported that neuropsychiatric symptoms are associated with cognitive abilities in Parkinson's disease (PD) patients, and we have recently found a strong correlation between MBI and cognitive performance. However, the underlying neural activity patterns of cognitive performance linked to MBI in PD are unknown. Fifty-nine non-demented PD patients and 26 healthy controls were scanned using fMRI during performance of a modified version of the Wisconsin card sorting task. MBI was evaluated using the MBI-checklist, and PD patients were divided into two groups, PD-MBI and PD-noMBI. Compared to the PD-noMBI group and healthy controls, the PD-MBI group revealed less activation in the prefrontal and posterior parietal cortices, and reduced deactivation in the medial temporal region. These results suggest that in PD, MBI reflects deficits in the frontoparietal control network and the hippocampal memory system.

Investigating the relationship between the SNCA gene and cognitive abilities in idiopathic Parkinson's disease using machine learning.

Cognitive impairments are prevalent in Parkinson's disease (PD), but the underlying mechanisms of their development are unknown. In this study, we aimed to predict global cognition (GC) in PD with machine learning (ML) using structural neuroimaging, genetics and clinical and demographic characteristics. As a post-hoc analysis, we aimed to explore the connection between novel selected features and GC more precisely and to investigate whether this relationship is specific to GC or is driven by specific cognitive domains. 101 idiopathic PD patients had a cognitive assessment, structural MRI and blood draw. ML was performed on 102 input features including demographics, cortical thickness and subcortical measures, and several genetic variants (APOE, MAPT, SNCA, etc.). Using the combination of RRELIEFF and Support Vector Regression, 11 features were found to be predictive of GC including sex, rs894280, Edinburgh Handedness Inventory, UPDRS-III, education, five cortical thickness measures (R-parahippocampal, L-entorhinal, R-rostral anterior cingulate, L-middle temporal, and R-transverse temporal), and R-caudate volume. The rs894280 of SNCA gene was selected as the most novel finding of ML. Post-hoc analysis revealed a robust association between rs894280 and GC, attention, and visuospatial abilities. This variant indicates a potential role for the SNCA gene in cognitive impairments of idiopathic PD.

Mild behavioral impairment in Parkinson's disease is associated with altered corticostriatal connectivity.

BACKGROUND: Mild behavioral impairment (MBI) is a syndrome characterized by later life onset, sustained neuropsychiatric symptoms as a marker of dementia risk. In Parkinson's disease (PD), MBI has been associated with worse cognitive abilities and increased cortical atrophy. However, the circuit level correlates of MBI have not been investigated in this population. Our objective was to investigate the relationship between MBI and corticostriatal connectivity in PD patients. This emphasis on corticostriatal connectivity was due to the significant role of these circuits in neuropsychiatric and cognitive symptoms across disease conditions. METHODS: Seventy-four non-demented patients with PD were administered the MBI-checklist, and classified as having high MBI (PD-MBI; n = 21) or low MBI scores (PD-noMBI; n = 53). Corticostriatal connectivity was assessed with both an atlas and seed-based analysis. The atlas analysis consisted of calculating the average connectivity between the striatal network and the default mode (DMN), central executive (CEN), and saliency networks (SAN). Structural measurements of cortical thickness and volume were also assessed. PD-MBI and PD-noMBI patients were compared, along with a group of age matched healthy control subjects (HC; n = 28). Subsequently, a seed analysis assessed the relationship of MBI scores with the connectivity of twelve seeds within the striatum while controlling for cognitive ability. A complementary analysis assessed the relationship between striatal connectivity and cognition, while controlling for MBI-C. RESULTS: PD-MBI demonstrated decreased connectivity between the striatum and both the DMN and SAN compared to PD-noMBI and HC. The decreased connectivity between the striatum and the SAN was explained partly by increased atrophy within the SAN in PD-MBI. The seed analysis revealed a relationship between higher MBI scores and lower connectivity of the left caudate head to the dorsal anterior cingulate cortex and left middle frontal gyrus. Higher MBI-C scores were also related to decreased connectivity of the right caudate head with the anterior cingulate cortex, precuneus, and left supramarginal gyrus, as well as increased connectivity to the left hippocampus and right cerebellar hemisphere. Caudate-precuneus connectivity was independently associated with both global behavioural and cognitive scores. CONCLUSION: These results suggest PD-MBI is associated with altered corticostriatal connectivity, particularly between the head of the caudate and cortical regions associated with the DMN and SAN. In particular, caudate-precuneus connectivity is associated with both global behavioral and cognitive symptoms in PD.