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Background Corticobasal degeneration (CBD) is a complex neurodegenerative disorder. Accurate diagnosis is increasingly important, with the advent of clinical trials of drugs aimed at modifying the underlying tau pathology. CBD often presents with a ‘corticobasal syndrome’ including impairments of movement and cognition. However, patients with similar corticobasal syndromes can have neurodegenerative pathologies that are not CBD. In addition, patients with CBD may present with aphasia or behavioural change. The clinical diversity of CBD and mimicry by non-CBD pathologies hinders accurate diagnosis. Methods We applied the new consensus criteria of Armstrong and colleagues et al 1 to a cohort of patients with detailed longitudinal clinical evaluation and neuropathology. Results In patients with pathologically confirmed CBD, accuracy of diagnosis was similar under the new and previous criteria: 9/19 (47%) met criteria for probable CBD at presentation, 13/19 (68%) at last clinical assessment. Patients with a corticobasal syndrome but without CBD pathology all (14/14) met the new diagnostic criteria of probable or possible CBD, demonstrating that the new criteria lacks the necessary specificity for an accurate ante mortem clinical diagnosis of CBD. None of the clinical features used in the new criteria were more common in the patients with CBD pathology (n=19) than without (n=14). Conclusions The Armstrong criteria usefully broadens the recognised clinical phenotype of CBD but does not sufficiently improve the specificity of diagnosis to increase the power of clinical trials or targeted applications of tau-based disease-modifying therapies. Further work is required to show whether biomarkers could be more effective than clinical signs in the diagnosis of CBD.

Christer Betsholtz, Christine Klein, Maria Sobrido and colleagues report the identification of mutations in the gene encoding PDGF-B that cause idiopathic basal ganglia calcification. They also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications. Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait (idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor β (PDGF-Rβ) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-Rβ. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.

Fahr’s disease or Fahr’s syndrome is a rare, neurological disorder characterized by abnormal calcified deposits in basal ganglia and cerebral cortex. Calcified deposits are made up of calcium carbonate and calcium phosphate, and are commonly located in the Basal Ganglia, Thalamus, Hippocampus, Cerebral cortex, Cerebellar Subcortical white matter and Dentate Nucleus. Molecular genetics of this disease haven’t been studied extensively; hence evidence at the molecular and genetic level is limited. Fahr’s disease commonly affects young to middle aged adults. Etiology of this syndrome does not identify a specific agent but associations with a number of conditions have been noted; most common of which are endocrine disorders, mitochondrial myopathies, dermatological abnormalities and infectious diseases. Clinical manifestations of this disease incorporate a wide variety of symptoms, ranging from neurological symptoms of extrapyramidal system to neuropsychiatric abnormalities of memory and concentration to movement disorders including Parkinsonism, chorea and tremors amongst others. Diagnostic criteria for this disease has been formulated after modifications from previous evidence and can be stated briefly, it consist of bilateral calcification of basal ganglia, progressive neurologic dysfunction, absence of biochemical abnormalities, absence of an infectious, traumatic or toxic cause and a significant family history. Imaging modalities for the diagnosis include CT, MRI, and plain radiography of skull. Other investigations include blood and urine testing for hematologic and biochemical indices. Disease is as yet incurable but management and treatment strategies mainly focus on symptomatic relief and eradication of causative factors; however certain evidence is present to suggest that early diagnosis and treatment can reverse the calcification process leading to complete recovery of mental functions. Families with a known history of Fahr’s disease should be counseled prior to conception so that the birth of affected babies can be prevented. This review was written with the aim to remark on the current substantial evidence surrounding this disease.

IntroductionThere are no well-established criteria for patients with corticobasal syndrome. The authors have attempted to clarify this area by comparing and applying three sets of well-known criteria (from Toronto, the Mayo Clinic and Cambridge).Patient and methodsThe authors first compared the three criteria for overlap and differences, and then applied them to a group of 40 consecutive patients (22 men, mean age 67 years) with focal cortical syndrome characterised by apraxia and Parkinsonism, at both the early stages and later in their illness.ResultsDespite an overall similarity, there were major differences in the criteria which affect their applicability. Cognitive impairment was ubiquitous even at presentation, with speech and language impairment the commonest feature. Some classic features, alien limb and myoclonus, were present in a minority only even late in their course. The three criteria were equally applicable to patients with advanced disease (Toronto 92.5%, Cambridge 90% and Mayo 87.5%). Thirty patients (75%) satisfied all three criteria. Using this group as a ‘gold standard’, 73.3% fulfilled the Cambridge criteria at presentation compared with 46.7% and 36.7% for the Toronto and Mayo Clinic criteria, respectively. Concordance between criteria was poor.ConclusionCognitive impairment, especially language impairment, was prominent from onset of disease. The Cambridge criteria apply to a higher proportion of cases at an early stage of corticobasal syndrome. The authors suggest a minor modification to capture the high prevalence of aphasia.

Brain calcification is often detected incidentally, but basal ganglia calcification has a wide differential diagnosis, including genetic and acquired causes. Primary familial brain calcification (PFBC) (formerly ‘Fahr’s disease’) refers to neurological disorders characterised by bilateral, symmetrical deposition of calcium-hydroxyapatite crystals in the basal ganglia and other encephalic regions, with a presumed genetic basis. Its clinical picture encompasses motor, cognitive and psychiatric manifestations in various combinations. Seven genes have been linked to PFBC since 2012, with either autosomal dominant (SLC20A2, PDGFRB, PDGFB and XPR1) or recessive (MYORG, JAM2 and NAA60) mode of inheritance. Mendelian gene discovery has provided critical insights into the pathogenesis of PFBC. Dyshomeostasis of inorganic phosphate, impaired endothelial functions and disrupted blood–brain barrier integrity has been identified as converging pathomechanisms, which could highlight the targets of potential disease-modifying treatments. We provide a state-of-the-art overview on phenotypic features, diagnosis, aetiopathogenesis and management of PFBC.

Chronic manganese (Mn) exposure is associated with neuromotor and neurocognitive deficits, but the exact mechanism of Mn neurotoxicity is still unclear. With the advent of magnetic resonance imaging (MRI), in-vivo analysis of brain structures has become possible. Among different sub-cortical structures, the basal ganglia (BG) has been investigated as a putative anatomical biomarker in MR-based studies of Mn toxicity. However, previous investigations have yielded inconsistent results in terms of regional MR signal intensity changes. These discrepancies may be due to the subtlety of brain alterations caused by Mn toxicity, coupled to analysis techniques that lack the requisite detection power. Here, based on brain MRI, we apply a 3D surface-based morphometry method on 3 bilateral basal ganglia structures in school-age children chronically exposed to Mn through drinking water to investigate the effect of Mn exposure on brain anatomy. Our method successfully pinpointed significant enlargement of many areas of the basal ganglia structures, preferentially affecting the putamen. Moreover, these areas showed significant correlations with fine motor performance, indicating a possible link between altered basal ganglia neurodevelopment and declined motor performance in high Mn exposed children.

Abstract Background and Hypothesis There is a substantial gap in life expectancy between patients with severe mental illness (SMI) and the general population and it is important to understand which factors contribute to this difference. Research suggests an association between tardive dyskinesia (TD) and mortality; however, results are inconclusive. In addition, studies investigating associations between parkinsonism or akathisia and mortality are rare. We hypothesized that TD would be a risk factor for mortality in patients with SMI. Study Design We studied a cohort of 157 patients diagnosed predominantly with schizophrenia on the former Netherlands Antilles. TD, parkinsonism, and akathisia were assessed with rating scales on eight occasions over a period of 18 years. Twenty-four years after baseline, survival status and if applicable date of death were determined. Associations between movement disorders and survival were analyzed using Cox regression. Sex, age, antipsychotics, antidepressants and benzodiazepines at each measurement occasion were tested as covariates. Study Results Parkinsonism was a significant risk factor with an HR of 1.02 per point on the motor subscale of the Unified Parkinson’s Disease Rating Scale (range 0–56). TD and akathisia were not significantly associated with mortality. Conclusions Parkinsonism may be an important risk factor for mortality in SMI patients. This finding calls for more follow-up and intervention studies to confirm this finding and to explore whether treatment or prevention of parkinsonism can reduce excess mortality.

Extrapyramidal symptoms encompass features of Parkinsonism, including bradykinesia, cogwheel rigidity, and resting tremors, which contribute to motor impairments hindering handwriting and speech. In this study, we analyzed voice data captured using a voice sensor setup from 94 patients exhibiting varying levels of EPS and 30 unaffected controls. Each participant provided 13 recordings of repeated vowel and consonant sounds. The Drug-Induced Extrapyramidal Side Effect Scale and Glasgow Antipsychotic Side Effect Scales were used when grading patients into mild, moderate, and severe extrapyramidal symptoms, both administered by trained clinicians. To develop an objective assessment tool, we employed a transfer learning approach using a DenseNet architecture for feature extraction and classification. Its architecture enables the hierarchical concatenation of features at each layer. In this study, we identified that key acoustic features, MFCC, chroma, and spectral contrast vary significantly with the severity of extrapyramidal symptoms. Based on these findings, we developed a DenseNet-based model capable of predicting extrapyramidal symptoms from voice data. This model can classify with an accuracy of 81.9% and a precision of 82.0%. To the best of our knowledge, this is the first study to introduce a voice-based model for assessing the severity of extrapyramidal symptoms.

PurposeTo conduct an overview to summarize the efficacy and safety of aripiprazole for the treatment of schizophrenia.MethodsA literature search was performed in PubMed, the Cochrane Library, LILACS, and the Centre for Reviews and Dissemination, for articles published until March 31, 2017. We included systematic reviews with meta-analyses of randomized controlled trials assessing the efficacy, and/or the safety of aripiprazole, for patients with schizophrenia. Two authors independently performed the study selection, data extraction, and quality assessment. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach and the Risk of Bias in Systematic Review (ROBIS) tool were used to appraise the quality of evidence and the risk of bias in the reviews, respectively.ResultsFourteen studies fulfilled the inclusion criteria. Aripiprazole showed efficacy similar to that of both typical and atypical antipsychotic drugs (except olanzapine and amisulpride). Aripiprazole caused significantly lower weight gain and alterations in glucose and cholesterol levels, as compared to clozapine, risperidone, and olanzapine. In addition, aripiprazole caused significantly fewer general extrapyramidal side effects, less use of antiparkinsonian drugs, and akathisia, compared with typical antipsychotic drugs and risperidone. The overall quality of evidence in the reviews ranged from “very low” to “moderate,” principally because of the risk of bias of original trials, inconsistency, and imprecision in the outcomes. According to the ROBIS tool, there are four reviews with “high” risk of bias and five with “unclear” risk of bias.ConclusionsAripiprazole exhibited efficacy similar to that of other antipsychotic drugs and a better safety profile than that of typical (i.e., less some extrapyramidal side effects) and atypical (i.e., less metabolic changes) antipsychotic drugs.

Fahr’s syndrome is a rare neurological condition marked by unusual calcifications in the basal ganglia and other brain regions, often resulting from metabolic disorders, such as hypoparathyroidism. Secondary hypoparathyroidism, a frequent complication of total thyroidectomy, can lead to Fahr’s syndrome, manifesting as movement disorders, seizures, psychiatric symptoms and indications of calcium deficiency. This case report discusses a woman in her mid-30s who developed Fahr’s syndrome due to secondary hypoparathyroidism after total thyroidectomy. She exhibited signs of calcium deficiency and had a history of seizures diagnosed a few years postsurgery, without any movement disorders or psychiatric symptoms. Her lab results showed low calcium levels, elevated phosphate and high thyroid-stimulating hormone levels. Imaging revealed bilateral calcifications in the basal ganglia, dentate nucleus and cerebral hemispheres. Treatment with intravenous calcium gluconate, calcitriol and thyroxine significantly improved the patient’s symptoms. This case underscores the necessity of monitoring calcium and phosphate levels in patients after thyroidectomy and highlights the possibility of Fahr’s syndrome presenting solely with seizures. The early detection and diagnosis of this condition are crucial for preventing further neurological damage and enhancing patient outcomes.