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Primary familial brain calcification (PFBC; formerly Fahr's disease) and early-onset Alzheimer's disease (EOAD) may share partially overlapping pathogenic principles. Although the heterozygous loss-of-function mutation c.1523 + 1G > T in the PFBC-linked gene SLC20A2 was detected in a patient with asymmetric tremor, early-onset dementia, and brain calcifications, CSF β-amyloid parameters and FBB-PET suggested cortical β-amyloid pathology. Genetic re-analysis of exome sequences revealed the probably pathogenic missense mutation c.235G > A/p.A79T in PSEN1. The SLC20A2 mutation segregated with mild calcifications in two children younger than 30 years. We thus describe the stochastically extremely unlikely co-morbidity of genetic PFBC and genetic EOAD. The clinical syndromes pointed to additive rather than synergistic effects of the two mutations. MRI data revealed the formation of PFBC calcifications decades before the probable onset of the disease. Our report furthermore exemplifies the value of neuropsychology and amyloid PET for differential diagnosis., (© 2023. The Author(s).)

Primary familial brain calcification (PFBC), also known as Fahr's disease, is a rare inherited disorder characterized by bilateral calcification in the basal ganglia according to neuroimaging. Other brain regions, such as the thalamus, cerebellum, and subcortical white matter, can also be affected. Among the diverse clinical phenotypes, the most common manifestations are movement disorders, cognitive deficits, and psychiatric disturbances. Although patients with PFBC always exhibit brain calcification, nearly one-third of cases remain clinically asymptomatic. Due to advances in the genetics of PFBC, the diagnostic criteria of PFBC may need to be modified. Hitherto, seven genes have been associated with PFBC, including four dominant inherited genes ( SLC20A2 , PDGFRB , PDGFB , and XPR1 ) and three recessive inherited genes ( MYORG , JAM2 , and CMPK2 ). Nevertheless, around 50% of patients with PFBC do not have pathogenic variants in these genes, and further PFBC-associated genes are waiting to be identified. The function of currently known genes suggests that PFBC could be caused by the dysfunction of the neurovascular unit, the dysregulation of phosphate homeostasis, or mitochondrial dysfunction. An improved understanding of the underlying pathogenic mechanisms for PFBC may facilitate the development of novel therapies.

Primary brain calcification (PBC), also known as idiopathic basal ganglia calcification (IBGC), primary familial brain calcification (PFBC) and so on, is a rare intractable disease characterized by abnormal mineral deposits, including mostly calcium in the basal ganglia, thalamus, and cerebellum. The causative gene of familial PBC is SLC20A2, which encodes the phosphate transporter PiT-2. Despite this knowledge, the molecular mechanism underlying SLC20A2-associated PBC remains unclear. In the present study, we investigated whether haploinsufficiency or a dominant-negative mechanism reduced Pi uptake in two PiT-2 variants (T115 M and R467X). We demonstrated that the presence of T115 M or R467X had no dominant-negative effect on Pi transport activity of wild-type (WT). In addition, the subcellular localization of R467X completely differed from that of WT, indicating that there is no interaction between R467X and WT. Conversely, T115 M and WT showed almost the same localization. Therefore, we examined the interaction between T115 M and WT using the bioluminescence resonance energy transfer (BRET) method. Although WT and T115 M interact with each other, T115 M does not inhibit WT's Pi transport activity. These results suggest that the role of SLC20A2 in the pathogenesis of PBC may involve decreased intracellular Pi uptake by a haploinsufficiency mechanism rather than a dominant-negative mechanism; agents promoting PiT-2 dimerization may be promising potential therapeutic agents for PBC., Competing Interests: Declaration of competing interest The authors declared no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Calcium (Ca 2+ ) plays a central role in regulating many cellular processes and influences cell survival. Several mechanisms can disrupt Ca 2+ homeostasis to trigger cell death, including oxidative stress, mitochondrial damage, excitotoxicity, neuroinflammation, autophagy, and apoptosis. Voltage-gated Ca 2+ channels (VGCCs) act as the main source of Ca 2+ entry into electrically excitable cells, such as neurons, and they are also expressed in glial cells such as astrocytes and oligodendrocytes. The dysregulation of VGCC activity has been reported in both Parkinson's disease (PD) and Huntington's (HD). PD and HD are progressive neurodegenerative disorders (NDs) of the basal ganglia characterized by motor impairment as well as cognitive and psychiatric dysfunctions. This review will examine the putative role of neuronal VGCCs in the pathogenesis and treatment of central movement disorders, focusing on PD and HD. The link between basal ganglia disorders and VGCC physiology will provide a framework for understanding the neurodegenerative processes that occur in PD and HD, as well as a possible path towards identifying new therapeutic targets for the treatment of these debilitating disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: Woodhouse-Sakati syndrome is a rare autosomal recessive syndrome caused by homozygous mutations in the DCAF17 gene, characterized by marked neurologic and endocrine manifestations in the setting of brain iron accumulation and white matter lesions on neuroimaging. Here, we report electrophysiologic profiles in Woodhouse-Sakati syndrome and their possible value in understanding disease pathophysiology and phenotypic variability., Methods: Thirteen genetically confirmed Woodhouse-Sakati syndrome patients were evaluated via different evoked potential (EP) modalities, including brainstem auditory EPs, pattern reversal visual EPs, and somatosensory EPs to tibial and/or median nerves., Results: All EP modalities showed variable abnormalities. Pattern reversal visual EPs were recorded in all patients, with nine patients exhibiting abnormal results. From those, seven patients showed prolonged P100 latencies after stimulation of right and left eyes for each in turn. Two patients showed P100 latency abnormality after single eye stimulation recorded from midoccipital electrode. Median somatosensory EPs were recorded in 10 patients, with 6 patients having a prolonged cortical N19 response. Tibial somatosensory EP was performed for 11 patients, and 8 patients showed abnormal results where P37 cortical response was absent or prolonged, whereas peripheral potentials at the popliteal fossa were normal. Brainstem auditory EPs were abnormal only in two patients, with prolonged wave III and V latencies. Five patients with hearing impairment presented with normal brainstem auditory EP results., Conclusions: Multiple EP abnormalities are observed in Woodhouse-Sakati syndrome patients, mainly in pattern reversal visual EPs and somatosensory EPs. These findings indicate potential myelin dysfunction that has a role in the underlying pathophysiology, disease course, and phenotypic variability., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2020 by the American Clinical Neurophysiology Society.)

Background: Basal ganglia germ cell tumors (BGGCTs) are rare intracranial germ cell tumors (iGCTs) that often presents with cognitive impairment., Objective: To assess structural brain plasticity in the presence of unilateral basal ganglia germ cell tumors (BGGCTs), and the correlation between gray matter volume (GMV) changes and cognitive tests., Materials and Methods: We applied voxel-based morphometry (VBM) to structural magnetic resonance imaging (MRI) scans to compare a sample of 41 patients with BGGCTs in the left (n = 22) or right (n = 19) and a sample of 16 patients as control group using a two-sample t-test, correcting for family-wise-errors. A battery of cognitive tests was administered to all BGGCTs patients prior to MRI. We used Pearson correlation analysis to assess the correlation between cognitive test scores and GMV changes., Results: In patients with left BGGCTs, whole-brain VBM analysis revealed a large cluster of voxels reflecting an increase in GMV in the left parahippocampal region (k = 529 voxels, T = 4.18, p < 0.01), right middle cingulate cortex (k = 172 voxels, T = 3.96, p < 0.01), and a decrease in volume in the left thalamus (k = 527 voxels, T = -4.88, p < 0.01), right inferior frontal gyrus (k = 495 voxels, T = -4.29, p < 0.01). Pearson correlation analysis showed that the GMV were significantly correlated with the Integrated Visual and Auditory continuous performance test (IVA-CPT) scale (r = 0.637, P = 0.002), abstract reasoning (r = 0.597, P = 0.011), Self-rating Depression Scale (SAS) scale (r = -0.623, P = 0.004) and memory recall (r = 0.648, P = 0.003)., Conclusion: These results demonstrate that slow growing but destructive BGGCTs markedly and asymmetrically effect the GMV in left parahippocampal, left thalamus, right middle cingulate cortex, right inferior frontal gyrus and GMV changes were significantly associated with cognitive test., (Copyright © 2021. Published by Elsevier Inc.)

Background: Woodhouse-Sakati syndrome is a rare autosomal recessive disease with endocrine and neuroectodermal aberrations with heterogeneous phenotypes and disease course. The most common phenotypes of the disease are progressive sensorineural hearing loss and alopecia, mild-to-moderate mental retardation and hypogonadism. The disease results from mutations in the DCAF17 gene., Method: Here, we reported a large consanguineous pedigree with multiple affected individuals with Woodhouse-Sakati syndrome phenotypes. Laboratory tests confirmed the endocrine perturbance in affected individuals. To find out the underlying genetic change, whole-exome sequencing was carried out., Result: Analysis of the exome data identified a splicing-site deletion NM&#95;025000.3:c.1423-1&#95;1425delGACA in DCAF17 gene. Sanger sequencing confirmed the co-segregation of the variant with the disease phenotypes in the family., Conclusion: The variant is predicted to cause aberrant splicing, i.e., exon skipping, resulting in the translation of a truncated functionless protein which results in appearance of typical phenotypic features and clinical laboratory findings of Woodhouse-Sakati syndrome in affected members of the family., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

We report autopsy results of a female patient who was confirmed pathologically as having corticobasal degeneration (CBD). This patient presented with progressive gait disturbance at the age of 66 years, and subsequently showed parkinsonism with a right-sided predominance and dementia. She was clinically diagnosed as having possible corticobasal syndrome without palatal myoclonus throughout the disease course. An autopsy at 72 years of age revealed that neuronal loss with gliosis was severe in the substantia nigra and the portion from hippocampal cornu ammonis (CA1) region to the parahippocampal gyrus, and mild-to-moderate in the basal ganglia, thalamus, red nucleus, dentate nucleus, and cerebral cortices, predominantly in the frontal lobe. Myelin pallor was observed in the pyramidal tract of the brainstem and central tegmental tract. Neurodegenerative or axonal degenerative findings were observed predominantly on the left side, except for the dentate nucleus, which was more affected on the right side. The inferior olivary nucleus exhibited hypertrophic degeneration predominantly on the left side. The topography of neurodegeneration was likely to correspond to the dentate nucleus and inferior olivary nucleus. Phosphorylated tau-immunoreactive pretangles, neurofibrillary tangles, coiled bodies, and threads were diffusely observed in the whole brain. The distribution of tau deposits was prominent in the deeper affected lesions of the dentate nucleus and inferior olivary nucleus. Inferior olivary hypertrophy is unusual in patients with CBD. It is highly possible that the neurodegeneration of the inferior olivary nucleus followed that of the dentate nucleus in our patient. Moreover, these results indicate not only the severity of neurodegenerative changes, but also that of tau deposition that could be related to the topography of the projections of the dentato-olivary pathway. Tau propagation and subsequent neurodegeneration along the fiber connections may have occurred. Our results support the possibility that progression of CBD lesions can be mediated by tau propagation., (© 2021 Japanese Society of Neuropathology.)

Different conformational strains of tau have been implicated in the clinicopathological heterogeneity of tauopathies. In this study, we hypothesized that distinct strains are degraded in a different manner. Lithium, a drug for bipolar disorder, had previously been reported to reduce aggregation-prone protein content by promoting autophagy. Here, we assessed the effects of lithium on tau aggregates using different tauopathy brain seeds. SH-SY5Y cells were transfected with C-terminal tau fragment Tau-CTF24 (residues 243-441), and Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) brain seeds were introduced. After 48-h lithium treatment, sarkosyl-insoluble fractions were prepared. Lithium treatment was found to reduce the amount of insoluble tau and p62, and increase LC3-II levels along with the number of autophagic vacuoles in AD-seeded cells. The effects were lower in case of CBD seeds, and comparable between PSP and AD seeds. An inhibitor of myo-inositol monophosphatase (IMPase) also demonstrated similar effects. Overall, the study suggested that aggregated tau protein is degraded by lithium-induced autophagy, influencing IMPase in a strain-specific manner., Competing Interests: Declaration of competing interest The authors declare that they have no known competing interest in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Multiple neuropathological processes can manifest in life as a corticobasal syndrome. We sought to relate retention of the tau-PET tracer 18F-AV-1451 and structural magnetic resonance measures of regional atrophy to clinical features in clinically diagnosed and neuropathologically confirmed cases of corticobasal syndrome and to determine whether these vary with the underlying neuropathological changes. In this observational, cross-sectional study, 11 subjects (eight female and three male, median age 72 years) with corticobasal syndrome underwent structural MRI, tau-PET with 18F-AV-1451, amyloid-PET with 11C-Pittsburgh compound B, detailed clinical examinations and neuropsychological testing. Of the 11, three had evidence of high amyloid burden consistent with Alzheimer's disease while eight did not. Neuropathological evaluations were acquired in six cases. Mixed effects general linear models were used to compare 18F-AV-1451 retention and atrophy in amyloid-negative corticobasal syndrome cases to 32 age-matched healthy control subjects and to relate cortical and subcortical 18F-AV-1451 retention and atrophy to clinical features. Subjects without amyloid, including three with pathologically confirmed corticobasal degeneration, showed greater regional 18F-AV-1451 retention and associated regional atrophy in areas commonly associated with corticobasal degeneration pathology than healthy control subjects [retention was higher compared to healthy controls (P = 0.0011), driven especially by the precentral gyrus (P = 0.011) and pallidum (P < 0.0001), and greater atrophy was seen in subjects compared to control subjects (P = 0.0004)]. Both 18F-AV-1451 retention and atrophy were greater in the clinically more affected hemisphere [on average, retention was 0.173 standardized uptake value ratio units higher on the more affected side (95% confidence interval, CI 0.11-0.24, P < 0.0001), and volume was 0.719 lower on the more affected side (95% CI 0.35-1.08, P = 0.0001)]. 18F-AV-1451 retention was greater in subcortical than in cortical regions, P < 0.0001. In contrast to these findings, subjects with amyloid-positive corticobasal syndrome, including two neuropathologically confirmed cases of Alzheimer's disease, demonstrated greater and more widespread 18F-AV-1451 retention and regional atrophy than observed in the amyloid-negative cases. There was thalamic 18F-AV-1451 retention but minimal cortical and basal ganglia uptake in a single corticobasal syndrome subject without neuropathological evidence of tau pathology, likely representing non-specific signal. Asymmetric cortical and basal ganglia 18F-AV-1451 retention consonant with the clinical manifestations characterize corticobasal syndrome due to corticobasal degeneration, whereas the cortical retention in cases associated with Alzheimer's disease is greater and more diffuse., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Hypoparathyroidism and pseudohypoparathyroidism are rare disorders of mineral metabolism which may be associated with soft tissue calcification in the basal ganglia in the brain, and occasionally the skin and other tissues. The basal ganglia are the most common sites of calcification in the central nervous system in these disorders, and were first associated with this manifestation in a report from the Mayo Clinic in 1939. The reasons why the basal ganglia are a common site of soft tissue calcification in these rare disorders has been a matter of investigation for many years., Findings: Due to recent increased understanding of phosphate transport and new insights gained from mRNA expression in the basal ganglia, the pathophysiology of basal ganglia calcification (BGC) is now clearer. There is evidence that the absence of parathyroid hormone in hypoparathyroidism may play a direct role, but this is clearly not the case in pseudohypoparathyroidism, which is associated with increased parathyroid hormone levels. Maintaining the calcium/phosphorus ratio as close to normal as possible, and maintaining normal serum phosphate levels, may help mitigate the progression of BGC. There is no evidence of regression of BGC with conventional treatment, and long-term data with adjunctive or replacement therapy with parathyroid hormone or its analogues are not yet available., Purpose of the Review: This review will focus on the pathophysiology of BGC in hypoparathyroidism and pseudohypoparathyroidism, and review the proposed pathophysiologic mechanisms, as well as the clinical implications of BGC on patient quality of life.

Background: Severe socio-emotional impairments characterize the behavioral variant of frontotemporal dementia (bvFTD). However, literature reports social cognition disorders in other dementias., Objective: In this study, we investigated the accuracy of social cognition performances in the early and differential diagnosis of bvFTD., Methods: We included 131 subjects: 32 bvFTD, 26 Alzheimer's disease (AD), 16 primary progressive aphasia (PPA), 17 corticobasal syndrome (CBS), and 40 healthy control (HC). Each subject completed the Ekman 60 faces (Ek-60F) test assessing basic emotion recognition and the Story-based Empathy Task (SET) assessing attribution of intentions/emotions. A combined social measure (i.e., Emotion Recognition and Attribution (ERA) index) was calculated. One-way ANOVA has been used to compare performances among groups, while receiver operating characteristic (ROC) curve tested measures ability to distinguish subjects with and without bvFTD., Results: Ek-60F and ERA index scores were significantly lower in bvFTD versus HC, AD, and PPA groups. ROC analyses significantly distinguished bvFTD from HC (AUC 0.82-0.92), with the Ek-60F test showing the highest performance, followed by the ERA index. These two social measures showed the best accuracy in detecting bvFTD from AD (AUC 0.78-0.74) and PPA (AUC 0.80-0.76). Investigated measures failed in detecting bvFTD from CBS., Conclusion: Accuracy analyses support the advantage of using social cognition tests for bvFTD diagnosis. Short social battery may reduce uncertainties and improve disease identification in clinical settings. We recommend a revision of current clinical criteria considering neuropsychological deficits in emotion recognition and processing tasks as key cognitive markers of this neurodegenerative syndrome.

There is evidence that glycemic fluctuations trigger vascular-mediated dysfunction in both the retina and the striatopallidal regions in patients with diabetes. The latter is associated with a variety of hyperkinetic disorders that are rare but disabling and potentially preventable. We conducted a systematic review of the potential association between diabetic retinopathy and the risk and prognosis of hyperkinetic disorders in patients with diabetes. We identified a total of 461 articles and 147 were eligible for review. Nine out of 147 articles (6.12%) reported 13 patients with information on diabetic retinopathy. Glycemic fluctuations were present at onset in 10 patients (77%) and retinopathy was present in nine of them (69.23%). The degree of retinopathy was reported in four patients. Two had severe, bilateral proliferative retinopathy, one had moderate-to-severe non-proliferative retinopathy and one had non-proliferative retinopathy. In the nine patients with retinopathy, hyperkinesia persisted, required higher doses of dopamine receptor antagonists or deep brain stimulation. Retinopathy was absent in four cases (30.77%). In these patients, hyperkinesia resolved spontaneously or with lower doses of dopamine receptor antagonists. Diabetic retinopathy could be an indirect marker of striatopallidal microangiopathy in patients with diabetes. The severity of retinopathy may be associated with increased risk or worse prognosis for patients who develop hyperkinetic disorders of the diabetic striatopathy spectrum. Early detection of retinopathy could identify patients in which avoiding glycemic fluctuations may prevent the development of striatopathy and hyperkinetic disorders., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We present the clinicopathological findings of a case of combined Fahr's disease (FD) and dementia with Lewy bodies (DLB), associated with a novel pathogenic mutation. The patient presented with visual hallucinations, fluctuating confusion and parkinsonism, leading to a presumptive diagnosis of DLB. CT scan showed extensive bilateral parenchymal calcifications, suggestive of FD. DNA sequencing identified a novel missense variant (c.92A>T p.(Asn31Ile)) in the SLC20A2 gene, a gene known to be associated with FD. This change has not been previously recorded in genetic repositories, and in silico analyses classified it as likely to be disease-causing. The patient died aged 77, four years after symptom onset. Neuropathological examination revealed, macroscopically and microscopically, extensive calcification in the striatum, globus and cerebellar white matter. There was also neuronal loss in the substantia nigra and residual neurones contained alpha-synuclein-positive Lewy bodies. The neuropathology was therefore consistent with DLB and FD. A literature review identified 3 other cases of co-existing Fahr's and Lewy body pathology, thus the frequency of dual pathology (44%) is higher than expected by random association. Further studies are needed to determine whether alpha-synucleinopathy is linked mechanistically to FD and/or represents a phenotypic subtype.

Objective: The authors examined the effects of two common functional polymorphisms-brain-derived neurotrophic factor (BDNF) Val66Met and catechol- O -methyltransferase (COMT) Val158Met-on cognitive, neuropsychiatric, and motor symptoms and MRI findings in persons with frontotemporal lobar degeneration (FTLD) syndromes., Methods: The BDNF Val66Met and COMT Val158Met polymorphisms were genotyped in 174 participants with FTLD syndromes, including behavioral variant frontotemporal dementia, primary progressive aphasia, and corticobasal syndrome. Gray matter volumes and scores on the Delis-Kaplan Executive Function System, Mattis Dementia Rating Scale, Wechsler Memory Scale, and Neuropsychiatric Inventory were compared between allele groups., Results: The BDNF Met allele at position 66 was associated with a decrease in depressive symptoms (F=9.50, df=1, 136, p=0.002). The COMT Val allele at position 158 was associated with impairment of executive function (F=6.14, df=1, 76, p=0.015) and decreased bilateral volume of the head of the caudate in patients with FTLD (uncorrected voxel-level threshold of p<0.001). Neither polymorphism had a significant effect on motor function., Conclusions: These findings suggest that common functional polymorphisms likely contribute to the phenotypic variability seen in patients with FTLD syndromes. This is the first study to implicate BDNF polymorphisms in depressive symptoms in FTLD. These results also support an association between COMT polymorphisms and degeneration patterns and cognition in FTLD.

Competing Interests: Declaration of competing interest No conflict of interest.

An irreversible extrapyramidal syndrome occurs in man after intravenous abuse of "homemade" methcathinone (ephedrone, Mcat) that is contaminated with manganese (Mn) and is accompanied by altered basal ganglia function. Both Mcat and Mn can cause alterations in nigrostriatal function but it remains unknown whether the effects of the 'homemade' drug seen in man are due to Mcat or to Mn or to a combination of both. To determine how toxicity occurs, we have investigated the effects of 4-week intraperitoneal administration of Mn (30 mg/kg t.i.d) and Mcat (100 mg/kg t.i.d.) given alone, on the nigrostriatal function in male C57BL6 mice. The effects were compared to those of the 'homemade' mixture which contained about 7 mg/kg of Mn and 100 mg/kg of Mcat. Motor function, nigral dopaminergic cell number and markers of pre- and postsynaptic dopaminergic neuronal integrity including SPECT analysis were assessed. All three treatments had similar effects on motor behavior and neuronal markers. All decreased motor activity and induced tyrosine hydroxylase positive cell loss in the substantia nigra. All reduced 123 I-epidepride binding to D2 receptors in the striatum. Vesicular monoamine transporter 2 (VMAT2) binding was not altered by any drug treatment. However, Mcat treatment alone decreased levels of the dopamine transporter (DAT) and Mn alone reduced GAD immunoreactivity in the striatum. These data suggest that both Mcat and Mn alone could contribute to the neuronal damage caused by the 'homemade' mixture but that both produce additional changes that contribute to the extrapyramidal syndrome seen in man.

Corticobasal degeneration typically progresses gradually over 5-7 years from onset till death. Fulminant corticobasal degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics. Of the 124 autopsy-confirmed corticobasal degeneration cases collected from 14 centres, we identified 6 RP-CBD cases (4.8%) who died of advanced disease within 3 years of onset. These RP-CBD cases had different clinical phenotypes including rapid global cognitive decline (N = 2), corticobasal syndrome (N = 2) and Richardson's syndrome (N = 2). We also studied four corticobasal degeneration cases with an average disease duration of 3 years or less, who died of another unrelated illness (Intermediate-CBD). Finally, we selected 12 age-matched corticobasal degeneration cases out of a cohort of 110, who had a typical gradually progressive course and reached advanced clinical stage (End-stage-CBD). Quantitative analysis showed high overall tau burden (p = 0.2) and severe nigral cell loss (p = 0.47) in both the RP-CBD and End-stage-CBD groups consistent with advanced pathological changes, while the Intermediate-CBD group (mean disease duration = 3 years) had milder changes than End-stage-CBD (p < 0.05). These findings indicated that RP-CBD cases had already developed advanced pathological changes as those observed in End-stage-CBD cases (mean disease duration = 6.7 years), but within a significantly shorter duration (2.5 years; p < 0.001). Subgroup analysis was performed to investigate the cellular patterns of tau aggregates in the anterior frontal cortex and caudate by comparing neuronal-to-astrocytic plaque ratios between six RP-CBD cases, four Intermediate-CBD and 12 age-matched End-stage-CBD. Neuronal-to-astrocytic plaque ratios of Intermediate-CBD and End-stage-CBD, but not RP-CBD, positively correlated with disease duration in both the anterior frontal cortex and caudate (p = 0.02). In contrast to the predominance of astrocytic plaques we previously reported in preclinical asymptomatic corticobasal degeneration cases, neuronal tau aggregates predominated in RP-CBD exceeding those in Intermediate-CBD (anterior frontal cortex: p < 0.001, caudate: p = 0.001) and End-stage-CBD (anterior frontal cortex: p = 0.03, caudate: p = 0.01) as demonstrated by its higher neuronal-to-astrocytic plaque ratios in both anterior frontal cortex and caudate. We did not identify any difference in age at onset, any pathogenic tau mutation or concomitant pathologies that could have contributed to the rapid progression of these RP-CBD cases. Mild TDP-43 pathology was observed in three RP-CBD cases. All RP-CBD cases were men. The MAPT H2 haplotype, known to be protective, was identified in one RP-CBD case (17%) and 8 of the matched End-stage-CBD cases (67%). We conclude that RP-CBD is a distinct aggressive variant of corticobasal degeneration with characteristic neuropathological substrates resulting in a fulminant disease process as evident both clinically and pathologically. Biological factors such as genetic modifiers likely play a pivotal role in the RP-CBD variant and should be the subject of future research.

We describe a rare case of a patient with rapid onset, prominent cognitive and behavioral changes who presented to our rapidly progressive dementia program with symptoms ultimately attributed to bilateral basal ganglia infarcts involving the caudate heads. We review the longitudinal clinical presentation and neuropsychological testing for this patient, and discuss the implicated basal ganglia and frontal lobe neuroanatomy.

Corticobasal degeneration (CBD) is a neurodegenerative tauopathy-a class of disorders in which the tau protein forms insoluble inclusions in the brain-that is characterized by motor and cognitive disturbances 1-3 . The H1 haplotype of MAPT (the tau gene) is present in cases of CBD at a higher frequency than in controls 4,5 , and genome-wide association studies have identified additional risk factors 6 . By histology, astrocytic plaques are diagnostic of CBD 7,8 ; by SDS-PAGE, so too are detergent-insoluble, 37 kDa fragments of tau 9 . Like progressive supranuclear palsy, globular glial tauopathy and argyrophilic grain disease 10 , CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats 11-15 . This distinguishes such '4R' tauopathies from Pick's disease (the filaments of which are made of three-repeat (3R) tau isoforms) and from Alzheimer's disease and chronic traumatic encephalopathy (CTE) (in which both 3R and 4R isoforms are found in the filaments) 16 . Here we use cryo-electron microscopy to analyse the structures of tau filaments extracted from the brains of three individuals with CBD. These filaments were identical between cases, but distinct from those seen in Alzheimer's disease, Pick's disease and CTE 17-19 . The core of a CBD filament comprises residues lysine 274 to glutamate 380 of tau, spanning the last residue of the R1 repeat, the whole of the R2, R3 and R4 repeats, and 12 amino acids after R4. The core adopts a previously unseen four-layered fold, which encloses a large nonproteinaceous density. This density is surrounded by the side chains of lysine residues 290 and 294 from R2 and lysine 370 from the sequence after R4.

Idiopathic basal ganglia calcification (IBGC), also known as Fahr disease, is a rare neurodegenerative disorder characterized by the accumulation of extensive parenchymal and vascular calcifications in the basal ganglia, with variable calcifications elsewhere in the brain. Typically, IBGC presents with neurologic and psychiatric symptoms in middle-aged adults. Recent genetic studies have identified alterations in 4 genes causing IBGC, including alterations in SLC20A2 on chromosome 8p11.2. Currently, there are no clinical descriptions of patients with IBGC occurring within the context of a complex genetic syndrome. Here, we present a case of pediatric 8p11 deletion with IBGC, hereditary spherocytosis, vitreoretinopathy, and focal cortical dysplasia. We review multiple cases of IBGC with pediatric onset due to SLC20A2 deletion in the literature, and raise the consideration of IBGC in the evaluation of pediatric patients with 8p11.2 deletion syndromes., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative disorders that show parkinsonism as their main symptom. Both PSP and CBD are sporadic tauopathies associated with hyperphosphorylated four-repeat tau aggregation in neurons and glial cells. The characteristic pathologies of PSP are midbrain atrophy and the appearance of tufted astrocytes and globose-type neurofibrillary tangles. PSP shows severe degeneration in the globus pallidus, substantia nigra, subthalamic nucleus, and cerebellar dentate nuclei. Conversely, the characteristic pathologies of CBD are cortical atrophy and the appearance of astrocytic plaques and argyrophilic threads. CBD is associated with severe degeneration in the cerebral white matter, substantia nigra, and globus pallidus. Clinical symptoms depend on the topographical distribution and severity of degeneration rather than on the type of aggregated protein or inclusions. PSP and CBD present clinically differential diagnostic difficulties because of their overlapping pathological distributions., (© 2019 Japanese Society of Neuropathology.)

Background: Few studies have investigated the incidence of PSP and CBS in the population., Objective: To examine the incidence of and trends in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) in a population-based cohort of residents of Olmsted County, MN., Methods: We used the 1991-2005 population-based, Olmsted County Parkinsonism-cohort study, defined via the Rochester Epidemiology Project. A movement-disorder specialist reviewed medical records, to confirm PSP and CBS diagnoses., Results: We identified 21 patients with these diagnoses 1991-2005 : 18 (85.7%), PSP; 3 (14.3%), CBS. The median diagnosis age was 78 (range: 66-88). 13/21 (62.0%) were male. MRI was performed pre-diagnosis in 11 patients (8 PSP and 3 CBD); 10 showed atrophy consistent with clinical diagnoses. We observed concordance between clinical and pathological diagnoses in two PSP patients who underwent autopsy. Combined incidence for PSP and CBS in Olmsted County was 3.1 per 100,000 person-years (2.6 per 100,000 person-years, PSP; 0.4 per 100,000 person-years, CBS). Incidence was higher in men (4.5, 95% CI, 2.0-7.0) than women (1.8, 95% CI, 0.5-2.9). A combined, significant trend of increasing incidence was observed between 1991 and 2005 (B=0.69, 95% CI 0.42, 0.96, p<0.001). Median time from symptom onset to death among both groups was 6 years (range PSP, 1-10 years; range CBS, 3-8 years)., Conclusions: The combined incidence for PSP and CBS was 3.1 per 100,000 person-years, higher in men than women. We observed a significant increase in both PSP and CBS, likely due to advancing imaging technology and improved diagnostic ability among physicians.

Objective: The clinical diagnosis of corticobasal syndrome (CBS) represents a challenge for physicians and reliable diagnostic imaging biomarkers would support the diagnostic work-up. We aimed to investigate the neural signatures of CBS using multimodal T1-weighted and resting-state functional magnetic resonance imaging (MRI)., Methods: Nineteen patients with CBS (age 67.0 ± 6.0 years; mean±SD) and 19 matched controls (66.5 ± 6.0) were enrolled from the German Frontotemporal Lobar Degeneration Consortium. Changes in functional connectivity and structure were respectively assessed with eigenvector centrality mapping complemented by seed-based analysis and with voxel-based morphometry. In addition to mass-univariate statistics, multivariate support vector machine (SVM) classification tested the potential of multimodal MRI to differentiate patients and controls. External validity of SVM was assessed on independent CBS data from the 4RTNI database., Results: A decrease in brain interconnectedness was observed in the right central operculum, middle temporal gyrus and posterior insula, while widespread connectivity increases were found in the anterior cingulum, medial superior-frontal gyrus and in the bilateral caudate nuclei. Severe and diffuse gray matter volume reduction, especially in the bilateral insula, putamen and thalamus, characterized CBS. SVM classification revealed that both connectivity (area under the curve 0.81) and structural abnormalities (0.80) distinguished CBS from controls, while their combination led to statistically non-significant improvement in discrimination power, questioning the additional value of functional connectivity over atrophy. SVM analyses based on structural MRI generalized moderately well to new data, which was decisively improved when guided by meta-analytically derived disease-specific regions-of-interest., Conclusions: Our data-driven results show impairment of functional connectivity and brain structure in CBS and explore their potential as imaging biomarkers., Competing Interests: Declaration of Competing Interest The authors report no competing interests., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The product of thiamine phosphokinase is the cofactor for many enzymes, including the dehydrogenases of pyruvate, 2-ketoglutarate and branched chain ketoacids. Its deficiency has recently been described in a small number of patients, some of whom had a Leigh syndrome phenotype. The patient who also had a Leigh phenotype was initially found to have a low concentration of biotin in plasma and massive urinary excretion of biotin. Despite treatment with biotin and thiamine, her disease was progressive. Mutations c.311delG and c.426G > C were found in the TPK1 gene., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The clinical and imaging data in 6 patients with corticobasal syndrome were retrospectively analyzed. Six patients presented asymmetric clinical symptoms, including 5 with cognitive impairment, 6 with emotional disorders, 2 with cortical sensory deficit, 5 with lalopathy, and 4 with apraxia. All patients developed limb dystonia and limb or trunk stiffness, 4 with tumble, 4 with bradykinesia, and 2 with tremor. Brain magnetic resonance imaging (MRI) showed that 4 patients had unilateral cerebral atrophy and 2 had mild atrophy of bilateral hippocampus. Localized low glucose metabolism in the unilateral cerebral lobe was seen in four patients by positron emission computed tomography (PET) examination, suggesting that PET is helpful for the diagnosis of corticobasal syndrome.

Adult genetic disorders causing brain lesions have been mostly described as white matter vanishing diseases. We present here the investigations realized in patients referred for psychiatric disorder with magnetic resonance imaging showing atypical basal ganglia lesions. Genetic explorations of this family revealed a new hereditary disease linked to glutathione metabolism., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Background Woodhouse-Sakati syndrome (WSS) (OMIM#241080) is an extremely rare multisystemic disease. Alopecia, hypogonadism, loss of hearing, hypothyroidism, diabetes mellitus (DM) and neurological disorders are the components of this syndrome. The syndrome is caused by homozygous or compound heterozygous mutations in DCAF17, and has recently been implicated in the development of both male and female gonads, thus resulting in hypogonadism. Case report A 16-year-old girl with consanguineous parents was admitted to our hospital with absence of breast development and amenorrhea. Hypogonadism was detected, in the form of hypergonadotropic hypogonadism. Whole-exome sequencing was used to identify the genetic etiology underlying the hypogonadism. A novel homozygous variant c.1091 + 1G > A was detected in DCAF17. Both parents were sequenced and identified as heterozygous for the same mutation. Conclusions We report a novel mutation detected in the DCAF17 gene and discuss the clinical findings in patients with previously reported mutations. Various manifestations of WSS, such as alopecia, endocrinological and neurological disorders, do not emerge until later in life, and therefore this situation can be challenging to diagnose particularly in pediatric cases, as in the present report. Careful attention should be paid to these additional findings, which may lead to early diagnosis and reduced genetic analysis costs, in patients with hypogonadism. In addition, there was no obvious genetic-phenotype correlation in reported cases.

Idiopathic basal ganglia calcification (IBGC) is a rare intractable disease characterized by abnormal mineral deposits, including mostly calcium in the basal ganglia, thalamus, and cerebellum. SLC20A2 is encoding the phosphate transporter PiT-2 and was identified in 2012 as the causative gene of familial IBGC. In this study, we investigated functionally two novel SLC20A2 variants (c.680C > T, c.1487G > A) and two SLC20A2 variants (c.82G > A, c.358G > C) previously reported from patients with IBGC. We evaluated the function of variant PiT-2 using stable cell lines. While inorganic phosphate (Pi) transport activity was abolished in the cells with c.82G > A, c.358G > C, and c.1487G > A variants, activity was maintained at 27.8% of the reference level in cells with the c.680C > T variant. Surprisingly, the c.680C > T variant had been discovered by chance in healthy members of an IBGC family, suggesting that partial preservation of Pi transport activity may avoid the onset of IBGC. In addition, we confirmed that PiT-2 variants could be translocated into the cell membrane to the same extent as PiT-2 wild type. In conclusion, we investigated the PiT-2 dysfunction of four SLC20A2 variants and suggested that a partial reduced Pi transport function of PiT-2 might not be sufficient to induce brain calcification of IBGC.

Competing Interests: None

Basal ganglia calcifications could be incidental findings up to 20% of asymptomatic patients undergoing CT or MRI scan. The presence of neuropsychiatric symptoms associated with bilateral basal ganglia calcifications (which could occur in other peculiar brain structures, such as dentate nuclei) identifies a clinical picture defined as Fahr's Disease. This denomination mainly refers to idiopathic forms in which no metabolic or other underlying causes are identified. Recently, mutations in four different genes (SLC20A2, PDGFRB, PDGFB, and XPR1) were identified, together with novel mutations in the Myogenic Regulating Glycosylase gene, causing the occurrence of movement disorders, cognitive decline, and psychiatric symptoms. On the other hand, secondary forms, also identified as Fahr's syndrome, have been associated with different conditions: endocrine abnormalities of PTH, such as hypoparathyroidism, other genetically determined conditions, brain infections, or toxic exposure. The underlying pathophysiology seems to be related to an abnormal calcium/phosphorus homeostasis and transportation and alteration of the blood-brain barrier.

Background: The corticobasal syndrome (CBS) is heterogeneous in terms of postmortem neuropathology. While it has been previously studied with antemortem neuroimaging, clinicopathologic features of corticobasal syndrome associated with cerebrovascular pathology (vascular CBS) have yet to be reported., Methods: To identify vascular CBS, we searched the database of the CurePSP Brain Bank for patients with a clinical diagnosis of CBS who failed to meet neuropathologic criteria for corticobasal degeneration (CBD) or other neurodegenerative disease processes, but who had significant cerebrovascular pathology. Hemibrains were assessed macroscopically and processed for histological assessment. Medical records were reviewed to characterize clinical features of vascular CBS., Results: Of 217 patients with an antemortem diagnosis of CBS, we identified three patients with vascular CBS. Multiple infarcts in the watershed regions (frontal lobe and motor cortex), periventricular white matter, thalamus, and basal ganglia were observed in two patients. One patient had no cortical infarcts, but had multiple white matter infarcts and corticospinal tract degeneration. All were clinically thought to have CBS based on progressive asymmetric motor symptoms, including rigidity and apraxia, as well as cognitive impairment. Antemortem imaging studies showed findings of chronic cerebrovascular disease, with infarcts or white matter pathology., Conclusions: This autopsy study of vascular CBS shows that, while rare, cerebrovascular pathology involving the frontal lobe, white matter tracts, basal ganglia, thalamus, and corticospinal tract can underlie clinical features suggestive of CBS. When neuroimaging suggests an alternative explanation, including chronic infarcts in critical regions, caution is merited in considering CBD as the underlying pathology., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease with adult onset dystonia and subsequent parkinsonism. Postmortem and imaging studies revealed remarkable striatal pathology, with a predominant involvement of the striosomal compartment in the early phase. Here, we aimed to disentangle sequential neurodegeneration in the striatum of XDP patients, provide evidence for preferential loss of distinct striatal areas in the early phase, and investigate whether iron accumulation is present., Methods: We used multimodal structural magnetic resonance imaging (voxel-based morphometry and relaxometry) in 18 male XDP patients carrying a TAF1 mutation and 19 age-matched male controls., Results: Voxel-based relaxometry and morphometry revealed (1) a cluster in the anteromedial putamen showing high iron content and severe atrophy (-55%) and (2) a cluster with reduced relaxation rates as a marker for increased water levels and a lower degree of atrophy (-20%) in the dorsolateral putamen. Iron deposition correlated with the degree of atrophy (ρ = -0.585, p = 0.011) and disease duration (ρ = 0.632, p = 0.005) in the anteromedial putamen. In the dorsolateral putamen, sensorimotor putamen atrophy correlated with disease severity (ρ = -0.649, p = 0.004)., Interpretation: This multimodal approach identified a patchy pattern of atrophy within the putamen. Atrophy is advanced and associated with iron accumulation in rostral regions of the striatum, whereas neurodegeneration is moderate and still ongoing in dorsolateral areas. Given the short disease duration and predominant dystonic phenotype, these results are well in line with early and preferential degeneration of striosome-rich striatal areas in XDP. ANN NEUROL 2019;86:517-526., (© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Corticobasal degeneration (CBD), a tau-related neurodegenerative disease, is characterized by limb rigidity, dystonia, myoclonus, apraxia, and cognitive deficits. We report a patient with probable corticobasal syndrome, a major phenotype of CBD, who revealed both lower vertical and proximal radial attentional neglect on line bisection tests. Brain imaging revealed bilateral parietal atrophy with hypometabolism in the bilateral parietal, dorsolateral prefrontal, and premotor cortices. Bilateral impairment in the dorsal attentional network reduces the allocation of spatial attention to lower and proximal space, causing lower vertical and proximal radial attentional neglect. Screening for various types of spatial neglect may be important in tailoring management and rehabilitation strategies for patients with CBD.

We herein report a rare case of intraparenchymal meningioma in the right basal ganglia. The tumor was located incidentally and preoperatively diagnosed as malignant glioma. Preoperative magnetic resonance imaging revealed that the tumor involved the lenticulostriate artery, and open biopsy was performed to avoid postoperative neurologic deficits. Pathologic diagnosis was fibrous meningioma, and the patient was treated with stereotactic radiation therapy using intensity-modulated radiation therapy. The case illustrates that preoperative evaluation of tumors in the basal ganglia is challenging and that intraparenchymal meningioma should be included in the differential diagnosis of basal ganglia tumors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Status dystonicus (SD) is a rare and potentially life-threatening condition requiring intensive care management. Deep brain stimulation (DBS) has emerged as an effective treatment for SD refractory to medical management, but its application in this field is still limited. Here, we report the long-term outcome of four pediatric patients treated with DBS at the University Hospital of Padua, Italy, for SD refractory to medications. In addition, we present the results of a systematic literature review aimed at identifying published cases of SD treated with DBS, with focus on motor outcome. In our cohort, two children were affected by methylmalonic acidemia and suffered acute basal ganglia lesions, while the other two carried a pathogenic mutation in GNAO1 gene. DBS target was subthalamic nucleus (STN) in one case and globus pallidus internus (GPi) in three. All patients experienced SD resolution within 8-19 days after surgery. Mean post-operative follow-up was 5 years. We identified in the literature 53 additional SD cases treated with DBS (median age at DBS implantation: 12 years) with reported positive outcome in 51 and resolution of SD in a mean of 17 days after surgery. Our findings indicate that DBS is an effective treatment for SD refractory to medications, even in patients with acute basal ganglia lesions; STN can be an appropriate target when GPi is damaged. Moreover, data from long-term follow-up show that SD recurrences can be significantly reduced in frequency or abolished after DBS implantation.