Multisystem pathology in McLeod syndrome.

We present a comprehensive characterization of clinical, neuropathological, and multisystem features of a man with genetically confirmed McLeod neuroacanthocytosis syndrome, including video and autopsy findings. A 61-year-old man presented with a movement disorder and behavioral change. Examination showed dystonic choreiform movements in all four limbs, reduced deep-tendon reflexes, and wide-based gait. He had oromandibular dyskinesia causing severe dysphagia. Elevated serum creatinine kinase (CK) was first noted in his thirties, but investigations, including muscle biopsy at that time, were inconclusive. Brain magnetic resonance imaging showed white matter volume loss, atrophic basal ganglia, and chronic small vessel ischemia. Despite raised CK, electromyography did not show myopathic changes. Exome gene panel testing was negative, but targeted genetic analysis revealed a hemizygous pathogenic variant in the XK gene c.895C > T p.(Gln299Ter), consistent with a diagnosis of McLeod syndrome. The patient died of sepsis, and autopsy showed astrocytic gliosis and atrophy of the basal ganglia, diffuse iron deposition in the putamen, and mild Alzheimer's pathology. Muscle pathology was indicative of mild chronic neurogenic atrophy without overt myopathic features. He had non-specific cardiomyopathy and splenomegaly. McLeod syndrome is an ultra-rare neurodegenerative disorder caused by X-linked recessive mutations in the XK gene. Diagnosis has management implications since patients are at risk of severe transfusion reactions and cardiac complications. When a clinical diagnosis is suspected, candidate genes should be interrogated rather than solely relying on exome panels.

Cryptococcal granulomas of basal ganglia due to Cryptococcus neoformans in a cat: a case report and literature review.

A 3-year-old spayed female domestic short-haired cat presented with a head turning to the left, circling to the right, seizures, and opisthotonos for approximately one month. Neurological examination revealed a deficit in the postural reaction of the left limbs and visual abnormalities. Forensic computed tomography revealed a hyperattenuating round mass of 1.3 cm diameter with a hypoattenuating center in the right hemisphere. Histopathology showed multifocal granuloma lesions with the major mass mostly affecting the right basal ganglia. Cryptococcus neoformans variety grubii molecular type VNI/ST31 was isolated from the cryptococcal granulomas. This report highlights the epidemiological distribution and differential diagnosis of a feline central nervous system cryptococcosis caused by C. neoformans that occurred in an Asian country.

Secondary dystonia following parenchymal brain tumors.

BACKGROUND: Secondary dystonia has been associated with diverse etiologies. Dystonia associated with brain tumors has not been well characterized. OBJECTIVES: To characterize dystonia and relationship with parenchymal brain tumors. METHODS: We present six patients (1.03%) with dystonia related to parenchymal brain tumors, among 580 screened cases. RESULTS: Contralateral hemidystonia was observed in four cases, followed by focal limb (n = 1) and cervical dystonia (n = 1). Dystonia presented during the phase of tumor growth in four cases, and following tumor treatment in two, one case had re-emergent dystonia. Tumors were low-grade (WHO I or II) and located in the basal ganglia (n = 3), cortical areas (n = 2), thalamus (n = 1) and cerebral peduncle (n = 1). CONCLUSIONS: Secondary dystonia may be caused by brain tumors in diverse locations including basal ganglia, cortex and thalamus. It may be the presenting symptom of brain tumor or follow surgical resection combined with ancillary therapy.

An autopsy case of progressive supranuclear palsy treated with monoclonal antibody against tau.

We report an autopsy case of progressive supranuclear palsy (PSP-Richardson syndrome). The individual had been enrolled in a phase 2 trial and received a monoclonal tau antibody (tilavonemab, ABBV-8E12); he died of intrahepatic cholangiocarcinoma and gastrointestinal bleeding during the clinical trial. Neuropathological examination demonstrated neuronal loss, gliosis, and widespread deposits of phosphorylated tau in the neurofibrillary tangles, tufted astrocytes, coiled bodies, and threads, which mainly occurred in the inferior olive nucleus, dentate nucleus of the cerebellum, substantia nigra, midbrain tegmentum, subthalamic nuclei, globus pallidus, putamen, and precentral gyrus, confirming typical PSP pathology. Phosphorylated tau was also found to accumulate in Betz cells, Purkinje cells, and pencil fibers in the basal ganglia. In conclusion, no additional changes or pathological modifications, which were expected from immunotherapy targeting tau, were visible in the present case.

Role of phosphate transporter PiT-2 in the pathogenesis of primary brain calcification.

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.

Cryptococcal granuloma of the the basal ganglia with fatal haemorrhage after stereotactic biopsy: case report.

This paper presents a male, immunocompetent case aged 62-year-old with cryptococcal granuloma in the basal ganglia. No cryptococcal infection occurred in other areas. The diagnosis was made by biopsy. Cryptococcal granuloma was tough and unsuitable for sterotactic biopsy. The patient died of postoperative bleeding and we suggest avoiding stereotactic biopsy of lesions suspected of being cryptococcal granulomas.

Abnormal Brain Iron Accumulation is a Rare Finding in Down Syndrome Regression Disorder.

BACKGROUND: Down syndrome regression disorder (DSRD) is characterized by the sudden loss of adaptive function, cognitive-executive function, and language with abnormal sleep and/or motor control. METHODS: Clinical, laboratory, and imaging data from three individuals with DSRD and iron on brain imaging were reviewed. RESULTS: Three patients with Down syndrome presented with new onset of flat affect, depression, reduced speech, and other neurological symptoms consistent with DSRD. Magnetic resonance imaging showed abnormal iron accumulation in the basal ganglia, as well as calcification in two cases. Molecular diagnostic testing for neurodegeneration with brain iron accumulation was negative in the two individuals tested. CONCLUSIONS: These individuals presented suggest that a subset of individuals with DSRD have abnormal brain iron accumulation. Motor control symptoms reported in DSRD, such as stereotypies and parkinsonism, may reflect this basal ganglia involvement. The presence of abnormal brain iron should not delay or preclude diagnosis and treatment for DSRD.

Reduced basal ganglia tissue-iron concentration in school-age children with attention-deficit/hyperactivity disorder is localized to limbic circuitry.

Dopamine-related abnormalities in the basal ganglia have been implicated in attention-deficit/hyperactivity disorder (ADHD). Iron plays a critical role in supporting dopaminergic function, and reduced brain iron and serum ferritin levels have been linked to ADHD symptom severity in children. Furthermore, the basal ganglia is a central brain region implicated in ADHD psychopathology and involved in motor and reward functions as well as emotional responding. The present study repurposed diffusion tensor imaging (DTI) to examine effects of an ADHD diagnosis and sex on iron deposition within the basal ganglia in children ages 8-12 years. We further explored associations between brain iron levels and ADHD symptom severity and affective symptoms. We observed reduced iron levels in children with ADHD in the bilateral limbic region of the striatum, as well as reduced levels of iron-deposition in males in the sensorimotor striatal subregion, regardless of diagnosis. Across the whole sample, iron-deposition increased with age in all regions. Brain-behavior analyses revealed that, across diagnostic groups, lower tissue-iron levels in bilateral limbic striatum correlated with greater ADHD symptom severity, whereas lower tissue-iron levels in the left limbic striatum only correlated with anxious, depressive and affective symptom severity. This study sheds light on the neurobiological underpinnings of ADHD, specifically highlighting the localization of tissue-iron deficiency in limbic regions, and providing support for repurposing DTI for brain iron analyses. Our findings highlight the need for further investigation of iron as a biomarker in the diagnosis and treatment of ADHD and sex differences.

Decreased basal ganglia and thalamic iron in early psychotic spectrum disorders are associated with increased psychotic and schizotypal symptoms.

Iron deficits have been reported as a risk factor for psychotic spectrum disorders (PSD). However, examinations of brain iron in PSD remain limited. The current study employed quantitative MRI to examine iron content in several iron-rich subcortical structures in 49 young adult individuals with PSD (15 schizophrenia, 17 schizoaffective disorder, and 17 bipolar disorder with psychotic features) compared with 35 age-matched healthy controls (HC). A parametric approach based on a two-pool magnetization transfer model was applied to estimate longitudinal relaxation rate (R1), which reflects both iron and myelin, and macromolecular proton fraction (MPF), which is specific to myelin. To describe iron content, a synthetic effective transverse relaxation rate (R2*) was modeled using a linear fitting of R1 and MPF. PSD patients compared to HC showed significantly reduced R1 and synthetic R2* across examined regions including the pallidum, ventral diencephalon, thalamus, and putamen areas. This finding was primarily driven by decreases in the subgroup with schizophrenia, followed by schizoaffective disorder. No significant group differences were noted for MPF between PSD and HC while for regional volume, significant reductions in patients were only observed in bilateral caudate, suggesting that R1 and synthetic R2* reductions in schizophrenia and schizoaffective patients likely reflect iron deficits that either occur independently or precede structural and myelin changes. Subcortical R1 and synthetic R2* were also found to be inversely related to positive symptoms within the PSD group and to schizotypal traits across the whole sample. These findings that decreased iron in subcortical regions are associated with PSD risk and symptomatology suggest that brain iron deficiencies may play a role in PSD pathology and warrant further study.

The correlation between enlarged perivascular spaces and cognitive impairment in Parkinson's disease and vascular parkinsonism.

INTRODUCTION: The widespread use of brain magnetic resonance imaging (MRI) has revealed the correlation between enlarged perivascular spaces (EPVS) and cognitive impairment (CI). However, few studies have examined the correlation between MRI-visible EPVS and CI in patients with Parkinson's disease (PD) and vascular parkinsonism (VaP). This study explored how the number and main location of EPVS in PD and VaP are correlated with the occurrence of CI in these diseases to provide radiology markers and other evidence for early clinical diagnosis in a Chinese cohort. METHODS: Clinical data were prospectively collected from 77 patients: 26 patients clinically diagnosed with PD or probable PD, 19 patients clinically diagnosed with VaP, and 32 control subjects with normal cognitive function and no stroke or parkinsonism. The patients with PD and VaP were divided into a CI group and a no CI (NCI) group according to the Montreal Cognitive Assessment Beijing version (MoCA-BJ). The relevant clinical data were statistically analysed. RESULTS: The centrum semiovale (CSO)-EPVS, lacunes, Fazekas scores, global cortical atrophy scale (GCA) scores, Koedam posterior atrophy visual scale (KS) scores, and medial temporal atrophy (MTA) scores were higher in the PD-CI and VaP-CI groups than in the control group (adjusted P < 0.017). The number of basal ganglia (BG)-EPVS in the VaP group was higher than that in the PD and control groups (adjusted P < 0.017). BG-EPVS, Fazekas scores, GCA scores, KS scores, and MTA scores were higher in the VaP-CI group than in the PD-CI group (adjusted P < 0.017). Multivariate logistic regression analysis showed that the differences in BG-EPVS and Fazekas scores were not significant between PD-CI and VaP-CI patients (P > 0.05). CONCLUSION: VaP-CI results from multiple factors and is significantly associated with BG-EPVS, lacunes, white matter hyperintensities and brain atrophy. BG-EPVS can be used as an imaging marker to distinguish VaP-CI from PD-CI.

[Clinical analysis of 30 cases of basal ganglia germinoma in children].

OBJECTIVE: To summarize and analyze the clinical characteristics of children with basal ganglia germinoma and to improve the level of early clinical diagnosis. METHODS: The clinical data of children diagnosed with basal ganglia germinoma admitted to the Pediatric Surgery Ward of Peking University First Hospital from January 2013 to December 2020 were retrospectively analyzed, and descriptive statistics were used to analyze the clinical characteristics of children with basal ganglia germinoma. RESULTS: A total of 30 patients were included in the study, 28 were male, 2 were female, the mean age at onset was (9.7±2.2) years, the median disease duration was 7 months, 27 had unilateral disease, and 3 had bilateral disease. The clinical manifestations were decreased limb muscle strength, cognitive function disorders, polydipsia, precocious puberty, intracranial hypertension, dysphonia and swallowing dysfunction. The serum and cerebrospinal fluid tumor marker alpha-fetoprotein (AFP) were normal in the 30 patients, and the serum and cerebrospinal fluid tumor marker ß-human chorionic gonadotropin (ß-HCG) were normal in 8 patients.The serum ß-HCG was normal in 11 patients but the cerebrospinal fluid ß-HCG was slightly elevated, and the serum and cerebrospinal fluid ß-HCG were slightly elevated in 11 patients. A total of 33 lesions with irregular shapes were found by imaging examination, including 15 (45.5%) patchy lesions, 10 (30.3%) patchy lesions, and 8 (24.2%) round-like high-density lesions. Tumors showed obvious high-density shadows on computed tomography (CT) scan. Magnetic resonance imaging (MRI) scan of the tumors showed low or isointensity on T1WI and isointensity on T2WI, accompanied by mild peritumoral edema, hemispheric atrophy, cerebral peduncle atrophy, calcification, cystic degeneration, ventricular dilatation and wallerian degeneration. On contrast-enhanced scans, the tumor showed no enhancement or heterogeneous enhancement. CONCLUSION: The main age of onset of germ cell tumors in the basal ganglia in children is about 10 years old, and males are absolutely dominant. The clinical features and imaging manifestations have certain characteristics. With both combined, the early diagnosis of germ cell tumors in the basal ganglia can be improved.

Novel likely pathogenic SLC20A variant in primary familial brain calcification.

A woman in her 30s was referred to our neurology outpatient clinic following an incidental finding of significant bilateral and symmetric basal ganglia, thalamic, cerebellar and subcortical white matter calcification on brain CT and MRI. A diagnosis of asymptomatic primary familial brain calcification (PFBC) was made. Targeted genetic testing revealed a likely pathogenic variant in the SLC20A2 gene, the most common gene in which pathogenic variants have been implicated in PFBC. These findings prompted genetic testing and brain CT of our patient's asymptomatic 64-year-old father. These tests revealed the same variant in SLC20A2 and similar brain calcification on CT in the patient's father.

Anti-CD47 antibody administration via cisterna magna in proper dosage can reduce perihematomal cell death following intracerebral hemorrhage in rats.

OBJECTIVE: The secondary injury caused by RBC autolysis after intracerebral hemorrhage (ICH) can be reduced by increasing the efficiency of microglia (MG)/macrophages (Mø) phagocytizing red blood cells (RBCs). CD47 is an important regulator of MG/Mø phagocytosis. This study aims to clarify whether anti-CD47 antibody administrated into the cisterna magna after ICH can transfer to the hematoma site, promote MG/Mø gathering to phagocytize RBCs and ultimately reduce cell death. METHODS: Forty male Wistar rats were divided into sham, ICH, low-dosage (group A, 0.3 µg), medium-dosage (group B, 0.9 µg) and high-dosage (group C, 1.8 µg) anti-CD47 antibody groups. For the rats in group A, B and C, anti-CD47 antibody solution was administrated into the cisterna magna at 10 min after ICH. Brain tissue was harvested 3 days after the operation. Western blotting was performed to detect the expression of Caspase-3 and Bcl-2. Immunofluorescence was performed to detect the CD68 expression. TUNEL was performed to detect the cell death. RESULTS: The hematoma of the ICH rats was located in the basal ganglia, with a good homogeneity of hematoma volume. Low-dosage anti-CD47 antibody in group A had no effects on the perihematomal CD68 (P = 0.338), Caspase-3 (P = 0.769), Bcl-2 (P = 0.176) expression and cell death (P = 0.698), compared with the ICH group. CD68 and Bcl-2 expression increased and Caspase-3 expression decreased significantly in group B (P < 0.001 for all) and group C (P < 0.001 for all). The increase of CD68 expression in group C was greater than that in group B (P < 0.01) by a large margin, while there was no difference for Bcl-2 (P = 0.908) and Caspase-3 (P = 0.913) expression between the 2 groups. Compared with the ICH group, medium-dosage of anti-CD47 antibody in group B significantly reduced the number of TUNEL-positive cells (P < 0.005), but not for group C (P = 0.311). CONCLUSION: The results suggested that anti-CD47 antibody administration into the cisterna magna in proper dosage (0.9 µg) can effectively reach the hematoma, induce more MG/Møs to gather around the hematoma, and reduce cell death in perihematomal brain tissue. The results of this study has provided a basic theory for improving the efficiency of MG/Mø phagocytizing RBCs and hematoma clearance after ICH by administrating anti-CD47 antibody via the cisterna magna.

Chronic subdural hematoma-induced parkinsonism: A systematic review.

BACKGROUND: Chronic subdural hematoma (CSDH) is one of the most common neurosurgical cases, especially in elderly individuals. Secondary parkinsonism due to CSDH is a rare entity. The mechanism of parkinsonism symptoms in chronic subdural hematoma has been suggested to include direct mechanical compression of the basal ganglia due to hematoma or indirectly through brain structure changes due to space lesions and vascular disorders. Surgery on the subdural hematoma provides a favorable outcome for parkinsonism symptoms. OBJECTIVES: To systematically review the literature on CSDH-induced parkinsonism. SEARCH METHODS: This is a systematic review on case reports. Literature search was performed using the predefined keywords on PubMed, ProQuest, and Google Scholar. We also provided our own case report and compared it with published studies. RESULT: Sixteen cases from 13 case reports/series were identified, predominantly consisting of male patients with the mean age of 66.5 ± 9.73 years. The most common symptoms were rigidity, gait disturbance, and bradykinesia, observed in 12 (75%) cases each. The second and third most common symptoms were tremor (11; 68.75%) and facial masking (8; 50%), respectively. Other reported symptoms were dysphasia (3; 18.75%), dysarthria (3; 18.75%), and urinary incontinence (2; 12. 5%). Time gap between the symptom onset and CSDH diagnosis and unilateral location seemed to influence the outcome. CONCLUSION: Only 16 CSDH-induced parkinsonism were identified since the 1960s. This condition is thought to occur due to basal ganglia compression. Surgery on the subdural hematoma provides a favorable outcome for parkinsonism symptoms. Timely CSDH diagnosis might yield better outcome. However, further research on CSDH-induced parkinsonism is needed, especially in the mechanisms and treatment outcomes.

Paradoxical paramagnetic calcifications in the globus pallidus: An ex vivo MR investigation and histological validation study.

MR images based on phase contrast images have gained clinical interest as an in vivo tool for assessing anatomical and histological findings. The globus pallidus is an area of major iron metabolism and storage in the brain tissue. Calcium, another important metal in the body, is frequently deposited in the globus pallidus as well. Recently, we observed dense paramagnetic deposition with paradoxical calcifications in the globus pallidus and putamen. In this work, we explore detailed MR findings on these structures, and the histological source of the related findings using ex vivo CT and MR images. Ex vivo MR was obtained with a maximum 100 µm3 isotropic resolution using a 15.2 T MR system. 3D gradient echo images and quantitative susceptibility mapping were used because of their good sensitivity to metallic deposition, high signal-to-noise ratio, and excellent contrast to iron and calcium. We found dense paramagnetic deposition along the perforating arteries in the globus pallidus. This paramagnetic deposition was hyperdense on ex vivo CT scans. Histological studies confirmed this finding, and simultaneous deposition of iron and calcium, although more iron dominant, was observed along the vessel walls of the globus pallidus. This was an exclusive finding for the penetrating arteries of the globus pallidus. Thus, our results suggest that several strong and paradoxical paramagnetic sources at the globus pallidus can be associated with vascular degeneration.

Multi-institutional analysis of treatment modalities in basal ganglia and thalamic germinoma.

BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of nonmetastatic BGTGs, the 5- and 10-year event-free survivals (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survivals (OS) were 100% and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980-2400); WBI: 2340 cGy/cGy(RBE) (1800-3000); WVI: 2340 cGy/cGy(RBE) (1800-2550); focal: 3600 cGy (3060-5400). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p = .84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p = .0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.

Brainstem Infiltration Predicts Survival in Patients With High-grade Gliomas Treated With Chemoradiotherapy.

BACKGROUND/AIM: High-grade gliomas have a poor prognosis despite standard treatment. The aim of the study was to identify new prognostic factors to select patients who need more intense treatment. PATIENTS AND METHODS: Forty-three consecutive patients underwent surgery plus chemoradiotherapy for pathologically diagnosed high-grade gliomas (grade III, IV). RESULTS: The median survival time was 989 days, and the 1-year survival rate was 87.6%. Among patients with grade IV disease, the median survival time, 1-year, and 2-year survival rate were 814 days, 82.6%, and 58.7%, respectively. In the univariate analysis, unmethylated MGMT promoter (p=0.0495), brainstem infiltration (p=0.0004), basal ganglia as the primary lesion site (p=0.0056), 3-dimensional conformal radiotherapy (p=0.0286), and <50 Gy (p=0.0049) were associated with a poor prognosis. In the multivariate analysis, only brainstem infiltration retained significance (HR for death, 0.21; 95% CI=0.06-0.70; p=0.011). CONCLUSION: Brainstem infiltration is a novel prognostic factor for poor prognosis in patients with high-grade gliomas.