Evaluation of iron overload in nigrosome 1 via quantitative susceptibility mapping as a progression biomarker in prodromal stages of synucleinopathies.

Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of α-synucleinopathies, such as Parkinson's disease (PD), which are characterized by the loss of dopaminergic neurons in substantia nigra, associated with abnormal iron load. The assessment of presymptomatic biomarkers predicting the onset of neurodegenerative disorders is critical for monitoring early signs, screening patients for neuroprotective clinical trials and understanding the causal relationship between iron accumulation processes and disease development. Here, we used Quantitative Susceptibility Mapping (QSM) and 7T MRI to quantify iron deposition in Nigrosome 1 (N1) in early PD (ePD) patients, iRBD patients and healthy controls and investigated group differences and correlation with disease progression. We evaluated the radiological appearance of N1 and analyzed its iron content in 35 ePD, 30 iRBD patients and 14 healthy controls via T2*-weighted sequences and susceptibility (χ) maps. N1 regions of interest (ROIs) were manually drawn on control subjects and warped onto a study-specific template to obtain probabilistic N1 ROIs. For each subject the N1 with the highest mean χ was considered for statistical analysis. The appearance of N1 was rated pathological in 45% of iRBD patients. ePD patients showed increased N1 χ compared to iRBD patients and HC but no correlation with disease duration, indicating that iron load remains stable during the early stages of disease progression. Although no difference was reported in iron content between iRBD and HC, N1 χ in the iRBD group increases as the disease evolves. QSM can reveal temporal changes in N1 iron content and its quantification may represent a valuable presymptomatic biomarker to assess neurodegeneration in the prodromal stages of PD.

Discovering the Italian phenotype of cerebral amyloid angiopathy (CAA): the SENECA project.

Cerebral amyloid angiopathy (CAA) is one of the major types of cerebral small vessel disease, and a leading cause of spontaneous intracerebral hemorrhage and cognitive decline in elderly patients. Although increasingly detected, a number of aspects including the pathophysiology, the clinical and neuroradiological phenotype, and the disease course are still under investigation. The incomplete knowledge of the disease limits the implementation of evidence-based guidelines on patient's clinical management and the development of treatments able to prevent or reduce disease progression. The SENECA (SEarchiNg biomarkErs of Cerebral Angiopathy) project is the first Italian multicenter cohort study aimed at better defining the disease natural history and identifying clinical and neuroradiological markers of disease progression. By a multidisciplinary approach and the collection of a large and well-phenotyped series and biorepository of CAA patients, the study is ultimately expected to improve the diagnosis and the knowledge of CAA pathophysiological mechanisms.

Voltage-Gated Potassium Channel Antibodies in Slow-Progression Motor Neuron Disease.

BACKGROUND: The spectrum of autoimmune neurological diseases associated with voltage-gated potassium channel (VGKC)-complex antibodies (Abs) ranges from peripheral nerve disorders to limbic encephalitis. Recently, low titers of VGKC-complex Abs have also been reported in neurodegenerative disorders, but their clinical relevance is unknown. OBJECTIVE: The aim of the study was to explore the prevalence of VGKC-complex Abs in slow-progression motor neuron disease (MND). METHODS: We compared 11 patients affected by slow-progression MND with 9 patients presenting typical progression illness. Sera were tested for VGKC-complex Abs by radioimmunoassay. The distribution of VGKC-complex Abs was analyzed with the Mann-Whitney U test. RESULTS: The statistical analysis showed a significant difference between the mean values in the study and control groups. A case with long-survival MND harboring VGKC-complex Abs and treated with intravenous immunoglobulins is described. CONCLUSION: Although VGKC-complex Abs are not likely to be pathogenic, these results could reflect the coexistence of an immunological activation in patients with slow disease progression.

Diabetic Striatopathy: Parenchymal Transcranial Sonography as a Supplement to Diagnosis at the Emergency Department.

Background: Diabetic striatopathy (DS) is a rare condition with a debated pathophysiology; a local metabolic dysfunction is the most likely hypothesis. We present a case of DS mimicking an acute stroke, outline a few uncommon/atypical features, and report for the first time the parenchymal transcranial sonography (pTCS) findings. Case Report: An 86-year-old man, treated for insulin-dependent diabetes, presented at an emergency department because of the occurrence of isolated choreo-athetotic movements in his left limbs with fluctuations in the location, frequency, and duration. The blood glucose level was 569 mg/dL. Both urgent and follow-up brain computed tomography (CT) were negative for recent lesions whereas pTCS revealed hyperechogenicity in the right lenticular nucleus. Subsequent magnetic resonance imaging (MRI) showed T1-weighted hyperintensity in the right putamen with negative diffusion-weighted imaging. The symptoms were responsive to glucose control and haloperidol administration, although they persisted during sleep. Conclusions: Unlike previously described cases characterized by hemichorea and/or hemiballism, our patient presented with a stroke-like onset of unilateral irregular choreo-athetotic movements. Notably, based on CT alone, it would not have been possible to distinguish DS from a stroke. In this scenario, the pTCS hyperechogenicity of the right lenticular nucleus helped to hypothesize a metabolic disorder, which was subsequently confirmed by MRI.

Impact of COVID-19 pandemic on the neuropsychiatric status of Wilson's disease.

We have read with interest the Letter to the Editor by Drs. Zhuang and Zhong, who presented the clinical data of 68 patients with Wilson's disease (WD) who were admitted to the hospital before and during the coronavirus disease 2019 (COVID-19) pandemic, and appreciated their findings on hepatic and some extrahepatic manifestations. Nevertheless, given the strong impact of the pandemic on patients with neurological and psychiatric disorders, we would have expected a worsening of the psychiatric and/or neurological impairments in these patients. In contrast, according to the authors, these manifestations remained, somewhat unexpectedly, unchanged. This finding is in contrast with most of the current literature that highlights not only an increased incidence of mental health disorders in the general population but also an exacerbation of neurological and psychiatric symptoms in patients with chronic diseases, especially in those with pre-existing neuropsychiatric disorders, such as WD. Although the study was mainly focused on the hepatic features of WD patients taking anti-copper treatment, a generic and cumulative definition of neurological and psychiatric manifestations, as in this study, does not allow for further considerations. Future studies during and after the pandemic are necessary to clarify the real impact, either direct or indirect, of the COVID-19 pandemic on the neurological and psychiatric symptoms of WD patients.

Two Italian families with ITPR1 gene deletion presenting a broader phenotype of SCA15.

Spinocerebellar ataxia type15 (SCA15) is a pure ataxia characterized by very slow progression. Only seven families have been identified worldwide, in which partial deletions and a missense mutation of the inositol triphosphate receptor type I gene (ITPR1) have been reported. We examined a four-generation Italian family segregating an autosomal dominant cerebellar ataxia, in which linkage analysis was positive for the SCA15 locus. We performed a genomic real-time polymerase chain reaction to search for ITPR1 gene deletions in this family and in 60 SCA index cases negative for mutations in the SCA1-3, 6-8, 10, 12,and dentatorubral-pallidoluysian atrophy genes. The deleted segments were characterized using a custom array comparative genomic hybridization analysis. We have identified two families with an ITPR1 gene deletion: in one, the deletion involved ITPR1 only, while in the other both sulfatase-modifying factor 1 and ITPR1. Clinical data of ten patients and brain MRI (available for six) showed that the phenotype substantially overlapped known SCA15 cases,but we also noted buccolingual dyskinesias, facial myokymias,and pyramidal signs never reported in SCA15. ITPR1 expression analysis of two deleted cases showed a half dose. Our results further support ITPR1 gene as causative of SCA15. The families reported show that SCA15 is present in Italy and has a greater variability in the age at onset and clinical features than previously reported. We propose that the search for ITPR1 deletions is mandatory in the clinical hypothesis of SCA15 and that ITPR1-reduced expression in blood may be a useful marker to identify SCA15 patients harboring genomic deletions and possibly point mutations causing reduction of mRNA level.

Measles Inclusion-Body Encephalitis: Neuronal Phosphorylated Tau Protein is Present in the Biopsy but not in the Autoptic Specimens of the Same Patient.

Tauopathies are sporadic or familial neurodegenerative diseases characterized by the accumulation of phosphorylated tau in neurons and glial cells and include encephalitis related to measles virus such as subacute sclerosing panencephalitis. We describe a 45-year-old woman, with a history of lymphoma treated with immunosuppressant therapy who underwent an open biopsy of the right frontal cortex for a suspect of encephalitis, and died 4 days later. The neuropathological assessment on the bioptic sample revealed edema, severe gliosis and microglial activation, with lymphomonocytic perivascular cuffing and neurons containing both nuclear and cytoplasmic eosinofilic inclusions that ultrastructurally appeared as tubular and curvilinear non-membrane-bound 12-18 nm structures, leading to the diagnosis of measles inclusion-bodies encephalitis. The biopsy specimen showed several cortical neurons with intense perikaryal immunoreactivity for anti-tau antibodies recognizing phosphorylated epitopes while on autoptic specimens no phosphorylated tau immunoreactivity was detected. Our findings suggest that in specific conditions biopsy-derived human tau may be phosphorylated at sites that may result not phosphorylated in autopsy-derived specimens, most likely caused by post-mortem dephosphorylation.

Ataxia with Parkinsonism and dystonia after intentional inhalation of liquefied petroleum gas.

The practice of inhaling liquefied petroleum gas (LPG) to commit suicide is uncommon and almost exclusively a prerogative of the prison population. Numerous cases of sudden deaths caused by intentional propane and/or butane inhalation have been described, but these cases survived and a description of the consequences is very rare. We describe a prisoner who survived after voluntary inhalation of LPG, and who developed ataxia, Parkinsonism, and dystonia. Brain MRI showed bilateral hyperintensity in the basal ganglia and in the cerebellar hemispheres. The clinical evolution and the MRI abnormalities are similar to those described in cases of poisoning by CO where the mechanism of brain injury is related to histotoxic hypoxia. We believe that LPG, considered until now a mixture of gas with low neurotoxic power, may have caused direct toxic damage to the brain, mediated by a mechanism of hypoxia, such as in CO intoxication.

Central nervous system involvement in mycosis fungoides: relevance of tcr gene testing in cerebrospinal fluid.

INTRODUCTION: Mycosis Fungoides (MF) is a rare malignant T-cell lymphoma, involving mainly the skin. In 50%-75% of cases, it can involve organs other than skin, with a 11%-14% Central Nervous System involvement (CNS). CASE REPORT: A 82-year-old woman presented to our Department with a 15-years history of MF with skin lesions. Neurological examination showed dysarthria and a left facio-brachial-crural hemiparesis. A CT scan showed a right fronto-rolandic lesion. A MRI, including DWI, confirmed the presence of the "neoplastic" lesion with slight hemorrhagic component and leptomeningeal contrast enhancement. Molecular TCR rearrangement test by PCR analysis was performed on skin biopsy, showed the presence of a single peak which fits with a monoclonal TCRG gene rearrangement (size 67). Molecular TCR test was also performed on the cerebrospinal fluid (CSF), which confirmed the presence of lymphocyte clone T g/ more expressed with the same size of that observed in the skin biopsy A total body CT scan did not show any lymphnodal or extranodal disease. The patient died after ten days. CONCLUSION: MF usually occurs in the context of advanced and often histologically transformed cutaneous disease. Isolated CNS involvement is remarkably rare. This case highlights the need for regular neurologic follow-up after the diagnosis of MF, in particular when features that suggest risk of disease progression are present. Furthermore, the analysis of the skin biopsy and above all of CSF by PCR technique, based on our experience, should always be executed in MF patients with signs or symptoms suggesting CNS involvement.