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PURPOSE: Due to the indistinguishable clinical features of corticobasal syndrome (CBS), the antemortem differentiation between corticobasal degeneration (CBD) and its mimics remains challenging. However, the utility of conventional magnetic resonance imaging (MRI) for the diagnosis of CBD has not been sufficiently evaluated. This study aimed to investigate the diagnostic performance of conventional MRI findings in differentiating pathologically confirmed CBD from its mimics. METHODS: Semiquantitative visual rating scales were employed to assess the degree and distribution of atrophy and asymmetry on conventional T1-weighted and T2-weighted images. Additionally, subcortical white matter hyperintensity (SWMH) on fluid-attenuated inversion recovery images were visually evaluated. RESULTS: In addition to 19 patients with CBD, 16 with CBD mimics (progressive supranuclear palsy (PSP): 9, Alzheimer's disease (AD): 4, dementia with Lewy bodies (DLB): 1, frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kDa(FTLD-TDP): 1, and globular glial tauopathy (GGT): 1) were investigated. Compared with the CBD group, the PSP-CBS subgroup showed severe midbrain atrophy without SWMH. The non-PSP-CBS subgroup, comprising patients with AD, DLB, FTLD-TDP, and GGT, showed severe temporal atrophy with widespread asymmetry, especially in the temporal lobes. In addition to over half of the patients with CBD, two with FTLD-TDP and GGT showed SWMH, respectively. CONCLUSION: This study elucidates the distinct structural changes between the CBD and its mimics based on visual rating scales. The evaluation of atrophic distribution and SWMH may serve as imaging biomarkers of conventional MRI for detecting background pathologies.
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Multiple sclerosis (MS), a putative autoimmune disease of the central nervous system (CNS), commonly presents as relapsing-remitting MS (RRMS), characterized by recurrent episodes of peripheral disabling symptoms resulting from inflammatory CNS damage. Many RRMS patients transition to a chronic disease course with progressive neurological dysfunctions (secondary progressive MS, SPMS), with the progression rate varying between patients and over time. SPMS pathogenesis is now linked to immune-cell-mediated processes, although the mechanisms driving SPMS transition and progression remain elusive, and SPMS lacks biomarkers and effective treatments. We report the crucial involvement of cytotoxic CD4+ T cells expressing Eomes (Eomes+ Th cells) in SPMS pathogenesis-a Th cell subset previously identified in a mouse model of late/chronic autoimmune CNS inflammation. Few Eomes+ Th cells circulate in RRMS patient peripheral blood (n = 44), primary progressive MS (PPMS) patients (n = 25), or healthy controls (n = 42), but Eomes+ Th cells were significantly increased in SPMS (n = 105, P < 0.0001). Strikingly, lymphocytes isolated from SPMS autopsy brain samples revealed CD4+ T cells infiltrating CNS that coexpressed Eomes and the cytotoxic molecule granzyme B. In particular, the Eomes+ Th cell levels were increased in SPMS patients in progressive disease phases versus SPMS patients without current disability increases (P < 0.0001). Moreover, Eomes level acted as a biomarker to predict SPMS patients at risk of disease worsening with over 80% accuracy (ROC-AUC = 0.8276). Overall, our results indicate that granzyme B-expressing Eomes+ T helper cells are involved in the pathogenesis of SPMS, with significant implications for SPMS biomarkers and therapeutic targets.
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Esclerosis Múltiple Crónica Progresiva/patología , Proteínas de Dominio T Box/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo , Adulto , Anciano , Biomarcadores/sangre , Encéfalo/patología , Progresión de la Enfermedad , Femenino , Granzimas/metabolismo , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/sangre , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/patología , Adulto JovenRESUMEN
DnaJ homolog, subfamily B, member 4, a member of the heat shock protein 40 chaperones encoded by DNAJB4, is highly expressed in myofibers. We identified a heterozygous c.270 T > A (p.F90L) variant in DNAJB4 in a family with a dominantly inherited distal myopathy, in which affected members have specific features on muscle pathology represented by the presence of cytoplasmic inclusions and the accumulation of desmin, p62, HSP70, and DNAJB4 predominantly in type 1 fibers. Both Dnajb4F90L knockin and knockout mice developed muscle weakness and recapitulated the patient muscle pathology in the soleus muscle, where DNAJB4 has the highest expression. These data indicate that the identified variant is causative, resulting in defective chaperone function and selective muscle degeneration in specific muscle fibers. This study demonstrates the importance of DNAJB4 in skeletal muscle proteostasis by identifying the associated chaperonopathy.
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Miopatías Distales , Proteínas del Choque Térmico HSP40 , Animales , Ratones , Proteínas del Choque Térmico HSP40/genética , Proteínas del Choque Térmico HSP40/metabolismo , Músculo Esquelético/patología , Chaperonas Moleculares/genética , Debilidad Muscular/patología , Miopatías Distales/patología , Ratones NoqueadosRESUMEN
Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by JC virus infection of oligodendrocytes. Little has been reported on iron deposits in patients with PML. Herein, we report a case of PML with massive iron deposition in the juxtacortical regions attaching white matter lesions in a 71-year-old woman who developed bilateral visual disturbance and progressive aphasia after 16 months of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone treatment for follicular lymphoma. Magnetic resonance imaging revealed white matter lesions in the left parietal and other lobes with massive iron deposition in the juxtacortical lesions. A PCR test for JC virus was positive, confirming the diagnosis of PML. Despite treatment with mefloquine and mirtazapine, the patient died six months later. At autopsy, demyelination was found dominantly in the left parietal lobe. Moreover, hemosiderin-laden macrophages and reactive astrocytes containing ferritin were abundant in the juxtacortical regions adjacent to the white matter lesions. This is a previously unreported case of PML after lymphoma, in which iron deposition was confirmed both radiologically and pathologically.
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Virus JC , Leucoencefalopatía Multifocal Progresiva , Linfoma , Femenino , Humanos , Anciano , Leucoencefalopatía Multifocal Progresiva/patología , Autopsia , Rituximab , Ciclofosfamida , Linfoma/patología , Imagen por Resonancia Magnética , Encéfalo/patologíaRESUMEN
AIMS: Oculopharyngodistal myopathy (OPDM) is caused by the expansion of CGG repeats in NOTCH2NLC (OPDM_NOTCH2NLC) GIPC1 (OPDM_GIPC1), or LRP12 (OPDM_LRP12). Neuronal intranuclear inclusion disease (NIID) is clinically distinct from OPDM but is also caused by the expansion of CGG repeats in NOTCH2NLC, which may be an indicator of intranuclear inclusion in skin biopsy. We investigated the presence of intranuclear inclusions in skin biopsies from patients with OPDM and muscle diseases with a similar pathology to evaluate whether they will have similar diagnostic findings on skin biopsy. METHODS: We analysed the frequency of p62-positive intranuclear inclusions in sweat gland cells, adipocytes and fibroblasts in skin biopsy samples from patients with OPDM (OPDM_NOTCH2NLC [n = 2], OPDM_GIPC1 [n = 6] and OPDM_LRP12 [n = 3]), NIID (n = 1), OPMD (n = 1), IBM (n = 4) and GNE myopathy (n = 2). RESULTS: The p62-postive intranuclear inclusions were observed in all three cell types in both patients with OPDM_NOTCH2NLC and a patient with NIID, in at least one cell type in all six patients with OPDM_GIPC1, and all in three cell types in one of the three patients with OPDM_LRP12. These findings were not observed in patients with OPMD, IBM or GNE myopathy. CONCLUSION: Intranuclear inclusions in skin biopsy samples are not specific to NIID and are found in all three types of genetically confirmed OPDM, suggesting that the underlying mechanism of OPDM may be similar to NIID, regardless of causative genes.
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Cuerpos de Inclusión Intranucleares , Distrofias Musculares , Biopsia , Humanos , Cuerpos de Inclusión Intranucleares/patología , Distrofias Musculares/genética , Enfermedades NeurodegenerativasRESUMEN
Lewy body-related α-synucleinopathy (Lewy pathology) has been reported in patients with myotonic dystrophy (DM) type 1 (DM1), but no detailed report has described the prevalence and extent of its occurrence. We studied consecutive full autopsy cases of DM1 at the National Center of Neurology and Psychiatry (NCNP) Brain Bank for intractable psychiatric and neurological disorders. Thirty-two cases, genetically determined to be DM1 (59.0 ± 8.7 years), obtained from the NCNP Brain Bank, were compared with control cases obtained from the Brain Bank for Aging Research (BBAR) in Japan. The investigated anatomical sites followed the Dementia with Lewy Bodies Consensus Guideline, expanding to the peripheral autonomic nervous system, temporal pole, and occipital cortex, in addition to the olfactory epithelium and spinal cord. Of the 32 patients, 11 (34.4%) had Lewy pathology, with a significantly higher prevalence than that in the control cases from the BBAR (20.1%). Lewy pathology detected in DM1 was widespread, but no macroscopic depigmentation of the substantia nigra was observed in any DM1 case; this was commensurate with the microscopic paucity of Lewy pathology in the substantia nigra and amygdala. Lewy pathology in DM1 does not appear to follow either Braak's ascending paradigm or the olfactory-amygdala extension. Lewy neurites and dots in DM1 were very sparse in the cerebral cortex and distinct from those observed in BBAR control cases. This study was the first demonstration of unique Lewy pathology in DM1 and may contribute to the understanding of the protein propagation hypothesis of Lewy pathology.
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Enfermedad por Cuerpos de Lewy , Distrofia Miotónica , Enfermedad de Parkinson , Encéfalo/patología , Humanos , Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/patología , Distrofia Miotónica/patología , Enfermedad de Parkinson/patología , alfa-Sinucleína/metabolismoRESUMEN
AIM: The association between psychiatric symptoms in Lewy body disease (LBD) and the noradrenergic and serotonergic systems is still controversial. This study investigated the quantitative relationships of depression and delusion with these systems. METHODS: We studied 24 postmortem tissues from individuals with a pathological diagnosis of LBD with sufficient clinical history. The numbers of neurons and Lewy bodies (LBs) in the locus coeruleus (LC) and dorsal raphe nucleus (DRN) were counted, and the density of neurons in the DRN was analyzed. In addition, the densities of tryptophan hydroxylase-positive neurites and norepinephrine transporter-positive neurites in the amygdala and dorsal prefrontal cortex were measured. Finally, we divided the cases into two groups: with or without depressive mood, and with or without delusion. Quantitative histological data were compared between the groups. RESULTS: The group with depressive mood had a significantly smaller number of neurons in the LC compared with the group without depressive mood. The group with delusion had a significantly larger number of LBs in the DRN compared with the group without delusion. The density of norepinephrine transporter-positive neurites in the dorsal prefrontal cortex was significantly correlated with the number of neurons in the LC. CONCLUSIONS: The accumulation of LBs in the DRN of individuals with LBD was associated with delusion, whereas a decrease in the number of neurons in the LC was associated with depressive mood. These neurodegenerative changes involved the serotonergic and noradrenergic systems and may be associated with the formation of delusion and depression, respectively, in LBD.
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Enfermedad por Cuerpos de Lewy , Deluciones , Depresión , Núcleo Dorsal del Rafe/patología , Núcleo Dorsal del Rafe/fisiología , Humanos , Norepinefrina , Proteínas de Transporte de Noradrenalina a través de la Membrana PlasmáticaRESUMEN
BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. Pathologically, it is characterized by eosinophilic hyaline intranuclear inclusions in the cells of the visceral organs as well as central, peripheral, and autonomic nervous system cells. Recently, a GGC repeat expansion in the NOTCH2NLC gene has been identified as the etiopathological agent of NIID. Interestingly, this GGC repeat expansion was also reported in some patients with a clinical diagnosis of amyotrophic lateral sclerosis (ALS). However, there are no autopsy-confirmed cases of concurrent NIID and ALS. CASE PRESENTATION: A 60-year-old Taiwanese woman reported a four-month history of progressive weakness beginning in the right foot that spread to all four extremities. She was diagnosed with ALS because she met the revised El Escorial diagnostic criteria for definite ALS with upper and lower motor neuron involvement in the cervical, thoracic, and lumbosacral regions. She died of respiratory failure at 22 months from ALS onset, at the age of 62 years. Brain magnetic resonance imaging (MRI) revealed lesions in the medial part of the cerebellar hemisphere, right beside the vermis (paravermal lesions). The subclinical neuropathy, indicated by a nerve conduction study (NCS), prompted a potential diagnosis of NIID. Antemortem skin biopsy and autopsy confirmed the coexistence of pathology consistent with both ALS and NIID. We observed neither eccentric distribution of p62-positive intranuclear inclusions in the areas with abundant large motor neurons nor cytopathological coexistence of ALS and NIID pathology in motor neurons. This finding suggested that ALS and NIID developed independently in this patient. CONCLUSIONS: We describe a case of concurrent NIID and ALS discovered during an autopsy. Abnormal brain MRI findings, including paravermal lesions, could indicate the coexistence of NIID even in patients with ALS showing characteristic clinical phenotypes.
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Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Femenino , Humanos , Cuerpos de Inclusión Intranucleares/patología , Imagen por Resonancia Magnética , Persona de Mediana Edad , Enfermedades Neurodegenerativas/complicaciones , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/patologíaRESUMEN
Miliary brain metastasis is a rare type of brain metastasis, in which carcinoma cells disseminate to numerous foci confined to Virchow-Robin/subpial spaces. Symptoms usually progress within several months, and magnetic resonance imaging (MRI) shows multiple small contrast-enhancing lesions. We report an autopsy case of a patient who rapidly deteriorated within a week due to miliary brain metastasis after epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) discontinuation, without contrast-enhancing lesions on MRI. A 74-year-old woman was diagnosed with stage IV lung adenocarcinoma with EGFR L868R mutation 2 years before presentation. Gefitinib, an EGFR-TKI was started. After 7 months, multiple new punctate contrast-enhancing lesions in the cerebral cortex appeared. After switching to another EGFR-TKI, erlotinib, these lesions disappeared. One year later, erlotinib was discontinued because of disease progression in the lung and docetaxel was initiated. Sixteen days later, cognitive decline appeared which rapidly progressed to bedridden state in 4 days. MRI showed multiple cortical small fluid-attenuated inversion recovery high intensity lesions which lacked contrast enhancement. The patient exhibited a state of akinetic mutism within a few days, and died 52 days after the appearance of neurological symptoms. The rapid progression indicated disease flare after EGFR-TKI discontinuation. Autopsy revealed numerous foci of metastasis in the cerebral cortex, basal ganglia, thalamus, and cerebellum, in which cancer cells were mostly confined to the Virchow-Robin/subpial spaces. These pathological findings were compatible with previous reports of miliary brain metastasis. Recent reports suggest that early disseminated cancer cells can survive for a long time and even remain after chemotherapy in supportive niches, and Virchow-Robin spaces are the niches in the brain. Our case suggests that these cancer cells may rapidly proliferate as a withdrawal burst after discontinuation of molecular targeted drugs, and show pathological findings of miliary brain metastasis.
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Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Progresión de la Enfermedad , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Anciano , Neoplasias Encefálicas/genética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , MutaciónRESUMEN
ErbB4 is the protein implicated in familial amyotrophic lateral sclerosis (ALS), designated as ALS19. ErbB4 is a receptor tyrosine kinase activated by its ligands, neuregulins (NRG), and plays an essential role in the function and viability of motor neurons. Mutations in the ALS19 gene lead to the reduced autophosphorylation capacity of the ErbB4 protein upon stimulation with NRG-1, suggesting that the disruption of the NRG-ErbB4 pathway causes motor neuron degeneration. We used immunohistochemistry to study ErbB4 in the spinal cord of patients with sporadic ALS (SALS) to test the hypothesis that ErbB4 may be involved in the pathogenesis of SALS. ErbB4 was specifically immunoreactive in the cytoplasm of motor neurons in the anterior horns of the spinal cord. In patients with SALS, some of the motor neurons lost immunoreactivity with ErbB4, with the proportion of motor neurons with a loss of immunoreactivity correlated with the severity of motor neuron loss. The subcellular localization was altered, demonstrating nucleolar or nuclear localization, threads/dots and spheroids. The ectopic glial immunoreactivity was observed, mainly in the oligodendrocytes of the lateral columns and anterior horns. The reduction in the ErbB4 immunoreactivity was significantly correlated with the cytoplasmic mislocalization of transactivation response DNA-binding protein 43 kDa (TDP-43) in the motor neurons. No alteration in immunoreactivity was observed in the motor neurons of mice carrying atransgene for mutant form of the superoxide dismutase 1 gene (SOD1). This study provided compelling evidence that ErbB4 is also involved in the pathophysiology of SALS, and that the disruption of the NRG-ErbB4 pathway may underlie the TDP-43-dependent motor neuron degeneration in ALS.
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Esclerosis Amiotrófica Lateral/genética , Receptor ErbB-4/genética , Médula Espinal/metabolismo , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Ratones Transgénicos , Persona de Mediana Edad , Corteza Motora/metabolismo , Receptor ErbB-4/metabolismo , Superóxido Dismutasa-1/genéticaRESUMEN
BACKGROUND: The "dual-hit" and propagation hypotheses of α-synuclein suggests that the olfactory cells of the olfactory epithelium are among the earliest sites of involvement in Parkinson's disease (PD). We investigated the olfactory epithelium in consecutive cases that had been registered with a brain bank. OBJECTIVES: This study was undertaken to check the presence or absence of Lewy body pathology in olfactory cells. METHODS: Thirty-six male and 11 female patients were examined, including eight with PD, two with dementia with Lewy bodies, 11 with incidental Lewy body disease, and 26 with no Lewy-related alpha-synucleinopathy. The olfactory epithelium was sampled by craniotomy followed by resection of the cribriform plate, which was fixed in formalin and decalcified with ethylenediaminetetra-acetate. Coronal paraffin-embedded sections of the plate were stained with hematoxylin and eosin or immunohistochemically stained with antibodies against phosphorylated α-synuclein to detect Lewy body pathology and neuronal markers of protein gene product 9.5, phosphorylated neurofilament, and tyrosine hydroxylase. RESULTS: Lewy body pathology was detected in the olfactory cells of the olfactory epithelium in a single patient with incidental Lewy body disease and in six patients with PD, but it was not detected in patients who had dementia with Lewy bodies. CONCLUSIONS: We detected Lewy body pathology in the olfactory epithelium in six of the eight patients with Parkinson's disease and in one patient with incidental Lewy body pathology.
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Cuerpos de Lewy/patología , Mucosa Olfatoria/patología , Enfermedad de Parkinson/patología , Células Receptoras Sensoriales/patología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/patología , Masculino , Persona de Mediana Edad , Ubiquitina Tiolesterasa/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
BACKGROUND AND OBJECTIVES: In 2024, the sequalae of the acute phase of coronavirus disease-19 (COVID-19) infection, which include neurological symptoms and are commonly referred to as long COVID or post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC), continue to be a substantial health concern; however, similar symptoms are observed in individuals with no previous COVID-19 infection. METHODS: This was a single-center, retrospective, descriptive case series study. Data were obtained from patients who visited our outpatient clinic specializing in PASC between June 1, 2021, and May 31, 2023. We compared antibody test results between patients with confirmed acute phase infection and those without. We compared differences in demographic and clinical characteristics between patients with positive results during the acute phase of COVID-19 infection and positive anti-SARS-CoV-2 antibody tests (true-PASC), and those with neither (PASC-mimic). RESULTS: Of 437 patients diagnosed with PASC according to World Health Organization criteria, 222 underwent COVID-19 antibody tests. Of these, 193 patients (86.9%) had a history of confirmed acute phase infection, whereas 29 (13.1%) did not. Of the former, 186 patients (96.4%) were seropositive for anti-nucleotide SARS-CoV-2 antibodies (true-PASC), whereas 19 of the latter tested seronegative for anti-nucleotide SARS-CoV-2 antibodies (PASC-mimic). There were no significant differences in symptom characteristics between true-PASC and PASC-mimic participants. CONCLUSIONS: It was difficult to identify any clinical features to aid in diagnosing PASC without confirmation of acute COVID-19 infection. The findings indicate the existence of a "PASC-mimic" condition that should be acknowledged and excluded in future PASC-related research studies.
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Introduction: Low-grade epilepsy-associated tumors are the second most common histopathological diagnoses in cases of drug-resistant focal epilepsy. However, the connection between neuroimaging features and genetic alterations in these tumors is unclear, prompting an investigation into genotype-relevant neuroimaging characteristics. Methods: This study retrospectively analyzed neuroimaging and surgical specimens from 46 epilepsy patients with low-grade epilepsy-associated neuroepithelial tumors that had genetic mutations identified through panel sequencing to investigate their relationship to genotypes. Results: Three distinct neuroimaging groups were established: Group 1 had indistinct borders and iso T1-weighted and slightly high or high T2-weighted signal intensities without a diffuse mass effect, associated with 93.8% sensitivity and 100% specificity to BRAF V600E mutations; Group 2 exhibited sharp borders and very or slightly low T1-weighted and very high T2-weighted signal intensities with a diffuse mass effect and 100% sensitivity and specificity for FGFR1 mutations; and Group 3 displayed various characteristics. Histopathological diagnoses including diffuse low-grade glioma and ganglioglioma showed no clear association with genotypes. Notably, postoperative seizure-free rates were higher in Group 1 tumors (BRAF V600E) than in Group 2 tumors (FGFR1). Discussion: These findings suggest that tumor genotype may be predicted by neuroimaging before surgery, providing insights for personalized treatment approaches.
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Background: The characteristics of functional limb weakness (FLW) as one of the manifestations of functional neurological disorder after vaccination against coronavirus disease 2019 (COVID-19) remain controversial. Methods: In this descriptive case series, we aimed to elucidate the characteristics of Japanese patients with FLW who claimed muscle weakness after COVID-19 vaccination among patients who visited our outpatient clinic between 1 June 2021 and 31 December 2022. Results: Nine patients were diagnosed with FLW (mean age: 30.8 years), including two men and seven women. Seven patients were vaccinated with the BioNTech/Pfizer vaccine and two with the mRNA-1273 Moderna vaccine. All patients demonstrated various positive signs for FLW. Magnetic resonance imaging or computed tomography indicated no abnormality that could explain their symptoms. At the time of the clinic visit, five patients were treated for psychiatric disorders, including depression, insomnia, attention-deficit hyperactivity disorder, and Asperger's syndrome. Muscle weakness spread to the limbs beyond the vaccinated arm in seven patients. Conclusions: We describe the basic characteristics of FLW in Japanese patients after COVID-19 vaccination. Further recognition of these characteristics could aid the diagnosis of FLW by physicians allowing them to support these patients effectively.
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Functional neurological disorder (FND) may mimic various kinds of neurologic diseases and may coexist with other neurologic disorders. In cases overlapped by FND, it might be challenging to distinguish symptoms induced by FND and those induced by other underlying neurological disorders, especially when patients show no positive signs indicative of FND. Here, we present the case of a patient who was genetically diagnosed with paroxysmal kinesigenic dyskinesia (PKD). However, most of the patient's symptoms were considered to indicate FND. To our knowledge, there are no reports of FND overlapping PKD. This case illustrates the possibility that FND can coexist with and mimic symptoms of other diseases. It is necessary to rule out coexisting FND symptoms that may modify clinical presentations that cannot simply be explained by a recognized neurological disease.
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The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.
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Background: The clinical course, comorbidity, and management of symptoms after the acute phase of coronavirus disease 2019 (COVID-19) remain controversial. Methods: This was a descriptive case series study, examining the characteristics of patients with longstanding symptoms related to COVID-19 who visited our outpatient clinic between 1 June and 31 December 2021. We analyzed patients' background, chief complaints, clinical course after COVID-19 onset, and clinical examination results. Results: A total of 90 patients with a mean age of 39.8 years were confirmed as having long COVID. The median time between diagnosis of COVID-19 and visiting our clinic was 66.8 days, and 89 patients (98.9%) were unvaccinated. Depression was the most common comorbidity (nine patients, 10.0%). The most common chief complaint was disturbance of smell and/or taste (35, 38.9%), followed by memory disturbance (22, 24.4%) and fatigue (29, 31.1%). Head MRI was performed for 42 (46.7%) patients, and the most common finding was sinusitis (four patients). Olfactory testing was conducted in 25 patients (27.8%) using a T&T olfactometer, and 14 patients (56%) had mild olfactory impairment. Of the five odors in the T&T, recognition of ß-phenylethyl alcohol was most impaired. Conclusions: This study describes the basic characteristics of long COVID in Japan. It suggests that long COVID is complex because it results in a wide range of symptoms.
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Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are major neurodegenerative disorders that share commonalities in their pathology involving the formation of Lewy bodies, the main component of which is α-synuclein protein. Aberrancy and dysfunction in lysosomes have been suggested to play critical roles in the pathogenesis of Lewy body diseases. We recently identified a novel lysosomal degradation pathway in which various macromolecules, including α-synuclein protein, are directly imported into lysosomes and degraded. In this study, we analyzed the levels and localization of the lysosomal membrane protein SIDT2, a key factor in this pathway, in the postmortem brains of patients with PD and DLB. The levels of SIDT2 protein were significantly higher in the anterior cingulate cortex (ACC) of both PD and DLB cases than in age-matched control subjects, but this difference was not observed in the inferior frontal gyrus. The levels of SIDT2 also showed a strong correlation with α-synuclein levels in the ACC of all subjects, including controls. SIDT2 was colocalized with aggregates positive for phosphorylated α-synuclein protein, which is a hallmark of Lewy bodies, in all examined cases of both PD and DLB. These observations suggest that changes in the levels and localization of SIDT2 occur at the lesion site of Lewy body diseases in accordance with the progression of Lewy body pathology. Our findings provide mechanistic insights into the pathogenesis of Lewy body diseases, as well as other neurodegenerative disorders, and may provide clues for improved diagnosis, prevention, and therapeutic intervention for such diseases.
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Encéfalo/metabolismo , Enfermedad por Cuerpos de Lewy/patología , Proteínas de Transporte de Nucleótidos/metabolismo , Enfermedad de Parkinson/patología , alfa-Sinucleína/metabolismo , Animales , Autopsia/métodos , Encéfalo/patología , Humanos , Enfermedad por Cuerpos de Lewy/metabolismo , Ratones , Proteínas de Transporte de Nucleótidos/genética , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/genéticaRESUMEN
A 68-year-old woman with a history of schizophrenia developed coronavirus disease (COVID)-19 and was transferred to our hospital. Despite treatment, she died of respiratory failure 16 days after the onset. At the time of autopsy, polymerase chain reaction (PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA using swabs from the nasopharynx and the lung was positive; however, the cerebrospinal fluid was negative. An autopsy showed diffuse alveolar damage and recent multiple cerebral infarcts. Acute splenitis was observed with thrombi adhering to the vascular endothelium in areas of severe neutrophilic infiltration. Immunohistochemistry using an antibody against the SARS-CoV-2 nucleocapsid showed immunoreactivity along the hyaline membrane of the lung; however, the antibody showed no immunoreactivity in the medulla, the thalamus, the frontal lobe, and the pituitary. Future pathologic studies should clarify the mechanisms involved in a variety of clinical and pathological changes related to COVID-19.
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A 64-year-old female developed Parkinson's disease at the age of 52 years. She experienced muscle weakness in the upper right extremities and dropped head at 62 and 63 years, respectively; both symptoms were considered to be associated with Parkinson's disease (PD). The dosage of L-DOPA was increased from 200 mg/day to 900 mg/day; however, her neurological symptoms did not improve. Eventually, she was diagnosed with amyotrophic lateral sclerosis (ALS) at 64 years. She was placed under palliative care, and died of respiratory failure and malnutrition. Neuropathologic findings were consistent with the coexistence of PD and ALS. In fact, there were α-synuclein immunoreactive Lewy bodies (Braak stage 4) as well as TDP-43 immunoreactive deposits in the motor nuclei at the level of brainstem and spinal cord. Therefore, coexisting pathologies must be taken into account in a patient showing multi-system symptoms.