An autopsy case of type A FTLD-TDP with a GRN mutation presenting with the logopenic variant of primary progressive aphasia at onset and with corticobasal syndrome subsequently.

A 68-year-old woman presented with difficulty finding words and writing characters. Neurological examination led to clinical diagnosis at onset of the logopenic variant of primary progressive aphasia accompanied with ideomotor apraxia, visuospatial agnosia on the right, and Gerstmann syndrome. Bradykinesia and rigidity on the right with shuffling gait developed after one year. Treatment with L-dopa had no effect. The patient was diagnosed with corticobasal syndrome (CBS). Brain magnetic resonance imaging revealed diffuse cortical atrophy dominantly on the left, especially in the temporal, parietal, and occipital lobes. Positron emission tomography did not reveal any significant accumulation of amyloid ß or tau protein. She died five years later. Neuropathological examination revealed diffuse cortical atrophy with severe neuronal loss and fibrous gliosis in the cortex. Neuronal cytoplasmic inclusions, short dystrophic neurites, and, most notably, neuronal intranuclear inclusions, all immunoreactive for phosphorylated TDP-43, were observed. Western blotting revealed a full length and fragments of phosphorylated TDP-43 at 45 and 23 kDa, respectively, confirming the pathological diagnosis of type A FTLD-TDP. Whole exome sequencing revealed a pathogenic mutation in GRN (c.87dupC). FTLD-TDP should be included in the differential diagnosis of CBS.

Factors associated with drug retention of mepolizumab in patients with eosinophilic granulomatosis with polyangiitis: A multicentre REVEAL cohort study.

OBJECTIVES: To determine the current retention rate of mepolizumab (MPZ) and identify factors associated with drug retention in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in the Kansai multicentre cohort (REVEAL cohort). METHODS: Sixty patients diagnosed with EGPA and treated with MPZ between December 2016 and June 2023 were enrolled. The clinical characteristics, including laboratory data, treatments administered, and disease course outcomes were collected retrospectively. The patients were stratified into MPZ continuation (n=53) and discontinuation (n=7) groups, and drug retention was statistically compared using the log-rank test. RESULTS: The median age of patients was 54.5 years, with 55% females, and 33% antineutrophil cytoplasmic antibody-positive at disease onset. MPZ exhibited a retention rate of 78.7% after five years. The reasons for discontinuation included treatment of coexisting diseases, inadequate response, and remission. Patient characteristics at disease onset were comparable between the groups. Patients receiving immunosuppressants (IS) before MPZ introduction demonstrated significantly higher retention rates (P = 0.038). During the final observation, the MPZ continuation group had a lower vasculitis damage index score (P = 0.027). CONCLUSIONS: MPZ exhibited a high 5-year retention rate, particularly in patients requiring IS. This study implies that long-term use of MPZ may mitigate irreversible organ damage.

An autopsy case of progressive multifocal leukoencephalopathy with massive iron deposition in juxtacortical lesions.

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.

In Vivo Dynamic Movement of Polymerized Amyloid ß in the Perivascular Space of the Cerebral Cortex in Mice.

Disposition of amyloid ß (Aß) into the perivascular space of the cerebral cortex has been recently suggested as a major source of its clearance, and its disturbance may be involved in the pathogenesis of cerebral amyloid angiopathy and Alzheimer's disease. Here, we explored the in vivo dynamics of Aß in the perivascular space of anesthetized mice. Live images were obtained with two-photon microscopy through a closed cranial window. Either fluorescent-dye-labeled Aß oligomers prepared freshly or Aß fibrils after 6 days of incubation at 37 °C were placed over the cerebral cortex. Accumulation of Aß was observed in the localized perivascular space of the penetrating arteries and veins. Transportation of the accumulated Aß along the vessels was slow and associated with changes in shape. Aß oligomers were transported smoothly and separately, whereas Aß fibrils formed a mass and moved slowly. Parenchymal accumulation of Aß oligomers, as well as Aß fibrils along capillaries, increased gradually. In conclusion, we confirmed Aß transportation between the cortical surface and the deeper parenchyma through the perivascular space that may be affected by the peptide polymerization. Facilitation of Aß excretion through the system can be a key target in treating Alzheimer's disease.

Heavy Tau Burden with Subtle Amyloid ß Accumulation in the Cerebral Cortex and Cerebellum in a Case of Familial Alzheimer's Disease with APP Osaka Mutation.

We previously identified a novel mutation in amyloid precursor protein from a Japanese pedigree of familial Alzheimer's disease, FAD (Osaka). Our previous positron emission tomography (PET) study revealed that amyloid ß (Aß) accumulation was negligible in two sister cases of this pedigree, indicating a possibility that this mutation induces dementia without forming senile plaques. To further explore the relationship between Aß, tau and neurodegeneration, we performed tau and Aß PET imaging in the proband of FAD (Osaka) and in patients with sporadic Alzheimer's disease (SAD) and healthy controls (HCs). The FAD (Osaka) patient showed higher uptake of tau PET tracer in the frontal, lateral temporal, and parietal cortices, posterior cingulate gyrus and precuneus than the HCs (>2.5 SD) and in the lateral temporal and parietal cortices than the SAD patients (>2 SD). Most noticeably, heavy tau tracer accumulation in the cerebellum was found only in the FAD (Osaka) patient. Scatter plot analysis of the two tracers revealed that FAD (Osaka) exhibits a distinguishing pattern with a heavy tau burden and subtle Aß accumulation in the cerebral cortex and cerebellum. These observations support our hypothesis that Aß can induce tau accumulation and neuronal degeneration without forming senile plaques.

Relationship Turmoil and Emotional Empathy in Frontotemporal Dementia.

BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is characterized by marked deficits in empathy and social behavior; however, the effect of these symptoms on partner relationships has not been quantitatively measured. OBJECTIVE: We aimed to determine the effect of empathy loss and behavioral symptoms on partner and familial relationship status in bvFTD. We ascertained whether patients were currently in marriage/partner relationships or were separated/divorced, the timing and duration of these relationships, and whether the patients had relationship infidelity. We investigated the relationship status of 483 patients (156 with bvFTD, 38 with nonfluent variant primary progressive aphasia, 72 with semantic variant primary progressive aphasia, 49 with corticobasal syndrome, 45 with progressive supranuclear palsy syndrome, and 123 with Alzheimer disease) over the course of follow-up, and correlated relationship status with patients' first visit Interpersonal Reactivity Index and Neuropsychiatric Inventory. RESULTS: Relationship dissolution and infidelity were significantly more frequent among patients with bvFTD than in the other groups. Across all patients, empathy loss was associated with relationship dissolution. In the bvFTD group, patients who experienced relationship dissolution or infidelity had significantly lower empathy than those who did not. CONCLUSIONS: Changes in relationship status differed across dementia groups and were associated with empathy decline.

Paradoxical Brain Embolism Caused by Isolated Pulmonary Arteriovenous Fistula Successfully Treated with Recombinant Tissue Plasminogen Activator.

Pulmonary arteriovenous fistula (PAVF), a vessel malformation connecting the pulmonary circulation to the systemic circulation while bypassing the pulmonary capillaries, can cause paradoxical cerebral infarction. It is often associated with hereditary hemorrhagic telangiectasia (HHT), a genetic disease characterized by multiple dermal, mucosal, and visceral telangiectasia causing recurrent bleeding. Paradoxical cerebral embolism caused by PAVF without HHT is rare. Here, we report a patient with isolated PAVF who experienced an ischemic stroke caused by a paradoxical embolism from deep venous thrombosis; the patient was successfully treated with recombinant tissue plasminogen activator. She presented with a decrease in arterial oxygen saturation to 91%, and lung disease was suspected. A PAVF was subsequently found in the right S6 region using contrast computed tomography. Interventional radiologists successfully occluded the shunt using 6 microcoils. PAVF should be considered when determining the pathogenesis of cerebral ischemia in patients with hypoxia, which can be the only symptom of PAVF.

An autopsy case of globular glial tauopathy presenting with clinical features of motor neuron disease with dementia and iron deposition in the motor cortex.

Globular glial tauopathy (GGT) is a 4-repeat (4R) tauopathy in which 4R tau accumulates to form globular glial inclusions (GGIs), predominantly in oligodendroglia. To date, little has been reported on iron deposits in patients with GGT. We report a case of GGT with iron deposits in a 78-year-old woman presenting with an 8-year history of slowly progressing limb weakness and cognitive decline. Susceptibility-weighted imaging revealed a low signal intensity in the right precentral gyrus, suggesting iron deposition. A clinical diagnosis of motor neuron disease with dementia was made 4 years after onset. At autopsy, gross pathological findings showed atrophy of the frontal and temporal lobes. A localized area of the precentral gyrus corresponding to the most severely affected limb showed the strongest atrophy, macroscopically, and displayed 4R tau-immunoreactive GGIs and microscopically many ferritin-immunoreactive neurons. We diagnosed this patient as having GGT. This is the first GGT case with iron deposition confirmed both radiologically and pathologically.

A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma.

Among 249 patients with teratoma-associated encephalitis, 211 had N-methyl-D-aspartate receptor antibodies and 38 were negative for these antibodies. Whereas antibody-positive patients rarely developed prominent brainstem-cerebellar symptoms, 22 (58%) antibody-negative patients developed a brainstem-cerebellar syndrome, which in 45% occurred with opsoclonus. The median age of these patients was 28.5 years (range = 12-41), 91% were women, and 74% had full recovery after therapy and tumor resection. These findings uncover a novel phenotype of paraneoplastic opsoclonus that until recently was likely considered idiopathic or postinfectious. The triad of young age (teenager to young adult), systemic teratoma, and high response to treatment characterize this novel brainstem-cerebellar syndrome.

Diffusion-weighted imaging thermometry in multiple sclerosis.

PURPOSE: To prospectively investigate brain temperature using MR diffusion-weighted imaging thermometry in multiple sclerosis (MS) patients and age-matched healthy controls, to examine comparisons of brain temperature between MS patients and healthy volunteers, and to examine correlations between brain temperature and disease duration and between brain temperature and Expanded Disability Status Scale (EDSS) in MS patients. MATERIALS AND METHODS: Thirteen MS patients and 13 age-matched healthy controls were examined using a 3.0 Tesla MR unit from January 2011 to February 2013. Brain temperature in each participant was measured using diffusion-weighted imaging-based MR thermometry of the lateral ventricles. Group comparisons of brain temperature between MS patients and healthy controls were performed using the Student's t-test. The determination of correlation between brain temperature in MS patients and disease duration, and between brain temperature and EDSS were performed using a Pearson's correlation coefficient test. For statistical analyses, values of P < 0.05 were considered statistically significant. RESULTS: Median brain temperature was 35.81°C (range, 35.06-37.03°C) in MS patients, and 36.29°C (range, 35.51-37.89°C) in healthy controls representing a significant difference (P = 0.020). No significant correlation of both between brain temperature and disease duration and between brain temperature and EDSS were identified (r/P = -0.382/0.198, -0.026/0.933). CONCLUSION: Brain temperature was significantly lower in MS patients than in healthy controls, probably representing decreased brain metabolism in MS patients.

[Neuropsychological tests in multiple sclerosis].

The prevalence of cognitive impairment is about 40-65% in patients with multiple sclerosis (MS). Cognitive decline appears in MS in the early stages of the disease including clinically isolated syndrome and radiologically isolated syndrome. Cognitive impairments in patients with MS influence their social functioning and employment. Various domains of cognitive function, including processing speed/working memory, long-term memory, word retrieval, visuospatial processing, and executive function are affected in patients with MS. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) in MS and the Minimal Assessment of Cognitive Function in MS (MACFIMS) are commonly utilized to assess cognitive function in patients with MS. Neuropsychological assessments are important in MS to predict prognosis and cognitive outcome in treatment trials.

[Carcinomatous meningitis in a post-operative patient with lung adenocarcinoma for which erlotinib was effective - a case report].

A 53-year-old female was admitted to our hospital complaining of disturbance of consciousness and hallucinations. About one year and 5 months ago she had adenocarcinoma of the lung, which was treated with surgery and chemotherapy. Computed tomography and magnetic resonance imaging revealed that her lung cancer had relapsed as caricinomatous meningitis and multiple lung metastases. She was treated with erlotinib, which rapidly resulted in disappearance of her symptoms. She still continues to receive erlotinib therapy without suffering from evident relapse 7 months after the initiation of the treatment.

Multiple Cerebral Infarctions Accompanied by Subcortical and Subarachnoid Hemorrhaging in Bilateral Border Zone Areas in a Patient with Eosinophilic Granulomatosis with Polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is often associated with peripheral neuropathy, but reports of central nervous system involvement are quite rare. We herein report a patient with EGPA first identified as having hypereosinophilia who later developed asthma, eosinophilic otitis media, sinusitis, and hemorrhagic colitis. She subsequently developed hemiparesis. Head magnetic resonance imaging revealed multiple cerebral infarctions with subcortical and subarachnoid hemorrhaging colocalized at the bilateral border zone areas. She was diagnosed with EGPA-induced stroke and successfully treated with oral prednisolone. Inflammation in the small cerebral arteries in EGPA may induce bilateral border zone infarction with colocalizing subcortical and subarachnoid hemorrhaging.

[Sibling cases of four and a half LIM domains 1 (FHL1) myopathy who developed respiratory failure without apparent limb weakness].

A 60-year-old man developed dyspnea without apparent limb weakness. He had cardiomyopathy in his 30s and was treated for chronic heart failure since 42. He was diagnosed as having four and a half LIM domains 1 (FHL1) mutation at 53 following the same diagnosis of his younger brother. He was first admitted to the cardiology department for possible worsening of chronic cardiac failure. Blood gas analysis showing respiratory acidosis prompted his treatment with a respirator. Neurological examination revealed that he had mild weakness limited to the shoulder girdle muscles and contracture at jaw, spine, elbows and ankles. Skeletal muscle CT showed truncal atrophy. He, as well as his younger brother, was diagnosed with FHL1 myopathy resulting in ventilation failure and was discharged after successful weaning from the respirator in the daytime. The present sibling cases are the first with FHL1 mutation to develop respiratory failure without limb weakness and suggest that FHL1 myopathy as a differentially diagnosis of hereditary myopathies with early respiratory failure.

On-Reading (Chinese-Style Pronunciation) Predominance Over Kun-Reading (Native Japanese Pronunciation) in Japanese Semantic Dementia.

Japanese kanji (morphograms) have two ways of reading: on-reading (Chinese-style pronunciation) and kun-reading (native Japanese pronunciation). It is known that some Japanese patients with semantic dementia read kanji with on-reading but not with kun-reading. To characterize further reading impairments of patients with semantic dementia, we analyzed data from a total of 9 patients who underwent reading and writing tests of kanji and kana (Japanese phonetic writing) and on-kun reading tests containing two-character kanji words with on-on reading, kun-kun reading, and specific (so-called Jukujikun or irregular kun) reading. The results showed that on-reading preceding (pronouncing first with on-reading) and kun-reading deletion (inability to recall kun-reading) were observed in nearly all patients. In the on-kun reading test, on-reading (57.6% correct), kun-reading (46.6% correct), and specific-reading (30.0% correct) were more preserved in this decreasing order (phonology-to-semantics gradient), although on-reading and kun-reading did not significantly differ in performance, according to a more rigorous analysis after adjusting for word frequency (and familiarity). Furthermore, on-substitution (changing to on-reading) errors in kun-reading words (27.0%) were more frequent than kun-substitution (changing to kun-reading) errors in on-reading words (4.0%). These results suggest that kun-reading is more predominantly disturbed than on-reading, probably because kun-reading and specific-reading are closely associated with the meaning of words.

Liver injury after methylprednisolone pulse therapy in multiple sclerosis is usually due to idiosyncratic drug-induced toxicity rather than autoimmune hepatitis.

BACKGROUND: In patients with multiple sclerosis (MS), development of hepatic injury has been sporadically reported after methylprednisolone (MP) pulse therapy. Some studies suggest autoimmune hepatitis, while other studies reported direct hepatotoxicity as a cause for hepatic injury. Here, we studied the pathological mechanism of such liver injury in patients with MS. METHODS: From 2005 to 2016, eight patients with MS developed liver injury after MP pulse therapy. Their average age was 38 years (range: 28-49 years, all female). Autoimmune antibodies were measured and a liver biopsy was performed in seven patients. RESULTS: Liver injury developed within two weeks in two patients and later (30-90 days after MP) in six patients. No hepatitis-related autoantibody or hepatitis virus were found. All cases were classified as hepatocellular injury and none as cholestatic or mixed. A liver biopsy in five cases revealed centrilobular necrosis with lobular infiltrates of inflammatory cells, suggesting drug-induced acute hepatitis. The biopsy findings in another case suggested a residual stage of acute hepatitis. Only one patient showed portal expansion with periportal fibrosis, suggesting autoimmune hepatitis. All patients recovered spontaneously or with only hepatoprotective drugs, although one patient with possible autoimmune hepatitis recovered slowly. CONCLUSION: Liver injury develops usually later than two weeks after MP treatment. The prognosis is good in most cases and rarely autoimmune hepatitis may be involved.

Corrigendum: Age-Dependent Relationship Between Plasma Aß40 and Aß42 and Total Tau Levels in Cognitively Normal Subjects.

[This corrects the article DOI: 10.3389/fnagi.2019.00222.].

Age-Dependent Relationship Between Plasma Aß40 and Aß42 and Total Tau Levels in Cognitively Normal Subjects.

Both amyloid plaques and neurofibrillary tangles are pathological hallmarks in the brains of patients with Alzheimer's disease (AD). However, the constituents of these hallmarks, amyloid beta (Aß) 40, Aß42, and total Tau (t-Tau), have been detected in the blood of cognitively normal subjects by using an immunomagnetic reduction (IMR) assay. Whether these levels are age-dependent is not known, and their interrelation remains undefined. We determined the levels of these biomarkers in cognitively normal subjects of different age groups. A total of 391 cognitively normal subjects aged 23-91 were enrolled from hospitals in Asia, Europe, and North America. Healthy cognition was evaluated by NIA-AA guidelines to exclude subjects with mild cognitive impairment (MCI) and AD and by cognitive assessment using the Mini Mental State Examination and Clinical Dementia Rating (CDR). We examined the effect of age on plasma levels of Aß40, Aß42, and t-Tau and the relationship between these biomarkers during aging. Additionally, we explored age-related reference intervals for each biomarker. Plasma t-Tau and Aß42 levels had modest but significant correlations with chronological age (r = 0.127, p = 0.0120 for t-Tau; r = -0.126, p = 0.0128 for Aß42), ranging from ages 23 to 91. Significant positive correlations were detected between Aß42 and t-Tau in the groups aged 50 years and older, with Rho values ranging from 0.249 to 0.474. Significant negative correlations were detected between Aß40 and t-Tau from age 40 to 91 (r ranged from -0.293 to -0.582) and between Aß40 and Aß42 in the age groups of 30-39 (r = -0.562, p = 0.0235), 50-59 (r = -0.261, p = 0.0142), 60-69 (r = -0.303, p = 0.0004), and 80-91 (r = 0.459, p = 0.0083). We also provided age-related reference intervals for each biomarker. In this multicenter study, age had weak but significant effects on the levels of Aß42 and t-Tau in plasma. However, the age group defined by decade revealed the emergence of a relationship between Aß40, Aß42, and t-Tau in the 6th and 7th decades. Validation of our findings in a large-scale and longitudinal study is warranted.

Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease.

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.