Genetic Creutzfeldt-Jakob disease-M232R with the cooccurrence of multiple prion strains, M1 + M2C + M2T: Report of an autopsy case.

Genetic Creutzfeldt-Jakob disease (gCJD) with a methionine to arginine substitution at codon 232 of the prion protein gene (gCJD-M232R) is rare and has only been reported in Japan. We report an autopsy case of gCJD-M232R showing alleles of codon 129 that were homozygous for methionine and the presence of multiple strains of the protease-resistant, abnormal isoform of prion protein (PrPSc ), M1 + M2C + M2T. The patient, a 54-year-old Japanese man, died after a clinical course of 21 months characterized by slowly progressive dementia and sleep disturbance. At autopsy, the neuropil of the cerebral neocortex showed a widespread and severe spongiform change. Grape-like clusters of large confluent vacuoles were admixed with fine vacuoles. Neuronal loss was moderate, but reactive astrocytosis was mild. The dorsomedial nucleus of the thalamus and the inferior olivary nucleus showed moderate and severe neuronal loss, respectively. Many amyloid plaques were present in the cerebellar molecular layer. PrPSc deposition pattern was predominantly the synaptic type in the cerebrum and corresponded to the plaques in the cerebellum. Perivacuolar deposition was also seen. Western blot analysis of PrPSc revealed the predominance of type 2. Moreover, by employing Western blot analysis in combination with the protein misfolding cyclic amplification (PMCA) method, which selectively amplifies the minor M2T prion strain, we demonstrated the presence of M2T, in addition to M1 and M2C strains, in the brain of the patient. PMCA was a powerful method for demonstrating the presence of the M2T strain, although the amount is often small and the transmission is difficult.

Localized atrophy of the pontine base as a sequela of prolonged ischemia: Report of an autopsy case.

An 80-year-old man with a history of diabetes mellitus and hypertension died of a progressive neurological disorder characterized by truncal ataxia, extraocular movement disturbance, and muscular rigidity. Neuroradiological examination showed progressive atrophy restricted to the pontine base. Autopsy revealed localized atrophy of the pontine base, in which both neurons and nerve fibers were lost, especially in the central region. Medium-sized and small arteries in the parenchyma of the pontine base showed marked fibro-hyalinous thickening of the walls with luminal stenosis, but no distinct tissue defect as seen in lacunar infarct was observed. Perivascular lymphocytic infiltration was mostly absent, and reactive astrocytic proliferation was weak. The pontine tegmentum, midbrain, and medulla oblongata were well preserved. Localized atrophy of the pontine base is a rare pathological condition, and its pathogenesis in the present case can be best explained by a prolonged ischemic state (hypoperfusion) due to marked sclerotic changes of perforating arteries. It is unique that the lesions were restricted to the pontine base and the formation of lacunas was not observed. Localized metabolic derangement resembling that seen in central pontine myelinolysis might have also contributed to the pathogenesis of this peculiar localized atrophy.

Atypical lower motor neuron disease with enlargement of Nissl substance: Report of an autopsy case.

The patient was an 81-year-old woman diagnosed with atypical motor neuron disease who died after a long clinical course (7.5 years without mechanical assistance of ventilation) characterized by lower motor neuron signs and symptoms. Upper motor neuron signs and cognitive impairment were not apparent. Autopsy demonstrated severe neuronal loss in the anterior horn of the spinal cord, and some of the remaining neurons showed enlargement of Nissl substance and apparent thickening of the nuclear envelopes. No Bunina bodies, skein-like inclusions, or structures immunoreactive for phosphorylated transactivation response DNA-binding protein 43 were found. Immunoreactivity for superoxide dismutase-1 was focally seen in the enlarged Nissl substance. Ultrastructural examination demonstrated an increase of rough-surfaced endoplasmic reticulum (rough ER) and free ribosomes, disaggregation of polyribosomes, and dispersion of free ribosomes. Cisterns of rough ER were slightly dilated, and some of them were closely attached to the nuclear envelopes. Enlargement of Nissl substance may be related to "ER stress", and the abnormal findings of rough ER and free ribosomes may represent a degenerative process. However, another possibility, that they represent a compensatory hyperplastic change, cannot be excluded. The close attachment of cisterns of rough ER to the nuclear envelopes may be a mechanism to support or compensate for the abnormally-fragile nuclear envelopes.
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Novel intracytoplasmic inclusions immunoreactive for phosphorylated-TDP43 and cystatin C in anterior horn cells in a case of sporadic amyotrophic lateral sclerosis.

Novel intracytoplasmic inclusions immunoreactive for phosphorylated transactivation response DNA-binding protein 43 (p-TDP43), cystatin C, and transferrin were found in anterior horn cells in a case of sporadic amyotrophic lateral sclerosis (ALS). The patient was a 59-year-old woman, who died of ALS after a clinical course of 8 years. She had been receiving mechanical support for respiration for 6 years and in a "totally locked-in" state for 4 years prior to death. The spinal cord showed severe degeneration involving the anterior and lateral funiculi, whereas the posterior funiculus was preserved. Neurons in the anterior horn and Clarke's column were markedly lost, and many Bunina bodies and a few skein-like inclusions were found. Some remaining anterior horn cells had round and densely eosinophilic or amphophilic intracytoplasmic inclusions. They were immunoreactive for ubiquitin, p-TDP43, cystatin C and transferrin. On confocal laser microscopy, cystatin C was found to consistently surround p-TDP43 within the inclusions. The inclusions ultrastructurally consisted of granule-associated fibrils and, in the central portion, dense aggregates of fibrils were associated with masses of electron-dense, coarsely granular or amorphous material. Although their pathogenesis remains unknown, these unique inclusions may have been formed under a specific condition whereby p-TDP43 and cystatin C interacted with each other.

Early Onset of Diabetes Mellitus Accelerates Cognitive Decline in Japanese Patients with Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes.

Approximately 80% of patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) carry the A3243G mutation in the mitochondrial tRNALeu (UUR) gene. Conversely, this mutation has also been identified as one of the most prevalent genetic abnormalities in patients with diabetes mellitus. Mitochondrial diabetes mellitus complicated with MELAS is relatively common, and 12.5% of patients with the A3243G mutation develop MELAS after being diagnosed with diabetes mellitus. However, the clinical impact of diabetes mellitus in MELAS patients remains unclear. Therefore, we retrospectively studied 14 Japanese MELAS patients with the A3243G mutation: three men and eleven women, with the mean age of 48.0 (± 15.4) years. Eight patients had been diagnosed with diabetes mellitus prior to the diagnosis of mitochondrial disease, and all of them were treated with insulin. The other six included four patients with concurrent diagnosis of diabetes and mitochondrial disease, one patient diagnosed with diabetes after the diagnosis of mitochondrial disease, and one patient without developing diabetes currently. We thus compared the patients' characteristics between those with and without early onset of diabetes mellitus. Cognitive decline (75.0% vs. 0%; p = 0.03) and poor glycemic control with severe hypoglycemic events (75.0% vs. 16.7%; p = 0.05) were more common in MELAS patients with a prior diagnosis of diabetes than in those without the prior diagnosis of diabetes. Our data suggest that the latent progress of cognitive decline is accelerated because of early onset of diabetes mellitus in MELAS patients.

Successful Glycemic Control Decreases the Elevated Serum FGF21 Level without Affecting Normal Serum GDF15 Levels in a Patient with Mitochondrial Diabetes.

Mitochondrial diabetes mellitus is a subtype of diabetes linked to mutations in mitochondrial DNA. In patients with mitochondrial diabetes mellitus, the effect of glycemic control on the serum concentrations of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) has not been evaluated. FGF21 and GDF15 have been reported to be useful biomarkers for the diagnosis and severity assessment of mitochondrial diseases like mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Recent studies have shown FGF21 acts in an endocrine fashion to regulate glucose and lipid metabolism in type 2 diabetes mellitus, while the exact biological functions of GDF15 remain unknown. Although mitochondrial diabetes mellitus is commonly found in cases with mitochondrial diseases, the comparison of FGF21 and GDF15 levels between those with and without diabetes has not been performed. Here, we report a 24-year-old woman with mitochondrial diabetes mellitus, who showed a high level of serum FGF21, but not serum GDF15, at diagnosis. In our case, liraglutide, a glucagon-like peptide-1 receptor agonist, added to insulin glargine was effective for her glycemic control and showed no adverse effects, including gastrointestinal symptoms and hypoglycemia, during a 14-week observation. The successful glycemic control caused a decrease in the FGF21 level, without affecting the GDF15 level. Thus, we should consider patients' glycemic control levels in using FGF21 values for the diagnosis of mitochondrial diseases. In addition, sustained GDF15 levels during glycemic treatment in our case suggest the usefulness of GDF15 as a marker for clinical severity of muscle-manifested mitochondrial diseases.

Voxel-based Morphometry of Alzheimer's Disease Using a Localizer Image: A Comparative Study with Magnetization Prepared Rapid Acquisition with Gradient Echo.

PURPOSE: Magnetization prepared rapid acquisition with gradient echo (MPRAGE) sequence is a gold-standard technique for voxel-based morphometry (VBM) because of high spatial resolution and excellent tissue contrast, especially between gray matter (GM) and white matter (WM). Despite its benefits, MPRAGE exhibits distinct challenge for VBM in some patients with neurological disease because of long scan time and motion artifacts. Speedily acquired localizer images may alleviate this problem. This study aimed to evaluate the feasibility of VBM using 3D Fast Low Angle Shot image captured for localizer (L3DFLASH). METHODS: Consecutive 13 patients with pathologically confirmed Alzheimer's disease (AD) (82 ± 9 years) and 21 healthy controls (HC) (79 ± 4 years) were included in this study. Whole-brain L3DFLASH and MPRAGE were captured and preprocessed using the Computational Anatomy Toolbox 12 (CAT12). Agreement with MPRAGE was evaluated for L3DFLASH using regional normalized volume for segmented brain areas. In addition to brain volume difference on VBM and Bland-Altman analysis, atrophic pattern of AD on VBM was evaluated using L3DFLASH and MPRAGE. RESULTS: Acquisition time was 18 s for L3DFLASH and 288 s for MPRAGE. There was a slight systematic difference in all regional normalized volumes from L3DFLASH and MPRAGE. For the whole cohort, GM volume measured from MPRAGE was greater than that from L3DFLASH in most of the region on VBM. When AD and HC were compared, AD-related atrophic pattern was demonstrated in both L3DFLASH and MPRAGE on VBM, although the difference was noted in significant clusters between them. CONCLUSION: Although systematic difference was noted in regional brain volume measured from L3DFLASH and MPRAGE, AD-related atrophic pattern was preserved in L3DFLASH on VBM. VBM, using speedily acquired localizer image, may provide limited but useful information for evaluating brain atrophy.

Voxel-Based Morphometry of Progressive Supranuclear Palsy Using a 3D Fast Low-angle Shot Localizer Image: A Comparison with Magnetization-Prepared Rapid Gradient Echo.

PURPOSE: Voxel-based morphometry (VBM) is widely used to investigate white matter (WM) atrophy in patients with progressive supranuclear palsy (PSP). In contrast to high-resolution 3D T1-weighted imaging such as magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequences, the utility of other 3D sequences has not been sufficiently evaluated. This study aimed to assess the feasibility of using a 3D fast low-angle shot sequence captured as a localizer image (L3DFLASH) for VBM analysis of WM atrophy patterns in patients with PSP. METHODS: This retrospective study included 12 patients with pathologically or clinically confirmed PSP, and 18 age- and sex-matched healthy controls scanned with both L3DFLASH and MPRAGE sequences. Image processing was conducted with the Computational Anatomy Toolbox 12 in statistical parametric mapping 12. In addition to the atrophic WM pattern of PSP on VBM, we assessed the WM volume agreement between the two sequences using simple linear regression and Bland-Altman plots. RESULTS: Despite the slightly larger clusters on MPRAGE, VBM using both sequences showed similar characteristics of PSP-related WM atrophy, including in the midbrain, pons, thalamus, and precentral gyrus. In contrast, VBM showed gray matter (GM) atrophy of the precuneus and right superior parietal lobule exclusively on L3DFLASH. Unlike the measured values of total intracranial volume, GM, and cerebrospinal fluid on MPRAGE, the value of WM was larger on L3DFLASH. In contrast to the total intracranial volume, brainstem, and frontal and occipital lobes, the correlation with WM volume in other regions was relatively low. However, the Bland-Altman plots demonstrated strong agreement, with over 90% of the values falling within the agreement limits. CONCLUSION: Both MPRAGE and L3DFLASH are useful for detecting PSP-related WM atrophy using VBM.

The influence of limbic-predominant age-related TDP-43 encephalopathy on argyrophilic grain disease: A voxel-based morphometry analysis of pathologically confirmed cases.

BACKGROUND: The influence of limbic-predominant age-related TAR DNA-binding protein of 43 kDa encephalopathy neuropathological change (LATE-NC) on structural alterations in argyrophilic grain disease (AGD) have not been documented. This study aimed to investigate the morphological impact of LATE-NC on AGD through voxel-based morphometry (VBM) technique. MATERIALS AND METHODS: Fifteen individuals with pathologically verified AGD, comprising 6 with LATE-NC (comorbid AGD [cAGD]) and 9 without LATE-NC (pure AGD [pAGD]), along with 10 healthy controls (HC) were enrolled. Whole-brain 3D-T1-weighted images were captured and preprocessed utilizing the Computational Anatomy Toolbox 12. VBM was employed to compare gray matter volume among (i) pAGD and HC, (ii) cAGD and HC, and (iii) pAGD and cAGD. RESULTS: In comparison to HC, the pAGD group exhibited slightly asymmetric gray matter volume loss, particularly in the ambient gyrus, amygdala, hippocampus, anterior cingulate gyrus, and insula. Alternatively, the cAGD group exhibited greater gray matter volume loss, with a predominant focus on the inferolateral regions encompassing the ambient gyrus, amygdala, hippocampus, and the inferior temporal area, including the anterior temporal pole. The atrophy of the bilateral anterior temporal pole and right inferior temporal gyrus persisted when contrasting the pAGD and cAGD groups. CONCLUSION: Comorbidity with LATE-NC is linked to different atrophic distribution, particularly affecting the inferolateral regions in AGD. Consequently, the consideration of comorbid LATE-NC is crucial in individuals with AGD exhibiting more widespread temporal atrophy.

Voxel-Based and Surface-Based Morphometry Analysis in Patients with Pathologically Confirmed Argyrophilic Grain Disease and Alzheimer's Disease.

BACKGROUND: Due to clinicoradiological similarities, including amnestic cognitive impairment and limbic atrophy, differentiation of argyrophilic grain disease (AGD) from Alzheimer's disease (AD) is often challenging. Minimally invasive biomarkers, especially magnetic resonance imaging (MRI), are valuable in routine clinical practice. Although it is necessary to explore radiological clues, morphometry analyses using new automated analytical methods, including whole-brain voxel-based morphometry (VBM) and surface-based morphometry (SBM), have not been sufficiently investigated in patients with pathologically confirmed AGD and AD. OBJECTIVE: This study aimed to determine the volumetric differences in VBM and SBM analyses between patients with pathologically confirmed AGD and AD. METHODS: Eight patients with pathologically confirmed AGD with a lower Braak neurofibrillary tangle stage (

Asymmetric Cerebral Peduncle Atrophy: A Simple Diagnostic Clue for Distinguishing Frontotemporal Lobar Degeneration from Alzheimer's Disease.

BACKGROUND: Due to confusing clinicoradiological features such as amnestic symptoms and hippocampal atrophy in frontotemporal lobar degeneration (FTLD), antemortem differentiation between FTLD and Alzheimer's disease (AD) can be challenging. Although asymmetric atrophy of the cerebral peduncle is regarded as a representative imaging finding in some disorders of the FTLD spectrum, the utility of this finding has not been sufficiently evaluated for differentiating between FTLD and AD. OBJECTIVE: This study aimed to explore the diagnostic performance of asymmetric cerebral peduncle atrophy on axial magnetic resonance imaging as a simple radiological discriminator between FTLD and AD. METHODS: Seventeen patients with pathologically confirmed FTLD, including six with progressive supranuclear palsy, three with corticobasal degeneration, eight with TAR DNA-binding protein 43 (FTLD-TDP), and 11 with pathologically confirmed AD, were investigated. Quantitative indices representing the difference between the volumes of the bilateral cerebral peduncles (i.e., cerebral peduncular asymmetry index [CPAI]), the voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) Z-score representing the degree of hippocampal atrophy, and semiquantitative visual analysis to evaluate the asymmetry of the cerebral peduncle (visual assessment of cerebral peduncular asymmetry: VACPA) were compared between the two groups. RESULTS: Contrary to the VSRAD Z-score, the CPAI and VACPA scores demonstrated higher diagnostic performance in differentiating patients with FTLD from those with AD (areas under the receiver operating characteristic curve of 0.88, 082, and 0.60, respectively). CONCLUSIONS: Quantitative and visual analytical techniques can differentiate between FTLD and AD. These simple methods may be useful in daily clinical practice.

UBL3 Interaction with α-Synuclein Is Downregulated by Silencing MGST3.

Ubiquitin-like 3 (UBL3) is a membrane-anchored protein that plays a crucial role in sorting proteins into small extracellular vesicles. Aggregations of alpha-synuclein (α-syn) are associated with the pathology of neurodegenerative diseases such as Parkinson's disease. Recently, the interaction between UBL3 and α-syn was discovered, with potential implications in clearing excess α-syn from neurons and its role in disease spread. However, the regulator that can mediate the interaction between UBL3 and α-syn remains unclear. In this study, using the split gaussian luciferase complementation assay and RNA interference technology, we identified that QSOX2, HTATIP2, UBE3C, MGST3, NSF, HECTD1, SAE1, and ATG3 were involved in downregulating the interaction between UBL3 and α-syn. Notably, silencing MGST3 had the most significant impact. Immunocytochemistry staining confirmed the impact of MGST3 silencing on the co-localization of UBL3 and α-syn in cells. MGST3 is a part of the antioxidant system, and silencing MGST3 is believed to contribute to oxidative stress. We induced oxidative stress with hydrogen peroxide, observing its effect on the UBL3-α-syn interaction, and showing that 800 µM of H2O2 downregulated this interaction. In conclusion, silencing MGST3 downregulates the interaction between UBL3 and α-syn.

UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib.

Ubiquitin-like 3 (UBL3) acts as a post-translational modification (PTM) factor and regulates protein sorting into small extracellular vesicles (sEVs). sEVs have been reported as vectors for the pathology propagation of neurodegenerative diseases, such as α-synucleinopathies. Alpha-synuclein (α-syn) has been widely studied for its involvement in α-synucleinopathies. However, it is still unknown whether UBL3 interacts with α-syn, and is influenced by drugs or compounds. In this study, we investigated the interaction between UBL3 and α-syn, and any ensuing possible functional and pathological implications. We found that UBL3 can interact with α-syn by the Gaussia princeps based split luciferase complementation assay in cells and immunoprecipitation, while cysteine residues at its C-terminal, which are considered important as PTM factors for UBL3, were not essential for the interaction. The interaction was upregulated by 1-methyl-4-phenylpyridinium exposure. In drug screen results, the interaction was significantly downregulated by the treatment of osimertinib. These results suggest that UBL3 interacts with α-syn in cells and is significantly downregulated by epidermal growth factor receptor (EGFR) pathway inhibitor osimertinib. Therefore, the UBL3 pathway may be a new therapeutic target for α-synucleinopathies in the future.

Binucleated neurons in the pontine nuclei in neuro-Behcet's disease: a study of 3 autopsy cases.

Neuropathological findings of three autopsy cases of neuro-Behçet's disease are presented with special reference to the frequent occurrence of binucleated neurons in the pontine nuclei. All 3 patients were men and died after a protracted clinical course characterized by various brain stem symptoms. Autopsies revealed chronic non-specific brain stem encephalitis, which is a typical neuropathological feature of neuro-Behçet's disease. In all cases, many binucleated neurons (19, 20, and 55 neurons in each case) were found in the pontine nuclei. For comparison, the occurrence of binucleated neurons in the pontine nuclei was examined in 67 control cases including various neurological disorders. In 55 cases (82.1%) among them, no binucleated neurons were detected. In the remaining 12 cases (17.9%), the pontine nuclei contained 1 or 2 binucleated neurons. These observations confirmed that the occurrence of many binucleated neurons in the pontine nuclei was a characteristic finding in neuro- Behçet's disease. Although the pathogenetic mechanism for the formation of binucleated neurons is unknown, it is most likely the result of abortive cell division of neurons or fusion of the perikarya of the adjacent neurons. It probably reflects the presence of intense local noxious stimuli affecting neurons in the pontine nuclei.

Clinicoradiological Features in Progressive Supranuclear Palsy Comorbid with Argyrophilic Grains.

Background: Contrary to pure cases, the influence of comorbid argyrophilic grain disease (AGD) in progressive supranuclear palsy (PSP) has not been sufficiently evaluated. Objectives: We compared the clinicoradiological features of 12 patients with PSP with (PSPw/AG) and 8 patients without AGD (PSPw/oAG). Methods: Medical records and magnetic resonance imaging were checked retrospectively from a single brain bank database. Results: Other than AGD, no differences were observed in any other neurodegenerative pathologies between the 2 groups. Ages at onset and deaths of patients with PSPw/AG were higher than those of patients with PSPw/oAG (77.9 ± 4.9 vs. 68.9 ± 5.9, and 87.0 ± 5.7 vs. 78.1 ± 5.0; P = 0.003 and P = 0.002, respectively). In addition to the later onset of motor symptoms, initial amnestic presentations were limited to 5 patients with PSPw/AG. Both characteristic midbrain atrophy and severe ambient gyrus atrophy were detected exclusively in 8 patients with PSPw/AG. Conclusions: Initial amnestic presentations and ambient gyrus atrophy may be characteristic of PSPw/AG.

Diverse limbic comorbidities cause limbic and temporal atrophy in lewy body disease.

BACKGROUND: In contrast to Alzheimer's disease (AD)-related pathology, the influence of comorbid limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) or argyrophilic grains (AG) on structural imaging in Lewy body disease (LBD) has seldom been evaluated. OBJECTIVE: This study aimed to investigate whether non-AD limbic comorbidities, including LATE-NC and AG, cause cortical atrophy in LBD. METHODS: Seventeen patients with pathologically confirmed LBD with lower Braak neurofibrillary tangle stage (

Voxel-based specific regional analysis system for Alzheimer's disease utility as a screening tool for unrecognized cognitive dysfunction of elderly patients in diabetes outpatient clinics: Multicenter retrospective exploratory study.

AIMS/INTRODUCTION: An efficient screening strategy for identification of cognitive dysfunction remains a clinical issue in the management of elderly adults with diabetes. A magnetic resonance imaging voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) has been developed as an automated brain morphometry system that includes the hippocampus. We carried out a multicenter retrospective study to evaluate the utility of VSRAD for screening cognitive dysfunction in diabetes outpatient clinics. MATERIALS AND METHODS: We enrolled patients with diabetes aged >65 years who underwent brain magnetic resonance imaging scans for the purpose of a medical checkup between November 2018 and May 2019. Patients who were already suspected or diagnosed with mild cognitive impairment and/or dementia as well as those with a history of cerebrovascular disease were excluded. RESULTS: A total of 67 patients were enrolled. Five patients were diagnosed with mild cognitive impairment or dementia (clinical cognitive dysfunction). Patients with clinical cognitive dysfunction showed a significantly higher z-score in VSRAD analysis (2.57 ± 0.47 vs 1.15 ± 0.55, P < 0.01). The sensitivities and specificities for diagnosis of clinical cognitive dysfunction were 80 and 48% for the Mini-Mental State Examination, 100 and 89% for the z-score, and 100 and 90% for the combination of the Mini-Mental State Examination score and z-score, respectively. CONCLUSIONS: VSRAD analysis can distinguish patients with clinical cognitive dysfunction in the elderly with diabetes, and also shows reasonable sensitivity and specificity compared with the Mini-Mental State Examination alone. Thus, VSRAD analysis can be useful for early identification of clinical cognitive dysfunction in the elderly with diabetes.

[A case of Staphylococcus aureus meningitis-associated quadriparesis with its successful treatment with adrenocorticosteroid].

A 44-year-old woman was admitted to our hospital because of meningitis, with symptoms of an altered mental state and flaccid quadriparesis. Neurological examination revealed nuchal rigidity, flaccid quadriparesis without tendon reflexes, septic rash and urinary retention. Nerve conduction studies showed diminished F-wave ratios. However, the amplitudes and conduction velocities for bilateral motor and sensory nerves of the upper (medial and ulnar nerves) and lower (posterior tibial and sural nerves) limbs were all normal. Spinal MRI showed gadolinium enhancement of the bilateral sacral nerve roots, indicating radiculitis. In addition, T2*-weighed MRI of the brain revealed multiple microbleeds. Infectious endocarditis was detected on admission, and Staphylococcus aureus infection was confirmed by blood culturing. The patient was diagnosed with meningoradiculitis caused by S. aureus. Although antibiotic therapy did not improve quadriparesis, administration of dexamethasone led to a marked amelioration of the quadriparesis with a resultant complete recovery of the limb muscle powers in three months. Furthermore, as the quadriparesis improved, F-wave ratios gradually returned to normal and hearing loss remained as the only sequela. Therefore, adrenocorticosteroid therapy attenuated radiculitis-induced quadriparesis. Although radiculitis due to S. aureus is extremely rare, it should be considered because delayed treatment can lead to permanent injury and impairment.

[A case of non-atherothrombotic cerebroretinal small vessel disease].

BACKGROUND: There is an increasing interest in the relation between retinal artery abnormalities and cerebral small-vessel diseases (SVD), because retinal vessels share common properties with cerebral small vessels. We report a case of juvenile cerebrovascular disease presenting retinal vessel abnormalities, which clinically resembled cerebral autosomal dominant arteriopathy with stroke and ischemic leukoencephalopathy (CADASIL) but in which Notch3 gene mutations were not detected. CASE: A 42-year old woman was hospitalized at the department of Neurology in our hospital, complaining of headache and dysarthria. MRI showed bilateral spotted white matter lesions in the paraventricular area and the temporal lobe, and an ovoid lesion in the right corona radiata. Despite steroid pulse therapy, she developed right incomplete hemiparesis and new lesions were detected in the anterior temporal pole and external capsule. Her genetic analysis showed no mutations in the Notch 3 gene. Ophthalmological examination revealed arterial sheathing in the peripapillary region. Fluorescein angiography showed narrowing of the retinal arterioles and distinguished a peripheral vascular network. CONCLUSION: In this case, ophthalmological examination revealed retinal vessel abnormalities in a relatively young woman with no risk factors such as hypertention or artheriosclerosis, presenting recurrent subcortical strokes. This actual case indicates the association between retinal vessel abnormalities and cerebral SVDs.

Nasal Extracts from Patients with Alzheimer's Disease Induce Tau Aggregates in a Cellular Model of Tau Propagation.

BACKGROUND: Emerging evidence indicates that the misfolded tau protein can propagate aggregates between cells in a prion-like manner. This prion activity has been typically studied in brain extracts of patients with Alzheimer's disease (AD), but not in the olfactory region that can be a potential biomarker in AD. OBJECTIVE: To investigate the prion seeding activity of tau in nasal mucosa tissues using a cell culture model of tau propagation. METHODS: Brain and nasal mucosa homogenates were added to HEK293T cells expressing three repeat or four-repeat domains of tau with the L266V, V337M (3RD*VM) and P301L and V377M mutations (4RD*LM) fused to the enhanced green fluorescence protein (EGFP) respectively. We also measured the level of phosphorylated tau (p-tau), total tau (t-tau), and p-tau/t-tau ratio and performed correlation analysis between tau prion activity and the level of tau. RESULTS: We found that brain and nasal tissue homogenates from patients with AD significantly induced tau aggregation in HEK293T cells either expressing tau 3RD*VM-EGFP or 4RD*LM-EGFP compared with control brain and nasal tissue homogenates. The levels of p-tau and p-tau/t-tau ratio were significantly increased in the brain of patients with AD; however, no significant difference was found in nasal tissue compared with their respective control tissue homogenates. CONCLUSION: These results suggest that the nasal tissues contain tau seeds, similar to the brain, albeit without changes in the levels of p-tau and t-tau. Therefore, a cellular bioassay using nasal tissues would have great potential as an AD biomarker because of the usefulness of nasal tissue biopsy.