The clinical application of optimized AT(N) classification in Alzheimer's clinical syndrome (ACS) and non-ACS conditions.

We aimed to assess the utility of AT(N) classification in clinical practice. We measured the cerebrospinal fluid levels of amyloid-ß (Aß) 42, Aß40, phosphorylated tau, total tau, and neurofilament light chain (NfL) in samples from 230 patients with Alzheimer's clinical syndrome (ACS) and 328 patients with non-ACS. The concordance of two A-markers (i.e., Aß42 alone and the Aß42/Aß40 ratio) was not significantly different between the ACS (87.4%) and non-ACS (74.1%) groups. However, the frequency of discordant cases with AAß42-alone+/AAß-ratio- was significantly higher in the non-ACS (23.8%) than in the ACS group (7.4%). The concordance of two N-markers (i.e., total tau and NfL) was 40.4% in the ACS group and 24.4% in the non-ACS group. In the ACS samples, the frequency of biological Alzheimer's disease (i.e., A+T+) in Ntau+ cases was 95% while that in NNfL+ cases was 65%. Reflecting Aß deposition and neurodegeneration more accurately, we recommend the use of AT(N) classification defined by cerebrospinal fluid AAß-ratioTNNfL in clinical practice.

Development of a Novel Nutrition-Related Multivariate Biomarker for Mild Cognitive Impairment Based on the Plasma Free Amino Acid Profile.

Nutritional epidemiology has shown the importance of protein intake for maintaining brain function in the elderly population. Mild cognitive impairment (MCI) may be associated with malnutrition, especially protein intake. We explored blood-based biomarkers linking protein nutritional status with MCI in a multicenter study. In total, 219 individuals with MCI (79.5 ± 5.7 year) from 10 institutions and 220 individuals who were cognitively normal (CN, 76.3 ± 6.6 year) in four different cities in Japan were recruited. They were divided into the training (120 MCI and 120 CN) and validation (99 MCI and 100 CN) groups. A model involving concentrations of PFAAs and albumin to discriminate MCI from CN individuals was constructed by multivariate logistic regression analysis in the training dataset, and the performance was evaluated in the validation dataset. The concentrations of some essential amino acids and albumin were significantly lower in MCI group than CN group. An index incorporating albumin and PFAA discriminated MCI from CN participants with the AUC of 0.705 (95% CI: 0.632-0.778), and the sensitivities at specificities of 90% and 60% were 25.3% and 76.8%, respectively. No significant association with BMI or APOE status was observed. This cross-sectional study suggests that the biomarker changes in MCI group may be associated with protein nutrition.

Decreased circulating branched-chain amino acids are associated with development of Alzheimer's disease in elderly individuals with mild cognitive impairment.

Background: Nutritional epidemiology has shown that inadequate dietary protein intake is associated with poor brain function in the elderly population. The plasma free amino acid (PFAA) profile reflects nutritional status and may have the potential to predict future changes in cognitive function. Here, we report the results of a 2-year interim analysis of a 3-year longitudinal study following mild cognitive impairment (MCI) participants. Method: In a multicenter prospective cohort design, MCI participants were recruited, and fasting plasma samples were collected. Based on clinical assessment of cognitive function up to 2 years after blood collection, MCI participants were divided into two groups: remained with MCI or reverted to cognitively normal ("MCI-stable," N = 87) and converted to Alzheimer's disease (AD) ("AD-convert," N = 68). The baseline PFAA profile was compared between the two groups. Stratified analysis based on apolipoprotein E ε4 (APOE ε4) allele possession was also conducted. Results: Plasma concentrations of all nine essential amino acids (EAAs) were lower in the AD-convert group. Among EAAs, three branched-chain amino acids (BCAAs), valine, leucine and isoleucine, and histidine (His) exhibited significant differences even in the logistic regression model adjusted for potential confounding factors such as age, sex, body mass index (BMI), and APOE ε4 possession (p < 0.05). In the stratified analysis, differences in plasma concentrations of these four EAAs were more pronounced in the APOE ε4-negative group. Conclusion: The PFAA profile, especially decreases in BCAAs and His, is associated with development of AD in MCI participants, and the difference was larger in the APOE ε4-negative population, suggesting that the PFAA profile is an independent risk indicator for AD development. Measuring the PFAA profile may have importance in assessing the risk of AD conversion in the MCI population, possibly reflecting nutritional status. Clinical trial registration: [https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000025322], identifier [UMIN000021965].

A case of slowly progressive anti-Yo-associated paraneoplastic cerebellar degeneration successfully treated with antitumor and immunotherapy.

We report a case of slowly progressive anti-Yo-associated paraneoplastic cerebellar degeneration (PCD) with breast cancer in a 54-year-old woman. The symptoms of limb and truncal ataxia, and dysarthria gradually progressed during the course of 1 year, and the modified Rankin scale (mRS) score was 2. A mastectomy with sentinel lymph node resection was performed for the breast cancer. No malignant cells were found on histopathological examination of the lymph node. Combination chemotherapy with adriamycin and cyclophosphamide (AC) prevented neurologic deterioration. However, subsequent treatment with trastuzumab and paclitaxel did not prevent progression of the symptoms (mRS score 3). Brain magnetic resonance imaging showed atrophy of the cerebellar hemispheres without brain stem atrophy. Anti-Yo antibody was detected in the serum, which led to a diagnosis of anti-Yo-associated PCD. We resected an enlarged axillary lymph node, which was found on computed tomography. The histopathological analysis of the lymph node revealed foreign body granuloma, which suggested an association with necrotic malignant tissue. Following additional tegafur-uracil therapy and two courses of intravenous immunoglobulin (IVIg), the cerebellar signs and symptoms gradually improved (mRS score 2). The clinical course shows that PCD can present as a slowly progressive cerebellar symptom. We propose an active treatment for anti-Yo-associated PCD consisting of tumor resection, combined chemotherapy, and IVIg.

A Fulminant Case of Granulomatosis with Polyangiitis with Meningeal and Parenchymal Involvement.

Central nervous system (CNS) involvement, such as pachymeningitis and/or cerebrovascular events, is rare in patients with granulomatosis with polyangiitis (GPA). Furthermore, the details of pathological examinations of cases have rarely been described. We describe a case of GPA that manifested as an isolated paranasal sinus disease that invaded the subarachnoid space and caused a hemorrhagic venous infarction. We also describe the pathological characteristics of the biopsied brain material from the successful decompressive craniectomy. In particular, granulomatous inflammation with geographic necrosis and multinucleated giant cells were observed in the perivascular area of the thickened dura mater and leptomeninges. Small vessels in the meninges were involved in the granulomatous lesions, and the lumens of the veins were often occluded. In the cerebral cortices and white matter in these areas, hemorrhagic infarction was widely observed. We suggest that our findings represent a novel mechanism of CNS involvement in GPA. Moreover, we believe that the emergency decompressive craniectomy and partial lobectomy for the cerebral infarction in this patient with GPA likely contributed to his survival.

ApoE-isoform-dependent cellular uptake of amyloid-ß is mediated by lipoprotein receptor LR11/SorLA.

The formation of senile plaques composed of ß-amyloid (Aß) in the brain is likely the initial event in Alzheimer's disease (AD). Possession of the APOE ε4 allele, the strong genetic factor for AD, facilitates the Aß deposition from the presymptomatic stage of AD in a gene-dosage-dependent manner. However, the precise mechanism by which apoE isoforms differentially induce the AD pathology is largely unknown. LR11/SorLA is a type I membrane protein that functions as the neuronal lipoprotein endocytic receptor of apoE and the sorting receptor of the amyloid precursor protein (APP) to regulate amyloidogenesis. Recently, LR11/SorLA has been reported to be involved in the lysosomal targeting of extracellular amyloid-ß (Aß) through the binding of Aß to the vacuolar protein sorting 10 (VPS10) protein domain of LR11/SorLA. Here, we attempted to examine the human-apoE-isoform-dependent effect on the cellular uptake of Aß through the formation of a complex between an apoE isoform and LR11/SorLA. Cell culture experiments using Neuro2a cells revealed that the cellular uptake of secreted apoE3 and apoE4 was enhanced by the overexpression of LR11/SorLA. In contrast, the cellular uptake of apoE2 was not affected by the expression of LR11/SorLA. Co-immunoprecipitation assay revealed that apoE-isoform-dependent differences were observed in the formation of an apoE-LR11 complex (apoE4>apoE3>apoE2). ApoE-isoform-dependent differences in cellular uptake of FAM-labeled Aß were further investigated by coculture assay in which donor cells secrete one of the apoE isoforms and recipient cells express FL-LR11. The cellular uptake of extracellular Aß into the recipient cells was most prominently accentuated when cocultured with the donor cells secreting apoE4 in the medium, followed by apoE3 and apoE2. Taken together, our results provide evidence for the mechanism whereby human-apoE-isoform-dependent differences modulate the cellular uptake of Aß mediated by LR11/SorLA.

Hyperphosphorylation of Tau induced by naturally secreted amyloid-ß at nanomolar concentrations is modulated by insulin-dependent Akt-GSK3ß signaling pathway.

Alzheimer disease (AD) is neuropathologically characterized by the formation of senile plaques from amyloid-ß (Aß) and neurofibrillary tangles composed of phosphorylated Tau. Although there is growing evidence for the pathogenic role of soluble Aß species in AD, the major question of how Aß induces hyperphosphorylation of Tau remains unanswered. To address this question, we here developed a novel cell coculture system to assess the effect of extracellular Aß at physiologically relevant levels naturally secreted from donor cells on the phosphorylation of Tau in recipient cells. Using this assay, we demonstrated that physiologically relevant levels of secreted Aß are sufficient to cause hyperphosphorylation of Tau in recipient N2a cells expressing human Tau and in primary culture neurons. This hyperphosphorylation of Tau is inhibited by blocking Aß production in donor cells. The expression of familial AD-linked PSEN1 mutants and APP ΔE693 mutant that induce the production of oligomeric Aß in donor cells results in a similar hyperphosphorylation of Tau in recipient cells. The mechanism underlying the Aß-induced Tau hyperphosphorylation is mediated by the impaired insulin signal transduction because we demonstrated that the phosphorylation of Akt and GSK3ß upon insulin stimulation is less activated under this condition. Treating cells with the insulin-sensitizing drug rosiglitazone, a peroxisome proliferator-activated receptor γ agonist, attenuates the Aß-dependent hyperphosphorylation of Tau. These findings suggest that the disturbed insulin signaling cascade may be implicated in the pathways through which soluble Aß induces Tau phosphorylation and further support the notion that correcting insulin signal dysregulation in AD may offer a potential therapeutic approach.

A patient with fragile x-associated tremor/ataxia syndrome presenting with executive cognitive deficits and cerebral white matter lesions.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that primarily affects males who are carriers of a premutation of a CGG expansion in the FMR1 gene. In Asian populations, FXTAS has rarely been reported. Here, we report the case of a Japanese FXTAS patient who showed predominant executive cognitive deficits as the main feature of his disease. In contrast, the patient exhibited only very mild symptoms of intention tremor and ataxia, which did not interfere with daily activities. A gene analysis revealed that the patient carried a premutation of a CGG expansion (111 CGG repeats) in the FMR1 gene. The mRNA expression level of FMR1 in the patient was 1.5-fold higher than in controls. On brain MRI scans, fluid-attenuated inversion recovery images showed high-intensity lesions in the middle cerebellar peduncles and the cerebral white matter, with a frontal predominance. The present case extends previous notions regarding the cognitive impairment in FXTAS patients. Recognizing FXTAS patients with predominant cognitive impairment from various ethnic backgrounds would contribute to our understanding of the phenotypic variation of this disease.

Evidence for a Common Founder and Clinical Characteristics of Japanese Families with the MAPT R406W Mutation.

BACKGROUND/AIM: Mutations in MAPT cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Patients with the MAPT R406W mutation were reported to show phenotypic heterogeneity in different ethnic backgrounds. We here report the clinical and genetic characteristics of Japanese families with the R406W mutation. METHODS: We examined the clinical and neuroimaging features of 6 patients from three families with the R406W mutation. We determined the genotypes of intragenic MAPT single-nucleotide polymorphisms (SNPs) and the flanking microsatellite markers to search for a common founder. RESULTS: The initial symptom was memory loss with the average age at onset being 54 years. Anterograde amnesia with episodic memory impairment was the predominant phenotype. Behavioral and personality changes or parkinsonism is not a prominent feature. A brain MRI study revealed marked atrophy of the medial temporal lobe. Genetic analysis of SNPs and microsatellite markers revealed that the affected members of the three families share common genotypes. CONCLUSION: The findings of the affected members in this study, which corroborate previously reported findings of European families, suggest that the R406W mutation may represent a phenotype of predominant anterograde amnesia in FTLD-17. Our genetic data suggest that a founder effect may account for some families with the R406W mutation.

Reduced bowel sounds in Parkinson's disease and multiple system atrophy patients.

Digital auscultation of bowel sounds was performed in newly diagnosed, drug-naïve patients with Parkinson's disease (PD) (n = 10), multiple system atrophy (MSA) (n = 12), progressive supranuclear palsy/corticobasal degeneration (PSP/CBD) (n = 7), and control subjects (n = 18). The number of bowel sounds per minute and the integrated time of bowel sounds were significantly lower in PD and MSA patients than in control subjects. Reduced bowel sounds may herald compromised gastrointestinal motility in patients with PD and MSA.

[A case of amyotrophic lateral sclerosis/frontotemporal lobar degeneration with apraxia of eyelid opening].

We report the case of a 76-year-old man with apraxia of eyelid opening (AEO) and amyotrophic lateral sclerosis with dementia (ALS-D)/frontotemporal lobar degeneration with motor neuron disease (FTLD-MND). The initial symptom was AEO. Neurological examination revealed mainly bulbar symptoms with a neurogenic pattern on needle electromyograms of the tongue muscles and the biceps muscles. Furthermore, he developed severe dementia with frontal lobe dysfunction and progressive non-fluent aphasia. Brain magnetic resonance imaging revealed severe cerebral atrophy and leukoaraiosis in the bilateral frontal lobes and the anterior part of the bilateral temporal lobes; brain 99mTc ethyl cysteinate dimer single photon emission computed tomography (ECD SPECT) showed hypoperfusion in the same areas. The patient showed improvement in stereotyped behavior and AEO after treatment with 50 mg/day of fluvoxamine maleate (the initial dose was 25 mg/day). Because serotonin receptors are markedly reduced in the frontal and temporal cortexes of patients with FTLD, we considered that dysfunction of the serotonergic system in the frontotemporal lobe caused AEO. Considering the findings of this case along with those of previous reports, we propose that there is a relatively homogeneous development of ALS-D/FTLD-MND with AEO.