Longitudinal Changes of Tongue Thickness and Tongue Pressure in Neuromuscular Disorders.

BACKGROUND: Swallowing dysfunction is related to major cause of adverse events and an indicator of shorter survival among patients with neuromuscular disorders (NMD). It is critical to assess the swallowing function during disease progression, however, there are limited tools that can easily evaluate swallowing function without using videofluoroscopic or videoendoscopic examination. Here, we evaluated the longitudinal changes in tongue thickness (TT) and maximum tongue pressure (MTP) among patients with amyotrophic lateral sclerosis (ALS), myotonic dystrophy type 1 (DM1), and Duchenne muscular dystrophy (DMD). METHODS: Between 2010 and 2020, TT and MTP were measured from 21 ALS, 30 DM1, and 14 DMD patients (mean ages of 66.9, 44.5, and 21.4 years, respectively) at intervals of more than half a year. TT was measured, by ultrasonography, as the distance from the mylohyoid muscle raphe to the tongue dorsum, and MTP was determined by measuring the maximum compression on a small balloon when pressing the tongue against the palate. Then we examined the relationship between these evaluations and patient background and swallowing function. RESULTS: Mean follow-up periods were 24.0 months in the ALS group, 47.2 months in the DM1group, and 61.1 months in the DMD group. The DMD group demonstrated larger first TT than the other groups, while the DM1 group had lower first MTP than the ALS group. The ALS group showed a greater average monthly reduction in mean TT than the DM1 group and greater monthly reductions in mean body weight (BW) and MTP than the other groups. Significant differences between the first and last BW, TT, and MTP measures were found only in the ALS group. CONCLUSIONS: This study suggests that ALS is associated with more rapid degeneration of tongue function over several years compared to DMD and DM1.

Symmetrical glial hyperplasia in the brainstem of fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disease, characterized by the progressive ossification of skeletal muscles, fascia, tendons, and ligaments. In most cases, the great toes of patients show symmetrical congenital malformations. The causative gene for FOP has been identified as the activin A receptor, type 1 (ACVR1) gene (ACVR1). The ACVR1 R206H mutation is the most common mutation among FOP patients, and the ACVR1 G356D mutation has been identified as a rare mutation in a Japanese FOP patient with slow progression. In addition to musculoskeletal abnormalities, a series of autopsy studies described one FOP case, without genetic testing to identify ACVR1 mutation, showing nodular heterotopia at the edge of the fourth ventricle. Here, we report the general autopsy findings for a 75-year-old man with FOP, caused by the ACVR1 G356D mutation, including the precise examination of brainstem lesions. Postmortem examination revealed unique symmetrical glial hyperplasia of the pons and medulla oblongata. Microscopically, lesions of the pons involving residual neurons and lesions of the medulla oblongata consisted of subependymal cells. Immunohistochemical analysis of these lesions revealed developmental anomalies, with different cellular components. In this report, for the first time, we present the neuropathological description of a patient with genetically confirmed FOP and symmetrical glial hyperplasia of the pons and medulla oblongata. The presented pathological findings, in conjunction with previous reports implying that the glial hyperplasia of the brainstem is common in FOP, suggest that ACVR1 may play an unclarified developmental role in the human brainstem.

Relationship between tongue pressure and functional oral intake scale diet type in patients with neurological and neuromuscular disorders.

INTRODUCTION: Patients with neurological and neuromuscular disorders (NNMD) frequently experience swallowing disorders that increase aspiration pneumonia risk and therefore require specialized diets or tube feeding. Diet type level usually is assessed by video fluoroscopic swallowing study (VFSS). To identify a simpler assessment method, we examined the association between diet type (based on the Functional Oral Intake Scale [FOIS]) diet type and maximum tongue pressure (MTP). METHODS: From 2011-2020, FOIS diet type level and MTP were assessed in a sample of 927 patients. Of these patients, 186 had Parkinson's disease (PD), 69 had Parkinson-related disease (PRD), 61 had multiple system atrophy (MSA), 42 had spinocerebellar degeneration (SCD), 147 had amyotrophic lateral sclerosis (ALS), 180 had myotonic dystrophy type 1 (DM1), and 242 had Duchenne muscular dystrophy (DMD). VFSS was conducted while patients swallowed water and foods containing barium. MTP measurements were collected the same day. Participants' diet type level was adjusted based on the VFSS, with some participants requiring multiple examinations. Relationships between diet type level and MTP were tested using univariate and Spearman rank correlation analyses. RESULTS: Mean MTP for the entire NNMD group (25.5 ± 13.1 kPa) was lower than that of healthy elderly individuals, as determined in previous reports. The highest MTP was found in the MSA group (32.2 ± 15.7 kPa) and the lowest in the DM1 group (19.1 ± 9.0 kPa). Diet type level was highest in the MSA group (5.8 ± 1.4) and lowest in the DMD group (5.2 ± 1.7). A significant correlation was observed between diet type level and MTP (R = 0.384, p < 0.001). The optimum MTP cutoff values-detected using ROC curves to predict a requirement to change to a dysphagia diet-was highest in the DMD group (29.0 kPa) and lowest in the ALS group (12.3 kPa). CONCLUSIONS: The decision to change NNMD patients to a dysphagia diet can be made based on MTP. Modifying a patient's oral diet (FOIS level ≤ 5) should be considered for those with a MTP of 10-25 kPa, with the cutoff value varying by disease.

Clinical and pathologic features of cognitive-predominant corticobasal degeneration.

OBJECTIVE: To describe clinical and pathologic characteristics of corticobasal degeneration (CBD) with cognitive predominant problems during the disease course. METHODS: In a series of autopsy-confirmed cases of CBD, we identified patients with cognitive rather than motor predominant features (CBD-Cog), including 5 patients thought to have Alzheimer disease (AD) and 10 patients thought to have behavioral variant frontotemporal dementia (FTD). We compared clinical and pathologic features of CBD-Cog with those from a series of 31 patients with corticobasal syndrome (CBD-CBS). For pathologic comparisons between CBD-Cog and CBD-CBS, we used semiquantitative scoring of neuronal and glial lesion types in multiple brain regions and quantitative assessments of tau burden from image analysis. RESULTS: Five of 15 patients with CBD-Cog never had significant motor problems during their disease course. The most common cognitive abnormalities in CBD-Cog were executive and visuospatial dysfunction. The frequency of language problems did not differ between CBD-Cog and CBD-CBS. Argyrophilic grain disease, which is a medial temporal tauopathy associated with mild cognitive impairment, was more frequent in CBD-Cog. Apathy was also more frequent in CBD-Cog. Tau pathology in CBD-Cog was greater in the temporal and less in perirolandic cortices than in CBD-CBS. CONCLUSION: A subset of patients with CBD has a cognitive predominant syndrome than can be mistaken for AD or FTD. Our findings suggest that distribution of tau cortical pathology (greater in temporal and less in perirolandic cortices) may be the basis of this uncommon clinical variant of CBD.

The effects of chronic subthalamic stimulation on nonmotor symptoms in advanced Parkinson's disease, revealed by an online questionnaire program.

BACKGROUND: This study was designed to detect and assess the frequency and severity of nonmotor symptoms (NMSs) in advanced Parkinson's disease (PD) and to investigate the effects of subthalamic nucleus deep brain stimulation (STN-DBS) on NMSs. METHODS: We developed an online PC-based questionnaire program to assess NMSs in PD. Twenty-six PD patients who underwent bilateral STN-DBS were assessed. The NMS questionnaire consisted of 54 NMSs in three categories, based on Witjas et al. (2002). For each NMS, the patients were asked whether or not it was present, whether or not the fluctuating manifestations correlated with the timing of levodopa-induced motor fluctuations, and how severe the NMS was. Patients were assessed by this system before surgery and at the follow-up visit, 3 to 6 months after surgery. At the postoperative assessment, patients were also assessed on preoperative NMSs using recall. RESULTS: The most frequent preoperative NMSs were constipation and visual disorders, while the most frequent postoperative NMSs were difficulty in memorizing and pollakiuria. The ranking of most frequent NMSs changed from before to after surgery. NMSs of drenching sweats, dysphagia, and constipation were significantly ameliorated, while NMSs of dyspnea and slowness of thinking were significantly deteriorated after surgery. The preoperative assessment by postoperative recall gave very different results from that of the preoperative assessment. CONCLUSION: An online questionnaire system to assess NMSs in patients with advanced PD suggested that STN-DBS might influence the frequencies of some kinds of NMSs.

Clinicopathologic subtype of Alzheimer's disease presenting as corticobasal syndrome.

INTRODUCTION: The corticobasal syndrome (CBS) is associated with several neuropathologic disorders, including corticobasal degeneration and Alzheimer's disease (AD). METHOD: In this report, we studied 43 AD patients with CBS (AD-CBS) and compared them with 42 AD patients with typical amnestic syndrome (AD-AS), as well as 15 cases of corticobasal degeneration and CBS pathology. RESULTS: Unlike AD-AS, AD-CBS had prominent motor problems, including limb apraxia (90%), myoclonus (81%), and gait disorders (70%). Alien limb phenomenon was reported in 26% and cortical sensory loss in 14%. Language problems were also more frequent in AD-CBS, and memory impairment was less frequent. AD-CBS had more tau pathology in perirolandic cortices but less in superior temporal cortex than AD-AS. In addition, AD-CBS had greater neuronal loss in the substantia nigra. DISCUSSION: AD-CBS is a clinicopathological subtype of AD with an atypical distribution of Alzheimer-type tau pathology. Greater neuronal loss in the substantia nigra may contribute to Parkinsonism which is not a feature of typical AD.

Neuropathologic basis of frontotemporal dementia in progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuronal loss in the extrapyramidal system with pathologic accumulation of tau in neurons and glia. The most common clinical presentation of PSP, referred to as Richardson syndrome, is that of atypical parkinsonism with vertical gaze palsy, axial rigidity, and frequent falls. Although cognitive deficits in PSP are often ascribed to subcortical dysfunction, a subset of patients has dementia with behavioral features similar to the behavioral variant of frontotemporal dementia. In this study we aimed to identify the clinical and pathological characteristics of PSP presenting with frontotemporal dementia. METHODS: In this study, we compared clinical and pathologic characteristics of 31 patients with PSP with Richardson syndrome with 15 patients with PSP with frontotemporal dementia. For pathological analysis, we used semiquantitative methods to assess neuronal and glial lesions with tau immunohistochemistry, as well image analysis of tau burden using digital microscopic methods. RESULTS: We found greater frontal and temporal neocortical neuronal tau pathology in PSP with frontotemporal dementia compared with PSP with Richardson syndrome. White matter tau pathology was also greater in PSP with frontotemporal dementia than PSP with Richardson syndrome. Genetic and demographic factors were not associated with atypical distribution of tau pathology in PSP with frontotemporal dementia. CONCLUSIONS: The results confirm the subset of cognitive-predominant PSP mimicking frontotemporal dementia in PSP. PSP with frontotemporal dementia has distinct clinical features that differ from PSP with Richardson syndrome, as well as differences in distribution and density of tau pathology. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Microglia in frontotemporal lobar degeneration with progranulin or C9ORF72 mutations.

OBJECTIVE: To identify clinicopathological differences between frontotemporal lobar degeneration (FTLD) due to mutations in progranulin (FTLD-GRN) and chromosome 9 open reading frame 72 (FTLD-C9ORF72). METHODS: We performed quantitative neuropathologic comparison of 17 FTLD-C9ORF72 and 15 FTLD-GRN with a focus on microglia. For clinical comparisons, only cases with high quality medical documentation and concurring diagnoses by at least two neurologists were included (14 FTLD-GRN and 13 FTLD-C9ORF72). Neuropathological analyses were limited to TDP-43 Type A to assure consistent assessment between the groups, acknowledging that Type A is a minority of C9ORF72 patients. Furthermore, only cases with sufficient tissue from all regions were studied (11 FTLD-GRN and 11 FTLD-C9ORF72). FTLD cases were also compared to age- and sex-matched normal controls. Immunohistochemistry was performed for pTDP-43, IBA-1, CD68, and GFAP. Morphological characterization of microglia was performed in sections of cortex blinded to clinical and genetic information. RESULTS: FTLD-GRN patients had frequent asymmetric clinical features, including aphasia and apraxia, as well as more asymmetric cortical atrophy. Neuropathologically, FTLD-C9ORF72 had greater hippocampal tau pathology and more TDP-43 neuronal cytoplasmic inclusions. FTLD-GRN had more neocortical microvacuolation, as well as more IBA-1-positive ameboid microglia in superficial cortical layers and in subcortical white matter. FTLD-GRN also had more microglia with nuclear condensation, possibly indicating apoptosis. Microglial morphology with CD68 immunohistochemistry in FTLD-GRN and FTLD-C9ORF72 differed from controls. INTERPRETATION: Our findings underscore differences in microglial response in FTLD-C9ORF72 and FTLD-GRN as shown by significant differences in ameboid microglia in gray and white matter. These results suggest the differential contribution of microglial dysfunction in FTLD-GRN and FTLD-C9ORF72 and suggest that clinical, neuroimaging and pathologic differences could in part be related to differences in microglia response.

Evaluation of Associations of Alzheimer's Disease Risk Variants that Are Highly Expressed in Microglia with Neuropathological Outcome Measures.

A number of Alzheimer's disease (AD) susceptibility loci are expressed abundantly in microglia. We examined associations between AD risk variants in genes that are highly expressed in microglia and neuropathological outcomes, including cerebral amyloid angiopathy (CAA) and microglial activation, in 93 AD patients. We observed significant associations of CAA pathology with APOEɛ4 and PTK2B rs28834970. Nominally significant associations with measures of microglial activation in white matter were observed for variants in PTK2B, PICALM, and CR1. Our findings suggest that several AD risk variants may also function as disease modifiers through amyloid-ß metabolism and white matter microglial activity.

Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease.

Frontotemporal lobar degeneration (FTLD) is heterogeneous in clinical presentation, neuropathological characteristics and genetics. An expanded GGGGCC hexanucleotide repeat in C9ORF72 is the most common genetic cause of both FTLD and motor neuron disease (MND). Dipeptide repeat polymers (DPR) are generated through repeat-associated non-ATG translation, and they aggregate in neuronal inclusions with a distribution distinct from that of TDP-43 pathology. Recent studies from animal and cell culture models suggest that DPR might be toxic, but that toxicity may differ for specific DPR. Arginine containing DPR (poly-GR and poly-PR) have the greatest toxicity and are less frequent than other DPR (poly-GP, poly-GA). A unique feature of arginine-containing DPR is their potential for post-translational modification by methyl-transferases, which produces methylarginine DPR. In this report, we explored the relationship of DPR and methylarginine to markers of neurodegeneration using quantitative digital microscopic methods in 40 patients with C9ORF72 mutations and one of three different clinicopathologic phenotypes, FTLD, FTLD-MND or MND. We find that density and distribution of poly-GR inclusions are different from poly-GA and poly-GP inclusions. We also demonstrate colocalization of poly-GR with asymmetrical dimethylarginine (aDMA) immunoreactivity in regions with neurodegeneration. Differences in aDMA were also noted by clinical phenotype. FTLD-MND had the highest burden of poly-GR pathology compared to FTLD and MND, while FTLD-MND had higher burden of aDMA than FTLD. The results suggest that poly-GR pathology is associated with toxicity and neurodegeneration. It remains to be determined if dimethylarginine modification of poly-GR could contribute to its toxicity.

Diffuse Lewy body disease manifesting as corticobasal syndrome: A rare form of Lewy body disease.

OBJECTIVE: To describe clinical and pathologic characteristics of diffuse Lewy body disease (DLBD) manifesting as corticobasal syndrome (CBS). METHODS: In 523 autopsy-confirmed cases of DLBD, we identified 11 patients diagnosed with CBS. For comparison, we studied 22 DLBD brains with antemortem presentation of dementia with Lewy bodies (DLB). Given previous studies suggesting the importance of pathology in peri-Rolandic cortices in CBS, we used digital pathology to count Lewy bodies and to quantify intracytoplasmic and neuritic α-synuclein and phospho-tau burden in the motor cortex. RESULTS: DLBD patients with antemortem features of CBS were significantly younger at disease onset and less likely to have REM sleep behavior disorder than DLBD cases who met clinical criteria for DLB during life. Patients with DLBD manifesting as CBS had more Lewy bodies in the motor cortex than DLBD manifesting as clinically probable DLB. Three cases had concomitant progressive supranuclear palsy and 4 cases had concomitant Alzheimer disease as probable correlates of CBS. CONCLUSION: The neuropathology underlying CBS is heterogeneous, including corticobasal degeneration, Alzheimer disease, and progressive supranuclear palsy. This study suggests that atypical variants of Lewy body disease with severe peri-Rolandic Lewy-related pathology can present clinically as CBS. Patients with DLBD who present as CBS tend to have an earlier age at onset and are less likely to have clinical features of DLB, such as dream enactment behavior during sleep, visual hallucinations, and levodopa-responsive parkinsonism. Future studies with biofluid or molecular imaging biomarkers for α-synuclein will permit better recognition of this uncommon pathologic substrate of CBS.

Vitamin D receptor gene polymorphisms, smoking, and risk of sporadic Parkinson's disease in Japan.

Epidemiological evidence on the relationships between the vitamin D receptor (VDR) single nucleotide polymorphisms (SNPs) rs731236 (TaqI), rs7975232 (ApaI), rs1544410 (BsmI), and rs2228570 (FokI) and Parkinson's disease (PD) is inconsistent. We investigated these relationships in 229 sporadic PD patients within six years of onset in Japan. Controls were 357 patients without neurodegenerative disease. Adjustment was made for sex, age, region of residence, and smoking. A significant inverse association was found between SNP rs2228570 and the risk of sporadic PD under the additive but not the co-dominant or dominant model (P=0.048); however, this fell below significance after adjustment for multiple comparisons (adjusted P=0.46). No significant relationships were found between SNPs rs731236, rs7975232, or rs1544410 and the risk of sporadic PD in any genetic model. VDR haplotypes inferred in the current study were not associated with sporadic PD. Compared with subjects with the GA or AA genotype of SNP rs2228570 who had ever smoked, those with the GG genotype who had never smoked had a 3.78-fold increased risk of sporadic PD; however, no significant interaction was observed. VDR SNP rs2228570 may be associated with sporadic PD in Japan. Smoking did not significantly modify the relationship between SNP rs2228570 and sporadic PD.

Expression and processing analyses of wild type and p.R47H TREM2 variant in Alzheimer's disease brains.

BACKGROUND: Genetic analyses showed that the triggering receptor expressed in myeloid cells 2 (TREM2) p.R47H variant increases the risk for Alzheimer's disease (AD). The question of whether the p.R47H mutation affects expression or function of the receptor remains unanswered. To address this question we quantified mRNA and analyzed protein profiles of WT and p.R47H TREM2 in human brains. METHODS: Quantitative real-time PCR (qPCR) was performed using 2 sets of primers one that detects all TREM2 mRNA isoforms and one specific for the alternative spliced isoform (TREM2alt) that encodes for the extracellular domain (soluble TREM2). Because in the brain TREM2 is expressed primarily in microglial cells, we also assessed the levels of IBA1 to control for microglial variability across samples. For TREM2 protein quantitation and N-glycosylation processing, RIPA brain extracts were analyzed by Western blot before and after EndoH and PNGaseF treatments. RESULTS: We identified statistically significant increased levels of TREM2 transcripts in the temporal cortex of AD subjects when compared with controls; TREM2alt was likewise higher in AD cases, but was not significant after adjustment for covariates. Quantitative analysis of TREM2 protein confirmed qPCR results that showed higher levels in AD than in control brains. Among AD subjects, we observed a trend towards higher mRNA and protein TREM2 levels in carriers of the p.R47H risk allele. Analysis of individual TREM2 species found no difference in the relative amounts of mature and immature species, and carboxyl terminal fragments between non carriers and p.R47H samples. Furthermore, TREM2 species from either non carriers or p.R47H brains were equally susceptible to EndoH and PNGaseF treatments. CONCLUSIONS: Our results suggest that TREM2 expression is increased in AD. Furthermore, we provide evidence indicating that p.R47H mutation does not affect the levels of TREM2 either directly by altering expression or indirectly by affecting processing of the protein. Our data support previous findings that suggest that p.R47H variant affects TREM2 function by altering binding properties of the receptor rather than expression.

ABCA7 Deficiency Accelerates Amyloid-ß Generation and Alzheimer's Neuronal Pathology.

In Alzheimer's disease (AD), the accumulation and deposition of amyloid-ß (Aß) peptides in the brain is a central event. Aß is cleaved from amyloid precursor protein (APP) by ß-secretase and γ-secretase mainly in neurons. Although mutations inAPP,PS1, orPS2cause early-onset familial AD,ABCA7encoding ATP-binding cassette transporter A7 is one of the susceptibility genes for late-onset AD (LOAD), in which itsloss-of-functionvariants increase the disease risk. ABCA7 is homologous to a major lipid transporter ABCA1 and is highly expressed in neurons and microglia in the brain. Here, we show that ABCA7 deficiency altered brain lipid profile and impaired memory in ABCA7 knock-out (Abca7(-/-)) mice. When bred to amyloid model APP/PS1 mice, plaque burden was exacerbated by ABCA7 deficit.In vivomicrodialysis studies indicated that the clearance rate of Aß was unaltered. Interestingly, ABCA7 deletion facilitated the processing of APP to Aß by increasing the levels of ß-site APP cleaving enzyme 1 (BACE1) and sterol regulatory element-binding protein 2 (SREBP2) in primary neurons and mouse brains. Knock-down of ABCA7 expression in neurons caused endoplasmic reticulum stress highlighted by increased level of protein kinase R-like endoplasmic reticulum kinase (PERK) and increased phosphorylation of eukaryotic initiation factor 2α (eIF2α). In the brains of APP/PS1;Abca7(-/-)mice, the level of phosphorylated extracellular regulated kinase (ERK) was also significantly elevated. Together, our results reveal novel pathways underlying the association of ABCA7 dysfunction and LOAD pathogenesis. SIGNIFICANCE STATEMENT: Gene variants inABCA7encoding ATP-binding cassette transporter A7 are associated with the increased risk for late-onset Alzheimer's disease (AD). Importantly, we found the altered brain lipid profile and impaired memory in ABCA7 knock-out mice. The accumulation of amyloid-ß (Aß) peptides cleaved from amyloid precursor protein (APP) in the brain is a key event in AD pathogenesis and we also found that ABCA7 deficit exacerbated brain Aß deposition in amyloid AD model APP/PS1 mice. Mechanistically, we found that ABCA7 deletion facilitated the processing of APP and Aß production by increasing the levels of ß-secretase 1 (BACE1) in primary neurons and mouse brains without affecting the Aß clearance rate in APP/PS1 mice. Our study demonstrates a novel mechanism underlying how dysfunctions of ABCA7 contribute to the risk for AD.

PARK16 polymorphisms, interaction with smoking, and sporadic Parkinson's disease in Japan.

Epidemiological evidence on the relationships between PARK16 single nucleotide polymorphisms (SNPs) and Parkinson's disease (PD) is inconsistent. We examined this issue in Japan. Included were 229 cases within six years of PD onset. Controls were 356 patients without neurodegenerative disease. Compared with subjects with the AA genotype of SNP rs823128, those with the AG genotype, but not the GG genotype, had a significantly reduced risk of sporadic PD. Compared with the AA genotype of SNP rs947211, both the AG genotype and the GG genotype were significantly related to an increased risk of sporadic PD. Using subjects with the AA genotype of SNP rs823156 as a reference group, there were significant inverse relationships under the additive and dominant models. No significant relationships were found between SNPs rs16856139 or rs11240572 and sporadic PD. The CAAAC, the TGAGA, and the CAGAC haplotypes were significantly related to sporadic PD. The additive interaction between SNP rs823128 and smoking affecting sporadic PD was significant, although the multiplicative interaction was not significant. The PARK16 SNPs rs823128, rs947211, and rs823156 and the CAAAC, TGAGA, and CAGAC haplotypes may be significantly associated with sporadic PD in Japan. New evidence of an additive interaction between SNP rs823156 and smoking is suggested.

TAR DNA-binding protein 43 pathology in a case clinically diagnosed with facial-onset sensory and motor neuronopathy syndrome: an autopsied case report and a review of the literature.

We report an autopsy case of a 48-year-old female clinically diagnosed with facial-onset sensory and motor neuronopathy (FOSMN) syndrome with TAR DNA-binding protein 43 (TDP-43) pathology. She developed paresthesia involving her whole face, right upper extremity and the right side of her upper trunk, followed by dysphagia, dysarthria, muscle atrophy and weakness with fasciculation in both upper extremities. Her symptoms showed a marked cranial and right-sided dominancy. She had anti-sulfoglucuronyl paragloboside (SGPG) IgG and anti-myelin-associated glycoprotein (MAG) IgG, and repeatedly showed limited response to immunotherapies. Her disease was essentially progressive, culminating in death due to respiratory failure three and a half years after onset. The autopsy revealed severe degeneration of the nuclei of the right trigeminal nerve and right facial nerve and widespread TDP-43-positive glial inclusions in the brainstem tegmentum. Neurons in the hypoglossal nerve nuclei were also shrunken and lost, with TDP-43-positive neuronal inclusions. Neuronal loss and gliosis in the anterior horn, predominantly in the cervical cord, were prominent with TDP-43-positive skein-like inclusions. Bilateral ventral roots were obviously atrophic. Spinal tract degeneration was also prominent in the ventral columns, essentially sparing the anterior corticospinal tracts at the cervical cord level. Additionally there was severe myelin pallor in the right spinal trigeminal tract and right fasciculus cuneatus of the cervical cord. The right spinal root ganglion showed numerous Nageotte's nodules and focal lymphocytic infiltration. The present case manifested FOSMN syndrome clinically, while the pathological findings suggested a motor neuron disease like TDP-43 proteinopathy and a possible involvement of immune-mediated neuropathy.

Intracellular accumulation of toxic turn amyloid-ß is associated with endoplasmic reticulum stress in Alzheimer's disease.

Amyloid-ß protein (Aß) accumulates in the neurons of Alzheimer's disease (AD) patients at an early stage of the disease. Recently, we found that Aß with a toxic turn at positions 22 and 23 accumulates in neurons in AD brain. Here, we studied the accumulation of Aß, toxic turn Aß and high-molecular-weight Aß oligomers in presenilin 1 (PS1) gene-transfected SH-SY5Y cells as well as in the brains of 3xTg-AD mice and AD patients. Immunostaining revealed that accumulation of toxic turn Aß was promoted in G384A- and I143T-mutant PS1-transfected cells and further enhanced by co-transfection of cells with the Aß-precursor protein (AßPP) gene. In contrast, accumulation of high-molecular-weight Aß oligomers was promoted in mutant PS1 cells but attenuated by co-transfection of cells with the AßPP gene. Toxic turn Aß was detected in the neurons of 3xTg-AD mice aged 2 months, when the mice were cognitively unimpaired. In contrast, high-molecular-weight Aß oligomers were detected in the neurons of 7-month-old mice, when memory dysfunction is apparent. Furthermore, immunostaining and western blotting for Rab4, Rab6 and GRP78 revealed increased levels of these proteins in mutant PS1 cells and their accumulation in the neurons of 3xTg-AD mice. Remarkably, GRP78 immunoreactivity was increased at 2 months of age. Double-label immunostaining of AD brain revealed an apparent association between toxic turn Aß and GRP78, an endoplasmic reticulum (ER) stress marker. Intraneuronal accumulation of toxic turn Aß may be associated with ER stress in the brains of AD model mice and AD patients at an early stage.

MDR1 C3435T polymorphism and interaction with environmental factors in risk of Parkinson's disease: a case-control study in Japan.

It has been suggested that P-glycoprotein (P-gp), the product of multidrug resistance 1 (MDR1) gene, regulates the brain entry of various xenobiotics. Impaired function of P-gp may be associated with an increased risk of Parkinson's disease (PD). The aim of this study was to investigate the impact of a MDR1 C3435T polymorphism on PD risk alone or in combination with environmental factors. A total of 238 patients with PD and 368 controls were genotyped for the MDR1 C3435T polymorphism. Subjects with the TT genotype of the C3435T polymorphism showed a nonsignificantly increased risk of PD [odds ratio (OR)=1.49, 95% confidence interval (CI)=0.85-2.25] compared with those with the CC genotype. A gene-environment interaction was suggested, with a combination of at least one T allele and ever drinking conferring significantly higher risk (OR=1.83, 95% CI=1.07-3.15, p=0.029), compared with the CC genotype and never drinking. No significant interaction of smoking or occupational pesticide use with the C3435T polymorphism was observed. Our results suggest that the C3435T polymorphism may not play an important role in PD susceptibility in Japanese. Evidence of an interaction between the C3435T polymorphism and alcohol consumption was suggested.

Lack of association between BST1 polymorphisms and sporadic Parkinson's disease in a Japanese population.

Several genome-wide association studies and case-control studies have investigated the relationships between single nucleotide polymorphisms (SNPs) in the BST1 gene and Parkinson's disease (PD), but the results have been inconsistent. We examined the relationships between SNPs rs11931532, rs12645693, and rs11724635 and the risk of sporadic PD in Japan. Included were 229 cases within 6years of onset of PD as defined according to the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 357 inpatients and outpatients without neurodegenerative disease. SNPs rs11931532 and rs12645693 were not significantly related to sporadic PD. Compared with a reference group of subjects with the CC genotype of SNP rs11724635, those with the AA genotype had a marginally significantly increased risk of sporadic PD: the adjusted OR was 1.57 (95% CI: 0.95-2.61, P=0.08). No significant interactions were found between BST1 SNP rs11724635 and smoking or caffeine intake with respect to sporadic PD. The current study failed to detect significant relationships between BST1 SNPs rs11931532, rs12645693, and rs11724635 and sporadic PD; however, the relationship between SNP rs11724635 and sporadic PD was of borderline significance. We do not find evidence for interactions between smoking or caffeine intake and SNP rs11724635 affecting sporadic PD.

UCHL1 S18Y variant is a risk factor for Parkinson's disease in Japan.

BACKGROUND: A recent meta-analysis on the UCHL1 S18Y variant and Parkinson's disease (PD) showed a significant inverse association between the Y allele and PD; the individual studies included in that meta-analysis, however, have produced conflicting results. We examined the relationship between UCHL1 S18Y single nucleotide polymorphism (SNP) and sporadic PD in Japan. METHODS: Included were 229 cases within 6 years of onset of PD, defined according to the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 357 inpatients and outpatients without neurodegenerative disease. Adjustment was made for sex, age, region of residence, smoking, and caffeine intake. RESULTS: Compared with subjects with the CC or CA genotype of UCHL1 S18Y SNP, those with the AA genotype had a significantly increased risk of sporadic PD: the adjusted OR was 1.57 (95 % CI: 1.06 - 2.31). Compared with subjects with the CC or CA genotype of UCHL1 S18Y and the CC or CT genotype of SNCA SNP rs356220, those with the AA genotype of UCHL1 S18Y and the TT genotype of SNP rs356220 had a significantly increased risk of sporadic PD; the interaction, however, was not significant. Our previous investigation found significant inverse relationships between smoking and caffeine intake and PD in this population. There were no significant interactions between UCHL1 S18Y and smoking or caffeine intake affecting sporadic PD. CONCLUSIONS: This study reveals that the UCHL1 S18Y variant is a risk factor for sporadic PD. We could not find evidence for interactions affecting sporadic PD between UCHL1 S18Y and SNCA SNP rs356220, smoking, or caffeine intake.