Sarcopenia Is Associated with Fecal Incontinence in Patients with Dysphagia: Implication for Anal Sarcopenia.

OBJECTIVES: To examine the relationship between sarcopenia and fecal incontinence in patients with dysphagia. DESIGN: Cross-sectional study using the Japanese sarcopenic dysphagia database. SETTING: 19 hospitals including 9 acute care hospitals, 8 rehabilitation hospitals, 2 long-term care hospitals, and 1 home visit rehabilitation center. PARTICIPANTS: 460 dysphagic patients, aged 20 years and older. MEASUREMENTS: Sarcopenia was diagnosed by the 2019 criteria of the Asian Working Group for Sarcopenia. Fecal incontinence was assessed by health care professionals at baseline according to the definition of the Japanese Practice Guidelines for Fecal Incontinence. We examined whether there was a significant difference between the rate of fecal incontinence in patients with/without sarcopenia. Age, sex, type of dwelling, Barthel index, Charlson comorbidity index (CCI), calf circumference, handgrip strength, body mass index, malnourishment, C-reactive protein level, serum albumin level, and delivery of enteral nutrition by nasogastric and/or gastrostomy tube were measured. To examine the relationship between sarcopenia and fecal incontinence, logistic regression analysis was performed with adjustments for age, sex, sarcopenia, CCI, enteral nutrition, and dwelling. RESULTS: The mean age of patients was 81 ± 10 years. Of the 460 study patients, 404 (88%) patients had sarcopenia and 104 had fecal incontinence (23%). The rate of fecal incontinence was higher in the sarcopenia group than the non-sarcopenia group (25% vs. 7%, P = 0.003). Logistic regression analysis showed that sarcopenia was independently associated with fecal incontinence (odds ratio: 3.114, 95% confidence interval: 1.045, 9.282). CONCLUSION: The prevalence of fecal incontinence was 23% in patients with dysphagia. Sarcopenia was independently associated with fecal incontinence, which suggests the presence of anal sarcopenia. Defecation control should be assessed in patients with sarcopenia.

Construction and Quality Evaluation of the Japanese Sarcopenic Dysphagia Database.

OBJECTIVES: To describe the activity and evaluate the quality of the Japanese sarcopenic dysphagia database. DESIGN: Cohort registry study. SETTING: 19 hospitals including 9 acute care hospitals, 8 rehabilitation hospitals, 2 long-term care hospitals, and 1 home visit rehabilitation team. PARTICIPANTS: 467 dysphagic patients, aged 20 years and older. MEASUREMENTS: The following indices were assessed at baseline: age, sex, main disease, sarcopenic dysphagia, whole body sarcopenia, Food Intake Level Scale (FILS), malnutrition diagnosed by the Global Leadership Initiative on Malnutrition criteria, oral status assessed by the Revised Oral Assessment Guide or the Oral Health Assessment Tool, activities of daily living assessed by the Functional Independence Measure (FIM) or the Barthel Index (BI), Charlson comorbidity index, C-reactive protein and serum albumin levels, dysarthria, hoarseness, aphasia, pressure ulcers, bladder, bowel, and kidney function, respiratory status, polypharmacy, number of drugs, and involvement of health care professionals and rehabilitation nutrition team. FILS, FIM or BI, and outcome including discharge destination were assessed at follow-up. A simple comparison of cases and evaluation of the quality of data were performed. RESULTS: The mean age was 80.4 ± 11.4 yr. The variable input error was 0. The number of patients with missing data was high for estimated glomerular filtration rate, C-reactive protein, serum albumin, skeletal mass index, and tongue pressure. The prevalence of either probable, possible, or no sarcopenic dysphagia was 105 (23%), 182 (39%), or 179 (38%), respectively. Doctors including physiatrists, nurses, physical therapists, and registered dietitians were involved with most patients, while the rehabilitation nutrition team was involved in only 16% of patients. CONCLUSIONS: The quality of the database was relatively high. Sarcopenic dysphagia is common in patients with dysphagia.

Global and region-specific analyses of apparent diffusion coefficient in dentatorubral-pallidoluysian atrophy.

BACKGROUND AND PURPOSE: Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant spinocerebellar ataxia. Techniques for the quantitative assessment of neurodegenerative lesions remain to be established in this disease. We attempted to quantify global and region-specific neurodegeneration in DRPLA using analysis of apparent diffusion coefficient (ADC) maps. METHODS: Diffusion-weighted images (b = 1000 s/mm(2)) by echo-planar sequences were obtained with the use of a 1.5T clinical scanner. Whole-brain histogram and region of interest (ROI) analyses of ADC values as well as conventional MR imaging studies were performed in 6 patients with genetically confirmed DRPLA. RESULTS: Histograms demonstrated significantly higher mean ADC values in the patients than in age- and sex-matched control subjects (P < .01). ROI analysis revealed that the patients had significantly higher ADC values in the cerebellum and globus pallidus, preferentially affected regions (P < .05), but not in the thalamus, the region relatively spared in this disease. ADC values in the white matter were higher only in patients with adult-onset disease. Histogram analyses could more sensitively identify abnormalities than ROI analyses, because the former avoided errors associated with setting ROIs and thus had smaller P values on statistical analysis than the latter. CONCLUSIONS: Histogram ADC analyses were more sensitive for the detection of neurodegeneration in DRPLA than ROI analyses, whereas ROI analyses revealed regional alterations reflecting the distribution of pathologic changes. Thus, histogram and ROI analyses complement each other and may permit the sensitive, quantitative evaluation of neurodegeneration in DRPLA, especially that involving the globus pallidus showing normal T2 signals.

Plasma levels of amyloid beta 40 and 42 are independent from ApoE genotype and mental retardation in Down syndrome.

In Down syndrome (DS) brain an early, selective accumulation of amyloid beta (Abeta) peptides ending at residue 42 (Abeta42) occurs. Whether this event depends on an altered processing of amyloid beta precursor protein (APP) or on defective clearance is uncertain. To investigate this issue, we measured Abeta species 40 and 42 in plasma from 61 patients with DS, 77 age-matched normal controls, and 55 mentally retarded subjects without chromosomal abnormalities. The Abeta 40 and 42 plasma levels were then correlated with apolipoprotein E (apoE) genotypes in all groups of cases, and with I. Q. and Mini Mental Status Examination values in DS subjects. Both Abeta species were significantly elevated in DS compared to control groups, and the extent of their increase reflects that expected from APP gene overexpression. Plasma levels of Abeta 40 and 42 did not correlate with apoE genotypes in DS and control cases, and with the extent of mental retardation in DS subjects. The results indicate that accumulation and clearance of plasma and cerebral Abeta are regulated by different and independent factors.

[A case of Fisher syndrome showing pharyngeal-cervical-brachial weakness with an elevation of anti-GQ 1 b and anti-GT 1 a antibodies].

A 15-year-old boy developed ataxic gait, diplopia and hoarseness. Within 3 days after the onset, he had additional symptoms of dysphagia and dysarthria. He was admitted to our hospital 7 days after the onset of the disease. On admission, he had total ophthalmoplegia, ataxia, areflexia, facial diplegia, bulbar palsy and weakness of the neck and upper arms. Serum anti-GQ 1 b and anti-GT 1 a antibodies were significantly elevated. A diagnosis of Fisher syndrome associated with pharyngeal-cervical-brachial weakness was made. He was placed on a high dose of intravenous immunoglobins (12.5 g/day x 2 days) and had steroid pulse therapy (methylprednisolone 1 g x 3 days), which resulted in an almost complete recovery. There have been no reports of Fisher syndrome associated with brachio-pharyngeal-palsy. As in the case of the pharyngeal-cervical-brachial variant of Guillain Barré syndrome, anti-GT 1 a antibodies may be associated with Fisher syndrome with pharyngeal-cervical-brachial weakness.

Increased CSF tau protein in corticobasal degeneration.

Using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA) method, we measured the concentration of total tau protein in the cerebrospinal fluid (CSF) from nine patients with corticobasal degeneration (CBD) in comparison with 12 normal control subjects in order to assess its diagnostic value. The CSF concentration of tau in patients with CBD (0.69, 0.20 ng/ml; mean, SD) was higher than that in, the normal controls (0.48, 0.14 ng/ml, P = 0.0076 unpaired t test). This increase in CBD patients may reflect widespread tau pathology in CBD, but should be interpreted with reserve as an aid to diagnosis.

[A case of basilar artery occlusion associated with one-and-a-half syndrome, paralytic pontine exotropia and WEBINO-syndrome].

We report a 79-year-old woman with basilar artery occlusion. She had a sudden onset of tetraplegia and disturbed consciousness, and within four days from the onset she showed a varied, fluctuating eye symptoms. On admission, she showed ocular bobbing, skew deviation with the right eye lower-positioned, upward gaze palsy, one-and-a-half syndrome, and paralytic pontine exotropia (PPE). On the third day after the onset, she showed wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome, and on the fourth day, she showed one-and-a-half syndrome again. Her right-gaze palsy improved repeatedly, and on the 19th day from the onset, only right MLF syndrome remained. Her eye symptoms fluctuated probably according to the distal migration of emboli, there by the responsible lesion and the mechanism of these eye symptoms are considered to be closely inter-correlated. On the fourth day after onset, the magnetic resonance imaging revealed cerebral infarctions in bilateral middle pons, the left paramedian lower pons, and the right paramedian midbrain, and a hemorrhagic infarction in the right inferior cerebellar hemisphere. We believe that that the eye symptoms of this patient were caused by lesions in the paramedian midbrain or pons.

Amyloid beta protein 42(43) in cerebrospinal fluid of patients with Alzheimer's disease.

To investigate the pathomechanism of amyloid beta protein (A beta) deposition in brains with Alzheimer's disease (AD), cerebrospinal fluid (CSF) levels of A beta species (CSF-A beta) with different carboxy termini, i.e. A betaX-40 and A betaX-42(43) as well as A beta1-40 and A beta1-42(43), were measured in patients with AD and age-matched controls without dementia (CTR) using sandwich enzyme-linked immunosorbent assays (ELISAs). The present study revealed that both CSF-A betaX-42(43) and A beta1-42(43) levels were significantly lower in the AD patients (P<0.005) than in the CTR group, whereas neither CSF-A betaX-40 nor CSF-A beta1-40 levels showed any differences between the two groups. In addition, although there was no difference between the ratios of A betaX-40 to A beta1-40 in the AD and CTR groups, the ratios of A betaX-42(43) to A beta1-42(43) were increased in the AD group compared with those in the CTR group (P<0.05). Therefore, it can be assumed that the ratios of amino terminal truncations and/or modifications of CSF-A beta42(43) with carboxy termini ending at residue 42(43) were more increased in the AD group than in the CTR group. Increased adsorption of A beta42(43) to A beta deposition in AD brains, decreased secretion of A beta42(43) to CSF and/or increased clearance of A beta42(43) from CSF might explain the diminished levels of A beta42(43) in the CSF of AD patients. In addition, CSF-A beta42(43) could reflect increased amino terminal truncations and/or modifications of A beta42(43) in AD brains.

Glial tau-positive structures lack the sequence encoded by exon 3 of the tau protein gene.

Tau protein comprises six distinct isoforms defined by the presence or absence of sequences encoded by alternatively spliced exon 2, 3 and 10. We have investigated immunohistochemically the expression of exon 3-derived fragment (E-3) of tau protein in brains of patients with Alzheimer's disease (AD) and other neurodegenerative diseases in which the abnormal accumulation of tau protein takes place. In AD, a subset of neurofibrillary tangles, neuropil threads and dystrophic neurites in senile plaques were stained positively with an anti-E-3 antibody. In sharp contrast, glial tau-positive structures, such as astrocytic plaques and oligodendroglial coiled bodies, were negative for E-3 in all cases examined in this study. This is the first report to discriminate tau-positive inclusions in glial cells from those in neurons at the molecular level.

Transforming growth factor-beta is a survival factor for neonate cortical neurons: coincident expression of type I receptors in developing cerebral cortices.

Transforming growth factor-beta (TGF-beta) is a multifunctional polypeptide which plays a crucial role in the regulation of cell proliferation, differentiation, and organogenesis. In the present study, we investigated the expression of signaling receptors for TGF-beta in developing mice by in situ hybridization, revealing a significant difference in the expression of TGF-beta type I and type II receptors. Unexpectedly, the TGF-beta type I receptors were exclusively expressed without any detectable expression of the TGF-beta type II receptors in developing cerebral cortices. In primary cortical neurons, a neutralizing antibody for TGF-beta significantly reduced the expression of bcl-2 and subsequently induced neuronal cell death, indicating that TGF-beta functions as a survival factor for cortical neurons in vitro. Consistent with the result of in situ hybridization, the TGF-beta, type I but not type II receptors were detected in primary cortical neurons by affinity crosslink and RT-PCR analyses. The concomitant expression of TGF-beta2 and the TGF-beta type I receptors in developing cerebral cortices suggests that the TGF-beta signaling system plays a pivotal role in neuronal differentiation and that unidentified components may be involved in TGF-beta signaling in the development of the central nervous system.

Tau in cerebrospinal fluids: establishment of the sandwich ELISA with antibody specific to the repeat sequence in tau.

Clinical diagnosis for Alzheimer's disease (AD) is provided by the criteria of DSMIV and clinical progress in addition to imaging analysis with MRI after negative screening. The final exclusive diagnosis is confirmed by the neuropathological findings of neurofibrillary tangles and senile plaques in autopsy brains. We developed a new ELISA system to measure the amount of tau in cerebrospinal fluids (CSF) using phosphorylation-independent and sequence-specific antibodies. The present ELISA was sensitive enough to detect tau in CSF of normal subjects. The amount of tau was significantly elevated in CSF of AD subjects compared with those of normal subjects and subjects with dementia of cerebrovascular disease, suggesting that tau in CSF reflects the massive and continuous neuronal cell death in the AD brain. In conclusion, we established an ELISA system which enabled us to detect tau in CSF and demonstrated that tau was significantly and specifically elevated in CSF of AD subjects. This assay system can provide us with a potent diagnostic tool for clinical AD.

Racemization: its biological significance on neuropathogenesis of Alzheimer's disease.

Amyloid beta protein (A beta) in neuritic plaques of Alzheimer's disease has been found to be racemized and/or isomerized at their Asp residues. To elucidate the effect of racemization on the aggregation properties of A beta, we synthesized three kinds of A beta peptides in which D-Asp was substituted for L-Asp residues, i.e, normal A beta 1-40, [D-Asp7]A beta 1-40 and [D-Asp23]A beta 1-40. The aggregation and fibril formation of each peptide was examined by means of spectrofluorometry and electron microscopy. Of the three peptides, normal A beta showed the gradual increase of aggregation while [D-Asp7]A beta 1-40 and [D-Asp23] A beta 1-40 showed more enhanced aggregation at the final stage when the fibril formations were detected in all peptides solutions by electron microscopy. A comparative immunohistochemical study by anti-racemized A beta antibody and anti-A beta 1-42/43 antibody further showed the in vivo incorporation of D-Asp in senile plaques of Alzheimer's disease brains, which may be involved in plaque formation at the later stage than the deposition of the longer form of A beta (A beta 1-42/43). Taken together with the recent accumulated evidence on the aggregation mechanisms of A beta, the data presented here suggest that racemization may occur after the amyloid fibril formation but enhance the aggregation process by shifting the equilibrium of A beta from the soluble form to the insoluble form in Alzheimer's disease.

Racemization of Asp23 residue affects the aggregation properties of Alzheimer amyloid beta protein analogues.

The beta proteins in amyloid deposits of Alzheimer's disease have been found to be racemized and/or isomerized at their Asp residues (Roher, A. E., Lowenson, J. D., Clarke, S., Wolkow, C., Wang, R., Cotter, R. J., Reardon, I. M., Zurcher-Neely, H. A., Heinrikson, R. L., Ball, M. J., and Greenberg, B. D. (1993) J. Biol. Chem. 268, 3072-3083). To elucidate the effect of racemization on the aggregation properties of beta proteins, we synthesized four beta protein analogues in which D-Asp was substituted for L-Asp residues, i.e. normal beta 1-35, [D-Asp7]beta 1-35, [D-Asp23]beta 1-35, and [D-Asp7,D-Asp23]beta 1-35. The aggregation and fibril formation of the peptides were examined by means of spectrophotometry, sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE), and electron microscopy. Of the four peptides, [D-Asp23]beta 1-35 showed the earliest increase in turbidity and appearance of a smear in SDS-PAGE. This was followed by [D-Asp7,D-Asp23]beta 1-35 and normal beta 1-35. [D-Asp7]beta 1-35 was considerably delayed in showing these signs of aggregation. Corresponding with the increase in turbidity and the appearance of a smear in SDS-PAGE, fibril formation was observed in electron microscopy. These results reveal that the aggregation properties of beta 1-35 peptides are affected by racemization of their Asp residues depending on their position. Racemization at amino acid position 23 accelerated the peptide aggregation and fibril formation, while that at position 7 slowed down this reaction. This suggests that the site-specific racemization of beta protein may be involved in the amyloid fibril formation in Alzheimer's disease.

Okadaic acid enhances abnormal phosphorylation on tau proteins.

Tau proteins are one of the microtubule-associated proteins (MAPs) and show promoting activity on microtubule assembly. Tau proves to be the major constituent of Alzheimer's paired helical filaments, in which tau is found to be different from normal tau in that it is abnormally phosphorylated. To examine the effect of the abnormal phosphorylation on microtubule assembly, we obtained abnormally phosphorylated tau that was made in vitro by hyperphosphorylation with ATP or with ATP and okadaic acid, a drug inhibiting phosphatase, mainly 1 and 2A. We confirmed the biochemical properties of abnormally phosphorylated tau based on its retarded gel mobility and immunoreactivity to anti-PHF. We found that abnormally phosphorylated tau was able to promote the polymerization of microtubules but showed less activity as compared with normally phosphorylated tau. This effect of ATP on abnormal phosphorylation of tau was enhanced when okadaic acid was added in the phosphorylation reaction mixture during microtubule assembly. It is of significance that phosphatase activity as well as kinase activity are involved in the formation of abnormal tau. The present evidence suggests the simultaneous occurrence of microtubule disassembly and the pathogenesis of paired helical filaments following the abnormal phosphorylation of tau.