Masahiro Nakamori

Tongue thickness evaluation using ultrasonography can predict swallowing function in amyotrophic lateral sclerosis patients

OBJECTIVE Dysphagia is a critical issue in amyotrophic lateral sclerosis (ALS) patients. An evaluation of swallowing function is important for assessing the risk of aspiration. We investigated the validity of tongue sonography compared with videofluoroscopic examination for ALS patients. METHODS We investigated 18 ALS patients. Nine subjects underwent repeated investigations. All of the subjects underwent tongue sonography and videofluoroscopic examination. Additionally, tongue sonography was evaluated in 18 age- and sex-matched healthy volunteers. To determine tongue thickness, we measured the vertical distance from the surface of the mylohyoid muscle to the tongue dorsum using ultrasonography. RESULTS In the ALS patients, the tongue was significantly thinner than in healthy subjects. Tongue thickness was associated with body mass index and onset type in the ALS patients (p=0.006). Temporal analyses of videofluoroscopy revealed that tongue thickness was associated with oral preparatory and transit time (p=0.032) but not with pharyngeal transit time. Repeated measurement data revealed a decrease in tongue thickness over the course of the measurements (p=0.002). CONCLUSIONS In ALS patients, reduced tongue thickness suggests disease progression and tongue dysfunction. SIGNIFICANCE Tongue sonography is a useful modality for the non-invasive and quantitative evaluation of tongue thickness and dysphagia in ALS patients.

Cyclin-dependent kinase 5 immunoreactivity for granulovacuolar degeneration.

In addition to senile plaque and neurofibrillary tangles, granulovacuolar degeneration is a hallmark of Alzheimer’s disease. A number of tau kinases, such as c-jun N-terminal kinase (JNK), glycogen-synthase kinase-3&bgr; (GSK3&bgr;), and casein kinase 1 (CK1), have been reported to be markers of granulovacuolar degeneration. In addition, cyclin-dependent kinase 5 (CDK5), which phosphorylates tau, has been shown to be abundantly expressed in neurofibrillary tangles in the hippocampus. CDK5 has a unique staining pattern, and therefore, has the potential to be a novel marker for granulovacuolar degeneration. In this study, we investigated the ability of CDK5 to be a marker for granulovacuolar degeneration using immunohistochemical analysis. Four Alzheimer’s disease cases, three myotonic dystrophy (MyD) cases, and three control cases were subjected to immunohistochemistry and immunofluorescent techniques using anti-CDK5, anti-charged multivesicular body protein 2B (CHMP2B), anti-pSmad2/3, anti-ubiquitin (Ub), anti-phospho-TDP-43 and AT8 antibodies. Some CDK5-positive granules were morphologically similar to granulovacuolar degeneration intraluminal granules, and these granules overlapped with those immunopositive for pSmad2/3, Ub and phospho-TDP-43 established granulovacuolar degeneration markers. Moreover, CDK5-positive granulovacuolar degeneration and phosphorylated tau colocalized in pyramidal neurons in Alzheimer’s disease and MyD cases. The numbers of CDK5-positive granules showed an inverse relationship with the degree of mature neurofibrillary tangles in each cell, as was the case with CHMP2B-positive granulovacuolar degeneration granules and neurofibrillary tangles. The presence of tau kinases including CDK5 in granulovacuolar degeneration might implicate that granulovacuolar degeneration is structurally involved in tau modification.

The Multidisciplinary Swallowing Team Approach Decreases Pneumonia Onset in Acute Stroke Patients

Dysphagia occurs in acute stroke patients at high rates, and many of them develop aspiration pneumonia. Team approaches with the cooperation of various professionals have the power to improve the quality of medical care, utilizing the specialized knowledge and skills of each professional. In our hospital, a multidisciplinary participatory swallowing team was organized. The aim of this study was to clarify the influence of a team approach on dysphagia by comparing the rates of pneumonia in acute stroke patients prior to and post team organization. All consecutive acute stroke patients who were admitted to our hospital between April 2009 and March 2014 were registered. We analyzed the difference in the rate of pneumonia onset between the periods before team organization (prior period) and after team organization (post period). Univariate and multivariate analyses were performed using a Cox proportional hazards model to determine the predictors of pneumonia. We recruited 132 acute stroke patients from the prior period and 173 patients from the post period. Pneumonia onset was less frequent in the post period compared with the prior period (6.9% vs. 15.9%, respectively; p = 0.01). Based on a multivariate analysis using a Cox proportional hazards model, it was determined that a swallowing team approach was related to pneumonia onset independent from the National Institutes of Health Stroke Scale score on admission (adjusted hazard ratio 0.41, 95% confidence interval 0.19–0.84, p = 0.02). The multidisciplinary participatory swallowing team effectively decreased the pneumonia onset in acute stroke patients.

Phosphatidylinositol-4,5-bisphosphate is enriched in granulovacuolar degeneration bodies and neurofibrillary tangles

Among the pathological findings in Alzheimers disease (AD), the temporal and spatial profiles of granulovacuolar degeneration (GVD) bodies are characteristic in that they seem to be related to those of neurofibrillary tangles (NFTs), suggesting a common mechanism underlying the pathogenesis of these structures. Flotillin‐1, a marker of lipid rafts, accumulates in lysosomes of tangle‐bearing neurones in AD patients. In addition, recent reports have shown that GVD bodies accumulate at the nexus of the autophagic and endocytic pathways. The aim of this study was to elucidate the distribution of the lipid component of lipid rafts, phosphatidylinositol‐4,5‐bisphosphate [PtdIns(4,5)P2], in AD and other neurodegenerative disorders.

Prediction of Pneumonia in Acute Stroke Patients Using Tongue Pressure Measurements

Swallowing dysfunction caused by stroke is a risk factor for aspiration pneumonia. Tongue pressure measurement is a simple and noninvasive method for evaluating swallowing dysfunction. We have hypothesized that low tongue pressure may be able to predict pneumonia occurrence in acute stroke patients. Tongue pressure was measured using balloon-type equipment in 220 acute stroke patients. The modified Mann Assessment of Swallowing Ability (MASA) score was evaluated independently on the same day. Tongue pressure was measured every week thereafter. An improvement in tongue pressure was observed within the first 2 weeks. Receiver operating curve analysis was performed to determine the ability of tongue pressure to predict modified MASA score <95, which suggests swallowing dysfunction. The optimal cutoff for tongue pressure was 21.6 kPa (χ2 = 45.82, p<0.001, sensitivity 95.9%, specificity 91.8%, area under the curve = 0.97). The tongue pressure was significantly lower in patients with pneumonia than in those without pneumonia. Using a Cox proportional hazard model for pneumonia onset with a cutoff tongue pressure value of 21.6 kPa and adjustment for age, sex, and National Institutes of Health Stroke Scale score at admission, the tongue pressure had additional predictive power for pneumonia onset (hazard ratio, 7.95; 95% confidence interval, 2.09 to 52.11; p = 0.0013). In the group with low tongue pressure, 27 of 95 patients showed improvement of tongue pressure within 2 weeks. Pneumonia occurred frequently in patients without improvement of tongue pressure, but not in patients with improvement (31/68 and 2/27, p<0.001). Tongue pressure is a sensitive indicator for predicting pneumonia occurrence in acute stroke patients.

Characterization and distribution of adaptor protein containing a PH domain, PTB domain and leucine zipper motif (APPL1) in Alzheimer’s disease hippocampus: an immunohistochemical study

Adaptor protein containing a PH domain, PTB domain and leucine zipper motif (APPL1) is emerging as a critical regulator of various cellular processes in non-neuronal cells as well as in neurons where it localizes to dendritic spines and synapses. It regulates the development of these structures in hippocampal neurons. Although memory impairment in Alzheimers disease (AD) has been attributed to disruption of synaptic plasticity, there is scant information on this protein in the human brain. In the present study, we immunohistochemically characterized the localization of APPL1 in AD and control brains. APPL1 accumulated perisomatically as granules around neurons within vulnerable sectors of the hippocampus (CA1 and subiculum) in AD brain, whilst APPL1-positive granules were rarely identified in control brains derived from elderly individuals with no known cognitive impairment. Interestingly, in the AD hippocampus, APPL1 also co-localized with perisomatic granules (non-plaque dystrophic dendrites) expressing glutamate receptor 2 and ubiquitin, suggesting the possible involvement of APPL1 in the synaptic modifications in AD. Thus, the immunohistochemical distribution of APPL1 in AD brain was distinct from that in non-AD control brains, suggesting that signaling via APPL1 might play a critical role in the memory impairment in AD.

Blood Pressure Variability in Acute Ischemic Stroke: Influence of Infarct Location in the Insular Cortex

Background: The aim of this study was to elucidate the influence of insular infarction on blood pressure (BP) variability and outcomes according to the region of the insular cortex affected. Methods: A total of 90 patients diagnosed with acute unilateral ischemic stroke were registered. The BP variability was calculated over 24 h after admission (hyperacute) and for 2–3 days after admission (acute). Patients were classified into groups of right and left, and then right anterior, right posterior, left anterior, and left posterior insular infarction. Results: Patients with insular infarction showed a significantly larger infarct volume, higher modified Rankin scale scores, and lower SD and coefficient of variation (CV) of systolic BP in the hyperacute phase than shown by patients without insular infarction (p < 0.01, p < 0.01, p = 0.02, and p = 0.03, respectively). The SD and CV of systolic BP in the hyperacute phase showed significant differences among the 3 groups with right insular infarction, with left insular infarction, and without insular infarction (p < 0.05 and p < 0.05, respectively). There was a tendency for the systolic BP variability to be lower in patients with right anterior insular infarction than in patients with infarcts in other areas. Conclusion: The right insular cortex, especially the anterior part, might be a hub for autonomic nervous regulation.

Development of a candy-sucking test for evaluating oral function in elderly patients with dementia: A pilot study

To maintain oral intake in elderly patients with dementia, it is important to evaluate their oral function. However, these patients often have difficulties following instructions during oral function tests, especially with the progression of dementia. The task of sucking a lollipop candy is simple for elderly patients with mild or severe dementia. The present study aimed to develop a new oral function test – the “candy sucking test” (CST) – for elderly patients with dementia.

The identification of raft-derived tau-associated vesicles that are incorporated into immature tangles and paired helical filaments

Neurofibrillary tangles (NFTs), a cardinal pathological feature of neurodegenerative disorders, such as Alzheimers disease (AD) are primarily composed of hyper‐phosphorylated tau protein. Recently, several other molecules, including flotillin‐1, phosphatidylinositol‐4,5‐bisphosphate [PtdIns(4,5)P2] and cyclin‐dependent kinase 5 (CDK5), have also been revealed as constituents of NFTs. Flotillin‐1 and PtdIns(4,5)P2 are considered markers of raft microdomains, whereas CDK5 is a tau kinase. Therefore, we hypothesized that NFTs have a relationship with raft domains and the tau phosphorylation that occurs within NFTs.

Molecular markers for granulovacuolar degeneration are present in rimmed vacuoles.

Background Rimmed vacuoles (RVs) are round-oval cytoplasmic inclusions, detected in muscle cells of patients with myopathies, such as inclusion body myositis (IBM) and distal myopathy with RVs (DMRV). Granulovacuolar degeneration (GVD) bodies are spherical vacuoles containing argentophilic and hematoxyphilic granules, and are one of the pathological hallmarks commonly found in hippocampal pyramidal neurons of patients with aging-related neurodegenerative diseases, such as Alzheimers disease and Parkinsons disease. These diseases are common in the elderly and share some pathological features. Therefore, we hypothesized that mechanisms of vacuolar formation in RVs and GVD bodies are common despite their role in two differing pathologies. We explored the components of RVs by immunohistochemistry, using antibodies for GVD markers. Methods Subjects included one AD case, eight cases of sporadic IBM, and three cases of DMRV. We compared immunoreactivity and staining patterns for GVD markers. These markers included: (1) tau-modifying proteins (caspase 3, cyclin-dependent kinase 5 [CDK5], casein kinase 1δ [CK1δ], and c-jun N-terminal kinase [JNK]), (2) lipid raft-associated materials (annexin 2, leucine-rich repeat kinase 2 [LRRK2], and flotillin-1), and (3) other markers (charged multi-vesicular body protein 2B [CHMP2B] and phosphorylated transactive response DNA binding protein-43 [pTDP43]) in both GVD bodies and RVs. Furthermore, we performed double staining of each GVD marker with pTDP43 to verify the co-localization. Results GVD markers, including lipid raft-associated proteins and tau kinases, were detected in RVs. CHMP2B, pTDP43, caspase 3, LRRK2, annexin 2 and flotillin-1 were detected on the rim and were diffusely distributed in the cytoplasm of RV-positive fibers. CDK5, CK1δ and JNK were detected only on the rim. In double staining experiments, all GVD markers colocalized with pTDP43 in RVs. Conclusions These results suggest that RVs of muscle cells and GVD bodies of neurons share a number of molecules, such as raft-related proteins and tau-modifying proteins.