Kazushi Suzuki

DRPLA transgenic mouse substrains carrying single copy of full-length mutant human DRPLA gene with variable sizes of expanded CAG repeats exhibit CAG repeat length- and age-dependent changes in behavioral abnormalities and gene expression profiles

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant progressive neurodegenerative disorder with intellectual deterioration and various motor deficits including ataxia, choreoathetosis, and myoclonus, caused by an abnormal expansion of CAG repeats in the DRPLA gene. Longer expanded CAG repeats contribute to an earlier age of onset, faster progression, and more severe neurological symptoms in DRPLA patients. In this study, we have established DRPLA transgenic mouse lines (sublines) harboring a single copy of the full-length mutant human DRPLA gene carrying various lengths of expanded CAG repeats (Q76, Q96, Q113, and Q129), which have clearly shown motor deficits and memory disturbance whose severity increases with the length of expanded CAG repeats and age, and successfully replicated the CAG repeat length- and age-dependent features of DRPLA patients. Neuronal intranuclear accumulation of the mutant DRPLA protein has been suggested to cause transcriptional dysregulation, leading to alteration in gene expression and neuronal dysfunction. In this study, we have conducted a comprehensive analysis of gene expression profiles in the cerebrum and cerebellum of transgenic mouse lines at 4, 8, and 12 weeks using multiple microarray platforms, and demonstrated that both the number and expression levels of the altered genes are highly dependent on CAG repeat length and age in both brain regions. Specific groups of genes and their function categories were identified by further agglomerative cluster analysis and gene functional annotation analysis. Calcium signaling and neuropeptide signaling, among others, were implicated in the pathophysiology of DRPLA. Our study provides unprecedented CAG-repeat-length-dependent mouse models of DRPLA, which are highly valuable not only for elucidating the CAG-repeat-length-dependent pathophysiology of DRPLA but also for developing therapeutic strategies for DRPLA.

Ultrathin endoscope flexibility can predict discomfort associated with unsedated transnasal esophagogastroduodenoscopy

AIM To evaluate the effects of choice of insertion route and ultrathin endoscope types. METHODS This prospective study (January-June 2012) included 882 consecutive patients who underwent annual health checkups. Transnasal esophagogastroduodenoscopy (EGD) was performed in 503 patients and transoral EGD in 235 patients using six types of ultrathin endoscopes. Patients were given a choice of insertion route, either transoral or transnasal, prior to EGD examination. For transoral insertion, the endoscope was equipped with a thin-type mouthpiece and tongue depressor. Conscious sedation was not used for any patient. EGD-associated discomfort was assessed using a visual analog scale (VAS; no discomfort 0- maximum discomfort 10). RESULTS Rates of preference for transnasal insertion were significantly higher in male (male/female 299/204 vs 118/117) and younger patients (56.8 ± 11.2 years vs 61.3 ± 13.0 years), although no significant difference was found in VAS scores between transoral and transnasal insertion (3.9 ± 2.3 vs 4.1 ± 2.5). Multivariate analysis revealed that gender, age, operator, and endoscope were independent significant predictors of VAS for transnasal insertion, although gender, age, and endoscope were those for transoral insertion. Further analysis revealed only the endoscopic flexibility index (EFI) as an independent significant predictor of VAS for transnasal insertion. Both EFI and tip diameter were independent significant predictors of VAS for transoral insertion. CONCLUSION Flexibility of ultrathin endoscopes can be a predictor of EGD-associated discomfort, especially in transnasal insertion.

Association of subclinical carotid atherosclerosis with immediate memory and other cognitive functions

To clarify whether carotid atherosclerosis and its risk factors are associated with cognitive decline.

Effects of sex, educational background, and chronic kidney disease grading on longitudinal cognitive and functional decline in patients in the Japanese Alzheimer's Disease Neuroimaging Initiative study

The objective of this study was to determine whether sex or education level affects the longitudinal rate of cognitive decline in Japanese patients in the Alzheimers disease Neuroimaging Initiative study with defined mild cognitive impairment (MCI).

The past, present, and future of disease-modifying therapies for Alzheimer's disease

The development of disease-modifying therapies for Alzheimer’s disease (AD) is an urgent issue. Progress in the understanding of AD pathophysiology based on the amyloid hypothesis has led to the development of numerous candidate disease-modifying therapies over the past 15 years. The therapeutic target, amyloid β (Aβ), starts to accumulate in AD brains long before the onset of cognitive decline. γ-secretase inhibitors, γ-secretase modulators, and β-secretase inhibitors aim to reduce the production of toxic Aβ species by modifying the processing of amyloid precursor protein. Another strategy is to eliminate accumulated Aβ by active or passive immunotherapeutic approaches. Therapeutic strategies targeting tau protein are also currently emerging. Despite these efforts, successful disease-modifying therapies for AD have not yet been developed. Recently, very early interventional trials targeting preclinical stages of AD have begun; the paradigm shift in AD therapies from cure to prevention could be key to the success of disease modification.

Elevated Serum Uric Acid Levels Are Related to Cognitive Deterioration in an Elderly Japanese Population

Aims: The association between serum uric acid (UA) levels and cognitive function is controversial since UA can be a risk factor for cerebral ischemia as well as acting as a neuroprotective antioxidant. Methods: We conducted a cross-sectional analysis of 228 elderly participants and examined neuropsychological test results, clinical data as well as brain magnetic resonance imaging data. Patients: Overall, 64 participants were diagnosed with cognitive deterioration. To control for the effect of sex differences, 2 independent sets of single-variable and multivariate logistic regression analyses were performed with quartiles divided into non-sex-specific and sex-specific cutoff values for UA. Results: In non-sex-specific quartiles, the participants in the highest quartiles of UA levels were found to be at a significantly higher risk of cognitive deterioration than those in the lowest quartiles. In sex-specific quartiles, the highest quartile showed an increased risk of cognitive deterioration, and a greater than fourfold increase in the risk in the highest quartiles was confirmed using multivariate regression models. However, no significant association was observed between serum UA levels and the presence of white matter lesions. Conclusions: Elevated serum UA levels were independently associated with cognitive deterioration. UA might have unknown adverse effects on cognitive function, other than causing vascular pathology.


The early detection of cognitive deterioration in normal populations attending medical checkups of the brain

Background: The identification of preclinical cognitive markers of dementia is a crucial step in the search for the etiology and the development of therapeutic measures. Longitudinal studies with large samples of older individuals can identify potential markers by comparing the baseline performance of participants who remained cognitively healthy to those who became demented. Methods: In the ongoing Basel study on the Elderly (BASEL), an ApoE-E4-enriched sample of cognitively healthy participants (n 1⁄4 848; 377 women, 471 men; age 6 SD 1⁄4 69.4 6 7.89; education 6 SD 1⁄4 12.1 6 3.01, MMSE 6 SD 1⁄4 28.6 6 1.45, ApoE-E4 1⁄4 36.4%) were enrolled between 1997 and 2001 (baseline) and assessed with a comprehensive neuropsychological battery at baseline and bi-annually. To date, 51 participants (ie, NC-DEM) obtained a diagnosis of dementia an average of 6.9 6 2.8 years after baseline (probable AD: N 1⁄4 26, Vascular Dementia N1⁄4 2, Mixed causes N1⁄4 13, Not-otherwise-specified: N1⁄4 10): 19 women, 32 men; baseline age 6 SD1⁄4 73.8 6 5.56 and MMSE 6 SD1⁄4 28.2 6 1.59; education 6 SD1⁄4 12.3 6 3.44; ApoE-E41⁄4 43%). T-tests were used to compare the NC-DEM group’s baseline neuropsychological performance to that of a pairwise matched group of 51 participants (ie, NC-NC; 19 women, 32 men; baseline age 6 SD 1⁄4 73.8 6 5.75 and MMSE 6 SD 1⁄4 28.7 6 1.10; education 6 SD1⁄4 12.1 6 3.01; ApoE-E41⁄4 43%) who remained cognitively healthy an average of 8.3 6 2.9 years after baseline. Results: The comparison of baseline data revealed that NC-DEM participants performed significantly worse than NC-NC participants on word-list learning (p 1⁄4 .008), recall (p 1⁄4 .002) and recognition (p 1⁄4 .008), figural recall (p 1⁄4 0.005), block design (p 1⁄4 .001) and odor identification test for coffee (p 1⁄4 .003). No differences were found on: informantor self-report, depressive symptoms, psychomotor speed, general intellectual abilities, constructive abilities, measures of attention and executive functions. Conclusions: Comprehensive neuropsychological testing showed that memory functions are primarily affected in the preclinical stage of dementia, an average of seven years preceding diagnosis.