Etsuko Oshima

Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies

Lithium, a widely used drug for treating affective disorders, is known to inhibit glycogen synthase kinase-3 (GSK-3), which is one of the major tau kinases. Thus, lithium could have therapeutic benefit in neurodegenerative tauopathies by reducing tau hyperphosphorylation. We tested this hypothesis and showed that long-term administration of lithium at relatively low therapeutic concentrations to transgenic mice that recapitulate Alzheimer’s disease (AD)-like tau pathologies reduces tau lesions, primarily by promoting their ubiquitination rather than by inhibiting tau phosphorylation. These findings suggest novel mechanisms whereby lithium treatment could ameliorate tauopathies including AD. Because lithium also has been shown to reduce the burden of amyloid-β pathologies, it is plausible that lithium could reduce the formation of both amyloid plaques and tau tangles, the two pathological hallmarks of AD, and thereby ameliorate the behavioral deficits in AD.

Validation of Addenbrooke's cognitive examination for detecting early dementia in a Japanese population.

There is a clear need for brief, but sensitive and specific, cognitive screening instruments for dementia. We assessed the diagnostic accuracy of the Japanese version of Addenbrookes Cognitive Examination (ACE) in identifying early dementia in comparison with the conventional Mini-Mental State Examination (MMSE). Standard tests for evaluating dementia screening tests were applied. A total of 201 subjects (Alzheimers disease (AD)=65, frontotemporal dementia (FTD)=24, vascular dementia=26, dementia with Lewy bodies=11, mild cognitive impairment (MCI)=13, and controls=62) participated in this study. The reliability of the ACE was very good (alpha coefficient=0.82). In our patient series, the sensitivity for diagnosing dementia with an ACE score of ≤74 was 0.889 with a specificity of 0.987, and the sensitivity of an ACE score of ≤80 was 0.984 with a specificity of 0.867. The Japanese version of the ACE is a very accurate instrument for the detection of early dementia, and should be widely used in clinical practice.

Validation of the revised Addenbrooke's Cognitive Examination (ACE-R) for detecting mild cognitive impairment and dementia in a Japanese population

BACKGROUND Early detection of dementia will be important for implementation of disease-modifying treatments in the near future. We aimed to investigate the diagnostic validity and reliability of the Japanese version of the revised Addenbrookes Cognitive Examination (ACE-R J) for identifying mild cognitive impairment (MCI) and dementia. METHODS We translated and adapted the original ACE-R for use with a Japanese population. Standard tests for evaluating cognitive decline and dementing disorders were applied. A total of 242 subjects (controls = 73, MCI = 39, dementia = 130) participated in this study. RESULTS The optimal cut-off scores of ACE-R J for detecting MCI and dementia were 88/89 (sensitivity 0.87, specificity 0.92) and 82/83 (sensitivity 0.99, specificity 0.99) respectively. ACE-R J was superior to the Mini-Mental State Examination in the detection of MCI (area under the curve (AUC): 0.952 vs. 0.868), while the accuracy of the two instruments did not differ significantly in identifying dementia (AUC: 0.999 vs. 0.993). The inter-rater reliability (ICC = 0.999), test-retest reliability (ICC = 0.883), and internal consistency (Cronbachs α = 0.903) of ACE-R J were excellent. CONCLUSION ACE-R J proved to be an accurate cognitive instrument for detecting MCI and mild dementia. Further neuropsychological evaluation is required for the differential diagnosis of dementia subtypes.

Abuse of people with cognitive impairment by family caregivers in Japan (a cross-sectional study)

Caregiving is often stressful in an aging society. Our research questions were two. First, In Japan, how often does abusive behavior by the caregivers of elders with clinically mild cognitive dysfunction (mild cognitive impairment and clinically mild dementia) occur? Second, what risk factors affect the abusive behavior? We studied 123 Japanese caregivers and care recipients who had been referred to the Memory Clinic at Okayama University Hospital. We used the Japanese version of the modified Conflict Tactics Scale (m-CTS) to measure abusive behaviors. We estimate the prevalence of abusive behavior meeting threshold (m-CTS score of 2 or higher) for abuse case on the modified m-CTS. The prevalence of abusive behavior was 15.4%. Stepwise multiple regression analysis revealed that the sex of caregivers and scores on the Neuropsychiatric Inventory (NPI), Zarit Caregiver Burden scale, and Addenbrookes Cognitive Examination had significant effects on the m-CTS scores. We demonstrated that in Japan, caregivers of the elderly with even clinically mild cognitive dysfunction exhibit abusive behavior toward them. The severity of the disease might reflect the prevalence of and factors that affect the abusive conflict score.

Person-centered care and quality of life of patients with dementia in long-term care facilities.

Good quality of life (QOL) is an important goal of dementia care. However, there have been few studies on the relationship of care characteristics to QOL of dementia patients in long-term care facilities. We developed a questionnaire evaluating person-centered care and used it to assess person-centered care and QOL of elderly patients with dementia in both geriatric health service facilities (GHSF) and hospitals. In GHSF, person-centered care scores were not correlated with cognitive or activities of daily living (ADL) functions, but were significantly correlated with four subscale scores on a quality of life questionnaire for dementia (QOL-D) after controlling the effect of age, cognitive function, and ADL scores. In contrast, in hospitals, person-centered care scores were significantly correlated with cognitive and ADL function. We found quite different patterns in the relationship of person-centered care scores to clinical characteristics. Dementia care characteristics and QOL of dementia patients are significantly interrelated, especially in GHSF. Improvement of dementia care standards might affect the QOL of dementia patients. We should pay more attention to the quality of dementia care and QOL of dementia patients.

Trail making test B and brain perfusion imaging in mild cognitive impairment and mild Alzheimer's disease.

The trail making test (TMT) has long been used to investigate deficits in cognitive processing speed and executive function in humans. However, there are few studies that elucidate the neural substrates of the TMT. The aim of the present study was to identify the brain regional perfusion patterns associated with performance on TMT part B (TMT-B) in patients with amnestic mild cognitive impairment (aMCI) or mild Alzheimers disease (AD). Twenty-one patients with good TMT-B scores and 21 age- and sex-matched patients with poor TMT-B scores were selected. All 42 subjects underwent brain single photon emission computed tomography (SPECT), and the SPECT images were analyzed by statistical parametric mapping. No significant differences between good- and poor-scoring groups were found with respect to years of education, Addenbrookes Cognitive Examination scores, and scores on TMT-A. Compared to patients with good scores on TMT-B, patients with poor scores showed significant hypoperfusion in the bilateral anterior cingulate extending to the posterior region on the right side, bilateral caudate nucleus and putamen, and bilateral thalamus. Analysis of 63 AD or aMCI subjects revealed significant correlation a between regional cerebral blood flow in the right cingulate cortex and TMT-B scores. Our results suggest that functional activity of the anterior cingulate, striatum and thalamus is closely related to performance time on TMT-B. The performance time on the TMT-B score might be a promising index of dysfunction of the anterior cingulate, striatum, and thalamus among patients with aMCI or mild AD.

Frontal assessment battery and brain perfusion imaging in Alzheimer's disease

BACKGROUND The frontal assessment battery (FAB) is reported to be a useful tool for assessing frontal dysfunction. However, the neural substrates involved in patients with Alzheimers disease (AD) remain to be elucidated. The aim of the present study was to identify the regional perfusion patterns of the brain associated with performance scores on the FAB of patients with AD using brain perfusion assessed by single photon emission computed tomography (SPECT). METHODS Twenty-four AD patients with high scores and 24 age- and sex-matched AD patients with low scores on the FAB were selected from 470 consecutive Japanese patients of the Memory Clinic of Okayama University Hospital. All 48 participants underwent brain SPECT with 99mTc-ethylcysteinate dimer, and the SPECT images were analyzed by statistical parametric mapping. RESULTS No significant differences were found between high and low FAB scoring groups with respect to Addenbrookes Cognitive Examination scores, Mini-Mental State Examination scores, or the depression score of the Neuropsychiatric Inventory subscale. Compared with patients with high scores on the FAB, AD patients with low scores showed significant hypoperfusion in the left middle frontal gyrus (MFG) and the right superior frontal gyrus (SFG) extending to the left SFG. CONCLUSION Our results suggest that functional activity of the SFG and MFG is closely related to the FAB score. The FAB might be a promising strategy to detect early stages of AD with low SFG and MFG function.

Wisconsin card sorting test and brain perfusion imaging in early dementia.

Background/Aims: The presence of frontal or executive deficits in patients even at early stages of dementia is now widely recognized. We investigated the relationship between the scores of the Wisconsin card sorting test (WCST) and brain perfusion in patients with early dementia. Methods: A total of 77 subjects participated in this study. They underwent the WCST and brain single photon emission computed tomography with 99mTc-ethylcisteinate dimer. We analyzed the data using a regional cerebral blood flow (rCBF) quantification software program, 3DSRT. Results: The number of categories achieved (CA) scores of the WCST had a weakly positive correlation with regional cerebral blood flow in the bilateral precentral, bilateral callosomarginal, bilateral pericallosal, right thalamus, left central and left parietal segments. The number of perseverative errors of the Nelson type (PEN) scores had a weakly negative correlation with rCBF in the right thalamus. Conclusion: The results in this study suggest that CA scores mainly reflect the function of the precentral segments, especially the left side, and that PEN scores correlate with rCBF in the right thalamus. The results suggest that CA scores and PEN scores should be differentially estimated in the WCST.

Depressive symptoms and regional cerebral blood flow in Alzheimer's disease

Depressive symptoms are common in patients with Alzheimers disease (AD) and increase the caregiver burden, although the etiology and pathologic mechanism of depressive symptoms in AD patients remain unclear. In this study, we tried to clarify the cerebral blood flow (CBF) correlates of depressive symptoms in AD, excluding the effect of apathy and anxiety. Seventy-nine consecutive patients with AD were recruited from outpatient units of the Memory Clinic of Okayama University Hospital. The level of depressive symptoms was evaluated using the depression domain of the Neuropsychiatric Inventory (NPI). The patients underwent brain SPECT with 99mTc-ethylcysteinate dimer. After removing the effects of age, anxiety and apathy scores of NPI, and five subscales of Addenbrookes Cognitive Examination-revised (ACE-R), correlation analysis of NPI depression scores showed a significant cluster of voxels in the left middle frontal gyrus (Brodmann area 9), similar to the areas in the simple correlation analysis. The dorsolateral prefrontal area is significantly involved in the pathogenesis of depressive symptoms in AD, and the area on the left side especially may be closely related to the depressive symptoms revealed by NPI.

Accelerated Tau Aggregation, Apoptosis and Neurological Dysfunction Caused by Chronic Oral Administration of Aluminum in a Mouse Model of Tauopathies

To clarify whether long‐term oral ingestion of aluminum (Al) can increase tau aggregation in mammals, we examined the effects of oral Al administration on tau accumulation, apoptosis in the central nervous system (CNS) and motor function using tau transgenic (Tg) mice that show very slowly progressive tau accumulation. Al‐treated tau Tg mice had almost twice as many tau‐positive inclusions in the spinal cord as tau Tg mice without Al treatment at 12 months of age, a difference that reached statistical significance, and the development of pretangle‐like tau aggregates in the brain was also significantly advanced from 9 months. Al exposure did not induce any tau pathology in wild‐type (WT) mice. Apoptosis was observed in the hippocampus in Al‐treated tau Tg mice, but was virtually absent in the other experimental groups. Motor function as assessed by the tail suspension test was most severely impaired in Al‐treated tau Tg mice. Given our results, chronic oral ingestion of Al may more strongly promote tau aggregation, apoptosis and neurological dysfunction if individuals already had a pathological process causing tau aggregation. These findings may also implicate chronic Al neurotoxicity in humans, who frequently have had mild tau pathology from a young age.