Takaaki Mori

Caregiver burden associated with behavioral and psychological symptoms of dementia in elderly people in the local community

Background: Despite many studies about the association between caregiver burden and behavioral and psychological symptoms of dementia (BPSD), there have been no population-based studies to evaluate caregiver burden associated with each BPSD. Objective: To evaluate caregiver burden associated with the individual BPSD in elderly people living in the community. Methods: The subjects were 67 participants with dementia living with their caregivers (diagnosed in the third Nakayama study): 51 Alzheimer’s disease, 5 vascular dementia and 11 other. The Neuropsychiatric Inventory (NPI) and NPI Caregiver Distress Scale (NPI-D) were used to assess subjects’ BPSD and related caregiver distress, respectively. Results: In the subjects exhibiting BPSD, aberrant motor behavior had the highest mean NPI score, and depression/dysphoria had the lowest. Agitation/aggression had the highest mean NPI-D score, and euphoria/elation had the lowest. Delusion, agitation/aggression, apathy/indifference, irritability/lability and aberrant motor behavior showed a correlation between the NPI and NPI-D scores. Conclusion: The burden associated with BPSD is different for each symptom and does not always depend on frequency and severity of BPSD. These findings suggest that some symptoms, such as agitation/aggression and irritability/lability, may affect the caregivers significantly, although their frequency and severity are low.

Frequency and Clinical Characteristics of Early-Onset Dementia in Consecutive Patients in a Memory Clinic

Aims: To investigate the frequency, rate of causes of dementia, and clinical characteristics of early-onset dementia in consecutive patients of a memory clinic. Methods: A total of 668 consecutive demented patients were involved in this study. We examined the distribution of patients’ diagnosis, differences in sex, education, dementia severity and cognitive function at the first visit, and the duration from onset to consultation. We also examined the changes in the proportion of subjects during the research period. Results: There were 185 early-onset patients, 28% of all demented patients. No significant differences were observed between the early-onset and late-onset dementia groups in Clinical Dementia Rating and Mini-Mental State Examination score at the first consultation, but the duration from onset to consultation was significantly longer in the early-onset group. In the early-onset group, the rates of patients with Alzheimer’s disease and dementia with Lewy bodies were relatively low and the rate of patients with frontotemporal lobar degeneration was relatively high. There were no significant differences in the proportion between either demented subjects and nondemented subjects or early-onset dementia patients and late-onset dementia patients during the research period. Conclusion: We conclude that early-onset dementia is not rare and its clinical characteristics and causes are different from late-onset dementia.

Correlation of visual hallucinations with occipital rCBF changes by donepezil in DLB

The authors explored the neural substrate of visual hallucinations in dementia with Lewy bodies (DLB) by investigating changes in regional cerebral blood flow (rCBF) and psychiatric symptoms, before and after cholinesterase inhibitor treatment. Twenty subjects with DLB were treated with donepezil for a 12-week period. Hallucinations attenuated while receiving therapy, whereas occipital rCBF focally increased, suggesting that functional visual association cortex deficits may cause visual hallucinations in patients with DLB.

Apathy correlates with prefrontal amyloid β deposition in Alzheimer's disease

Objective Neuropsychiatric symptoms affect many patients with Alzheimers disease (AD). (11C)Pittsburgh Compound-B (PIB) positron emission tomography (PET) has enabled the in vivo visualisation of brain amyloid-β (Aβ) deposition. This study exploratively investigated the correlation between brain Aβ deposition measured by (11C)PIB PET and neuropsychiatric symptoms in AD. Methods Participants were 28 patients (15 women, 13 men) with PIB-positive AD. Clinical assessments included Mini-Mental State Examination, Clinical Dementia Rating scale, neuropsychiatry inventory (NPI) and frontal assessment battery. All patients underwent three-dimensional T1-weighted MRI and (11C)PIB PET. The distribution volume ratio (DVR), an index of (11C)PIB retention and, thus, Aβ deposition, was estimated voxel by voxel from (11C)PIB PET data with partial volume correction. Voxel-based correlation analysis was performed to assess the relationships between DVR and each NPI subscale. Additionally, voxel-based analysis of covariance (ANCOVA) of the DVR images was performed between Patients with AD with and without each neuropsychiatric symptom. Voxel-based morphometry analysis of MRI was also performed. Results Apathy subscale was correlated with (11C)PIB retention in the bilateral frontal and right anterior cingulate. (11C)PIB retention was greater in the bilateral frontal cortex of patients with AD with apathy than those of without apathy. Overlapping areas between the two analyses were the bilateral orbitofrontal gyrus and left superior frontal gyrus. Other NPI subscales were not correlated with (11C)PIB retention. Voxel-based morphometry analysis of MRI showed no significant cluster of correlation between grey matter volume and NPI subscales. Conclusions This study revealed that prefrontal Aβ deposition correlates with apathy.

DNA methylation changes at SNCA intron 1 in patients with dementia with Lewy bodies

It is difficult to diagnose dementia with Lewy bodies (DLB) because it exhibits clinical and neuropathological overlap with both Alzheimers disease and Parkinsons disease. The α‐synuclein protein is a major component of Lewy bodies, and accumulation of α‐synuclein aggregates causes synaptic dysfunction in DLB. Epigenetic changes at the synuclein alpha ( SNCA ) gene may be involved in DLB pathogenesis.

Molecular imaging of dementia

Diagnosis and treatment strategies for dementia are based on the sensitive and specific detection of the incipient neuropathological characteristics, combined with emerging treatments that counteract molecular processes in its pathogenesis. Positron emission tomography (PET) is used for diverse clinical and basic studies on dementia with a wide range of radiotracers. Approaches to visualize amyloid deposition in human brains non‐invasively with PET depend on imaging agents reacting with amyloid fibrils. The most widely used tracer is [11C]‐6‐OH‐BTA‐1, also known as Pittsburgh Compound‐B, which has a high affinity to amyloid β peptide (Aβ) aggregates. Some 18F‐labeled amyloid ligands with a longer radioactive half‐life have also been developed for broader clinical applications. In addition, there have been demonstrated advantages of tracers with high specific radioactivity in the sensitive detection of amyloid, which have indicated the significance of Aβ‐N3‐pyroglutamate as a new diagnostic and therapeutic target. Furthermore, beneficial outcomes of Aβ and tau immunization in humans and mouse models have highlighted crucial roles of immunocompetent glia in the protection of neurons against amyloid toxicities. The utility of PET with a radioligand for translocator protein as a biomarker for tau‐triggered toxicity, and as a complement to amyloid and tau imaging for diagnostic assessment of tauopathies with and without Aβ pathologies, has also been demonstrated. Meanwhile, brain cholinergic function can be estimated by measuring acetylcholinesterase activity in the brain with PET and radiolabeled acetylcholine analogues. It has been reported that patients with early Parkinsons disease exhibit a reduction in acetylcholinesterase activity in the cerebral cortex, and this decline is more profound in patients with Parkinsons disease with dementia and dementia with Lewy bodies than in patients with Parkinsons disease without dementia. The Alzheimers Disease Neuroimaging Initiative was a multicentre research project conducted over 6 years that studied changes in cognition, brain structure, and biomarkers in healthy elderly controls and subjects with mild cognitive impairment and Alzheimers disease. An international workgroup of the National Institute on Aging‐Alzheimers Association has suggested that Alzheimers disease would be optimally treated before significant cognitive impairment, defined as a ‘presymptomatic’ or ‘preclinical’ stage. Therefore, PET will be of technical importance for both clinical and basic research aimed at prodromal pathologies of Alzheimers disease.

Transition of Distinctive Symptoms of Semantic Dementia during Longitudinal Clinical Observation

Background/Aims: The aim of this study is to examine the clinical symptoms in a number of semantic dementia (SD) patients and to reveal the longitudinal progression and clinical course of these distinctive symptoms of SD. Methods: 19 consecutive SD patients were examined. Symptoms were classified into 23 distinct categories: behavioral symptoms, language and cognitive symptoms and symptoms concerning the impairment of activities of daily living (ADL). We divided patients into two subgroups, left- and right-dominant SD, and compared the onset of each symptom. Results: Language impairments occurred as the initial symptom in 16 cases. At the first examination, all cases showed both anomia and impairment of word comprehension. By around 3 years after onset, almost all language impairments were observed. Approximately 3–5 years after onset, prosopagnosia and behavioral symptoms appeared. Around the period when the loss of the language faculty and apathy became remarkable, impairment of ADL appeared. Patients spent all day in bed at this stage. Moreover, prosopagnosia appeared significantly earlier in right-dominant SD. Conclusion: Our findings clarify the progression of distinctive symptoms of SD patients. It is necessary to create a treatment strategy for SD patients with such a disease-specific course of SD.

Regional cerebral blood flow change in a case of Alzheimer's disease with musical hallucinations

We examined alteration of regional cerebral blood flow (rCBF) in a case of Alzheimers disease (AD) patient with musical hallucination. To detect regions related to musical hallucination, single–photon emission computed tomography (SPECT) imaging of the patient and nine sex, age, and cognitive functionmatched AD patients without delusions and hallucinations were compared using statistical parametric mapping 99 (SPM99). In comparison with controls, the patient had increased rCBF in left temporal regions and left angular gyrus. This profile could be relevant to the neuroanatomical basis of musical hallucinations.

TREM2 mRNA Expression in Leukocytes Is Increased in Alzheimer’s Disease and Schizophrenia

TREM2 and TYROBP are causal genes for Nasu–Hakola disease (NHD), a rare autosomal recessive disease characterized by bone lesions and early-onset progressive dementia. TREM2 forms a receptor signaling complex with TYROBP, which triggers the activation of immune responses in macrophages and dendritic cells, and the functional polymorphism of TREM2 is reported to be associated with neurodegenerative disorders such as Alzheimer’s disease (AD). The objective of this study was to reveal the involvement of TYROBP and TREM2 in the pathophysiology of AD and schizophrenia. Methods: We investigated the mRNA expression level of the 2 genes in leukocytes of 26 patients with AD and 24 with schizophrenia in comparison with age-matched controls. Moreover, we performed gene association analysis between these 2 genes and schizophrenia. Results: No differences were found in TYROBP mRNA expression in patients with AD and schizophrenia; however, TREM2 mRNA expression was increased in patients with AD and schizophrenia compared with controls (P < 0.001). There were no genetic associations of either gene with schizophrenia in Japanese patients. Conclusion: TREM2 expression in leukocytes is elevated not only in AD but also in schizophrenia. Inflammatory processes involving TREM2 may occur in schizophrenia, as observed in neurocognitive disorders such as AD. TREM2 expression in leukocytes may be a novel biomarker for neurological and psychiatric disorders.

Differences of Behavioral and Psychological Symptoms of Dementia in Disease Severity in Four Major Dementias

Background/Aims Behavioral and psychological symptoms of dementia (BPSDs) negatively impact the prognosis of dementia patients and increase caregiver distress. The aims of this study were to clarify the differences of trajectories of 12 kinds of BPSDs by disease severity in four major dementias and to develop charts showing the frequency, severity, and associated caregiver distress (ACD) of BPSDs using the data of a Japan multicenter study (J-BIRD). Methods We gathered Neuropsychiatric Inventory (NPI) data of patients with Alzheimer’s disease (AD; n = 1091), dementia with Lewy bodies (DLB; n = 249), vascular dementia (VaD; n = 156), and frontotemporal lobar degeneration (FTLD; n = 102) collected during a 5-year period up to July 31, 2013 in seven centers for dementia in Japan. The NPI composite scores (frequency × severity) of 12 kinds of items were analyzed using a principal component analysis (PCA) in each dementia. The factor scores of the PCA were compared in each dementia by disease severity, which was determined with Clinical Dementia Rating (CDR). Results Significant increases with higher CDR scores were observed in 1) two of the three factor scores which were loaded for all items except euphoria in AD, 2) two of the four factor scores for apathy, aberrant motor behavior (AMB), sleep disturbances, agitation, irritability, disinhibition, and euphoria in DLB, and 3) one of the four factor scores for apathy, depression, anxiety, and sleep disturbances in VaD. However, no increases were observed in any of the five factor scores in FTLD. Conclusions As dementia progresses, several BPSDs become more severe, including 1) apathy and sleep disturbances in AD, DLB, and VaD, 2) all of the BPSDs except euphoria in AD, 3) AMB, agitation, irritability, disinhibition, and euphoria in DLB, and 4) depression and anxiety in VaD. Trajectories of BPSDs in FTLD were unclear.