Search

Frontotemporal lobar degeneration (FTLD) is a comprehensive term encompassing a group of clinically overlapping but heterogeneous conditions with selective frontal and temporal lobar neurodegeneration. Among the three clinical subtypes of FTLD, behavioral variant frontotemporal dementia (bvFTD) and semantic dementia (SD) were specified as "designated intractable diseases" by the Japanese Ministry of Health, Labor and Welfare in 2015. Under this designation system, relatively young patient with bvFTD or SD of certain severities can receive partial financial support from the Japanese local government. Here we introduce financial and social support for FTLD, including utilization of the designated intractable disease system and other support available in Japan. In addition, we describe the methods for coping and care of prominent symptoms in FTLD. Lastly, we address the current status of a nationwide Japanese FTLD study cohort named FTLD-J.

Aside from the current conventional pharmaceutical therapies that have limited effects on patients with Alzheimer's disease, disease-modifying therapies have been developed to inhibit the pathological processes of Alzheimer's disease. These include immunotherapies, β/γ secretase inhibitors, and aggregation inhibitors targeting amyloid β. The involvement of genetic risk factors in the effectiveness of such processes has been confirmed. For example, apolipoprotein E ε4 carriers have been reported to have a risk of ARIA (Amyloid Related Imaging Abnormality) as an adverse effect by those therapies. In this paper, we review clinical studies examining patients with Alzheimer's disease, having genetic risk factors.

The Dominantly Inherited Alzheimer's Network (DIAN) observational study compared pathophysiological markers between mutation carriers and non-carriers in autosomal dominant Alzheimer's disease. This study revealed that changes in the biomarkers in the mutation carrier's brain start as early as 20 or even 25 years prior to the onset of symptoms. Doctors of the DIAN-Japan team have successfully implemented the DIAN study in Japan (DIAN-J) with effort and enthusiasm. The DIAN-J study is completely compatible with the DIAN study. All members of the DIAN-J team were certified by the NIH and Washington University. The DIAN researchers started a prevention trial (DIAN-TU) testing two monoclonal antibodies in 2013. Together with the DIAN global members including the Japanese team, they will start the new DIAN-TU NexGen Trial testing a BACE inhibitor in 2017. The API study is another clinical trial of anti-amyloid monoclonal antibody therapy for family members of patients with early-onset familial AD who carry the PSEN1 E280A mutation. This study has shown the same biomarker changes that were reported in the DIAN study.

Cerebral small vessel disease (SVD), including subcortical lacunar infarcts (lacunes) and white matter hyperintensities (WMH), is commonly observed on MRI of elderly individuals with and without dementia. SVD is frequently observed in patients with Alzheimer's disease (AD). However, the association between SVD and clinical symptoms exhibited by patients with AD remains unclear. Our recent studies suggest that cerebral SVD observed on CT/MRI of patients with AD is associated with delusions and delirium as well as depression. Mechanisms underlying these psychiatric symptoms in patients with AD remain unclear.

John Russell Hodges is an English behavioral neurologist, who is mainly engaged in neuropsychological research for neurocognitive disorders. He contributed to symptomatology of transient global amnesia (TGA), semantic dementia, and behavioral variant frontotemporal dementia (bvFTD). Extensive features of his research work are based on his excellent clinician's approach and his outstanding neuropsychological viewpoint, always keeping that neural basis of the symptoms using neuroimaging and neuropathological techniques, and concerning cure and care for patients. Collaboration with psychiatrists, neuroradiologists, neuropsychologists, neuropathologists, social workers, occupational therapists, research nurses, molecular biologists have supported his broad research work. Karalyn Patterson who is an outstanding clinical and experimental neuropsychologist has been particularly important guiding light for his clinical research. He is an excellent clinician and also looks like a commander of a large and well organized research group.

Hirotaka Tanabe was a Japanese neuropsychiatrist engaged in neuropsychological research on cerebrovascular disease and dementia. He contributed widely to the symptomatology of dementia, especially in the field of frontotemporal dementia (FTD). He focused on clarifying the clinical features of a language disturbance, termed Gogi-aphasia by Imura (1943), in 7 patients with anterior temporal circumscribed atrophy. He attributed the nature of Gogi-aphasia to a selective impairment of semantic memory for words and proposed that the pathological process of lobar atrophy with temporal predominance might affect the semantic memory system. In addition, he described in detail the behavioral symptoms of FTD. In his later years, he adovocated a neuropsychological approach to psychiatry.

Objective: The Cognitive Fluctuation Inventory (CFI) was developed to evaluate cognitive fluctuation in patients with dementia with Lewy bodies (DLB). The objective of this study was to assess the content validity and inter-rater reliability of the CFI., Subjects and Methods: Nine specialists in DLB treatment were invited to participate in the survey to assess the content validity of the CFI. They were asked to assess the relevance and comprehensibility of the question items. In the validation study, inter-rater reliability was assessed using the intraclass correlation coefficient (ICC)., Results: Regarding content validity, all nine specialists considered the main question and sub-questions to be relevant to cognitive fluctuation in patients with DLB. Eight out of nine specialists considered the CFI to be a comprehensive measure for detecting cognitive fluctuation in patients with DLB. In the analysis, which used data from 29 patients and their caregivers, the ICC of the CFI was 0.746, which suggests good inter-rater reliability., Conclusion: We found that the CFI showed good content validity and inter-rater reliability for evaluating cognitive fluctuation in patients with DLB.

The Japanese government has tried to establish 150 Medical Centers for Dementia (MCDs) since 2008 to overcome the dementia medical service shortage. MCDs are required to provide special medical services for dementia and connect with other community resources in order to contribute to building a comprehensive support network for demented patients. The main specific needs are as follows: 1) special medical consultation; 2) differential diagnosis and early intervention; 3) medical treatment for the acute stage of BPSD; 4) corresponding to serious physical complications of dementia; 5) education for general physicians (GPs) and other community professionals. According to the population rate, two dementia medical centers were planned in Kumamoto Prefecture. However, it seemed to be too few to cover the vast Kumamoto area. Therefore, the local government and I proposed to the Japanese government that we build up networks that consist of one core MCD in our university hospital and several regional MCDs in local mental hospitals. The local government selected seven (nine at present) centers according to the area balance and condition of equipment. The Japanese government has recommended and funded such networks between core and regional centers since 2010. The main roles of the core centers are as follows: 1) early diagnosis such as Mild cognitive impairment, very mild Alzheimer's disease, Dementia with Lewy bodies, and Frontotemporal lobar degeneration using comprehensive neuropsychological batteries and neuroimagings, such as MRI and SPECT scans; 2) education for GPs; 3) training for young consultants. The core center opens case conferences at least every one or two months for all staff of regional centers to maintain the quality of all centers and give training opportunities for standardized international assessment scales. While the main roles of the regional centers are differential diagnosis, intervention for BPSD, and management of general medical problems using local networks with general hospitals and GPs, and organizing local networks for dementia with GPs and care staff In short, the regional centers take responsibility for ordinal clinical work for dementia. To construct a more extensive network, each regional center must hold regional case conferences and lectures on dementia for care staff and GPs sharing knowledge and skills acquired from case conferences by the core center.

Apathy includes aspontaneous, indifferent behavior, with loss of motor and affective drive. Apathy is related to the disruption, at various anatomical sites, of frontosubcortical pathways, such as anterior cingulate and bithalamic lesions. Apathy was frequently reported in patients with Alzheimer's disease, post-stroke, and frontotemporal dementia. It is very important to distinguish apathy from depression by the therapeutic view point.

It has been noted the relationship between depression and dementia in elderly. The prevalence of depression in Alzheimer's disease (AD) was reported 20 to 30% in population-based study. Apathy was more frequently observed than depression among demented outpatients in our study. Whereas the apathy has been considered to be a kind of depression traditionally, it has been found that the apathy is distinct from depression recently. In our clinical practice, we frequently realize the close relationship between depression and dementia. It has been reported that risk of AD was 1.71 (odds ratio) in the history of depression more than 25 years ago, and interval between diagnoses of depression and AD was positively related to increased risk of developing AD, suggesting that rather than a prodrome, depression may be a risk factor for AD. Furthermore, Rotterdam Scan Study reported recently that the risk of AD increased to 3.76 in the history of pre-senile depression, while 2.34 in the history of senile depression. On the other hand, it is interesting but still controversial whether depression is associated with the conversion from mild cognitive impairment (MCI) into dementia. The underlying neuropathological condition that causes MCI or dementia might also cause depressive symptoms.

Aim: The aim of this study was to use the Rivermead Behavioural Memory Test (RBMT) to evaluate everyday memory impairment among community-dwelling elderly who had normal cognitive function and performed daily activities normally but displayed memory impairments,and to diagnose the condition as either mild cognitive impairment or dementia., Method: Among the 1,290 community-dwelling elderly persons who participated in the study, 72 subjects scored higher than 24 on the Mini-Mental State Examination (MMSE): these subjects performed daily activities normally, but their family members reported that they showed memory impairments. Fifty-two subjects completed RBMT, Clinical Dementia Rating, and brain computed tomography, and a final diagnosis was established., Results: The mean standard profile score was 15.1+/-5.0 and mean screening score was 6.4+/-3.0. RBMT score was correlated with the MMSE score. Nine of the subjects were diagnosed with dementia and 26 of them were found to be normal. RBMT achieved 100% sensitivity and specificity with regard to the differentiation of subjects with Alzheimer's disease. However, some subjects were diagnosed with dementia even though their RBMT score was higher than the cut-off score., Conclusion: RBMT was useful in detecting memory impairments of AD subjects in community-based surveys. However, some subjects were diagnosed with dementia because of the existence of other cognitive impairments among community-dwelling elderly.

In frontotemporal lobar degeneration (FTLD), which primarily involves the front of the brain, characteristic psychiatric symptoms and disordered behaviors, such as disinhibition and stereotypical behaviors, often appear in the foreground at the initial stages of the disease. It is therefore an extremely difficult disease to treat. However, unlike diseases such as Alzheimer's disease, which involve general dementia, there is a clear dissociation between the conserved and disordered functions; therefore, it is possible to enhance the conserved functions and simultaneously modify the disordered functions into adaptive behaviors in order to provide care and increase the quality of life (QOL). In this paper, we report the use of routinizing therapy, which is an occupational therapeutic approach, involving speech therapy for semantic dementia (SD), drug therapy for stereotypic behaviors and psychiatric symptoms of FTLD, family education, etc.

Objective: Neuropsychiatric disturbances are common and burdensome symptoms of dementia. Assessment and measurement of neuropsychiatric disturbances are indispensable to the management of patients with dementia. Neuropsychiatric Inventory (NPI) is a comprehensive assessment tool that evaluates psychiatric symptoms in dementia. The Nursing Home Version (NPI-NH) of NPI was developed for use in extended care facilitate caring for residents with dementia. We translated the NPI-NH into Japanese and examined their validity and reliability., Subjects and Methods: The subjects were 100 demented inpatients and the nurses in charge of them. The Mini-Mental State Examination (MMSE) was conducted with all patients and NPI-NH, Cohen-Mansfield Agitation Inventory (CMAI), Cornell Scale for Depression in Dementia (CSDD), and Behavior Pathology in Alzheimer's Disease (BEHAVE-AD) Rating Scale were conducted with the nurses. We examined validity of NPI-NH by comparing its score with the CMAI, CSDD, and BEHAVE-AD. In order to evaluate test-retest reliability, NPI-NH was re-adopted to 30 randomly selected nurses in charge inpatients by a different examiner 1 week later., Results: The frequency score, severity score and occupational disruptiveness score in each NPI-NH item were significantly correlated with the score of the correspondent item in BEHAVE-AD. The agitation score of NPI-NH was significantly correlated with CMAI and the depression score of NPI-NH was significantly correlated with CSDD. Test-retest reliability of the scores of NPI-NH was acceptably high., Conclusion: The Japanese version of NPI-NH demonstrated sufficient validity and reliability as well as the original version of them. It is a useful tool for evaluating psychiatric symptoms in demented inpatients.

Behavioral changes in patients with FTD can be interpreted by considering damage to the frontal lobes themselves and considering the interaction between the frontal lobes and other neural systems such as the posterior association cortices, the limbic system, and basal ganglia. Loss of insight and apathy primarily result from frontal lobes involvement. The latter is probably correlated with the severity of medial frontal-anterior cingulate involvement. Stimulus-bound behavior such as imitation behavior, utilization behavior and environmental dependency syndrome is caused by an imbalance between the activities of the frontal and parietal lobes. Frontal lobe damage, particularly damage to the medial frontal area, result in liberation of the parietal lobe activity, leaving the patient subject to any stimuli from the external environment. Disinhibition such as antisocial behavior is produced by an imbalance between the activities of the frontal and limbic lobes. Namely, loss of control of the frontal lobe, especially the orbitofrontal area, over the limbic system results in acts led by instinctive desires and uncontrolled by reason. Stereotypic behavior is due to an imbalance between the activities of the frontal cortex and basal ganglia. These behaviors range from simple stereotypies to complex repeated actions such as roaming, clock-watching or adherence to a strict daily timetable.

Objective: Neuropsychiatric disturbances are common and burdensome symptoms of dementia. Assessment and measurement of neuropsychiatric disturbances are indispensable to the management of patients with dementia. Neuropsychiatric Inventory (NPI) is a comprehensive assessment tool that evaluates psychiatric symptoms in dementia. We translated the NPI-Caregiver Distress Scale part of NPI (NPI-D) and NPI-Brief Questionnaire Form (NPI-Q) into Japanese and examined their validity and reliability., Subjects and Methods: The subjects were 152 demented patients and the caregivers who lived with them. These patients consisted of 76 women and 76 men; their mean age was 73.9 +/- 7.8 (S.D.; range: 49 to 93) years. Their caregivers consisted of 46 men and 106 women; their mean age was 65.0 +/- 11.4 (S.D.; range: 35 to 90) years. The Mini-Mental State Examination (MMSE) was conducted with all patients and NPI-Q, NPI, NPI-D, and the Zarit caregiver burden interview (ZBI) were conducted with all caregivers. We examined validity of NPI-D by comparing its score with the MMSE and ZBI scores, and the validity of NPI-Q by comparing its score with the NPI and NPI-D scores. In order to evaluate test-retest reliability, NPI-D was re-adopted to 30 randomly selected caregivers by a different examiner one month later and NPI-Q was re-executed by 27 randomly selected caregivers one day later., Results: Total NPI-D score was significantly correlated with ZBI (rs = 0.59, p < 0.01). Test-retest reliability of NPI-D was adequate (ri = 0.47, p < 0.01). Total NPI-Q severity score and distress score were strongly correlated with NPI (r = 0.77, p < 0.01) and NPI-D (r = 0.80, p < 0.01) scores, respectively. Test-retest reliability of the scores of NPI-Q was acceptably high (the severity score; ri = 0.81, p < 0.01, the distress score; ri = 0.80, p < 0.01)., Conclusion: The Japanese version of NPI-D and NPI-Q demonstrated sufficient validity and reliability as well as the original version of them. These are useful tools for evaluating psychiatric symptoms in demented patients and their caregivers' distress attributable to these symptoms.

Interventional studies, with the aim of reducing the burden of care through drug or non-drug therapies of behavioral and psychological symptoms of dementia (BPSD), have been scarce. However, we are now able to do pharmacological management for BPSD with new drugs such as atypical neuroleptics, SSRIs, and cholinesterase inhibitors. Delusions of theft are one of the most frequently observed BPSD in patients with AD. In addition, the delusions and ensuing aggression and anxiety are major factors that increase the burden of caregivers. Delusions of theft in patients with AD were eliminated or reduced with low-dose atypical neuroleptics (risperidone). This significantly reduced the burden of care overall for caregivers. New therapeutic strategies such as cholinesterase inhibitors for visual hallucinations in DLB and SSRIs for overeating and stereotyped behavior in FTLD might also remarkably reduce the burden of care for these patients. For many dementia patients, there are still no drugs that offer a principal cure. It is, therefore, important to evaluate their BPSD correctly at the earliest possible time, so that the burden of caring can be reduced through appropriate drug treatment. This reduction is critical for the continuation of satisfactory at-home care and might contribute to the health economics.

As a result of the growing proportion of drivers aged 65 years and older, it is estimated that the number of elderly drivers with dementia is increasing in Japan. Since June 2002, if a driver is found to be "demented", his/her driving license shall be revoked in Japan. However, there are no consensus guidelines for demented drivers. Between September 1995 and September 2001, we evaluated 30 drivers with dementia (19 males and 11 females, mean age of 69.4 years) in out patients clinic of the Kochi Medical School Hospital and related hospitals. Clinical Diagnosis was Alzheimer's disease in 20, vascular dementia in 3, mixed type dementia in 2, frontotemporal lobar degeneration in 4, other type dementia in 1. We analyzed their driving behavior and family's attitude. Seventy-three point three percent of 30 drivers with dementia continued to drive after diagnosis. In follow-up periods, number of drivers continuing driving was decreased to 13 (43.3%), while six drivers (27.3%) had a traffic accident or violation. Our study suggests that several important medical and social factors should be considered for the management of drivers with dementia. A consensus medical guideline for demented drivers has to be established.

To determine the prevalence of Mild Cognitive Impairment (MCI) in community dwelling elderly, a door to door population survey was carried out on all persons aged 65 years and older residing at home on the prevalence day (1 August 1999). All assessments were conducted by neuropsychiatrists. The diagnosis was made with the Geriatric Mental State (GMS)--Automated Geriatric Examination for Computed Assisted Taxonomy (AGECAT) (Copeland et al, 1986). AGECAT organicity levels 1 and 2 (sub-cases) are referred to as MCI. Of 1461 inhabitants, 1156 (79.1%) completed the protocol. The prevalence of MCI was 5.3%, with 1.7% organic brain syndrome level 2 and 3.6% organic brain syndrome level 1. MCI is associated with an increased risk of developing dementia. However, research on the prevalence of MCI has produced inconsistent data. The operational consensus criteria of MCI should be established for future community-based longitudinal study.

We report a 71-year-old woman showing rapidly progressive non-fluent aphasia and dementia accompanied by motor neuron disease (MND). There was no family history of dementia or motor neuron disease. There was 10 months history of dysarthria and dysphagia. On examination, she showed profound difficulty in articulation. Her comprehension was impaired in that she was unable to obey three-stage command. Her written language was also impaired with phonological spelling errors, syntactic errors, and perseveration. Neuroradiological investigations showed atrophic changes and hypoperfusion of left temporal and bilateral parietal region revealed by MRI and SPECT, respectively. Her subsequent decline was rapid. It might be likely that aphasia is much more common in dementia with bulbar MND than is currently recognized because bulbar palsy might mask the language disorder.