Pathogenesis and Personalized Interventions for Pharmacological Treatment-Resistant Neuropsychiatric Symptoms in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia, with cognitive impairment as a core symptom. Neuropsychiatric symptoms (NPSs) also occur as non-cognitive symptoms during the disease course, worsening the prognosis. Recent treatment guidelines for NPSs have recommended non-pharmacological treatments as the first line of therapy, followed by pharmacological treatments. However, pharmacological treatment for urgent NPSs can be difficult because of a lack of efficacy or an intolerance, requiring multiple changes in psychotropic prescriptions. One biological factor that might be partly responsible for this difficulty is structural deterioration in elderly people with dementia, which may cause a functional vulnerability affecting the pharmacological response. Other causative factors might include awkward psychosocial interpersonal relations between patients and their caregiver, resulting in distressful vicious circles. Overlapping NPS sub-symptoms can also blur the prioritization of targeted symptoms. Furthermore, consistent neurocognitive reductions cause a primary apathy state and a secondary distorted ideation or perception of present objects, leading to reactions that cannot be treated pharmacologically. The present review defines treatment-resistant NPSs in AD; it may be necessary and helpful for clinicians to discuss the pathogenesis and comprehensive solutions based on three major hypothetical pathophysiological viewpoints: (1) biology, (2) psychosociology, and (3) neurocognition

Longitudinal Changes in the Government-Certified Index Stage and Requisite Costs for Long-Term Care Insurance System among the Community-Dwelling Demented Elderly in Japan

Background. A new public long-term care (LTC) insurance was launched in 2000 in Japan. However, there have been few studies involving factors that increase LTC costs of demented subjects; no follow-up studies involving the Government-Certified Index (GCI) and requisite costs related to the causes of dementia. Method. An epidemiological survey was conducted in a rural area in Japan in 1999, and 271 subjects were diagnosed as dementia patients. Age, sex, mini-mental state examination, clinical dementia rating, activity of daily living, causes of dementia, and coexisting physical disease were confirmed. After the LTC insurance has been launched, we tracked the GCI stages and payment amounts every month for 8 years. Result. 209 subjects were certified to be eligible for LTC insurance; however, 13 did not receive any payment. Only 49 out of 209 were alive after the follow-up period. The most common cause of dementia was Alzheimer’s disease (AD), followed by vascular dementia (VaD). There was no significant difference between the mortality rates of the two groups. VaD subjects required higher costs than AD subjects in the total certified period and in GCI stage 5. Conclusion. Our results indicate that causes of dementia can have an impact on the requisite costs for the LTC insurance

When a Little Knowledge Can Be Dangerous: False-Positive Diagnosis of Behavioral Variant Frontotemporal Dementia among Community Clinicians.

BackgroundAccurate diagnosis of behavioral variant frontotemporal dementia (bvFTD) is important as patients' behavioral symptoms have profound implications for their families and communities. Since the diagnosis of bvFTD derives from behavioral features, accurate identification of patients can be difficult for non-specialists. Concrete rates of diagnostic accuracy among non-specialists are unavailable.MethodsTo examine the accuracy of community clinicians' diagnoses of bvFTD and to identify patient characteristics leading to misdiagnosis, we reviewed the charts and referral letters of 3,578 patients who were seen at our specialized center. Referral diagnosis and reasons, manifesting symptoms, demographic data, Mini-Mental State Examination score, Clinical Dementia Rating score and Neuropsychiatric Inventory score were extracted.Results60% of patients assigned a single diagnosis of bvFTD by community clinicians did not have bvFTD according to specialists. Compared to specialist-confirmed bvFTD patients, false bvFTD patients were more likely to be depressed and to be non-Caucasian, showed less euphoria, apathy, disinhibition and abnormal eating behaviors, had milder disease severity and better overall cognition. bvFTD was mentioned by referring clinicians in 86% of specialist-confirmed bvFTD cases, but missed cases were called Alzheimer's, Parkinson's or Huntington's disease, or progressive aphasia.ConclusionThese results revealed a widespread lack of familiarity with core diagnostic symptoms among non-specialists and suggest that community clinicians require specialized diagnostic support before providing a definitive diagnosis of bvFTD

When a Little Knowledge Can Be Dangerous: False-Positive Diagnosis of Behavioral Variant Frontotemporal Dementia among Community Clinicians

BACKGROUND: Accurate diagnosis of behavioral variant frontotemporal dementia (bvFTD) is important as patients’ behavioral symptoms have profound implications for their families and communities. Since the diagnosis of bvFTD derives from behavioral features, accurate identification of patients can be difficult for non-specialists. Concrete rates of diagnostic accuracy among non-specialists are unavailable. METHODS: To examine the accuracy of community clinicians’ diagnoses of bvFTD and to identify patient characteristics leading to misdiagnosis, we reviewed the charts and referral letters of 3,578 patients who were seen at our specialized center. Referral diagnosis and reasons, manifesting symptoms, demographic data, Mini-Mental State Examination score, Clinical Dementia Rating score and Neuropsychiatric Inventory score were extracted. RESULTS: 60% of patients assigned a single diagnosis of bvFTD by community clinicians did not have bvFTD according to specialists. Compared to specialist-confirmed bvFTD patients, false bvFTD patients were more likely to be depressed and to be non-Caucasian, showed less euphoria, apathy, disinhibition and abnormal eating behaviors, had milder disease severity and better overall cognition. bvFTD was mentioned by referring clinicians in 86% of specialist-confirmed bvFTD cases, but missed cases were called Alzheimer’s, Parkinson’s or Huntington’s disease, or progressive aphasia. CONCLUSION: These results revealed a widespread lack of familiarity with core diagnostic symptoms among non-specialists and suggest that community clinicians require specialized diagnostic support before providing a definitive diagnosis of bvFTD

Age-Related Association between Apolipoprotein E ε4 and Cognitive Function in Japanese Patients with Alzheimer's Disease

Aims: In the present study, we investigated whether apolipoprotein E (APOE) polymorphisms influenced the cognitive function of Japanese patients with Alzheimer's disease (AD) at certain ages. Methods: Among 200 outpatients with dementia and amnestic mild cognitive impairment, 133 Japanese patients with AD were recruited and divided into two genotypic groups: APOE ε4 carriers and noncarriers. Then, we compared several neuropsychological test scores between the two genotypic groups for two different generations: 70s (70-79 years) and 80s (80-89 years). Results: The total Mini-Mental State Examination score (p Conclusion: The present results suggest that APOE may significantly influence comparatively simple memory processing in certain generations of Japanese patients with AD

Genetic Association between Neurotrophin-3 Polymorphisms and Alzheimer's Disease in Japanese Patients

Background: Some polymorphisms of the neurotrophin family have previously been investigated as candidate genes for Alzheimer's disease (AD). In the present study, we examined whether neurotrophin-3 (NTF-3) polymorphisms are genetic risk factors in patients with AD. Methods: From a sample of 507 subjects, we recruited 248 age-matched subjects divided into 2 groups: AD patients (n = 143) and normal controls (NCs) (n = 105). We identified 3 representative NTF-3 single nucleotide polymorphisms (SNPs): rs6332, rs6489630, and rs4930767. Next, we statistically compared the allele frequencies of each SNP between the AD and NC groups in the early-onset (Results: We found a significant association between rs6332 and the total group of AD patients (p = 0.013) and significant associations between both rs6332 (p = 0.033) and rs6489630 (p = 0.035) and early-onset AD patients. Conclusion: These results suggest that NTF-3 SNPs may not only be associated with AD itself, but also with early-onset AD in Japanese patients, assuming that the NTF-3 gene may have age-related effects on neurodegenerative diseases