Four-repeat tauopathies and late-onset psychiatric disorders: Etiological relevance or incidental findings?

Argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP) and corticobasal degeneration are four-repeat (4R) tauopathies that develop in the presenium or later. Whether these diseases are associated with the occurrence of late-onset psychiatric disorders remains unclear. To facilitate the accumulation of clinicopathological findings regarding this issue, we here present a selected series of 11 cases that clinically developed psychotic disorder (n = 7; age at onset: 41-75 years), depressive disorder (n = 1; 49 years), bipolar disorder (n = 2; 32 and 37 years) and somatoform disorder (n = 1; 88 years), and had at least one pathological hallmark of these tauopathies. The mean age at death was 74.3 years. No case showed dementia, at least in the early stage of the course. Nine cases had AGD. Granular fuzzy astrocytes in the amygdala were noted in all AGD cases and one non-AGD case. Two AGD cases had tufted astrocytes (TAs) in the amygdala but not in the frontal cortex and striatum. Three AGD and two non-AGD cases had TAs in the frontal cortex and/or striatum but not in the amygdala. One AGD case had a small number of astrocytic plaques in the frontal cortex, striatum and globus pallidus. Only one case was diagnosed as atypical PSP according to the NINDS-PSP neuropathological criteria. No case had high-level Alzheimer's disease pathology, Lewy body disease or limbic-predominant age-related TDP-43 encephalopathy. Two cases had mild neuronal loss in the hippocampus and substantia nigra, respectively. Clinicopathological studies focusing especially on early changes of 4R tauopathies, as well as the development of surrogate markers of these diseases, may be necessary for better understanding of the pathogenic backgrounds of late-onset psychiatric disorders.

Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases.

Fused in sarcoma (FUS) is genetically and clinicopathologically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We have previously reported that intranuclear interactions of FUS and splicing factor, proline- and glutamine-rich (SFPQ) contribute to neuronal homeostasis. Disruption of the FUS-SFPQ interaction leads to an increase in the ratio of 4-repeat tau (4R-tau)/3-repeat tau (3R-tau), which manifests in FTLD-like phenotypes in mice. Here, we examined FUS-SFPQ interactions in 142 autopsied individuals with FUS-related ALS/FTLD (ALS/FTLD-FUS), TDP-43-related ALS/FTLD (ALS/FTLD-TDP), progressive supranuclear palsy, corticobasal degeneration, Alzheimer's disease, or Pick's disease as well as controls. Immunofluorescent imaging showed impaired intranuclear co-localization of FUS and SFPQ in neurons of ALS/FTLD-FUS, ALS/FTLD-TDP, progressive supranuclear palsy and corticobasal degeneration cases, but not in Alzheimer's disease or Pick's disease cases. Immunoprecipitation analyses of FUS and SFPQ revealed reduced interactions between the two proteins in ALS/FTLD-TDP and progressive supranuclear palsy cases, but not in those with Alzheimer disease. Furthermore, the ratio of 4R/3R-tau was elevated in cases with ALS/FTLD-TDP and progressive supranuclear palsy, but was largely unaffected in cases with Alzheimer disease. We concluded that impaired interactions between intranuclear FUS and SFPQ and the subsequent increase in the ratio of 4R/3R-tau constitute a common pathogenesis pathway in FTLD spectrum diseases.

Facial expression recognition in mild cognitive impairment and dementia: is the preservation of happiness recognition hypothesis true?

AIM: Social cognition encompasses facial expression recognition (FER), theory of mind, and empathy. Although studies examining FER in large numbers of patients with mild cognitive impairment (MCI) or dementia are rare, relative preservation of happiness recognition in dementia was reported in some studies. In this study, we examined performance on FER tests and its relationship to clinical demographics and other cognitive function test scores in patients with cognitive decline. METHODS: The present study administered an FER test and several cognitive tests to outpatients at a memory clinic. The FER test presents four facial expressions (happiness, surprise, anger, and sadness). A total of 187 patients were placed in one of the three groups based on their cognitive status: dementia group (n = 63), MCI group (n = 92), and normal cognition group (n = 32). RESULTS: The total scores on the FER test significantly differed among the three groups (normal > MCI > dementia). In the recognition of happiness and surprise, the dementia group had significantly lower scores than the normal cognition group. There were no significant differences in the recognition of anger and sadness scores among the three groups. The FER scores for happiness and surprise were primarily related to executive function scores, but the FER scores for anger and sadness were primarily related to age. CONCLUSIONS: We note the difference in recognition of causative factors among the four emotions (happiness, surprise, anger, sadness). Our study raises serious doubts about the preservation of happiness recognition hypothesis in dementia based on FER tests.

Patient affect and caregiver burden in dementia.

BACKGROUND: Numerous studies focusing on the burden of caregivers of dementia patients have been published. However, there have been few studies focusing on positive affect as an important factor affecting the caregiver burden, and only a few studies comparing the caregiver burden between different dementia diseases have been reported. METHODS: Three hundred and thirty-seven consecutive caregivers of people with dementia participated in this study. The caregiver burden was evaluated by the short version of the Japanese version of the Zarit Burden Interview. RESULTS: Positive affect scores had a significant relationship with the scores of the short version of the Zarit Burden Interview. Caregivers for patients with dementia with Lewy bodies or frontotemporal dementia suffered from a greater burden than those for patients with Alzheimer's disease dementia. CONCLUSIONS: The caregiver burden differed between people caring for patients with different dementia diseases. Positive affect of dementia patients has a significant relationship with caregiver burden, independently from neuropsychiatric symptoms of patients.

Sally-Anne test and regional cerebral blood flow in Alzheimer's disease dementia.

AIM: It was recently reported that theory of mind is disturbed in mild Alzheimer's disease dementia (ADD). Some studies have reported reduced scores of ADD patients on false belief tests, even on first-order false belief tests. However, few studies have pursued the neural substrate of false belief tests in patients with ADD in a real-world setting. METHODS: Sixty-three patients with ADD from outpatient units took the Sally-Anne test and underwent brain single-photon emission computed tomography. Of these patients, 29 answered the Sally-Anne test correctly (successful group) and 34 incorrectly (unsuccessful group). We compared the regional cerebral blood flow between the successful and unsuccessful groups. RESULTS: A comparison of the two groups showed a significantly lower uptake in the bilateral posterior cingulate gyrus in the unsuccessful group than in the successful group. CONCLUSIONS: The posterior cingulate gyrus is known to be particularly activated when individuals remember personal events and infer the mental states of others. We suppose that memory or mentalization in the posterior cingulate gyrus-or both-is essential for patients with ADD to be able to pass the Sally-Anne test.

Validation of Addenbrooke's cognitive examination III for detecting mild cognitive impairment and dementia in Japan.

BACKGROUND: Early detection of mild cognitive impairment (MCI) and dementia is very important to begin appropriate treatment promptly and to prevent disease exacerbation. We investigated the screening accuracy of the Japanese version of Addenbrooke's Cognitive Examination III (ACE-III) to diagnose MCI and dementia. METHODS: The original ACE-III was translated and adapted to Japanese. It was then administered to a Japanese population. The Hasegawa Dementia Scale-revised (HDS-R) and Mini-mental State Examination (MMSE) were also applied to evaluate cognitive dysfunction. In total, 389 subjects (dementia = 178, MCI = 137, controls = 73) took part in our study. RESULTS: The optimal ACE-III cut-off scores to detect MCI and dementia were 88/89 (sensitivity 0.77, specificity 0.92) and 75/76 (sensitivity 0.82, specificity 0.90), respectively. ACE-III was superior to HDS-R and MMSE in the detection of MCI or dementia. The internal consistency, test-retest reliability, and inter-rater reliability of ACE-III were excellent. CONCLUSIONS: ACE-III is a useful cognitive test to detect MCI and dementia. ACE-III may be widely useful in clinical practice.

Neuropathological comorbidity associated with argyrophilic grain disease.

Argyrophilic grain disease (AGD) is a common four-repeat tauopathy in elderly people. While dementia is a major clinical picture of AGD, recent studies support the possibility that AGD may be a pathological base in some patients with mild cognitive impairment, late-onset psychosis, bipolar disorder and depression. AGD often coexists with various other degenerative changes. The frequency of AGD in progressive supranuclear palsy (PSP) cases was reported to range from 18.8% to 80%. The frequency of AGD in corticobasal degeneration (CBD) cases tends to be higher than that in PSP cases, ranging from 41.2% to 100%. Conversely, in our previous study of the frequencies of mild PSP and CBD pathologies in AGD cases, five of 20 AGD cases (25%) had a few Gallyas-positive tufted astrocytes, six cases (30%) had a few granular/fuzzy astrocytes, and one case (5.0%) had a few Gallyas-positive astrocytic plaques in the putamen, caudate nucleus and/or superior frontal gyrus. Both Gallyas-positive tufted astrocytes and Gallyas-negative tau-positive granular/fuzzy astrocytes preferentially developed in the putamen, caudate nucleus and superior frontal cortex in AGD cases, being consistent with the predilection sites of Gallyas-positive tufted astrocytes in PSP cases. Further, in AGD cases, the quantities of Gallyas-positive tufted astrocytes, overall tau-positive astrocytes, and tau-positive neurons in the subcortical nuclei and superior frontal cortex were significantly correlated with Saito AGD stage, respectively. The frequency of AGD in AD cases was reported to reach up to 25% when using four-repeat tau immunohistochemistry. Pretangles are essential pathologies in AGD; however, the Braak stage of three-repeat tau-positive NFTs, which may indicate mild AD pathology or primary age-related tauopathy, was not correlated with Saito AGD stage. Clinicians should be aware of the possibility that coexisting AGD may impact clinical and radiological features in cases of other degenerative diseases.

Frontotemporal lobar degeneration due to P301L tau mutation showing apathy and severe frontal atrophy but lacking other behavioral changes: A case report and literature review.

The clinical features in cases that have mutations in the microtubule-associated protein tau gene but lack prominent behavioral changes remain unclear. Here, we describe detailed clinical and pathological features of a case carrying the P301L tau mutation that showed only apathy until the middle stage of the course. The mother of this case was suspected to have mild cognitive decline at age 46. However, before she was fully examined, she had a subarachnoid hemorrhage at age 49 and died at age 53. An autopsy was not done. The proband of this pedigree, a 60-year-old right-handed Japanese man at the time of death, began to make mistakes at work at the age of 51 years. Until age 54, he showed only mild apathy with bradykinesia. Insight was well spared. Parkinsonism and echolalia developed at age 55, and pyramidal signs and oral tendency at age 57. Personality change, disinhibition, stereotypy, or semantic memory impairment was not found throughout the course. The final neurological diagnosis was unspecified dementia. Pathological examination demonstrated numerous round four-repeat tau-positive three-repeat tau-negative or perinuclear ring-like neuronal cytoplasmic inclusions with many ballooned neurons in the frontal and temporal cortices and hippocampus. Genetic analysis using frozen brain tissue demonstrated a P301L tau mutation. Among 31 previously reported cases bearing the P301L tau mutation for which the data regarding initial symptoms are available, one clinical case showed only apathy with depression in the early stage. Given these findings, clinicians should be aware that a clinical course characterized only by apathy for several years, which can be misdiagnosed as a psychiatric disorder, is one of the clinical presentations associated with P301L tau mutation.

Astrocytic Tau Pathologies in Argyrophilic Grain Disease and Related Four-repeat Tauopathies.

Neurodegenerative diseases in which tau accumulation plays a cardinal role in the pathogenic process are called tauopathies, and when tau isoforms having four repeats of the microtubule binding sites, four-repeat tau, are selectively accumulated as pathological hallmarks, the term four-repeat tauopathy is used. The major four-repeat tauopathies are progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD). Historically, neuronal cytopathologies, e.g., neurofibrillary tangles and ballooned neurons, were emphasized as characteristic lesions in PSP and CBD. Now, however, astrocytic tau pathologies, i.e., tufted astrocytes (TAs) and astrocytic plaques (APs), are considered to be highly disease-specific lesions. Although granular/fuzzy astrocytes (GFAs) frequently develop in the limbic system in AGD cases, the specificity is not conclusive yet. Some AGD cases have a few TAs, and to a lesser frequency, a few APs in the frontal cortex and subcortical nuclei. The number of astrocytic tau pathologies including TAs and GFAs increases with the progression of AGD. In this paper, histopathological features of astrocytic tau pathologies in PSP, CBD, and AGD are first reviewed. Then, recent findings regarding the coexistence of these tauopathies are summarized from a viewpoint of astrocytic tau pathologies. Further biochemical and pathological studies focusing tau-positive astrocytic lesions may be useful to increase understanding of the pathological process in four-repeat tauopathies and to develop novel therapeutic strategies for patients with these diseases.

Clinical features of the behavioural variant of frontotemporal dementia that are useful for predicting underlying pathological subtypes of frontotemporal lobar degeneration.

BACKGROUND: The behavioural variant of frontotemporal dementia (bvFTD) is the most common phenotype of frontotemporal lobar degeneration (FTLD). FTLD is divided into three main pathological subtypes: tau-positive FTLD (FTLD-tau), FTLD-TAR DNA-binding protein (TDP), and FTLD-Fused in sarcoma (FUS). At present, it is difficult to predict the underlying pathological subtypes of sporadic bvFTD before a patient's death. METHODS: We retrospectively investigated the clinical features of 34 Japanese patients with sporadic bvFTD, with or without motor neuron disease (MND), who had been pathologically diagnosed with FTLD. We examined whether, and how, the clinical features differed among Pick's disease, FTLD-TDP, and FTLD-FUS patients. RESULTS: Six of the 34 patients developed MND during the course of bvFTD. These six bvFTD-MND patients were all pathologically diagnosed with FTLD-TDP. The other 28 patients were composed of 12 FTLD-tau patients including 11 Pick's disease patients, 8 FTLD-TDP patients, and 8 FTLD-FUS patients. A comparison of the clinical features of the three pathological subtypes of the 33 patients demonstrated that the age at onset was significantly younger in FTLD-FUS patients than in Pick's disease or FTLD-TDP patients. Furthermore, while hyperorality and dietary changes in the early stage of the disease were present in approximately 40% of Pick's disease and FTLD-FUS patients, they were absent in FTLD-TDP patients. CONCLUSION: The comorbidity of MND, a younger age at onset, and hyperorality and dietary changes in the early stage may be useful clinical features for predicting underlying pathological subtypes of sporadic bvFTD. The results of our study should be confirmed by prospective studies employing a larger number of cases.

Tube feeding decreases pneumonia rate in patients with severe dementia: comparison between pre- and post-intervention.

BACKGROUND: It is widely supposed that there is no benefit, including extended survival and decreased rate of pneumonia, in patients with severe dementia receiving enteral tube feeding (TF). However, there have been few studies comparing the frequency of pneumonia before and after TF in severe dementia. METHODS: Nine psychiatric hospitals in Okayama Prefecture participated in this retrospective survey. All inpatients fulfilling the entry criteria were evaluated. All subjects suffered from difficulty in oral intake. Attending physicians thought that the patients could not live without long-term artificial nutrition, and they decided whether or not to make use of long-term artificial nutrition from January 1, 2014 to December 31, 2014. RESULTS: We evaluated 58 patients including 46 with TF and 12 without. The mean age of all patients was 79.6 ± 9.0 years old. Patients with probable Alzheimer's disease (n = 38) formed the biggest group, and those with vascular dementia the second (n = 14). Median survival times were 23 months among patients with TF and two months among patients without TF. The start of TF decreased the frequency of pneumonia and the use of intravenous antibiotics. CONCLUSIONS: TF decreased pneumonia and antibiotic use, even in patients with severe dementia. The results of this study do not necessarily indicate that we should administer TF to patients with severe dementia. We should consider the quality of life of patients carefully before deciding the use or disuse of TF for patients with severe dementia.

Pick's disease with neuronal four-repeat tau accumulation in the basal ganglia, brain stem nuclei and cerebellum.

It is very rare that cases of Pick's disease, a representative three-repeat (3R) tauopathy, also have significant four-repeat (4R) tau accumulation. Here, we report a Pick's disease case that clinically showed behavioral variant frontotemporal dementia without motor disturbance during the course, and pathologically had 3R tau-positive Pick bodies as well as numerous 4R tau-positive neuronal cytoplasmic inclusions (NCIs). Abundant 3R tau-positive 4R tau-negative spherical or horseshoe-shaped Pick bodies were found in the frontotemporal cortex, limbic region, striatum and pontine nucleus. On the other hand, many 4R tau-positive, 3R tau-negative, Gallyas-negative dot-, rod- or intertwined skein-like NCIs were found mainly in the subthalamic nucleus, pontine nucleus, inferior olivary nucleus and cerebellar dentate nucleus. Tufted astrocytes, astrocytic plaques, argyrophilic grains or globular glial inclusions were absent. Double-labeling immunofluorescence demonstrated that 3R tau was hardly accumulated in 4R tau-positive inclusions. On tau immunoblotting, while 60 and 64 kDa bands were demonstrated in the frontal cortex, 60, 64 and 68 kDa bands, as well as the 33 kDa tau fragments that are reported to be characteristic of progressive supranuclear palsy brains, were found in the basal ganglia and cerebellum. No mutation was identified in the tau gene. The present case suggests that, although probably rare, some Pick's disease cases have non-negligible 4R tau pathology in the subcortical nuclei, and that such 4R tau pathology can affect the evaluation of the distribution of AT8-positive tau pathology in Pick's disease cases.

Survival times with and without tube feeding in patients with dementia or psychiatric diseases in Japan.

BACKGROUND: It is widely supposed that there has been no evidence of increased survival in patients with advanced dementia receiving enteral tube feeding. However, more than a few studies have reported no harmful outcome from tube feeding in dementia patients compared to in patients without dementia. METHODS: This was a retrospective study. Nine psychiatric hospitals in Okayama Prefecture participated in this survey. All inpatients fulfilling the entry criteria were evaluated. All subjects suffered from difficulty with oral intake. Attending physicians thought that the patients could not live without long-term artificial nutrition. The physicians decided whether to make use of long-term artificial nutrition between January 2012 and December 2014. RESULTS: We evaluated 185 patients. Their mean age was 76.6 ± 11.4 years. Of all subjects, patients with probable Alzheimer's disease (n = 78) formed the biggest group, schizophrenia patients (n = 44) the second, and those with vascular dementia (n = 30) the third. The median survival times were 711 days for patients with tube feeding and 61 days for patients without tube feeding. In a comparison different types of tube feeding, median survival times were 611 days for patients with a nasogastric tube and more than 1000 days for those with a percutaneous endoscopic gastrostomy tube. CONCLUSION: Patients with tube feeding survived longer than those without tube feeding, even among dementia patients. This study suggests that enteral nutrition for patients with dementia prolongs survival. Additionally, percutaneous endoscopic gastrostomy tube feeding may be safer than nasogastric tube feeding among patients in psychiatric hospitals.

Comparison of QOL between patients with different degenerative dementias, focusing especially on positive and negative affect.

BACKGROUND: Quality of life (QOL) has become an important outcome measure in the care of dementia patients. However, there have been few studies focusing on the difference in QOL between different dementias. METHODS: Two-hundred seventy-nine consecutive outpatients with Alzheimer's disease (AD), dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD) were recruited. The QOL was evaluated objectively using the QOL Questionnaire for Dementia (QOL-D).The QOL-D comprises six domains: positive affect, negative affect and actions, communication, restlessness, attachment to others, and spontaneity. General cognition, daily activities, and behavioral and psychological symptoms of dementia were also evaluated. RESULTS: The scores of positive affect of QOL-D of AD patients were significantly higher than those of patients with DLB or FTD (AD 3.1 ± 0.8, DLB 2.6 ± 0.9, FTD 2.6 ± 0.7). The scores of negative affect and action of QOL-D of FTD patients were significantly higher than those of patients with AD or DLB (FTD 2.0 ± 0.8, AD 1.4 ± 0.5, DLB 1.5 ± 0.6). The apathy scores of FTD and DLB patients were significantly higher than those of patients with AD. The disinhibition scores of FTD patients were significantly higher than those of patients with AD or DLB. CONCLUSIONS: The apathy of FTD and DLB patients and depression of DLB patients might affect the lower positive affect of FTD and DLB patients compared to AD patients. The disinhibition of FTD patients might affect the abundance of negative affect & actions in FTD patients compared to AD and DLB patients.

Behavioral variant of frontotemporal dementia: Fundamental clinical issues associated with prediction of pathological bases.

Behavioral variant of frontotemporal dementia (bvFTD) is a clinical syndrome characterized mainly by behavioral symptoms due to frontal dysfunction. Major neurodegenerative bases of bvFTD include Pick's disease, frontotemporal lobar degeneration with trans-activation response DNA protein 43-positive inclusions, corticobasal degeneration, and progressive supranuclear palsy. Early disinhibition characterized by socially inappropriate behaviors, loss of manners, and impulsive, rash and careless actions is the most important clinical feature of bvFTD. On the other hand, it was reported that clinical presentations of some Alzheimer's disease cases and patients with psychiatric disorders (e.g., addictive disorders, gambling disorder and kleptomania) often resemble that of bvFTD. Although clinical differentiation of 'true' bvFTD cases with frontotemporal lobar degeneration (FTLD) pathology from mimicking cases without it is not always easy, evaluation of the following features, which were noted in autopsy-confirmed FTLD cases and/or clinical bvFTD cases with circumscribed lobar atrophy, may often provide clues for the diagnosis. (i) The initial symptoms frequently develop at 65 years or younger, and (ii) 'socially inappropriate behaviors' can be frequently interpreted as contextually inappropriate behaviors prompted by environmental visual and auditory stimuli. Taking a detailed history usually reveals various kinds of such behaviors in various situations in everyday life rather than the repetition of a single kind of behavior (e.g., repeated shoplifting). (iii) A correlation between the distribution of cerebral atrophy and neurological and behavioral symptoms is usually observed, and the proportion of FTLD cases with right side-predominant cerebral atrophy may be higher in a psychiatric setting than a neurological setting. Finally, (iv) whether the previous course and the combination of symptoms observed at the first medical visit can be explained by major evolution patterns of clinical syndromes in pathologically confirmed FTLD cases should be considered. These views may provide clues to differentiate FTLD from Alzheimer's disease and to predict a subsequent clinical course and therapeutic interventions needed in the future.

Heterogeneity of patients receiving artificial nutrition in Japanese psychiatric hospitals: a cross-sectional study.

AIM: Artificial nutrition, including tube feeding, continues to be given to dementia patients in numerous geriatric facilities in Japan. However, the clinical characteristics of patients receiving artificial nutrition have not been fully investigated. Therefore, we tried to evaluate the clinical features of those patients in this study. METHODS: Various clinical characteristics of all inpatients at 18 of 20 psychiatric hospitals in Okayama Prefecture, Japan, with a percutaneous endoscopic gastrostomy tube, nasogastric tube, or total parenteral nutrition were evaluated. RESULTS: Two hundred twenty-one patients (5.4% of all inpatients) had been receiving artificial nutrition for more than 1 month, and 187 (130 women, 57 men; 84.6% of 221 patients) were fully investigated. The mean age was 78.3 years old, and the mean duration of artificial nutrition was 29.8 months. Eighty-four patients (44.7% of 187 patients) were receiving artificial nutrition for more than 2 years. Patients with Alzheimer's disease (n = 78) formed the biggest group, schizophrenia (n = 37) the second, and vascular dementia (n = 26) the third. CONCLUSION: About one-fifth of the subjects receiving artificial nutrition were in a vegetative state. More than a few patients with mental disorders, including schizophrenia, also received long-term artificial nutrition. We should pay more attention to chronic dysphasia syndrome in mental disorders.

Development and evaluation of a short version of the quality of life questionnaire for dementia.

BACKGROUND: There are many quality of life (QOL) instruments for evaluating dementia patients. The QOL questionnaire for Dementia (QOL-D) is one of such instruments and a validated objective measure of QOL for patients with dementia. It comprises 31 items encompassing six domains. However, with 31 items, its length is a disadvantage. The purpose of this study was to develop a short version of QOL-D (short QOL-D). METHODS: We used data from two studies. The participants were 264 inpatients with dementia in the first sample and 395 outpatients at a memory clinic in the second sample. We used maximum likelihood factor analysis with promax rotation to reduce the number of items. RESULTS: We produced a nine-item version of QOL-D (short QOL-D) with positive (six items) and negative (three items) dimensions. The correlation coefficients of short and total versions of QOL-D were 0.892-0.918 for total scores, 0.903-0.936 for positive dimension scores, and 0.788-0.837 for negative dimension scores. Total short QOL-D scores showed a significant correlation to the Geriatric Depression Scale score and the apathy score of the Neuropsychiatric Inventory. CONCLUSIONS: The short QOL-D produced results comparable with that of the full version. Reducing the number of items may make administration of the instrument easier.

Argyrophilic grain disease as a neurodegenerative substrate in late-onset schizophrenia and delusional disorders.

To study the relationship between neurodegenerative diseases including argyrophilic grain disease (AGD) and late-onset schizophrenia and delusional disorders (LOSD; onset ≥40 years of age), we pathologically examined 23 patients with LOSD, 71 age-matched normal controls, and 22 psychiatric disease controls (11 depression, six personality disorder, two bipolar disorders, and three neurotic disorders cases). In all LOSD cases (compared to age-matched normal controls), the frequencies of Lewy body disease (LBD), AGD, and corticobasal degeneration (CBD) were 26.1 % (11.3 %), 21.7 % (8.5 %), and 4.3 % (0.0 %), respectively. There was no case of pure Alzheimer's disease (AD). The total frequency of LBD, AGD, and CBD was significantly higher in LOSD cases than in normal controls. Argyrophilic grains were significantly more severe in LOSD than in controls, but were almost completely restricted to the limbic system and adjacent temporal cortex. In LOSD patients whose onset occurred at ≥65 years of age (versus age-matched normal controls), the frequencies of LBD and AGD were 36.4 % (19.4 %) and 36.4 % (8.3 %), respectively, and AGD was significantly more frequent in LOSD patients than in normal controls. In LOSD patients whose onset occurred at <65 years of age, the frequencies of LBD, AGD, and CBD were 16.7, 8.3, and 8.3 %, comparable to those of age-matched normal controls (10.2, 5.1, and 0.0 %). In all psychiatric cases, delusion was significantly more frequent in AGD cases than in cases bearing minimal AD pathology alone. Given these findings, LOSD patients may have heterogeneous pathological backgrounds, and AGD may be associated with the occurrence of LOSD especially after 65 years of age.

Subjective depressive mood and regional cerebral blood flow in mild Alzheimer's disease.

BACKGROUND: Depressive symptoms are common in patients with Alzheimer's 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 subjective depressive symptoms in AD. METHODS: Seventy-six consecutive patients with AD were recruited from outpatient units of the Memory Clinic of Okayama University Hospital. Subjective depressive symptoms were evaluated using the short version of the Geriatric Depression Scale (GDS). All patients underwent brain SPECT with 99mTc-ethylcysteinate dimer, and the SPECT images were analyzed by the Statistical Parametric Mapping 8 program. RESULTS: No significant differences between groups with high and low GDS scores were found with respect to age, sex, years of education, and revised Addenbrooke's Cognitive Examination scores. Compared to patients with low scores on GDS, patients with high scores showed significant hypoperfusion in the left inferior frontal region. CONCLUSIONS: The left inferior frontal region may be significantly involved in the pathogenesis of subjective depressive symptoms in AD. Subjective and objective depressive symptoms may have somewhat different neural substrates in AD.