Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): Estimation of pathological lesion stage from brain images.

BACKGROUND: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a disease responsible for cognitive impairment in adult humans. It is caused by mutations in the colony stimulating factor 1 receptor gene (CSF1R) or alanyl-transfer (t) RNA synthetase 2 (AARS2) gene and affects brain white matter. Settlement of stages of the pathological brain lesions (Oyanagi et al. 2017) from the findings of brain imaging will be inevitably essential for prognostication. METHODS: MRI images of eight patients with ALSP were analyzed semiquantitatively. White matter degeneration was assessed on a scale of 0 to 4 (none, patchy, large patchy, confluent, and diffuse) at six anatomical points, and brain atrophy on a scale 0 to 4 (none, slight, mild, moderate, and severe) in four anatomical areas. The scores of the two assessments were then summed to give total MRI scores of 0-40 points. Based on the scores, the MRI features were classified as Grades (0-4). Regression analysis was applied to mutual association between mRS, white matter degeneration score, brain atrophy score, the total MRI score and disease duration. RESULTS: White matter degeneration score, brain atrophy score, and the total MRI score were significantly correlated with the disease duration. MRI Grades (2-4) based on the total MRI scores and the features of the images were well correlated with the pathological lesion stages (II - IV); i.e., 'large patchy' white matter degeneration in the frontal and parietal lobes (MRI Grade 2) corresponded to pathological Stage II, 'confluent' degeneration (Grade 3) to Stage III, and 'diffuse' degeneration (Grade 4) to Stage IV. CONCLUSION: MRI Grades (2-4) resulted from the total MRI scores were well correlated with the pathological lesion Stages (II - IV).

Prevalence and modifiable risk factors for dementia in persons with intellectual disabilities.

BACKGROUND: People with intellectual disability (ID) without Down syndrome (DS) are presumed to be at higher risk of developing dementia due to their lower baseline cognitive reserve. We aimed to determine the prevalence of dementia in people with ID without DS and to identify risk factors of dementia. METHODS: This was a cross-sectional survey and multicenter study in Japan. Adults with ID without DS residing in the facilities were included. Caregivers of all participants were interviewed by medical specialists, and participants suspected of having cognitive decline were examined directly. ICD-10 criteria for dementia, DC-LD criteria for dementia, and DSM-5 criteria for neurocognitive disorders were used to diagnose dementia. The severity of ID, educational history, and comorbidities were compared by dividing the groups into those with and without dementia. RESULTS: A total of 1831 participants were included; 118/1831 (6.44%) were diagnosed with dementia. The prevalence of dementia for each age group was 8.8%, 60-64 years; 9.0%, 65-69 years; 19.6%, 70-74 years; and 19.4%, 75-79 years. Age, severity of ID, duration of education, hypertension, depression, stroke, and traumatic brain injury were significantly associated with the presence of dementia. CONCLUSIONS: Although the prevalence of dementia in people with ID without DS was found to be higher at a younger age than in the general population, the results of this study suggested that adequate education, prevention of head trauma and stroke, and treatments of hypertension and depression may reduce the risk of dementia. These may be potentially important modifiable risk factors for the prevention of dementia in these people.

Venous Thromboembolism in Eating Disorders: A Retrospective Observational Study.

Eating disorders (EDs) are associated with a high mortality rate. Patients with EDs often experience severe dehydration due to food restriction and/or vomiting. Severely underweight patients are often prescribed bed rest during inpatient care to reduce their energy consumption, and they may thus develop multiple risk factors for venous thromboembolism (VTE). We compared the clinical features of ED inpatients with VTE to those of ED inpatients without VTE. Seventy-one inpatients with ED were treated at Okayama University Hospital's psychiatric ward in 2016-2020; five were experienced a VTE. Compared to the non-VTE group, the VTE group's median age and disease duration were greater and the median body mass index (BMI) was lower. The VTE group's D-dimer peak values were > 5 mg/L. Physical restraint and central venous catheter use were associated with VTE. Longer ED duration and lower BMI might be risk factors for VTE. To make inpatient treatment for ED safer, it is important to avoid the use of physical restraints and central venous catheters. Continuous D-dimer monitoring is necessary for the early detection of VTE in ED patients at high risk of VTE.

Initial Outcomes of the Safe and Sound Protocol on Patients with Adult Autism Spectrum Disorder: Exploratory Pilot Study.

Sensory impairments are common features of autism spectrum disorder (ASD) and are associated with its social impairments. However, there is no established treatment for these impairments in adults with ASD. The Safe & Sound Protocol (SSP) is a listening program designed to improve social communication skills by reducing auditory hypersensitivity. We investigated the effectiveness of the SSP for adults with ASD. We administered the SSP to six participants with ASD aged 21-44 years old, and the effects were assessed using the Social Responsiveness Scale, Second Edition (SRS-2). Secondary outcomes were assessed using the Center for Epidemiological Studies Depression Scale (CES-D), State-Trait Anxiety Inventory (STAI), WHO Quality of Life 26 (WHOQOL-BREF), and Adolescent/Adult Sensory Profile (A/ASP). In this study, only the Social Awareness scale of the SRS-2 Family-Report showed a significant improvement after the intervention. In addition, it was significantly correlated with physical health of WHOQOL-BREF (r = -0.577, p = 0.012), state and trait anxiety of STAI (r = 0.576, p = 0.012; r = 0.708, p = 0.00009, respectively), and CES-D (r = 0.465, p = 0.05). In conclusion, the SSP has a partial effect on social impairments in adults with ASD, specifically on the Social Awareness subscale of the SRS-2.

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.

Secondary autoimmune hypothalamitis with severe memory impairment 7 years after the onset of diabetes insipidus due to lymphocytic hypophysitis: a case report.

BACKGROUND: Autoimmune hypothalamitis is a very rare neuroendocrine disorder that causes central diabetes insipidus, headache, visual impairment, and sometimes cognitive impairment. Autoimmune hypothalamitis may occur in association with autoimmune hypophysitis, including lymphocytic hypophysitis, or in isolation. It is not known whether autoimmune hypothalamitis and autoimmune hypophysitis are consecutive diseases. CASE PRESENTATION: A 52-year-old woman developed autoimmune hypothalamitis 7 years after developing central diabetes insipidus due to lymphocytic hypophysitis, resulting in severe memory impairment. High-dose intravenous methylprednisolone therapy improved her cognitive function and decreased the size of the lesion. CONCLUSION: This case presented a unique clinical course, with a long period of time between the onset of autoimmune hypopituitaritis and the development of autoimmune hypothalamitis.

Safety and Effectiveness of Perospirone in Comparison to Risperidone for Treatment of Delirium in Patients with Advanced Cancer: A Multicenter Prospective Observational Study in Real-World Psycho-Oncology Settings.

The clinical benefit of perospirone for treatment of delirium in patients with advanced cancer is not sufficiently clear. The objective of this study was to compare the safety and effectiveness of perospirone to those of risperidone for the treatment of delirium in patients with advanced cancer. This is a secondary analysis of a multicenter prospective observational study in nine psycho-oncology consultation services in Japan. The study used the Delirium Rating Scale (DRS) Revised-98 to measure effectiveness and the CTCAE (Common Terminology Criteria for Adverse Events) version 4 to assess safety. Data from 16 patients who received perospirone and 53 patients who received risperidone were analyzed. The mean age was 70 years in the perospirone group and 73 years in the risperidone group. Both groups showed a significant decrease in the total score of DRS-R-98 after three days of treatment (perospirone: 11.7 (7.9-15.4) to 7.0 (3.3-10.7), difference -4.7, effect size=0.72, p=0.003; risperidone: 15.5 (13.6-17.4) to 12.2 (10.1-14.2), difference -3.3, effect size=0.55, p=0.00). The risperidone group showed significant improvements in sleep-wake cycle disturbance, orientation, attention, and visuospatial ability. In the perospirone group, there was a significant improvement of sleep-wake cycle disturbance. The median daily dose of perospirone was 4 mg/day. There were fewer episodes of somnolence as an adverse event in the perospirone group. Low-dose perospirone was thus found to be effective for the treatment of delirium in patients with advanced cancer and may be associated with fewer episodes of over-sedation as an adverse event.

Prevalence of Gender Dysphoria by Gender and Age in Japan: A Population-Based Internet Survey Using the Utrecht Gender Dysphoria Scale.

BACKGROUND: Several studies have attempted to estimate the prevalence of gender dysphoria (GD) from a general population sample. However, no previous studies used reliable questionnaires. AIM: To estimate the prevalence of GD in Japan by gender and age using the Utrecht Gender Dysphoria Scale (UGDS). METHODS: A cross-sectional observational study was conducted with 20,000 respondents between the ages of 20 and 69 who were registered with an internet research company. The study consisted of two phases. First, the participants were asked to self-identify their gender on two 5-point Likert scales. Second, the screened participants completed the UGDS. OUTCOMES: Self-identified gender and GD were defined as follows: ambivalent gender (equally feeling like the birth gender and another gender), incongruent gender (a stronger sense of the latter vs the former), narrow GD (incongruent gender + UGDS score ≥ 41), and broad GD (ambivalent or incongruent gender + UGDS score ≥ 41). RESULTS: Among the eligible participants, the age-adjusted proportions of those classified as male (n = 7827) and female (n = 8903) at birth were 6.0% and 5.9%, respectively, for ambivalent gender, and 0.93% and 1.0%, respectively, for incongruent gender. The age-adjusted prevalence of GD was 0.27% (95% confidence interval, 0.18-0.42) and 0.35% (95% confidence interval, 0.25-0.50) for narrow GD and 0.87% (95% confidence interval, 0.69-1.1) and 1.1% (95% confidence interval, 0.86-1.3) for broad GD, respectively. No significant gender differences were found within the age groups, except for broad GD in respondents in their 50s (P = .016). However, for both genders, significant differences were found between age groups such that GD was more prevalent in younger vs older respondents, except for broad GD in respondents classified as female at birth (P = .063). CLINICAL IMPLICATIONS: Clinicians should be aware that the prevalence of GD is not negligible and that it varies with age. GD should be assessed in detail from various perspectives in addition to self-identified gender. STRENGTHS & LIMITATIONS: This study used a reliable questionnaire to examine the prevalence of GD in a large population. However, the participants did not represent the general population because this was an internet survey. CONCLUSION: The prevalence of GD was much higher than previously estimated by clinic-based studies, and was more frequently associated with participant age vs gender. Oshima Y, Matsumoto Y, Terada S, et al. Prevalence of Gender Dysphoria by Gender and Age in Japan: A Population-based Internet Survey Using the Utrecht Gender Dysphoria Scale. J Sex Med 2022;19:1185-1195.

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.

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.

Factors associated with development and distribution of granular/fuzzy astrocytes in neurodegenerative diseases.

Granular/fuzzy astrocytes (GFAs), a subtype of "aging-related tau astrogliopathy," are noted in cases bearing various neurodegenerative diseases. However, the pathogenic significance of GFAs remains unclear. We immunohistochemically examined the frontal cortex, caudate nucleus, putamen and amygdala in 105 cases composed of argyrophilic grain disease cases (AGD, N = 26), and progressive supranuclear palsy (PSP, N = 10), Alzheimer's disease (AD, N = 20) and primary age-related tauopathy cases (PART, N = 18) lacking AGD, as well as 31 cases bearing other various neurodegenerative diseases to clarify (i) the distribution patterns of GFAs in AGD, and PSP, AD and PART lacking AGD, (ii) the impacts of major pathological factors and age on GFA formation and (iii) immunohistochemical features useful to understand the formation process of GFAs. In AGD cases, GFAs consistently occurred in the amygdala (100%), followed by the putamen (69.2%) and caudate nucleus and frontal cortex (57.7%, respectively). In PSP cases without AGD, GFAs were almost consistently noted in all regions examined (90-100%). In AD cases without AGD, GFAs were less frequent, developing preferably in the putamen (35.0%) and caudate nucleus (30.0%). PART cases without AGD had GFAs most frequently in the amygdala (35.3%), being more similar to AGD than to AD cases. Ordered logistic regression analyses using all cases demonstrated that the strongest independent factor of GFA formation in the frontal cortex and striatum was the diagnosis of PSP, while that in the amygdala was AGD. The age was not significantly associated with GFA formation in any region. In GFAs in AGD cases, phosphorylation and conformational change of tau, Gallyas-positive glial threads indistinguishable from those in tufted astrocytes, and the activation of autophagy occurred sequentially. Given these findings, AGD, PSP, AD and PART cases may show distinct distributions of GFAs, which may provide clues to predict the underlying processes of primary tauopathies.

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.

Prevalence of dementia in people with intellectual disabilities: Cross-sectional study.

BACKGROUND: There are only a few studies of the prevalence of dementia in people with intellectual disability (ID) without Down syndrome (DS), and there is a large difference in the prevalences between reported studies. Moreover, the prevalence of mild cognitive impairment (MCI) in ID has not been reported. We aimed to evaluate the prevalence of dementia in adults of all ages and the prevalence of MCI in people with ID. Furthermore, we tried to clarify the differences depending on the various diagnostic criteria. METHODS: The survey included 493 adults with ID at 28 facilities in Japan. The caregivers answered a questionnaire, and physicians directly examined the participants who were suspected of cognitive decline. Dementia and MCI were diagnosed according to ICD-10, DC-LD, and DSM-5 criteria. RESULTS: The prevalence of dementia was 0.8% for the 45 to 54 years old group, 3.5% for the 55 to 64 years old group, and 13.9% for the 65 to 74 years old group in people with ID without DS. The prevalence of MCI was 3.1% for patients 45 to 54, 3.5% for patients 55 to 64, and 2.8% for patients 65 to 74 with ID without DS. DSM-5 was the most inclusive in diagnosing dementia and MCI in people with ID. CONCLUSIONS: People with ID without DS may develop dementia and MCI at an earlier age and higher rate than the general population. Among the diagnostic criteria, DSM-5 was the most useful for diagnosing their cognitive impairment.

Competency of aMCI patients to consent to cholinesterase treatment.

BACKGROUND: In medical practice, a patient's loss of competency is a major obstacle when choosing a treatment and a starting treatment program smoothly. A large number of studies have revealed the lack of medical competency in patients with dementia. However, there have been only a few reports focusing on the capacity of patients with mild cognitive impairment (MCI) to make a medical choice. METHODS: In this study, we evaluated the competency of 40 patients with amnestic MCI (aMCI) and 33 normal subjects to make a medical choice using the MacArthur Competence Assessment Tool-Treatment (MacCAT-T). We compared the judgement of a team conference using the recorded semi-structured interview with the clinical judgement of a chief clinician. RESULTS: A team conference concluded that 12 aMCI patients had no competency, and the clinical judgement, without any special interview, judged that five aMCI patients had no competency. All subjects in the control groups were judged to be competent to consent to treatment by both clinicians and the team conference. CONCLUSIONS: Without supplementary tools such as explanatory documents, not a few patients with aMCI were judged by a team conference to have no competency to consent to therapy even in a relatively simple and easy case. In contrast, clinical physicians tended to evaluate the competency of aMCI patients in a generous manner.

Diagnostic utility of the Addenbrooke's Cognitive Examination - III (ACE-III), Mini-ACE, Mini-Mental State Examination, Montreal Cognitive Assessment, and Hasegawa Dementia Scale-Revised for detecting mild cognitive impairment and dementia.

BACKGROUND: Early detection of mild cognitive impairment (MCI) and dementia is important to promptly start appropriate intervention. However, it is difficult to examine a patient using long and thorough cognitive tests in a general clinical setting. In this study, we aimed to investigate the diagnostic validity of the Addenbrooke's Cognitive Examination - III (ACE-III), Mini-ACE (M-ACE), Montreal Cognitive Assessment (MoCA), Hasegawa Dementia Scale-Revised (HDS-R), and Mini-Mental State Examination (MMSE) to identify MCI and dementia. METHODS: A total of 249 subjects (controls = 50, MCI = 94, dementia = 105) at a memory clinic participated in this study, and took the ACE-III, M-ACE, MoCA, HDS-R, and MMSE. After all examinations had been carried out, a conference was held, and the clinical diagnoses were established. RESULTS: The areas under the curve (AUC) of the ACE-III, M-ACE, MoCA, HDS-R, and MMSE for diagnosing MCI were 0.891, 0.856, 0.831, 0.808, and 0.782. The AUC of the ACE-III was significantly larger than those of the MoCA, HDS-R, and MMSE. The AUCs of the ACE-III, M-ACE, MoCA, HDS-R, and MMSE for diagnosing dementia were 0.930, 0.917, 0.854, 0.871, and 0.856. Thus, the AUCs of the ACE-III and M-ACE were significantly larger than those of the MoCA, HDS-R, and MMSE. CONCLUSION: The ACE-III is a useful cognitive instrument to detect MCI. For distinguishing dementia patients from non-dementia patients, the ACE-III and M-ACE are superior to the MoCA, HDS-R, and MMSE.

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.

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.