Pure argyrophilic grain disease revisited: independent effects on limbic, neocortical, and striato-pallido-nigral degeneration and the development of dementia in a series with a low to moderate Braak stage.

Agyrophilic grains (AGs) are age-related limbic-predominant lesions in which four-repeat tau is selectively accumulated. Because previous methodologically heterogeneous studies have demonstrated inconsistent findings on the relationship between AGs and dementia, whether AGs affect cognitive function remains unclear. To address this question, we first comprehensively evaluated the distribution and quantity of Gallyas-positive AGs and the severity of neuronal loss in the limbic, neocortical, and subcortical regions in 30 cases of pure argyrophilic grain disease (pAGD) in Braak stages I-IV and without other degenerative diseases, and 34 control cases that had only neurofibrillary tangles with Braak stages I-IV and no or minimal Aß deposits. Then, we examined whether AGs have independent effects on neuronal loss and dementia by employing multivariate ordered logistic regression and binomial logistic regression. Of 30 pAGD cases, three were classified in diffuse form pAGD, which had evident neuronal loss not only in the limbic region but also in the neocortex and subcortical nuclei. In all 30 pAGD cases, neuronal loss developed first in the amygdala, followed by temporo-frontal cortex, hippocampal CA1, substantia nigra, and finally, the striatum and globus pallidus with the progression of Saito AG stage. In multivariate analyses of 30 pAGD and 34 control cases, the Saito AG stage affected neuronal loss in the amygdala, hippocampal CA1, temporo-frontal cortex, striatum, globus pallidus, and substantia nigra independent of the age, Braak stage, and limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) stage. In multivariate analyses of 23 pAGD and 28 control cases that lacked two or more lacunae and/or one or more large infarctions, 100 or more AGs per × 400 visual field in the amygdala (OR 10.02, 95% CI 1.12-89.43) and hippocampal CA1 (OR 12.22, 95% CI 1.70-87.81), and the presence of AGs in the inferior temporal cortex (OR 8.18, 95% CI 1.03-65.13) affected dementia independent of age, moderate Braak stages (III-IV), and LATE-NC. Given these findings, the high density of limbic AGs and the increase of AGs in the inferior temporal gyrus may contribute to the occurrence of dementia through neuronal loss, at least in cases in a low to moderate Braak stage.

Potential dopaminergic deficit in patients with geriatric psychiatric disorders as revealed by DAT-SPECT: a cross-sectional study.

BACKGROUND: It has been reported that patients with geriatric psychiatric disorders include many cases of the prodromal stages of neurodegenerative diseases. Abnormal 123I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl) nortropane dopamine transporter single-photon emission computed tomography (DAT-SPECT) reveals a nigrostriatal dopaminergic deficit and is considered useful to detect dementia with Lewy bodies and Parkinson's disease as well as progressive supranuclear palsy and corticobasal degeneration. We aimed to determine the proportion of cases that are abnormal on DAT-SPECT in patients with geriatric psychiatric disorders and to identify their clinical profile. METHODS: The design is a cross-sectional study. Clinical findings of 61 inpatients aged 60 years or older who underwent DAT-SPECT and had been diagnosed with psychiatric disorders, but not neurodegenerative disease or dementia were analysed. RESULTS: 36 of 61 (59%) had abnormal results on DAT-SPECT. 54 of 61 patients who had DAT-SPECT (89%) had undergone 123I-metaiodobenzylguanidine myocardial scintigraphy (123I-MIBG scintigraphy); 12 of the 54 patients (22.2%) had abnormal findings on 123I-MIBG scintigraphy. There were no cases that were normal on DAT-SPECT and abnormal on 123I-MIBG scintigraphy. DAT-SPECT abnormalities were more frequent in patients with late-onset (55 years and older) psychiatric disorders (69.0%) and depressive disorder (75.7%), especially late-onset depressive disorder (79.3%). CONCLUSION: Patients with geriatric psychiatric disorders include many cases showing abnormalities on DAT-SPECT. It is suggested that these cases are at high risk of developing neurodegenerative diseases characterised by a dopaminergic deficit. It is possible that patients with geriatric psychiatric disorders with abnormal findings on DAT-SPECT tend to show abnormalities on DAT-SPECT first rather than on 123I-MIBG scintigraphy.

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.

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.

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.

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.

Clinical characteristics of elderly depressive patients with low metaiodobenzylguanidine uptake.

BACKGROUND: Recently, depression with Lewy body pathology before the appearance of parkinsonism and cognitive dysfunction has been drawing attention. Low cardiac metaiodobenzylguanidine (MIBG) uptake is helpful for early differentiation of Lewy body disease (LBD) from late-onset psychiatric disorders even before parkinsonism or dementia appears. In this study, we used MIBG uptake as a tool in suspected LBD, and evaluated the relationship of MIBG results to clinical characteristics and depressive symptoms. METHODS: Fifty-two elderly inpatients with depression were included in this study. The Hamilton Depression Rating Scale (HDRS) was administered at admission, and 123 I-MIBG cardiac scintigraphy was performed. Of 52 patients, 38 had normal and 14 had reduced MIBG uptake. RESULTS: Correlation analyses of the late phase heart-to-mediastinum (H/M) ratio on the MIBG test and each item of the HDRS revealed that the H/M ratio was significantly correlated with scores of 'agitation', 'anxiety-somatic', and 'retardation' on the HDRS. Mean HDRS composite scores of 'somatic and psychic anxiety (Marcos)' and 'somatic anxiety/somatization factor (Pancheri)' were higher in the low uptake group than in the normal uptake group. CONCLUSION: Elderly patients with depression who manifested an obvious somatic anxiety tend to show low MIBG uptake, and are more likely to have Lewy body pathology.

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.

Creutzfeldt-Jakob disease with Alzheimer pathology, presenting with status epilepticus following repeated partial seizures: a case report and literature review.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease. Common first symptoms are dementia, cerebellar ataxia, visual disturbance, and psychiatric symptoms. Seizure as the first symptom of CJD is a very rare finding. CASE PRESENTATION: We experienced an elderly woman who presented initially with status epilepticus following repeated partial seizures in the course of Alzheimer disease (AD) dementia. Anti-convulsive therapy had no effect. Autopsy revealed definite CJD with AD pathology. COCLUSIONS: This is the first reported CJD case presenting with status epilepticus in the course of AD dementia.