Thalamic Deep Brain Stimulation for Refractory Atypical Tremor after Encephalitis of Unknown Etiology: A Case Report.

Tremor associated with encephalitis is usually transient and rarely becomes chronic and refractory. Treatment for such tremor using deep brain stimulation (DBS) has not yet been reported. We report an uncommon case of chronic tremor after encephalitis of unknown etiology and its outcome treated with thalamic DBS. A 47-year-old man presented with a 6-month history of medically refractory tremor after non-infectious and probable autoimmune encephalitis. The patient showed an atypical mixture of resting, postural, kinetic, and intention tremor. The tremor significantly disabled the patient's activities of daily life (ADL). The patient underwent bilateral thalamic DBS surgery. DBS leads were placed to cross the border between the ventralis oralis posterior (Vop) nucleus and ventralis intermedius (Vim) nucleus of the thalamus. Stimulation of both the Vop and Vim using the bipolar contacts controlled the mixed occurrence of tremor. The ADL and performance scores on The Essential Tremor Rating Assessment Scale (TETRAS) improved from 47 to 0 and from 44 to 9, respectively. The therapeutic effects have lasted for 24 months. Administration of combined Vop and Vim DBS may control uncommon tremor of atypical etiology and phenomenology.

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.

A case of human immunodeficiency virus infection with cerebellar ataxia that suggested by an association with autoimmunity.

We report a case of human immunodeficiency virus (HIV) infection that showed subacute progressive cerebellar ataxia without HIV encephalopathy or other encephalopathies, including progressive multifocal leukoencephalopathy or encephalitis of other human herpes virus (HHV) infections. A 43-year-old man exhibited unsteady gait. Neurological examination disclosed ataxia of the trunk and lower extremities. Personality change and dementia were absent. Magnetic resonance imaging did not reveal any abnormal finding, including of the cerebellum. The serum HIV-1-RNA was 1.2 × 10(5) copies/ml, and the absolute CD4 lymphocyte count was 141 cells/ml. Remarkably, the serum anti-Yo antibody, as an anti-cerebellar antibody of paraneoplastic syndrome, and anti-gliadin antibody, associated with celiac disease or gluten ataxia, were positive. The cerebrospinal fluid (CSF) immunoglobulin G index was 1.2 (< 0.8), and oligoclonal bands were present. PCR of the CSF was negative for HIV, JC virus, other HHVs, and mycosis. Previous reports presented HIV-infected patients with concurrent autoimmune diseases such as systemic lupus erythematosus, anti-phospholipid syndrome, autoimmune thrombocytopenia, vasculitis, polymyositis and dermatomyositis, sarcoidosis, Graves' disease, and hepatic diseases. These might have been present in patients with a CD4 T lymphocyte count of more than 200 cells/ml. On the other hand, paraneoplastic syndrome, gluten ataxia, cerebellar ataxia associated with anti-glutamic acid decarboxylase antibody, and Hashimoto's encephalopathy might manifest as autoimmune cerebellar ataxia. As regards the association of HIV infection and autoimmune cerebellar ataxia, a previous report suggested that anti-gliadin antibody was detected in about 30% of HIV-infected children, though there is no reference to an association with cerebellar ataxia. Moreover, to our knowledge, detection of anti-Yo antibody in an HIV-infected patient with cerebellar ataxia has not been reported. These findings suggest that, although it is extremely rare, clinicians need to consider HIV infection in a patient exhibiting autoimmune cerebellar ataxia.

The Relationship Between Development of Neuronal and Astrocytic Tau Pathologies in Subcortical Nuclei and Progression of Argyrophilic Grain Disease.

Progressive supranuclear palsy (PSP) cases frequently have argyrophilic grain disease (AGD). However, the PSP-like tau pathology in AGD cases has not been fully clarified. To address this, we examined tau pathologies in the subcortical nuclei and frontal cortex in 19 AGD cases that did not meet the pathological criteria of PSP or corticobasal degeneration, nine PSP cases and 20 Braak NFT stage-matched controls. Of the 19 AGD cases, five (26.3%) had a few Gallyas-positive tau-positive tufted astrocytes (TAs) and Gallyas-negative tau-positive TA-like astrocytic inclusions (TAIs), and six (31.6%) had only TAIs in the striatum and/or frontal cortex. Subcortical tau pathology was sequentially and significantly greater in AGD cases lacking these tau-positive astrocytic lesions, AGD cases having them, and PSP cases than in controls. There was a significant correlation between three histologic factors, including the AGD stage and the quantities of subcortical neuronal and astrocytic tau pathologies. Tau immunoblotting demonstrated 68- and 64-kDa bands and 33-kDa low-molecular mass tau fragments in PSP cases, and although with lesser intensity, in AGD cases with and without TAs and TAIs also. Given these findings, the progression of AGD may be associated with development of the neuronal and astrocytic tau pathologies characteristic of PSP.

Corticobasal degeneration initially developing motor versus non-motor symptoms: a comparative clinicopathological study.

BACKGROUND: Clinical presentations of pathologically confirmed corticobasal degeneration (CBD) vary, and the heterogeneity makes its clinical diagnosis difficult, especially when a patient lacks any motor disturbance in the early stage. METHODS: We compared clinical and pathological features of four pathologically confirmed CBD cases that initially developed non-motor symptoms, including behavioural and psychiatric symptoms but without motor disturbance (CBD-NM), and five CBD cases that initially developed parkinsonism and/or falls (CBD-M). The age range at death for the CBD-NM and CBD-M subjects (58-85 years vs 45-67 years) and the range of disease duration (2-18 years vs 2-6 years) did not significantly differ between the groups. RESULTS: Prominent symptoms in the early stage of CBD-NM cases included self-centred behaviours such as frontotemporal dementia (n = 1), apathy with and without auditory hallucination (n = 2), and aggressive behaviours with delusion and visual hallucination (n = 1). Among the four CBD-NM cases, only one developed asymmetric motor disturbance, and two could walk without support throughout the course. Final clinical diagnoses of the CBD-NM cases were frontotemporal dementia (n = 2), senile psychosis with delirium (n = 1), and schizophrenia (n = 1). Neuronal loss was significantly less severe in the subthalamic nucleus and substantia nigra in the CBD-NM cases than in the CBD-M cases. The severity of tau pathology in all regions examined was comparable in the two groups. CONCLUSION: CBD cases that initially develop psychiatric and behavioural changes without motor symptoms may have less severe degenerative changes in the subthalamic nucleus and substantia nigra, and some CBD cases can lack motor disturbance not only in the early stage but also in the last stage of the course.

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.

Depressive symptoms and regional cerebral blood flow in Alzheimer's disease.

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 depressive symptoms in AD, excluding the effect of apathy and anxiety. Seventy-nine consecutive patients with AD were recruited from outpatient units of the Memory Clinic of Okayama University Hospital. The level of depressive symptoms was evaluated using the depression domain of the Neuropsychiatric Inventory (NPI). The patients underwent brain SPECT with 99mTc-ethylcysteinate dimer. After removing the effects of age, anxiety and apathy scores of NPI, and five subscales of Addenbrooke's Cognitive Examination-revised (ACE-R), correlation analysis of NPI depression scores showed a significant cluster of voxels in the left middle frontal gyrus (Brodmann area 9), similar to the areas in the simple correlation analysis. The dorsolateral prefrontal area is significantly involved in the pathogenesis of depressive symptoms in AD, and the area on the left side especially may be closely related to the depressive symptoms revealed by NPI.

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.

Trail making test part a and brain perfusion imaging in mild Alzheimer's disease.

BACKGROUND/AIMS: The Trail Making Test (TMT) has long been used to investigate deficits in cognitive processing speed and executive function in humans. However, there are few studies that elucidate the neural substrates of the TMT. The aim of the present study was to identify the regional perfusion patterns of the brain associated with performance on the TMT part A (TMT-A) in patients with Alzheimer's disease (AD). METHODS: Eighteen AD patients with poor performance on the TMT-A and 36 age- and sex-matched AD patients with good performance were selected. All subjects underwent brain single photon emission computed tomography. RESULTS: No significant differences between the good and poor performance groups were found with respect to years of education and revised Addenbrooke's Cognitive Examination scores. However, higher z-scores for hypoperfusion in the bilateral superior parietal lobule were observed in the group that scored poorly on the TMT-A compared with the good performance group. CONCLUSION: Our results suggest that functional activity of the bilateral superior parietal lobules is closely related to performance time on the TMT-A. Thus, the performance time on the TMT-A might be a promising index of dysfunction of the superior parietal area among mild AD patients.

Trail making test B and brain perfusion imaging in mild cognitive impairment and mild Alzheimer's disease.

The trail making test (TMT) has long been used to investigate deficits in cognitive processing speed and executive function in humans. However, there are few studies that elucidate the neural substrates of the TMT. The aim of the present study was to identify the brain regional perfusion patterns associated with performance on TMT part B (TMT-B) in patients with amnestic mild cognitive impairment (aMCI) or mild Alzheimer's disease (AD). Twenty-one patients with good TMT-B scores and 21 age- and sex-matched patients with poor TMT-B scores were selected. All 42 subjects underwent brain single photon emission computed tomography (SPECT), and the SPECT images were analyzed by statistical parametric mapping. No significant differences between good- and poor-scoring groups were found with respect to years of education, Addenbrooke's Cognitive Examination scores, and scores on TMT-A. Compared to patients with good scores on TMT-B, patients with poor scores showed significant hypoperfusion in the bilateral anterior cingulate extending to the posterior region on the right side, bilateral caudate nucleus and putamen, and bilateral thalamus. Analysis of 63 AD or aMCI subjects revealed significant correlation a between regional cerebral blood flow in the right cingulate cortex and TMT-B scores. Our results suggest that functional activity of the anterior cingulate, striatum and thalamus is closely related to performance time on TMT-B. The performance time on the TMT-B score might be a promising index of dysfunction of the anterior cingulate, striatum, and thalamus among patients with aMCI or mild AD.

Burden of caregivers for patients with mild cognitive impairment in Japan.

BACKGROUND: Caregivers of patients with mild cognitive impairment (MCI) already experience a need for increased services comparable to that of individuals caring for Alzheimer's disease patients. However, there have been only a few studies on the MCI caregiver burden. In this study, we examined MCI caregiver burden in a larger number of consecutive outpatients in Japan. METHODS: One hundred and four consecutive caregivers of people with MCI participated in this study. The caregiver burden was evaluated by the short version of the Japanese version of the Zarit Burden Interview (sZBI). RESULTS: About 20% of the caregivers reported a clinically significant burden. The multiple linear regression analysis showed that the caregiver burden was significantly associated with neurobehavioral symptoms (p < 0.001) and memory problems (p = 0.022) of the patient. CONCLUSIONS: The caregiver burden of MCI patients should be given more attention. The management of neurobehavioral symptoms may be important to reduce the burden on caregivers of MCI patients.

Accelerated tau aggregation, apoptosis and neurological dysfunction caused by chronic oral administration of aluminum in a mouse model of tauopathies.

To clarify whether long-term oral ingestion of aluminum (Al) can increase tau aggregation in mammals, we examined the effects of oral Al administration on tau accumulation, apoptosis in the central nervous system (CNS) and motor function using tau transgenic (Tg) mice that show very slowly progressive tau accumulation. Al-treated tau Tg mice had almost twice as many tau-positive inclusions in the spinal cord as tau Tg mice without Al treatment at 12 months of age, a difference that reached statistical significance, and the development of pretangle-like tau aggregates in the brain was also significantly advanced from 9 months. Al exposure did not induce any tau pathology in wild-type (WT) mice. Apoptosis was observed in the hippocampus in Al-treated tau Tg mice, but was virtually absent in the other experimental groups. Motor function as assessed by the tail suspension test was most severely impaired in Al-treated tau Tg mice. Given our results, chronic oral ingestion of Al may more strongly promote tau aggregation, apoptosis and neurological dysfunction if individuals already had a pathological process causing tau aggregation. These findings may also implicate chronic Al neurotoxicity in humans, who frequently have had mild tau pathology from a young age.

Person-centered care and quality of life of patients with dementia in long-term care facilities.

Good quality of life (QOL) is an important goal of dementia care. However, there have been few studies on the relationship of care characteristics to QOL of dementia patients in long-term care facilities. We developed a questionnaire evaluating person-centered care and used it to assess person-centered care and QOL of elderly patients with dementia in both geriatric health service facilities (GHSF) and hospitals. In GHSF, person-centered care scores were not correlated with cognitive or activities of daily living (ADL) functions, but were significantly correlated with four subscale scores on a quality of life questionnaire for dementia (QOL-D) after controlling the effect of age, cognitive function, and ADL scores. In contrast, in hospitals, person-centered care scores were significantly correlated with cognitive and ADL function. We found quite different patterns in the relationship of person-centered care scores to clinical characteristics. Dementia care characteristics and QOL of dementia patients are significantly interrelated, especially in GHSF. Improvement of dementia care standards might affect the QOL of dementia patients. We should pay more attention to the quality of dementia care and QOL of dementia patients.

Progressive supranuclear palsy presenting as primary lateral sclerosis but lacking parkinsonism, gaze palsy, aphasia, or dementia.

We report an autopsy case of progressive supranuclear palsy (PSP) that clinically showed only slowly progressive and symmetric upper motor neuron syndrome over a disease course of 12 years. A female patient initially exhibited dysarthria at the age of 65, followed by gait disturbance and dysphagia. Neurological examination at age 67 disclosed pseudobulbar palsy, spastic gait, hyperreflexia, and presence of bilateral Hoffmann and Babinski signs. However, muscle atrophy, weakness, evidence of denervation on electromyography, vertical gaze palsy, parkinsonism, gait freezing, aphasia, speech apraxia, or dementia was not noted throughout the course. She was clinically diagnosed as having motor neuron disease consistent with so-called primary lateral sclerosis. Pathological examination disclosed histopathological features of PSP, including argyrophilic and tau-positive tufted astrocytes, neurofibrillary tangles, coiled bodies, and thread-like processes in the motor cortex and superior frontal gyrus, and to a lesser degree, in the basal ganglia and brain stem nuclei. In addition, severe fibrillary gliosis was noted in the precentral gyrus and corticospinal tract, being consistent with upper motor neuron syndrome observed in this case. No TAR-DNA binding protein 43-positive lesion, FUS pathology, Bunina body, or Lewy body-like hyaline inclusion was noted in the motor cortex or lower motor neurons. These findings suggest that when tau pathology is prominent in the motor cortex but is minimal in the basal ganglia and brain stem nuclei, a PSP case can lack all classic clinical features of PSP and show only slowly progressive upper motor syndrome, consistent with clinical picture of primary lateral sclerosis.

Frontal assessment battery and brain perfusion imaging in Alzheimer's disease.

BACKGROUND: The frontal assessment battery (FAB) is reported to be a useful tool for assessing frontal dysfunction. However, the neural substrates involved in patients with Alzheimer's disease (AD) remain to be elucidated. The aim of the present study was to identify the regional perfusion patterns of the brain associated with performance scores on the FAB of patients with AD using brain perfusion assessed by single photon emission computed tomography (SPECT). METHODS: Twenty-four AD patients with high scores and 24 age- and sex-matched AD patients with low scores on the FAB were selected from 470 consecutive Japanese patients of the Memory Clinic of Okayama University Hospital. All 48 participants underwent brain SPECT with 99mTc-ethylcysteinate dimer, and the SPECT images were analyzed by statistical parametric mapping. RESULTS: No significant differences were found between high and low FAB scoring groups with respect to Addenbrooke's Cognitive Examination scores, Mini-Mental State Examination scores, or the depression score of the Neuropsychiatric Inventory subscale. Compared with patients with high scores on the FAB, AD patients with low scores showed significant hypoperfusion in the left middle frontal gyrus (MFG) and the right superior frontal gyrus (SFG) extending to the left SFG. CONCLUSION: Our results suggest that functional activity of the SFG and MFG is closely related to the FAB score. The FAB might be a promising strategy to detect early stages of AD with low SFG and MFG function.