Suicide and Microglia: Recent Findings and Future Perspectives Based on Human Studies.

Suicide is one of the most disastrous outcomes for psychiatric disorders. Recent advances in biological psychiatry have suggested a positive relationship between some specific brain abnormalities and specific symptoms in psychiatric disorders whose organic bases were previously completely unknown. Microglia, immune cells in the brain, are regarded to play crucial roles in brain inflammation by releasing inflammatory mediators and are suggested to contribute to various psychiatric disorders such as depression and schizophrenia. Recently, activated microglia have been suggested to be one of the possible contributing cells to suicide and suicidal behaviors via various mechanisms especially including the tryptophan-kynurenine pathway. Animal model research focusing on psychiatric disorders has a long history, however, there are only limited animal models that can properly express psychiatric symptoms. In particular, to our knowledge, animal models of human suicidal behaviors have not been established. Suicide is believed to be limited to humans, therefore human subjects should be the targets of research despite various ethical and technical limitations. From this perspective, we introduce human biological studies focusing on suicide and microglia. We first present neuropathological studies using the human postmortem brain of suicide victims. Second, we show recent findings based on positron emission tomography (PET) imaging and peripheral blood biomarker analysis on living subjects with suicidal ideation and/or suicide-related behaviors especially focusing on the tryptophan-kynurenine pathway. Finally, we propose future perspectives and tasks to clarify the role of microglia in suicide using multi-dimensional analytical methods focusing on human subjects with suicidal ideation, suicide-related behaviors and suicide victims.

Influence of anticholinergic activity in serum on clinical symptoms of Alzheimer's disease.

Alzheimer's disease (AD) is well known as a disease characterized by degeneration of cholinergic neuronal activity in the brain. It follows that patients with AD would be sensitive to an 'anticholinergic burden', and also that medicine with anticholinergic properties would promote various clinical symptoms of AD. Despite the relevance of this important phenomenon to the clinical therapeutics of AD patients, few reports have been seen concerning the relationship between anticholinergic burden and clinical AD symptoms. Therefore, we wished to investigate the relationship between serum anticholinergic activity (SAA) and the severity of clinical symptoms of AD patients. Twenty-six out of 76 AD patients referred by practitioners to our hospital were positive for anticholinergic activity in their serum, and the remaining 50 patients were negative. Cognitive and psychiatric symptoms in AD patients were compared between the positive SAA (SAA+) group and the negative SAA (SAA-) group. The SAA+ group showed a significantly (p < 0.05) lower total score on the Mini-Mental State Examination, and significantly (p < 0.05) higher scores on the Functional Assessment Staging and the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). In particular, certain subscales of the BEHAVE-AD, i.e. the items of paranoid and delusional ideation, hallucinations and diurnal rhythm disturbances, had higher scores in the SAA+ group. Moreover, it was shown that many more psychotropic medicines were prescribed to the SAA+ group. By means of logistic regression analysis, the items of paranoid and delusional ideation and diurnal rhythm disturbances in the BEHAVE-AD were positively correlated with SAA in patients. We hypothesized that SAA in AD patients would be associated with clinical symptoms, especially delusion and diurnal rhythm disturbances.

Argyrophilic grain disease with delusions and hallucinations: a pathological study.

No clear clinical syndrome for argyrophilic grain disease (AGD) has yet been identified. Previous studies have documented its clinical features, namely, personality changes characterized by emotional disorder involving aggression or ill temper and relatively well-preserved cognitive function, but the clinical manifestations of delusions and hallucinations as they appear in AGD have not been thoroughly described. Here, we report on a 72-year-old Japanese AGD patient who showed psychiatric symptoms, memory impairment and emotional change. He perceived and described a person who was not present and tried to grasp things on the floor though nothing was there. He also insisted that somebody was watching him and consequently always kept his curtains closed. These psychiatric symptoms were observed at an early stage in the patient's disease course. Serial neuroradiological examination showed progressive atrophy of the bilateral temporal lobes. The patient died at 79 years-of-age. Microscopic neuropathological examination showed transactivation responsive region (TAR)-DNA-binding protein of 43 kDa (TDP-43) positive structures in addition to widespread argyrophilic grains and coiled bodies. According to recent recommendations for pathological diagnosis, this case corresponds to AGD with limbic TDP-43 pathology. This case shows that patients with AGD that is eventually confirmed through autopsy can present with delusions and hallucinations early in the course of their disease. The clinical significance of TDP-43 pathology in the brains of patients with AGD remains uncertain.

Adverse effects of anticholinergic activity on cognitive functions in Alzheimer's disease.

BACKGROUND: Elderly patients with Alzheimer's disease (AD) take more medicines, other than those for anti-dementia agents, than healthy people and are sensitive to anticholinergic medications. There are only a few reports, however, on the relationship between cognitive function and anticholinergic activity in AD patients, which is caused by taking prescribed medication. METHODS: We measured serum anticholinergic activity (SAA) in 76 AD patients referred to a Psychogeriatric Unit and separated them into SAA positive group (n= 26, SAA (+) group) and SAA negative group (n= 50, SAA (-) group). The difference in demographic data and cognitive functions were compared between the two groups. RESULTS AND CONCLUSIONS: The total scores of the Mini-Mental State Examination (MMSE), the score of MMSE domain of registration and recall were significantly lower (P < 0.05) and the Functional Assessment Staging (FAST) score, the number of different kinds of prescribed psychotropic medications (the number of prescribed psychotropic medications) were significantly higher (P < 0.05) in the SAA (+) group than in the SAA (-). These results suggest that a higher number of psychotropic medications prescribed leads to a tendency for SAA to be positive and that anticholinergic activity accelerates Alzheimer's pathology and decreases cognitive function, especially memory in AD patients. We should more prudently prescribe psychotropic medications to AD patients, because the prescribed psychotropic medications are one of the important causes of decline in cognitive function of AD patients by way of anticholinergic activity.

Pick's disease with Pick bodies: an unusual autopsy case showing degeneration of the pontine nucleus, dentate nucleus, Clarke's column, and lower motor neuron.

We report a 51-year-old female with Pick's disease with Pick bodies (PDPB) showing a brainweight of 530 g. This case was considered to be a very rare case of PDPB, in which the lesion developed in the temporal and frontal lobes and later spread to the parietal lobe, occipital lobe, brainstem, cerebellum and spinal cord. This case showed very atypical clinicopathological findings. Clinically, bulging eyes and myoclonus were observed. Neuropathologically, Pick bodies were widely distributed beyond the usual distribution areas to the parietal cortices, occipital cortices, dentate nuclei, motor neuron nuclei in the brain stem, and spinal cord. The atypical clinical symptoms and the widespread neuropathological abnormalities observed in this case seem to represent an extremely extended form of PDPB.

Ubiquitin-positive frontotemporal lobar degeneration presenting with progressive Gogi (word-meaning) aphasia. A neuropsychological, radiological and pathological evaluation of a Japanese semantic dementia patient.

A patient with progressive anomia and alexia with agraphia for kanji (Japanese morphograms) is described. The patient showed a deficit in single-word comprehension and on-reading (a type of reading that conveys phonetic value) dominance in kanji reading, i.e. on-preceding (pronouncing first with on-reading, irrespective of its preferred reading) and kun-deletion (inability to recall and recognize kun-reading [another type of reading that conveys meaning]) when reading a single-character kanji. These features were due to loss of lexico-semantic information and thus the patient was regarded as having progressive Gogi (word-meaning) aphasia by Imura, a Japanese manifestation of semantic dementia. Macroscopically, neuropathological examination disclosed atrophy of the left frontotemporal lobe with accentuation in the anterior portion of the temporal lobe. Histologically, there was neuronal loss in the cerebral cortex, hippocampus, parahippocampal gyrus, amygdala, caudate nucleus, and putamen. Ubiquitin-immunoreactive neuronal inclusions were present in the hippocampal dentate granular cells. This case demonstrates that progressive Gogi aphasia is semiologically identical to semantic dementia, and our patient clinicopathologically resembled those of Rossor et al. [Rossor, M.N., Revesz, T., Lantos, P.L., Warrington, E.K. Semantic dementia with ubiquitin-positive tau-negative inclusion bodies. Brain 2000; 123: 267-76.] and Hodges et al. [Hodges, J.R., Davies, R.R., Xuereb, J.H., Casey, B., Broe, M., Bak, T.H., et al. Clinicopathological correlates in frontotemporal dementia. Ann Neurol 2004; 56: 399-406.].

Neurofibrillary tangles and deposition of oxidative products in the brain in cases of myotonic dystrophy.

Myotonic dystrophy (MyD) is a neuromuscular degenerative disorder that is neuropathologically characterized by minor changes, such as the presence of neurofibrillary tangles (NFT), thalamic inclusions and functional brainstem lesions. In the current study, we conducted an immunohistochemical analysis to examine the distribution of NFT and formation of oxidative products in the brain specimens of 12 patients with MyD. Neurofibrillary tangles were found in the limbic system and/or the brainstem of all the cases examined but there were no senile plaques. The density of distribution of the NFT was not significantly correlated with clinicopathological findings, although cases with fewer NFTin the brain frequently showed sleep disturbances and lack of spontaneity. Nuclear and cytoplasmic immunoreactivities for 8-hydroxy-2'-deoxyguanosine and advanced glycation end products were observed in the glial cells and/or neurons in the brainstem, but not in the cerebral cortex. On the other hand, 10 out of the 12 cases showed cytoplasmic immunoreactivity for 4-hydroxy-2-nonenal-modified protein (4-HNE) in neurons of the temporal cortex and raphe nucleus. Deposition of 4-HNE was also recognized in the hippocampus and mesencephalic central gray matter, but not in the subiculum. The distribution pattern of the immunoreactivity for 4-HNE showed no clear correlation with either the psychological disturbances or the distribution of the NFT. Altered expression of monoaminergic neurons in the brainstem of MyD patients has already been reported, and it is worth noting that most of our cases showed NFT in the brainstem. The selective deposition of 4-HNE in the limbic system and brainstem suggests that lipid peroxidation may be involved in the neurodegenerative process in MyD. Using immunohistochemical analysis to determine the distribution of neurotransmitters in the mesencephalic central gray matter and/or pontine raphe nucleus may help elucidate the relationship between the clinical abnormalities, distribuion of NFT, and 4-HNE deposition in the brain in patients with MyD.

Pathological heterogeneity of the precentral gyrus in Pick's disease: a study of 16 autopsy cases.

This report concerns the upper motor neuron involvement in 16 autopsy cases of Pick disease with Pick bodies, including 11 cases reported by us previously. Prominent, circumscribed atrophy of the precentral gyrus, conspicuously in the lower portion, was noted in one case. Loss of Betz cells and astrocytosis of the precentral gyrus layer V were encountered in 15 cases (94%) and eight cases (50%), respectively. Appearance of Pick bodies and ballooned neurons in the precentral gyrus layer V was confirmed in seven cases (44%). Degeneration of the pyramidal tract in the medulla oblongata was noted in all 15 cases in which this structure was examined. Pyramidal signs were observed in four (67%) of the six cases that were neurologically sufficiently examined: hyperreflexia in four cases (67%), spasticity in one case (17%). Babinski sign was not encountered in any of the six cases. In all four cases having pyramidal signs, degeneration of the pyramidal tract was observed. In contrast, two cases having degeneration of the pyramidal tract did not develop pyramidal signs. In Pick's disease with Pick bodies, obvious involvement of the precentral gyrus and pyramidal tract was not previously noticed. Furthermore, we suggest that pyramidal signs in Pick's disease with Pick bodies have been underestimated.

[Intramedullary lipomatous ependymoma: case report]. / Ependymome lipomateux intramédullaire.

A 51 year-old man was admitted to our hospital with poor general health and neurological disturbances with paresthesia, dysuria and defecation disorder. Neuroimaging showed a syringomyelia cyst from C1 to conus medullaris, together with a intramedullar tumoral mass in T6-T7. Histological examination of the surgical specimen led to the diagnosis of lipomatous ependymoma.

Degeneration of the inferior olive in spinocerebellar ataxia 6 may depend on disease duration: report of two autopsy cases and statistical analysis of autopsy cases reported to date.

This report concerns a clinicopathological study of two autopsied patients with spinocerebellar ataxia 6 (SCA6), and a statistical analysis between neuronal loss of the inferior olive and disease duration of 15 SCA6 autopsy cases reported to date, including the two cases reported in this study. Cases 1 and 2 came from independent Japanese families. Case 1 developed gait disturbance at age 35 years and died at age 78 years; she had a CAG-repeat expansion of the SCA6 gene (25/13). Case 2 presented with gait disturbance at age 68 years and died at age 78 years; he had an expanded CAG-repeat of the SCA6 gene (22/13). Neuropathological examination of both cases disclosed not only neuronal loss of the Purkinje cells and inferior olive, but also some unnoticed features, including cactus-like expansion of the dendrite of Purkinje cells and relative preservation of Golgi cells in the granular layer of the cerebellum. Exploratory statistical analysis between 11 SCA6 autopsy cases with neuronal loss in the inferior olive (average disease duration: 27 years) and four SCA6 autopsy cases without neuronal loss in the olive (average disease duration: 14.5 years) was investigated by Kaplan-Meier estimates of survival and log-rank test, retrospectively. Kaplan-Meier estimates of survival revealed an obvious difference between the two groups. Survival of 10 years after the disease onset was 90.9% in the former 11 SCA6 autopsy cases, but was 50% in the latter four SCA6 autopsy cases. Furthermore, a log-rank test on the two groups disclosed a significant difference (P=0.0450). We postulate that the neuronal loss of the inferior olive in SCA6 may depend on disease duration.

First episodes of behavioral symptoms in Alzheimer's disease patients at age 90 and over, and early-onset Alzheimer's disease: comparison with senile dementia of Alzheimer's type.

We evaluated dementia symptoms to clarify the character of dementia with Alzheimer's disease (AD) observed in the oldest old patients and that of dementia with early-onset AD. Subjects were consecutive AD inpatients admitted for the first time at age of 90 years and over because of behavioral symptoms (demented nonagenarian group: D90G; n=18) and those with 24 consecutive inpatients with AD with early-onset (EOG). The Gottfries, Brane and Steen's scale and the Dementia Behavior Disturbance scale were used to evaluate the symptoms and troublesome behaviors. The scores of these scales in D90G and in EOG were compared with those of 26 sex distribution-, severity of dementia-, and disease duration-matched inpatients with AD with late-onset (LOG). Compared with LOG, wakefulness was more impaired and waking up at night was more frequent in D90G, while memory, orientation and inappropriate behaviors were more severe in EOG. These results suggest that the clinical features of dementia in EOG were quantitatively different from those of LOG. In contrast, the clinical feature of dementia of D90G were sleep-wake pattern disturbance and were qualitatively different from those of LOG.

[Argyrophilic grain disease clinically mimicking Parkinson's disease with dementia: report of an autopsy case].

Argyrophilic grain disease (AGD) is a neurodegenerative dementia, which is neuropathologically characterized by the spindle-or comma-shaped argyrophilic grains scattered in the neuropil of hippocampal area. Several research reports have disclosed the pathological, biochemical and genetic characteristics of AGD, whereas the clinical aspects have not been fully investigated. Here we report an autopsy case of AGD. She developed tremor at age 63, and then developed dyskinesia, rigidity and gait disturbance. Thereafter, she had cognitive impairment and emotional disturbance at age 71, and died of pneumonia at age 76. She was clinically diagnosed as Parkinson's disease with dementia due to the presence of parkinsonism and dementia. Macroscopically, the brain demonstrated mild atrophy, and the weight was 1,240 g. Many argyrophilic grains were found in the hippocampus and amygdala. Coiled bodies and ballooned neurons were also present, while Alzheimer-type neurofibrillary changes were mild, consistent with stage 2 of Braak's classification. This case was neuropathologically diagnosed as AGD. In contrast, no remarkable pathological changes, including neuronal loss and Lewy bodies, were found in the nigra, locus ceruleus and basal nuclei. On the basis of the above-mentioned clinicopathological findings, parkinsonism with dementia is considered to be one of the clinical manifestations of AGD.

One-step capillary isoelectric focusing of the proteins in cerebrospinal fluid and serum of patients with neurological disorders.

One-step capillary isoelectric focusing (cIEF), which uses reduced but non-zero electroosmosis flow to mobilize the focused proteins, was applied to the analysis of proteins in cerebrospinal fluid (CSF) and serum of patients with various neurological disorders. Under the conditions employed, pathological changes in the CSF proteins were clearly detected on the electropherograms within 25 min, although the serum proteins did not vary significantly between samples. The present one-step cIEF system seems to be useful in routine laboratory examinations of a large number of CSF samples as an aid in neurological diagnosis.