Hideki Ishizu

Diagnostic significance of tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy

Distinguishing corticobasal degeneration (CBD) from progressive supranuclear palsy (PSP) is clinically and pathologically difficult, and a useful biological marker to discriminative these two diseases has been a subject of clinical interest. In the present study, we assessed tau protein levels in cerebrospinal fluids by sandwich ELISA to distinguish CBD from PSP. The subjects consisted of 27 cases of CBD, 30 cases of PSP, and 36 healthy controls (CTL). The tau values in CBD were significantly higher than those in PSP (P<0.001) and those in CTL (P<0.001). The assay of CSF tau provided diagnostic sensitivity of 81.5% and specificity of 80.0% between CBD and PSP according to receiver-operating characteristic (ROC) curve analysis. When values were compared separately with respect to stage of the disease, differences in the values for moderate CBD vs. moderate PSP had the greatest significance (P<0.001 sensitivity 92.3%, specificity 100.0%), followed by cases of mild CBD and PSP (P<0.005, sensitivity 100.0%, specificity 87.5%). The values in severe CBD and PSP were not significantly different (P=0.07, sensitivity 100%, specificity 75.0%). Using data obtained from a larger number of disease cases, we confirmed our previous findings that tau protein levels in cerebrospinal fluids in patients with CBD are significantly higher than those in patients with PSP. Because tau protein levels in cerebrospinal fluids are significantly higher in early CBD cases than in early PSP cases, measurement of tau protein levels in cerberospinal fluids may be useful for the differential diagnosis of early CBD from early PSP.

Frequency of early and late-onset dementias in a Japanese memory disorders clinic

The aim of this study was to compare the diagnostic profiles of patients with early (age <65 years) and late (age ≥65 years) onset of dementia in a memory disorders clinic in Japan. A total of 512 consecutive memory clinic patients were evaluated using clinical information and results of examinations. Diagnosis of dementia was made according to DSM‐III‐R, and that of subtypes according to standard diagnostic criteria. A total of 464 patients met the criteria for dementia. Amongst late‐onset patients (n = 430), Alzheimers disease (AD) (48.1%) was the most frequent cause of dementia, followed by AD with cerebrovascular disease (CVD) (31.4%), vascular dementia (VaD) (9.1%), dementia with Lewy bodies (DLB) (3.7%), frontotemporal lobar degeneration (FTLD) (1.6%), and others (5.8%). On the contrary, amongst early onset patients (n = 34), the most common dementia diagnosis was AD (38.2%), followed by VaD (23.5%), FTLD (14.7%), AD with CVD (5.9%), DLB (2.9%), and others (17.6%). FTLD and VaD were significantly more common in the early onset group. All patients, but one, with DLB and Parkinsons disease dementia were late‐onset. The relative frequencies of AD, VaD, and DLB in our series are consistent with epidemiologic findings in several Western countries; however, the frequency of FTLD is not consistent with the previous findings presenting high frequency in late‐onset patients in some Western countries.

Clinicopathological characterization of Pick’s disease versus frontotemporal lobar degeneration with ubiquitin/TDP-43-positive inclusions

Although frontotemporal lobar degeneration with ubiquitin/TDP-43-positive inclusions (FTLD-TDP) and Pick’s disease are common pathological substrates in sporadic FTLD, clinical differentiation of these diseases is difficult. We performed a retrospective review of medical records and semiquantitative examination of neuronal loss of 20 sporadic FTLD-TDP and 19 Pick’s disease cases. Semantic dementia as the first syndrome developed only in FTLD-TDP patients. Impaired speech output in the early stage was five times more frequent in Pick’s disease than in FTLD-TDP. The total frequency of asymmetric motor disturbances (e.g., parkinsonism, pyramidal signs, and contracture) during the course was significantly more frequent in FTLD-TDP (78%) than in Pick’s disease cases (14%). Asymmetric pyramidal signs were found in 7 of 13 FTLD-TDP cases with corticospinal tract degeneration similar to primary lateral sclerosis. Frontotemporal dementia as the first syndrome was noted in both FTLD-TDP (28%) and Pick’s disease cases (64%); however, only FTLD-TDP cases subsequently developed asymmetric motor disturbances, and some of the cases further exhibited hemineglect. Concordant with these clinical findings, degeneration in the temporal cortex, caudate nucleus, putamen, globus pallidus, substantia nigra, and corticospinal tract was significantly more severe in FTLD-TDP, and degeneration in the frontal cortex tended to be more severe in Pick’s disease. Given these findings, the initial impairment of semantic memory or comprehension and subsequent asymmetric motor disturbances in sporadic FTLD patients predict sporadic FTLD-TDP rather than Pick’s disease, while initial behavioral symptoms or non-fluent aphasia without subsequent asymmetric motor disturbances predict Pick’s disease rather than sporadic FTLD-TDP.

Glial involvement in diffuse Lewy body disease.

Abstract. Diffuse Lewy body disease (DLBD) is characterized by the presence of Lewy bodies (LB) in the neurons and neurites of cortical, subcortical, and brain stem structures. Recently, α-synuclein (αS) has been found to be a central constituent of LB. In DLBD, abnormal accumulation of αS has been reported in both neurons and glia, but studies on glial lesions in DLBD have been limited. We examined in detail the constituents and distribution of glial lesions in eight patients with DLBD and report the pathogenesis of the glial lesions. αS-positive neuronal cytoplasmic inclusions (NI), neuropil threads (NT), and coiled bodies (CB) showed similar immunostaining profiles. Without pretreatment, NI, NT, and CB were detected by all antibodies against αS. The immunostaining profile of star-like astrocytes (SLA) was quite different from those of NI, NT, and CB. A few SLA were stained by an antibody against the non-Aβ component portion of αS without pretreatment, but formic acid pretreatment dramatically enhanced SLA immunoreactivity. SLA and CB were found in all eight brains with DLBD. SLA were scarce in the brain stem, but there were hundreds of SLA per visual field at ×100 magnification in the temporal cortex of most cases, while CB were found diffusely in both the cerebral cortex and brain stem, similar to NI. This suggests that the pathogenesis of SLA is different from those of NI and CB.

Lead content of brain tissue in diffuse neurofibrillary tangles with calcification (DNTC): the possibility of lead neurotoxicity.

Diffuse neurofibrillary tangles with calcification (DNTC) is a form of presenile dementia, characterized pathologically by fronto-temporal atrophy with neurofibrillary tangles (NFTs), neuropil threads and Fahr-type calcification, in which no senile plaques are observed. As already noted, chronic exposure to lead (Pb) might be one of the etiological factors of Fahr-type calcification. Until now, there have been no reports in which Pb concentration has been quantified in DNTC brains. We examined the concentration of Pb in fresh-frozen brain tissue and in 10% formalin-fixed brain tissue from six cases of DNTC, four cases of Alzheimers disease, and in nine non-demented elderly controls by flameless atomic absorption spectrometry, and demonstrated a high concentration of Pb in DNTC brains. Although it remains unclear how these findings are related to the formation of NFTs, they suggest that Pb neurotoxicity may be involved in the pathogenesis of DNTC.

NACP/α-synuclein immunoreactivity in diffuse neurofibrillary tangles with calcification (DNTC)

Abstract. Diffuse neurofibrillary tangles with calcification (DNTC) is a rare tangle-predominant dementia, as well as one of the tauopathies lacking Aβ deposition. It is characterized by temporo-frontal lobar atrophy, Fahr-type calcification and, histopathologically, numerous neurofibrillary tangles in the limbic system and neocortex. Recently, accumulation of α-synuclein (αS), the precursor of the non-β amyloid component (NAC) of Alzheimers disease, has been shown in diverse neurodegenerative disorders, including Parkinsons disease, dementia with Lewy bodies, Alzheimers disease, multiple system atrophy and parkinsonism-dementia complex of Guam. To clarify whether αS accumulates in other neurodegenerative disorders, we investigated eight DNTC brains using immunohistochemistry and demonstrated remarkable αS deposition in the neurons and astrocytes in many anatomical regions. Abundant Lewy bodies were observed in the amygdala (seven cases) and hippocampus (seven cases), and, to a lesser degree, in the substantia nigra (six cases) and dorsal vagal nucleus (five cases). In the hippocampus, many Lewy neurites were distributed in the stratum oriens and stratum pyramidale in the CA2–3 and the subiculum. Furthermore, numerous NAC-positive astrocytes were detected in the hippocampus and temporal cortex. This investigation reveals that neurons and astrocytes are extensively involved in remarkable αS pathology in the DNTC brain, and that the αS pathology compounds the cardinal pathological features of tau pathology. These findings suggest that (1) DNTC shares a common pathophysiological background with Parkinsons disease, dementia with Lewy bodies, and multiple system atrophy in which abnormal αS aggregation is observed, and (2) there is an interaction between αS and tau pathology that does not involve amyloid in DNTC.

Amyotrophic lateral sclerosis with dementia: an autopsy case showing many Bunina bodies, tau-positive neuronal and astrocytic plaque-like pathologies, and pallido-nigral degeneration

We report the case of a 54-year-old woman with mental retardation who developed frontotemporal dementia and amyotrophic lateral sclerosis (ALS) in the presenium. She presented with dementia at age 48, and motor neuron signs developed at age 53. She had no family history of dementia or ALS. Postmortem examination disclosed histopathological features of ALS, including pyramidal tract degeneration, mild loss of motor neurons, and many Bunina bodies immunoreactive for cystatin C, but not ubiquitin-positive inclusions. Unusual features of this case included severe neuronal loss in the substantia nigra and medial globus pallidus. The subthalamic nucleus, limbic system, and cerebral cortex were well preserved. In addition, neurofibrillary tangles (NFTs) were found in the frontal, temporal, insular, and cingulate cortices, nucleus basalis of Meynert, and locus coeruleus, and to a lesser degree, in the dentate nucleus, cerebellum, hippocampus, and amygdala. No ballooned neurons, tufted astrocytes, or astrocytic plaques were found. Tau immunostaining demonstrated many pretangles rather than NFTs and glial lesions resembling astrocytic plaques in the frontal and temporal cortices. This glial tau pathology predominantly developed in the middle to deep layers in the primary motor cortex, and was frequently associated with the walls of blood vessels. NFTs were immunolabeled with 3-repeat and 4-repeat specific antibodies against tau, respectively. Although the pathophysiological relationship between tau pathology and the selective involvement of motor neurons, substantia nigra, and globus pallidus was unclear, we considered that it might be more than coincidental.

NACP/α-Synuclein, NAC, and β-amyloid pathology of familial Alzheimer's disease with the E184D presenilin-1 mutation: a clinicopathological study of two autopsy cases

Abstract. Approximately 60% of familial and sporadic Alzheimers disease (AD) cases manifest Lewy bodies (LBs), of which a major component is α-synuclein. Although the pathogenic role of α-synuclein in AD remains unclear, LB formation might be associated with pathological β-amyloid (Aβ) overproduction. Here, we present the clinical and pathological characteristics of two affected family members from a pedigree with the E184D mutation of presenilin-1. One case presented with typical clinical features of AD, but the other case also developed clinical characteristics of dementia with Lewy bodies (DLB), including visual hallucinations, delusions, and parkinsonism. In both cases, neuropathological examination revealed numerous neurofibrillary tangles and severe Aβ deposition in senile plaques and amyloid angiopathy, in which Aβ42 rather than Aβ40 was predominant. Furthermore, remarkable α-synuclein pathology, including LBs and the accumulation of the non-Aβ component of AD amyloid (NAC) in plaques and astrocytes, was detected only in the case that presented with the symptoms of DLB. These findings suggest that (1) LB pathology can influence the clinical features of familial AD, (2) the E184D mutation of presenilin-1 may be associated with the LB formation through Aβ overproduction, although the process of LB formation is strongly affected by other unknown mechanisms, (3) in neurodegenerative disorders with LBs, there is a common pathophysiological background inducing NAC accumulation in neuritic plaques and astrocytes, and (4) the NAC accumulation in neuritic plaques is modulated by the abnormally aggregated tau protein.

Intractable hiccup caused by medulla oblongata lesions: A study of an autopsy patient with possible neuromyelitis optica

We report the first autopsy verification of medulla oblongata lesions involving bilateral nucleus tractus solitarius (NTS) as a cause of intractable hiccup in an autopsy patient. The female patient first developed pain and weakness in the lower limbs and urinary incontinence at age 48, and was given a diagnosis of myelitis. Intractable hiccup was accompanied by urinary retention on the third attack. She died of respiratory failure when the fifth attack occurred at age 51. Autopsy disclosed severe involvement of the medulla oblongata and entire spinal cord. Optic nerve lesions were also identified unexpectedly. Dual involvement of the optic nerve and spinal cord, necrotic spinal cord lesions involving not only myelin but also neurons and axon, and marked extension of the spinal cord lesions in both the longitudinal and transverse directions suggested the diagnosis of neuromyelitis optica rather than multiple sclerosis. Although animal experiments have shown that NTS is a critical structure in the hiccup reflex, we demonstrated for the first time the involvement of the NTS in an autopsy patient with intractable hiccup.

Neuronal expression of cyclooxygenase-2, a pro-inflammatory protein, in the hippocampus of patients with schizophrenia

Several types of evidence suggesting that the inflammatory response system is associated with pathophysiology of schizophrenia have been accumulated. Recently, a prospective double-blind study demonstrated that supplementary treatment with celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, produced significantly greater improvement in scores on the Positive and Negative Syndrome Scale (PANSS) and on all subscales during the acute phase in patients with schizophrenia compared with risperidone alone therapy. The therapeutic effect of celecoxib on the psychopathology of schizophrenia is speculated to be based on COX activity inhibition; however, the detailed pharmacological mechanisms are unclear. To clarify whether or not COX-2 expression is altered in schizophrenia, we examined neuronal COX-2 expression in the hippocampus from cases of schizophrenia (n = 17), normal controls (n = 22), and cases of Alzheimers disease (AD) as a positive control (n = 17). Quantitative immunohistochemical analysis demonstrated that neuronal COX-2 expression was significantly up-regulated in each CA1-4 region in Alzheimers disease compared with controls, and that the mean COX-2 immunointensity in CA1-4 was significantly correlated with Abeta load in cases of Alzheimers disease. In contrast, COX-2 expression was not up-regulated in any subdivision of the hippocampus in the schizophrenia group. These results suggest that celecoxib may affect the pathophysiology of schizophrenia through COX-2-independent actions rather than by inhibiting activity of up-regulated COX-2 protein.