Sadao Takase

Consensus Report of the Working Group on : Molecular and Biochemical Markers of Alzheimer's Disease

The ideal biomarker for Alzheimers disease (AD) should detect a fundamental feature of neuropathology and be validated in neuropathologically-confirmed cases; it should have a sensitivity >80% for detecting AD and a specificity of >80% for distinguishing other dementias; it should be reliable, reproducible, non-invasive, simple to perform, and inexpensive. Recommended steps to establish a biomarker include confirmation by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. Our review of current candidate markers indicates that for suspected early-onset familial AD, it is appropriate to search for mutations in the presenilin 1, presenilin 2, and amyloid precursor protein genes. Individuals with these mutations typically have increased levels of the amyloid Abeta42 peptide in plasma and decreased levels of APPs in cerebrospinal fluid. In late-onset and sporadic AD, these measures are not useful, but detecting an apolipoprotein E e4 allele can add confidence to the clinical diagnosis. Among the other proposed molecular and biochemical markers for sporadic AD, cerebrospinal fluid assays showing low levels of Abeta42 and high levels of tau come closest to fulfilling criteria for a useful biomarker.The ideal biomarker for Alzheimers disease (AD) should detect a fundamental feature of neuropathology and be validated in neuropathologically-confirmed cases: it should have a sensitivity >80% for detecting AD and a specificity of >80% for distinguishing other dementias: it should be reliable, reproducible non-invasive, simple to perform, and inexpensive. Recommended steps to establish a biomarker include confirmation by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. Our review of current candidate markers indicates that for suspected early-onset familial AD. it is appropriate to search for mutations in the presenilin 1, presenilin 2, and amyloid precursor protein genes. Individuals with these mutations typically have increased levels of the amyloid Aβ 42 peptide in plasma and decreased levels of APPs in cerebrospinal fluid. In late-onset and sporadic AD. these measures are not useful. but detecting an apolipoprotein E e4 allele can add confidence to the clinical diagnosis. Among the other proposed molecular and biochemical markers for sporadic AD. cerebrospinal fluid assays showing low levels of Aβ 42 and high levels of tau come closest to fulfilling criteria for a useful biomarker.

Microsatellite polymorphism in the human heme oxygenase-1 gene promoter and its application in association studies with Alzheimer and Parkinson disease

Abstract Oxidative stress has been suggested to be involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer disease (AD) and Parkinson disease (PD). Heme oxygenase-1 (HO-1), a key enzyme in heme catabolism, also functions as an antioxidant enzyme. Here, we show that a (GT)n repeat in the human HO-1 gene promoter region is highly polymorphic, although no particular alleles are associated with AD or PD. This newly identified genetic marker should allow us to study the possible involvement of HO-1 in certain human diseases.

Chemokine receptor expression on T cells in blood and cerebrospinal fluid at relapse and remission of multiple sclerosis: imbalance of Th1/Th2-associated chemokine signaling

The expression of chemokine receptors on lymphocytes in the blood and CSF of multiple sclerosis (MS) patients was analyzed at relapse and remission. Both CD4+ and CD8+ cells in CSF at relapse were enriched for Th1-type receptors CXCR3 and CCR5 expression, and were reduced for Th2-type receptors CCR3 and CCR4 expression compared with those of the blood. CCR1 and CCR2 expressions on T cells were increased in CSF and blood, respectively. At remission, CCR5 expression, but not CXCR3 expression, was reduced in CSF CD4+ cells. A biased Th1/Th2 balance may play a critical role in active inflammation and CCR5 on CSF CD4+ cells is a good marker of the disease activity.

Hypoperfusion in the supplementary motor area, dorsolateral prefrontal cortex and insular cortex in Parkinson's disease.

The changes of regional cerebral blood flow (rCBF) in Parkinsons disease (PD) were investigated. Because of individual differences in brain volume and the extent of brain atrophy, previous functional imaging studies involved potential methodological difficulties. In this study, using the statistical parametric mapping technique, 99mTechnetium-labeled hexamethylpropyleneamineoxime brain single-photon emission computed tomography images from 18 patients with PD were transformed into standard brain-based stereotaxic coordinate spaces and then compared with such images for 11 control subjects matched for age and extent of brain atrophy. A rCBF decrement in the supplementary motor area (SMA) and such decrement in the dorsolateral prefrontal cortex (DLPFC) were observed in the summarized PD images as compared with controls (p<0.005). In a subgroup in the Hoehn-Yahr III/IV stage (11 cases), the rCBF decrement was demonstrated not only in the SMA, but also in the DLPFC and insular cortex (p<0.001). There was a correlation between the degree of the rCBF decrement in the DLPFC or the insular cortex and the score of the unified Parkinsons disease rating scale (p<0.05), while the rCBF decrement in the SMA showed no relationship with the severity of disease. The function of the SMA is closely associated with the nigro-striatal pathway and its impairment can explain the basic akinetic symptoms in PD, which are responsive to L-DOPA treatment. On the other hand, the DLPFC and insular cortex may play key roles in specific symptoms of impairment at advanced stages, such as impaired working memory, postural instability and autonomic dysfunction. We hypothesize that the impairment of the DLPFC and insular function is correlated with the progression of the disease and is related to DOPA-refractory symptoms, which are major problems in the care of patients with advanced PD.

Increased bilirubins and their derivatives in cerebrospinal fluid in Alzheimer’s disease

Bilirubin, an efficient antioxidant, is the end product of the heme cleavage pathway, which is catalyzed by heme oxygenase (HO) and biliverdin reductase. Although an inducible form of HO is overexpressed in the Alzheimers disease (AD) brain, it has not been determined whether bilirubin metabolism is actually activated or not. In this study, we measured CSF-bilirubins and their derivatives using an enzyme-linked immunosorbent assay with two kinds of anti-bilirubin monoclonal antibodies, designated 24G7 and 5M2. In AD patients, the levels of CSF bilirubin derivatives increased significantly compared with those of controls. This increase was not due to the increased permeability of the blood-brain barrier, because the levels of unconjugated bilirubin were not different between AD and controls. These data may reflect the increase of degraded bilirubin metabolites in the AD brain derived from the scavenging reaction against chronic oxidative stress.

No increase in cerebrospinal fluid tau protein levels in patients with vascular dementia

Tau protein levels in cerebrospinal fluid (CSF-tau) were determined in 29 patients with old cerebrovascular disease (CVD, 21 demented and eight non-demented), 69 patients with Alzheimers disease (AD) and 17 age-matched normal controls. The CSF-tau level in the vascular dementia (VD) group (24.0 +/- 17.0 pg/ml) was significantly lower (P < 0.0001) than that in the AD group (90.0 +/- 45.3 pg/ml), but not significantly different from that in the non-demented patients with CVD (18.1 +/- 10.2 pg/ml) or controls (20.3 +/- 13.0 pg/ml). Among the VD patients, 1/21 exceeded a cut-off value (mean +/- 2 SD of controls), whereas 8/69 of the AD patients had CSF-tau levels below this value. These findings suggest that VD constitutes a group of dementias that can be separated from AD by normal CSF-tau levels. CSF-tau determinations in combination with other clinical findings may provide another diagnostic aid in the differential diagnosis between VD and AD.

Clinical analysis of longstanding subacute myelo-optico-neuropathy: sequelae of clioquinol at 32 years after its ban

One thousand and thirty-one longstanding patients with subacute myelo-optico-neuropathy (SMON; 275 males, 756 females; mean age +/- S.D., 72.9 +/- 9.6 years; age at onset 37.6 +/- 9.8 years; duration of illness 35.3 +/- 4.0 years) were examined in 2002, 32 years after banning of clioquinol. At onset, 66.7% of patients were unable to walk, and 4.7% complete blindness. At present time, about 41% of patients were still difficult to walk independently, including 15.8% of completely loss of locomotion. One point six percent of patients were in complete blindness and 5.8% had severe visual impairment. The majority (95.6 - 97.7%) of patients exhibited sensory disturbances including superficial and vibratory sensations and dysesthesia. Dysautonomia was observed as leg hypothermia in 79.8%, urinary incontinence in 60.7%, and bowel disturbance in 95.3%. As complication, high incidence was revealed with cataract (56.2%), hypertension (40.2%), vertebral disease (35.5%), and limb articular disease (31.5%). These results indicate the serious sequelae of clioquinol intoxication, SMON.

Clinical and MRI study of brain stem and cerebellar involvement in Japanese patients with multiple sclerosis

OBJECTIVES To investigate the clinical and MRI features of brain stem and cerebellar lesions in Japanese patients with multiple sclerosis. METHODS A retrospective study of 66 consecutive Japanese patients with multiple sclerosis (42 women and 24 men) was done by reviewing the medical records and MRI films. Forty nine patients were diagnosed as having clinically definite multiple sclerosis and 17 patients as having clinically probable multiple sclerosis according to Poser’s criteria. Prevalence rates of each brain stem and cerebellar manifestation and frequency and distribution of MRI lesions in these patients were studied. RESULTS Forty three patients (65%) had one or more infratentorial manifestations. Cranial nerves were clinically involved in 28 patients (42%), and most of the lesions were identified by MRI. Among them, manifestations of facial, trigeminal, and abducens nerves were relatively common. Cerebellar ataxia was found in 20 patients (30%). The MRI study showed that the lesions responsible for ataxia in these patients were mainly found in the cerebellar peduncles, but cerebellar hemispheric lesions were detected in only four patients (6.4%). CONCLUSION The low frequency (6.4%) of the cerebellar MRI lesions in these patients is in sharp contrast with the figures reported for white patients with multiple sclerosis (50%-90%). Racial and genetic differences may have an influence on the susceptibility of each part of the CNS to demyelination in multiple sclerosis.

Distribution of substance P-like immunoreactivity in the lower brainstem of the human fetus: an immunohistochemical study.

The regional distribution of substance P-like immunoreactive (SPI) structures in the lower brainstem of the human fetus was investigated using the indirect immunofluorescence technique. SPI cells were found in a number of areas including the inferior colliculus, central gray matter of the midbrain, n. laterodorsalis tegmenti, midbrain and medullary reticular formation, n. vestibularis inferior, and n. prepositus hypoglossi. An extensive network of SPI fibers of varying densities were identified throughout the lower brainstem.

Isolation and characterization of subacute sclerosing panencephalitis virus (Yamagata-1 strain) from a brain autopsy.

Subacute sclerosing panencephalitis (SSPE) is a rare, progressive and usually fatal disease of the central nervous system which affects children and young adults. Structures like nucleocapsids of paramyxoviruses (2) and the viral antigens of measles virus (5) have been found in the brains of patients. High titers of antibody against measles virus in patients serum and cerebrospinal fluid (5) have also been demonstrated. Since Chen et al (3) and Horta-Barbosa et al (8, 9) succeeded in recovering measles-like viruses by co-cultivation of brain cells of the patients with susceptible tissue culture cells, a large number of SSPE virus-carrying cell lines have been established (1, 7). There is considerable variation, however, in their properties, e.g., virion production, synthesis of M protein as well as other virion constituents, and neurovirulence in experimental animals (7), that makes it difficult to relate a particular property of the virus to the etiology of SSPE. All of the four isolates in Japan have been reported to be defective in production of infectious virus (6, 11, 16, 19). We studied three of them and succeeded in recovering a small number of cell-free infectious virus particles from each of the virus-carrying cell lines by treatment of the cells with either EDTA or freezing and thawing though spontaneous release of the infectious virus was still not demonstrable (12, 13). Nevertheless, neurovirulence of these virus-carrying cells for mice was evident (14); thus these viruses differed from the so-called productive SSPE virus such as the Mantooth, Halle and LEC-S strains (18). These results seem to indicate that the property of less production of SSPE virus, like the isolates in Japan, is a requisite for neurovirulence. Accordingly, comparative study of these less-productive strains should provide a better understanding of the neurovirulent factors of this virus. In this paper, we describe preliminarily an additional new isolate, from the brain of an SSPE patient, of an SSPE virus which has characteristics similar to those of the other Japanese strains in terms of growth of the virus but distinct from them in neurovirulence and histopathology of the brain in mice.