Yasuko Komatsuzaki

Amyloid β protein in plasma from patients with sporadic Alzheimer's disease

Abstract Fibrillar amyloid β protein (Aβ) deposition is increased in the brains of patients with Alzheimers disease (AD), and is manifested as senile plaques (SPs) and congophilic angiopathy (CA). Aβ40 and Aβ42(43), two chief species of Aβ, are documented in SPs and CA, as well as in cerebrospinal fluid (CSF) and cell culture media. Aβ42(43) is the major component of diffuse plaques, the earliest form of SPs. Thus, we hypothesized that determination of the amount of Aβ42(43) in CSF or plasma might provide a diagnostic laboratory test for AD. We measured amounts of different Aβ species in plasma from 28 patients with sporadic probable AD, 40 age-matched neurologic patients without dementia and 25 age-matched normal controls using enzyme-linked immunosorbent assays (ELISAs). Plasma concentrations of Aβ1-40 and Aβ1-42(43) did not significantly differ among these groups. These findings suggest the unlikelihood that plasma Aβ assays would be useful as a diagnostic tool for AD.

Aβ42-positive non-pyramidal neurons around amyloid plaques in Alzheimer's disease

Immunohistochemistry with end-specific antibodies against C-termini of Aβ40 and Aβ42 in Alzheimers disease showed that Aβ42 immunoreactivity was localised intracellularly in subpopulations of neurons of patients with Alzheimers disease.

Calbindin-D 28k immunoreactivity in the cerebellum of spinocerebellar degeneration

We studied immunoreactivity for calbindin-D 28k (CaBP), an intracellular calcium-binding protein, in the cerebellum of control subjects and of patients with spinocerebellar degeneration (SCD) including sporadic olivopontocerebellar atrophy and familial cortical cerebellar atrophy. In the cerebellum, CaBP immunoreactivity was seen exclusively in the Purkinje cell in both SCD and control groups. However, the number of CaBP-immunoreactive Purkinje cells was significantly reduced in SCD. CaBP immunohistochemistry also disclosed abnormal morphological changes of Purkinje cells, which was not visualized on conventional strains or not clearly demonstrated on immunohistochemistry for neurofilaments. Moreover, reduced CaBP immunoreactivity was observed even in some remaining Purkinje cells of SCD suggesting that loss of CaBP precedes neuronal loss of Purkinje cell. We conclude that CaBP is a useful marker for Purkinje cell degeneration, and that reduced CaBP expression might have some association with the mechanism of the Purkinje cell degeneration in SCD.

Screening of the mis-sense mutation producing the 717Val → Ile substitution in the amyloid precursor protein in Japanese familial and sporadic Alzheimer's disease

We investigated a C to T transition at base pair 2149 in the amyloid precursor protein gene in 41 Japanese cases of early-onset familial Alzheimers disease (FAD), late-onset FAD and sporadic Alzheimers disease (AD) by polymerase chain reaction and restriction enzyme polymorphism with BclI. Among 9 early-onset FAD patients derived from independent families, only one patient had the mis-sense mutation. Neither 5 patients with late-onset FAD nor 27 patients with sporadic AD had the mutation. Our result and the previous reports from Japan indicate that this type of mis-sense mutation is present in several cases of Japanese early-onset FAD. On the other hand, our data suggest that this mutation is not a common cause of Japanese early-onset FAD. Moreover, this mutation could be absent in late-onset FAD and sporadic AD in Japan. Because the mutation has been reported to be rare in Caucasian early-onset FAD and to be absent in Caucasian late-onset FAD and sporadic AD, the situation of this mutation in Alzheimers disease may be common beyond the ethnic background.

Frontotemporal dementia with ubiquitinated neuronal inclusions presenting with primary lateral sclerosis and parkinsonism: clinicopathological report of an autopsy case

We report a case displaying upper motor sign, parkinsonism, and behavioral abnormality, with marked degeneration of the precentral cortex, neostriatum and frontotemporal lobes, as well as ubiquitinated neuronal inclusions. The patient was a 66-year-old male at the time of death. At age 57, he noticed progressive difficulties in speaking and swallowing. At age 60, he was severely anarthric and displayed emotional lability and incontinence. Neurologically, very poor movement of tongue was observed, but without atrophy or fasciculation. Deep tendon reflexes were hyperactive. Grasp reflex and snout reflex were also positive. Needle electromyography revealed no abnormalities. A diagnosis of primary lateral sclerosis and character change was made. At age 62, he developed bradykinesia and rigidity of the neck and all extremities. Treatment with carbidopa-levodopa was initiated, but resulted in minimal improvement. At age 65, he was bed-ridden, and had repeated occurrences of aspiration pneumonia; he died of pneumonia. Neuropathological examination revealed marked atrophy of the frontal and temporal lobes with Betz cells completely absent and moderate atrophy of the neostriatum. The spinal cord and nerve roots appeared normal. Immunohistochemically, ubiquitin-positive but tau-negative intraneuronal inclusions were found in the frontal and temporal cortices, including the precentral cortex and the hippocampal dentate gyrus, and the neostriatum. This case could be included with inclusion-associated disorders such as frontotemporal dementia or amyotrophic lateral sclerosis with dementia, and furthermore, predominant upper motor sign and parkinsonism could represent phenotypes of clinical manifestations with such inclusions.

Amyloid-β-protein isoforms in brain of subjects with PS1-linked, βAPP-linked and sporadic alzheimer disease

To determine whether similar abnormalities of various soluble full-length and N-terminal truncated Abeta peptides occur in postmortem cerebral cortex of affected PS1 mutation carriers, we examined the amounts of two amyloid species ending at residue 40 or at residues 42(43) using sandwich ELISA systems. Our results indicate that PS1 mutations effect a dramatic accumulation in brain of the highly insoluble potentially neurotoxic long-tailed isoforms of the Abeta peptide such as Abeta1-42(43) and Abetax-42(43). This enhancing effect of PS1 mutation on Abetax-42(43) deposition was highly similar to that of a betaAPP mutation (Val717Ile) but the effects on Abetax-40 production were significantly different between these two causal genes. In contrast to previous studies of soluble Abeta in plasma and in supernatants from cultured fibroblasts of subjects with PS1 mutations, our studies also show that there is an increase in insoluble Abetax-40 peptides in brain of subjects with PS1 mutations.

Association of Lewy bodies and glial cytoplasmic inclusions in the brain of Parkinson's disease.

Abstract. We report the histopathological and immunohistochemical findings from the brain of an elderly patient diagnosed with Parkinsons disease (PD). Neuropathological examination revealed moderate neuronal cell loss and astrocytosis in the substantia nigra. Lewy bodies were found in many sites characteristic for PD, including the substantia nigra, locus coeruleus, hypothalamus, substantia innominata, pontine raphe nucleus, and dorsal motor vagal nucleus, cingulate and insular cortices. Furthermore, argyrophilic glial intracytoplasmic inclusions were found predominantly in the ventral pons, cerebellar white matter, precentral and frontal white matter, internal and external capsule, claustrum, and putamen. Inclusions were triangular in shape, and immunopositive for ubiquitin and α-synuclein. In view of these histopathological and immunohistochemical findings and patterns of distribution, the inclusions were suggested to be glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA). These findings suggested that our case might have experienced two pathological processes; PD and the early stage of MSA (striatonigral degeneration) that had not progressed to striatal involvement. Alternatively a common pathological background including abnormal processing of α-synuclein could contribute to widespread accumulation of Lewy bodies and GCIs in a single condition accompanied by nigral degeneration.