Mitsuyasu Kanai

Combination assay of CSF Tau, Aβ1-40 and Aβ1-42(43) as a biochemical marker of Alzheimer's disease

Cerebrospinal fluid samples from a total of 157 subjects consisting of 55 patients with sporadic Alzheimers disease (AD), 34 normal controls, 23 patients with non-AD dementia, and 45 with other neurological diseases were examined by ELISA of tau, Aβ1-40, and Aβ1-42(43). The AD group had a significantly higher level of tau than the normal control group (P<0.001), and the diagnostic sensitivity was 31% and specificity was 94%. CSF Aβ1-40 levels did not show any significant differences. Although the level of Aβ1-42(43) was decreased significantly in the AD group compared to the control group (P<0.005), the overlap of Aβ1-42(43) levels among all groups meant that none of the AD samples exceeded the cut-off value, the mean 2SD of normal control subjects. Reduction of Aβ1-42(43) levels in AD resulted in a significant increase in the ratio of Aβ1-40 to Aβ1-42(43) (Aβ ratio) as an improved marker. The diagnostic sensitivity and specificity of Aβ ratio were 51% and 82% respectively. The three indexes, using the tau level and Aβ ratio (tau or Aβ ratio, deviation score and tau×Aβ ratio), showed better sensitivity (58%, 67%, 69%) and specificity (82%, 86%, 88%) than previously reported methods. Combination assay for CSF tau, Aβ1-40 and Aβ1-42(43) in CSF is a biological marker of AD and may be useful to biochemically monitor subjects under treatment.

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.

Apolipoprotein E4 accelerates dementia and increases cerebrospinal fluid tau levels in Alzheimer's disease

To examine the effect of apolipoprotein E (ApoE) 4 on the progression of Alzheimers disease (AD), the clinical course of 33 AD patients (17 cases with ApoE epsilon4 and 16 cases without ApoE epsilon4) was evaluated with the mini-mental state examination (MMSE) and cerebrospinal fluid (CSF) biological markers. The decline of MMSE scores to zero was shortened in the ApoE4 group. During a mean follow-up of 20 months, a significant increase of CSF tau levels was observed in the ApoE4 group. A lower level of CSF A beta1-42(43) was found in both the ApoE4 and non-ApoE4 groups than in age-matched normal controls. The ApoE epsilon4 allele accelerates the progression of dementia and increases the levels of CSF tau in AD patients.

Cerebrospinal fluid tau in dementia disorders: a large scale multicenter study by a Japanese study group

A large scale multicenter study of cerebrospinal fluid (CSF) tau levels was conducted to determine the cut-off value, sensitivity and specificity for clinical usage as a biomarker of Alzheimers disease (AD). Its use for early and differential diagnosis and the factors that increase CSF tau levels were also examined. CSF samples from a total of 1,031 subjects including 366 patients with AD, 168 patients with non-Alzheimer type dementia (NA), 316 patients with non-dementia neurological diseases (ND) and 181 normal controls (NC) were measured using ELISA for tau. The cut-off value of tau, 375 pg/ml, showed 59.1% sensitivity and 89.5% specificity for diagnosis of AD compared with the other groups. The tau levels were increased from the early to late stages of AD. Elevation of CSF tau in the non-tauopathy and tauopathy dementia groups, chronic and acute damage to the cerebrum, and meningeal disturbance were other factors that required attention for clinical practice. Measurement of CSF tau was useful as a biomarker for early and differential diagnosis of AD.

A comparison of tau protein in cerebrospinal fluid between corticobasal degeneration and progressive supranuclear palsy.

Many clinical and pathological discussions have been focused on the difficulty of differential diagnosis between corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) in recent years. This study was conducted to evaluate the usefulness of tau proteins in cerebrospinal fluid (CSF) for the differentiation of these two diseases. Subjects consisted of 10 patients with CBD (four males and six females with a mean age of 67.9+/-5.8 years), 12 patients with PSP (eight males and four females with a mean age of 62.6+/-5.8 years) and 36 control subjects (CTL) (16 males and 20 females with a mean age of 65.8+/-9.9 years). The CBD group included patients with probable CBD, while all the patients in the PSP group satisfied the diagnostic criteria developed by the National Institute of Neurological Disorders and Stroke and Society for PSP (NINDS-SPSP). CSF tau proteins were measured with the sandwich ELISA method (Innogenetics, Belgium). The CSF tau protein level was 320.1+/-86.5 pg/ml in the CBD group, 151.5+/-52.7 pg/ml in the PSP group and 128.7+/-91.7 pg/ml in the CTL group. Significant differences were noted in tau protein levels between the CBD group and both the PSP group (P<0.001) and the CTL group (P<0.005). We suggested that the measurement of CSF tau proteins may be useful for the differentiation between CBD and PSP.

The levels of cerebrospinal fluid Aβ40 and Aβ42(43) are regulated age-dependently

Decreased levels of cerebrospinal fluid (CSF) Abeta42 is a diagnostic marker of Alzheimers disease. To clarify the biological basis of this marker, the physiological alterations of CSF Abeta40 and Abeta42 by aging were studied. CSF samples from 92 normal subjects between 8 and 89 years old were measured using a specific ELISA for Abeta40 and Abeta42(43). High concentrations of Abeta40 and Abeta42(43) in the young group, under 29 years old, changed to be at low concentrations in the adult group between 30 and 59 years old. Subsequently, the levels increased again with age. Third order regression analysis showed a significant correlation between the levels of Abeta40 and age (Y = - 169 X(3) + 3.1X(2)- 0.02X + 4135; P < 0.034) and between the levels of Abeta42(43) and age (Y = - 46 X(3) + 0.9 X(2)- 0.005X + 992; P < 0.005). The levels of CSF Abeta40 and Abeta42(43) were physiologically regulated to show a U-shaped natural course in normal aging. These findings suggested that the physiological increase of Abeta42(43) over 59 years of age is selectively inhibited in Alzheimers disease.

Decreased level of brain acetylcholine and memory disturbance in APPsw mice

To clarify whether amyloid beta protein (Abeta) amyloidosis induces a disturbance of cholinergic system leading to long-term memory deficits, we continuously examined memory disturbance using the passive-avoidance task, and measured Abeta burden and concentrations of acetylcholine in the brain of APPsw transgenic mice. Repetitive retention trials of the passive-avoidance task showed that the long-term memory impairment in APPsw mice appeared from approximately 7.75 months old and progressively advanced. Significant decreases in acetylcholine levels were found in the brains of 10-month-old mice. A few senile plaques appeared in the cerebral cortex and the hippocampus at 8 months old, and increased in size and number with aging. The concentrations of brain Abeta40/42(43) gradually increased from 8 months old and exponentially increased thereafter. Advance of long-term memory disturbance was closely correlated with Abeta40/42(43) burden. These findings suggested that Abeta accumulation induced long-term memory impairment and disturbance of the cholinergic system, and that the passive-avoidance task and measuring acetylcholine were useful methods for evaluating this mouse model as well as Abeta accumulation.

Accumulation of NACP/alpha-synuclein in Lewy body disease and multiple system atrophy

OBJECTIVES NACP/α-synuclein is an aetiological gene product in familial Parkinsons disease. To clarify the pathological role of NACP/α-synuclein in sporadic Parkinsons disease and other related disorders including diffuse Lewy body disease (DLBD) and multiple system atrophy (MSA), paraffin sections were examined immunocytochemically using anti-NACP/α-synuclein antibodies. METHODS A total of 58 necropsied brains, from seven patients with Parkinsons disease, five with DLBD, six with MSA, 12 with Alzheimers disease, one with Downs syndrome, one with amyotrophic lateral sclerosis (ALS), three with ALS and dementia, one with Huntingtons disease, two with progressive supranuclear palsy (PSP), one with Picks disease, one with myotonic dystrophy, and three with late cerebellar cortical atrophy (LCCA), and 15 elderly normal controls were examined. RESULTS In addition to immunoreactive Lewy bodies, widespread accumulation of NACP/α-synuclein was found in neurons and astrocytes from the brainstem and basal ganglia to the cerebral cortices in Parkinsons disease/DLBD. NACP/α-synuclein accumulates in oligodendrocytes from the spinal cord, the brain stem to the cerebellar white matter, and inferior olivary neurons in MSA. These widespread accumulations were not seen in other types of dementia or spinocerebellar ataxia. CONCLUSION Completely different types of NACP/α-synuclein accumulation in Parkinsons disease/DLBD and MSA suggest that accumulation is a major step in the pathological cascade of both diseases and provides novel strategies for the development of therapies.

Amyloid β-protein ending at Thr43 is a minor component of some diffuse plaques in the Alzheimer's disease brain, but is not found in cerebrovascular amyloid

The distribution of amyloid beta-protein ending at 40 (A beta 40), 42 (A beta 42), and 43 (A beta 43) were immunocytochemically examined in Alzheimers brains. A large number of diffuse plaques were stained with A beta 42 antibody (S42), but some were weakly labeled with A beta 43 antibody (S43). Immature and mature plaques were labeled with A beta 40 antibody (S40), S42, and S43. Thus, A beta 42 is the major component of diffuse plaques, the initial phase of plaque formation, and A beta 43 is present as a minor component. Only A beta 40 is present in cerebrovascular amyloid.

A presenilin‐1 mutation in a Japanese family with Alzheimer's disease and distinctive abnormalities on cranial MRI

Some patients with familial Alzheimers disease (FAD) have mutations in the presenilin-1 (PS-1) gene on chromosome 14. We report a Japanese family with AD and an Ala285Val substitution in exon 8 of the PS-1 gene. FAD in this family was characterized by relatively late onset (mean age, 50 years) and absence of myoclonus, seizures, or paratonia. Levels of tau were markedly elevated in CSF whereas CSF levels of amyloid P protein were normal. MRI of the cranium showed marked linear signal abnormalities within white matter in the parieto-occipital lobes, consistent with cortical amyloid angiopathy of the type encountered in patients with the PS-1 gene mutation.