Yukifusa Igeta

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.

Apolipoprotein E accumulates with the progression of Aβ deposition in transgenic mice

To study the role of apolipoprotein E (apoE) in vivo in deposits of amyloid β protein (Aβ), a major component of senile plaque amyloid in the brain of patients with Alzheimer disease, the transgenic mice were examined by apoE immunostaining. The mice were systcmically ovcrexpressing signal peptide and 99 amino acid residues of the carboxy-lcrminal fragment of human amyloid β protein precursor (βAPP) under control of the powerful cytomegalovirus enhancer/chicken β-actin promotor. Ap deposits appeared at 4 months and increased with aging in the acinar cells of the transgenic pancreas. Similarly, apoE deposits appeared in the pancreatic acinar cells at 4 months old. The number and size of apoE deposits increased with aging and correlated with the progression of Aβdeposits. Interstitial macrophages labeled by apoE immunostaining appeared at 8 months after birth and their number increased with aging. On serial section of the pancrcata of 24-month-old mice, approximately 70% of Aβ deposits were labeled with the apoE antiserum. ApoE was detected in the highly insoluble formic acid fraction of the transgenic pancreas by an immunoblot study. The Northern blot study revealed no increase in synthesis of endogenous apoE mRNA. These findings indicate that apoE is closely related to progression of Aβ deposits with aging and suggest that Aβ deposition in the transgenic pancreas is similar to that in the senile plaque of Alzheimer brains. Therefore, our experimental system using transgenic mice will provide a useful tool to analyze the molecular mechanism of Aβ deposition in association with apoE in vivo.

Luxury perfusion phenomenon in acute herpes simplex virus encephalitis

In a patient with acute herpes simplex virus (HSV) encephalitis, positron emission tomography (PET) demonstrated increased cerebral blood flow in the affected temporal lobe accompanied by reduction in the cerebral oxygen extraction fraction and the cerebral metabolic rate of oxygen, i.e., luxury perfusion. Follow-up PET studies showed reduction in cerebral perfusion until it was more closely coupled with oxygen metabolism after the resolution of the acute inflammation. These findings support previous single photon emission computed tomographic data and provide a pathophysiological background for the occurrence of hyperperfusion in HSV encephalitis. This is an interesting example of the luxury perfusion phenomenon occurring in a disease other than cerebral ischemia.

Massive myelinolytic leukoencephalopathy in a patient medicated with low-dose oral methotrexate for rheumatoid arthritis: an autopsy report

The authors describe a 68-year-old female who developed a rapidly progressing leukoencephalopathy involving the cerebrum and brain stem. The disease appeared during low-dose oral methotrexate (MTX) therapy for rheumatoid arthritis. An extensive clinical investigation discounted other possible causes of white matter lesions. Autopsy identified an uninterrupted severe demyelinating, partially liquefactive necrosis-like lesion in the white matter accompanied by astrogliosis and occasional swollen axons therein. The lesion was generally symmetrical, and distributed throughout the whole cerebral white matter except for the bilateral temporal lobes and the rostral part of the frontal lobes. The internal capsules and cerebral peduncles were spongy, and the central and lateral parts of the pons, especially the transverse cerebellopontine tracts, were affected similarly. It was of note that the lesion was accompanied by neither vascular diseases nor lymphocyte infiltration. Thus, the pathological findings were similar to those of a severe form of central and extrapontine myelinolysis, and clearly different from ordinary MTX leukoencephalopathy reported in patients receiving intrathecal or intravenous MTX therapy, known as “disseminated necrotizing leukoencephalopathy”. Another possibility is that synergistic effects of several white-matter-damaging disorders may have contributed to the hitherto unknown lesion. To our knowledge, this is the first autopsy record that describes an oral MTX-associated neurological disorder.

Accumulation of Amyloid β Protein in Transgenic Mice

Abstract Carboxyl-terminal fragments of β amyloid precursor protein (βAPP) were expressed in mice under the transcriptional control of an ubiquitous promoter system, based upon a chicken β-actin (βA) promoter combined with cytomegalovirus (CMV) enhancer to obtain a systemic overproduction of amyloid β protein (Aβ). Three transgene constructs were designed to encode signal peptide and carboxyl-terminal 99 amino acid residues to βAPP (NOR-β), methionine and C-terminal 103 amino acid residues of βAPP (ΔNOR-β), and methionine and C-terminal 103 amino acid residues with KM-NL substitution of βAPP (ΔNL-β). Although the transcriptional mRNA level and post-translational protein level from transgenes showed the same expression pattern, both the expression of Aβ and distribution of Aβ deposits were completely different among these strains. In NOR-β mice, considerable amounts of Aβ were detected in plasma and Aβ deposits were observed in the pancreas. Brain Aβ deposits and small amounts of plasma Aβ were recognized in ΔNL-β. These findings indicate that tissue specific processing and transgene constructs are major facters to determine the distribution of Aβ deposits.

Lysosomal generation of amyloid β protein species in transgenic mice

Abstract Soluble amyloid β protein (A β )1–40 and highly amyloidogenic A β 1–42/43 were immunocytochemically labeled in lysosomes of acinar cells and macrophages in the pancreas of transgenic mice systemically expressing a C-terminal fragment of the A β precursor. A β 1–42/43 and long A β species extending their C-termini were detected in the detergent-insoluble fraction. Immunoreactivity of cathepsin D was markedly increased in lysosomes filled with A β fibrils. These findings indicated that A β 1–40, A β 1–42, A β 1–43 and longer A β species were generated in the lysosomes of the transgenic pancreas, and suggested that the activation of cathepsin D, a candidate γ -secretase, leads to acceleration of A β amyloid formation.