Yasuko Matsumoto

Value of 123I-MIBG radioactivity in the differential diagnosis of DLB from AD

Objective: To evaluate the diagnostic reliability of cardiac iodine-123 metaiodobenzylguanidine (123I-MIBG) radioactivity in discriminating dementia with Lewy bodies (DLB) from Alzheimer disease (AD) regardless of parkinsonism. Background: The diagnosis of DLB may be confounded by the absence of parkinsonism. This highlights the need to improve the accuracy of antemortem diagnosis of DLB without parkinsonism. Methods: Cardiac sympathetic denervation was examined using myocardial 123I-MIBG scintigraphy in 37 patients with DLB, 42 patients with AD, and 10 normal elderly controls. The DLB patients consisted of seven patients without parkinsonism (DLB/P−) and 30 patients with parkinsonism (DLB/P+) at the time of the study. Results: The heart-to-mediastinum uptake ratio (H/M ratio) of myocardial MIBG uptake was decreased in both the DLB groups vs the AD group (p < 0.0001) and control group (p < 0.0001). The washout rate (WR) was higher in the DLB group than in the control group (p < 0.0001) and AD group (p < 0.0001). No differences were found between the AD and control groups or between the DLB/P+ and DLB/P− groups in either the early or delayed H/M ratio or WR. In discriminating between DLB and AD, regardless of parkinsonism, the delayed H/M ratio had a sensitivity of 100%, a specificity of 100%, and a positive predictive value of 100% at a cutoff value of 1.68. Conclusions: Our results indicate that dementia with Lewy bodies results in cardiac sympathetic denervation and that iodine-123 metaiodobenzylguanidine myocardial scintigraphy is a sensitive tool for discriminating dementia with Lewy bodies from Alzheimer disease even in patients without parkinsonism.

Decreased β-amyloid peptide42 in cerebrospinal fluid of patients with progressive supranuclear palsy and corticobasal degeneration

Several previous studies have identified biochemical markers for Alzheimers disease (AD): cerebrospinal fluid (CSF)-beta-amyloid peptide42 (CSF-Abeta42), CSF-total tau protein (CSF-tau) and CSF-phosphorylated tau protein (CSF-ptau). Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) as well as AD are diseases with tauopathies. CSF-Abeta42, CSF-tau, and CSF-ptau have not been rigorously investigated in PSP and CBD. In the present study, we assessed CSF-Abeta42, CSF-tau, and CSF-ptau as biochemical markers for PSP and CBD, compared with AD. The subjects consisted of 18 cases of PSP, 9 cases with CBD, 69 cases with AD, and 43 control subjects. Genotyping or phenotyping of apolipoprotein E (apoE) was also performed. CSF-Abeta42 levels were significantly decreased in patients with PSP and CBD as well as in AD patients. The ratio of CSF-ptau to CSF-Abeta42 provided high diagnostic accuracy to distinguish both PSP from AD, and CBD from AD. ApoE genotype/phenotype was not associated with CSF-Abeta42 levels in all groups. We concluded that CSF-Abeta42 levels are reduced in PSP and CBD as well as in AD.

Blood-Brain Barrier Permeability Correlates with Medial Temporal Lobe Atrophy but Not with Amyloid-β Protein Transport across the Blood-Brain Barrier in Alzheimer’s Disease

Background/Aims: Alterations in the blood-brain barrier (BBB) may play an important role in the pathogenesis and treatment of Alzheimer’s disease (AD). We investigated BBB disturbance and its influence on the equilibrium of amyloid-β protein (Aβ) between plasma and cerebrospinal fluid (CSF) in AD patients. Methods: We analyzed albumin ratio as a marker of the BBB permeability and correlated it with the severity of dementia, brain atrophy on MRI, apolipoprotein E isoform, CSF levels of total tau, CSF and plasma levels of Aβ 1–40 (Aβ40) and 1–42 (Aβ42), and CSF/plasma ratios of Aβ40 and Aβ42 in 42 AD patients. Results: The albumin ratio was positively correlated with the severity of medial temporal lobe atrophy but not with the other parameters including CSF/plasma ratios of Aβ40 or Aβ42. Conclusion: Our results suggest that progression of medial temporal lobe atrophy is associated with increased BBB permeability and that the transport of Aβ across the BBB is not influenced by the BBB alteration in AD.

Cerebrospinal fluid of Alzheimer patients promotes β-amyloid fibril formation in vitro

Cerebral deposition of amyloid beta-peptide (Abeta) is an invariant feature of Alzheimers disease (AD). To answer why soluble Abeta does not aggregate to beta-amyloid fibrils (fAbeta) in the brain of normal humans, we examined the influence of cerebrospinal fluid (CSF) obtained from AD and non-AD patients on the formation of fAbeta(1-40) and fAbeta(1-42) in vitro, by using fluorescence spectroscopy with thioflavin T and electron microscopy. Although the CSF obtained from both groups inhibited the formation of both fAbeta(1-40) and fAbeta(1-42), the CSF from non-AD patients inhibited the formation of fAbetas more strongly than that from AD patients. In AD patients, the final levels of fAbetas formation showed a significant negative correlation with the Abeta(1-42) level in CSF. These results indicate that fAbeta deposition in the brain of AD may be enhanced by the decrease of specific inhibitory factors and/or by the increase of specific accelerating factors in CSF.

Hypertrophic pachymeningitis as an initial and cardinal manifestation of microscopic polyangiitis.

The authors describe a 68-year-old man who developed hypertrophic pachymeningitis as an initial and cardinal manifestation of microscopic polyangiitis. The patient had a high titer of antineutrophil cytoplasmic antibody for myeloperoxidase. Biopsies revealed necrotizing glomerulonephritis in the kidney, small vessel vasculitis in the sural nerve, and infiltration of plasma cells and eosinophils in the thickened dura mater.

Acute autonomic sensory and motor neuropathy associated with central nervous system disturbance

We report a 45-year-old woman with acute autonomic sensory and motor neuropathy (AASMN) showing central nervous system (CNS) disturbance. She presented with disturbance of consciousness, complex partial seizures with automatisms, autonomic, sensory and motor neuropathy, showing severe orthostatic hypotension and neurogenic bladder. Nerve conduction studies and nerve biopsy indicated axonal degeneration involving both the myelinated and unmyelinated fibers. Muscle biopsy revealed neurogenic muscular atrophy. Electroencephalogram revealed theta wave activities and sharp wave abnormalities in the frontal lobe. Intravenous immunoglobulin therapy resulted in complete recovery of consciousness levels, but no obvious improvement of the other symptoms. Only eight patients with AASMN have been reported. This is the first report of AASMN showing CNS disturbance. Perivascular lymphocytic infiltration into the temporal lobe and brain stem was described in an autonomic neuropathy patient. An inflammatory pathogenesis of the CNS disturbance associated with this autonomic neuropathy was proposed.

Cerebrospinal Fluid/Serum IgG Index Is Correlated with Medial Temporal Lobe Atrophy in Alzheimer’s Disease

Background/Aim: Intrathecal inflammation has been suggested to play an important role in the pathogenesis of Alzheimer’s disease (AD). However, there is little clinical evidence in support of this hypothesis in AD patients. We previously reported that the blood-brain barrier permeability represented by the cerebrospinal fluid/serum albumin ratio correlates with medial temporal lobe atrophy (MTA) in AD.The aim of this study was to elucidate the relationship between intrathecal inflammation and the severity of AD. Methods: We investigated the correlations between the cerebrospinal fluid/serum IgG index and the indices of AD severity, including Clinical Dementia Rating and Mini-Mental State Examination, and MTA on magnetic resonance imaging in 42 AD patients. Further, the number of apolipoprotein E isoforms and the blood-brain barrier permeability were also examined for the correlation with the IgG index. Results: The IgG index showed a positive correlation with the severity of MTA but not with the other parameters examined. Conclusion: Our results suggest that intrathecal inflammation increases in association with the severity of MTA in AD.

Blood-borne factors inhibit Alzheimer's β-amyloid fibril formation in vitro

Abstract Soluble amyloid β-protein (Aβ) does not aggregate to β-amyloid fibrils (fAβ) in the brain of normal humans. We recently found that the cerebrospinal fluid (CSF) from non-Alzheimers disease (AD) subjects inhibited the formation of fAβ(1–40) and fAβ(1–42) more strongly than that from AD subjects, although the CSF obtained from both groups inhibited the fAβs formation in vitro. Here, we examined the influence of plasma obtained from AD, non-AD and healthy control (CTL) subjects on the formation of fAβ(1–40) and fAβ(1–42) in vitro. Although the plasma obtained from all groups inhibited the formation of fAβ(1–40) and fAβ(1–42), the plasma from non-AD and CTL subjects inhibited the formation of fAβs more strongly than that from AD subjects. These results indicate that the plasma as well as CSF in AD would provide a molecular environment favorable for fAβ formation, suggesting a decrease of specific inhibitory factors and/or increase of specific accelerating factors.

Peripheral neuropathy associated with chronic natural killer cell lymphocytosis.

We report a patient with steroid-responsive peripheral neuropathy which developed with chronic natural killer cell lymphocytosis (CNKL). A 70-year-old female with a 2-week history of progressive motor and sensory neuropathy showed a marked increase of natural killer (NK) cells in the blood, and was diagnosed as having CNKL. Nerve conduction studies (NCS) revealed a mixed axonal and demyelinating neuropathy. A sural nerve biopsy revealed infiltration of NK cells into the nerve fascicles, and demyelinating changes with axonal degeneration. The infiltrating NK cells were adjacent to myelinated fibers, showing damage of Schwann cell membrane. Treatment with oral prednisolone resulted in rapid improvement of the sensory disturbance and weakness with a significant decrease of NK cells in the blood and disappearance of the conduction blocks in NCS. This is the first case of CNKL associated neuropathy in which infiltration of NK cells was demonstrated in the nerve fascicles. Our observations suggest that the infiltrating NK cells may directly damage myelin and Schwann cells, thus causing demyelination.

Inclusion body myositis with granuloma formation in muscle tissue

Inclusion body myositis is a form of inflammatory myopathy. We identified 4 cases of inclusion body myositis showing granuloma formation in muscle tissue and aimed to assess the features of this atypical form of inclusion body myositis. We retrospectively reviewed consecutive patients who satisfied European Neuromuscular Centre IBM Research Diagnostic Criteria 2011. Then, we assessed clinical profiles and pathological findings in patients with inclusion body myositis with granuloma and compared these findings with those of typical inclusion body myositis without granuloma. We identified 15 patients with inclusion body myositis. Four patients showed granuloma formation in muscle tissue in addition to typical pathological features of inclusion body myositis. Granulomas comprised a mixture of inflammatory cells, such as macrophages, epithelioid histiocytic cells, and lymphocytes. One patient was found to have mediastinal granulomatous lymphadenopathy; however, the evidence in other patients was insufficient for a diagnosis of systemic sarcoidosis. There were no significant differences between groups with and without granuloma regarding clinical manifestations, laboratory findings, response to immunomodulating therapies, or myopathological profiles. We established a new form of inclusion body myositis showing granuloma formation in muscle tissue. Inclusion body myositis and granuloma formation could have identical pathomechanisms concerning dysregulation of autophagy.