Plasma MMP-9 Levels as the Future Risk of Conversion to Dementia in ApoE4-Positive MCI Patients: Investigation Based on the Alzheimer's Disease Neuroimaging Initiative Database.

BACKGROUND: Matrix metalloproteinase 9 (MMP-9) has been reported to be correlated with declines in hippocampal volume and cognitive function in ApoE4-positive MCI patients. OBJECTIVES: The present study was aimed to investigate the effects of plasma matrix MMP-9 on the conversion risk between mild cognitive impairment (MCI) patients with and without ApoE4. DESIGN AND SETTING: Retrospective observational study using the data extracted from the Alzheimer's Disease Neuroimaging Initiative database. PARTICIPANTS: We included 211 ApoE4-positive MCI subjects (ApoE4+ MCI) and 184 ApoE4-negative MCI subjects (ApoE4- MCI). MEASUREMENTS: We obtained demographic and data including plasma MMP-9 levels at baseline and longitudinal changes in Clinical Dementia Rating (CDR) up to 15 years. We compared conversion rates between ApoE4+ MCI and ApoE4- MCI by the Log-rank test and calculated the hazard ratio (HR) for covariates including age, sex, educational attainment, drinking and smoking histories, medications, and plasma MMP-9 levels using a multiple Cox regression analysis of ApoE4+ MCI and ApoE4- MCI. RESULTS: No significant differences were observed in baseline plasma MMP-9 levels between ApoE4+ MCI and ApoE4- MCI. High plasma MMP-9 levels increased the conversion risk significantly more than low plasma MMP-9 levels (HR, 2.46 [95% CI, 1.31-4.48]) and middle plasma MMP-9 levels (HR, 1.67 [95% CI, 1.04-2.65]) in ApoE4+ MCI, but not in ApoE4- MCI. CONCLUSION: Plasma MMP-9 would be the risk of the future conversion to dementia in ApoE4+ MCI.

A Japanese Multicenter Study on PET and Other Biomarkers for Subjects with Potential Preclinical and Prodromal Alzheimer's Disease.

BACKGROUND: PET (positron emission tomography) and CSF (cerebrospinal fluid) provide the "ATN" (Amyloid, Tau, Neurodegeneration) classification and play an essential role in early and differential diagnosis of Alzheimer's disease (AD). OBJECTIVE: Biomarkers were evaluated in a Japanese multicenter study on cognitively unimpaired subjects (CU) and early (E) and late (L) mild cognitive impairment (MCI) patients. MEASUREMENTS: A total of 38 (26 CU, 7 EMCI, 5 LMCI) subjects with the age of 65-84 were enrolled. Amyloid-PET and FDG-PET as well as structural MRI were acquired on all of them, with an additional tau-PET with 18F-flortaucipir on 15 and CSF measurement of Aß1-42, P-tau, and T-tau on 18 subjects. Positivity of amyloid and tau was determined based on the positive result of either PET or CSF. RESULTS: The amyloid positivity was 13/38, with discordance between PET and CSF in 6/18. Cortical tau deposition quantified with PET was significantly correlated with CSF P-tau, in spite of discordance in the binary positivity between visual PET interpretation and CSF P-tau in 5/8 (PET-/CSF+). Tau was positive in 7/9 amyloid positive and 8/16 amyloid negative subjects who underwent tau measurement, respectively. Overall, a large number of subjects presented quantitative measures and/or visual read that are close to the borderline of binary positivity, which caused, at least partly, the discordance between PET and CSF in amyloid and/or tau. Nine subjects presented either tau or FDG-PET positive while amyloid was negative, suggesting the possibility of non-AD disorders. CONCLUSION: Positivity rate of amyloid and tau, together with their relationship, was consistent with previous reports. Multicenter study on subjects with very mild or no cognitive impairment may need refining the positivity criteria and cutoff level as well as strict quality control of the measurements.

Head-to-Head Visual Comparison between Brain Perfusion SPECT and Arterial Spin-Labeling MRI with Different Postlabeling Delays in Alzheimer Disease.

BACKGROUND AND PURPOSE: Arterial spin-labeling MR imaging has been recently developed as a noninvasive technique with magnetically labeled arterial blood water as an endogenous contrast medium for the evaluation of CBF. Our aim was to compare arterial spin-labeling MR imaging and SPECT in the visual assessment of CBF in patients with Alzheimer disease. MATERIALS AND METHODS: In 33 patients with Alzheimer disease or mild cognitive impairment due to Alzheimer disease, CBF images were obtained by using both arterial spin-labeling-MR imaging with a postlabeling delay of 1.5 seconds and 2.5 seconds (PLD1.5 and PLD2.5, respectively) and brain perfusion SPECT. Twenty-two brain regions were visually assessed, and the diagnostic confidence of Alzheimer disease was recorded. RESULTS: Among all arterial spin-labeling images, 84.9% of PLD1.5 and 9% of PLD2.5 images showed the typical pattern of advanced Alzheimer disease (ie, decreased CBF in the bilateral parietal, temporal, and frontal lobes). PLD1.5, PLD2.5, and SPECT imaging resulted in obviously different visual assessments. PLD1.5 showed a broad decrease in CBF, which could have been due to an early perfusion. In contrast, PLD2.5 did not appear to be influenced by an early perfusion but showed fewer pathologic findings than SPECT. CONCLUSIONS: The distinctions observed by us should be carefully considered in the visual assessments of Alzheimer disease. Further studies are required to define the patterns of change in arterial spin-labeling-MR imaging associated with Alzheimer disease.

Menadione-induced tau dephosphorylation in cultured human neuroblastoma cells.

Oxidative stress has been implicated in the mechanism of aging and neurodegenerative disorders such as Alzheimer's disease (AD). Menadione causes oxidative stress by generating reactive oxygen species through its redox cycling and these free radicals are detoxified subsequently at the expense of intracellular thiol homeostasis. In non-neuronal cells, the cytoskeleton is a prime target of menadione-induced thiol oxidation. We used cultured human neuroblastoma MSN cells in this study to determine how tau proteins in neuronal cells are affected by menadione exposure. Menadione caused a dose-dependent thiol oxidation in these cells just like their non-neuronal counterparts. A prominent consequence of such oxidative insult in these neuronal cells was tau dephosphorylation. This dephosphorylation resulted in disappearance of phosphorylated 57-kDa tau with a concomitant emergence of 53-kDa tau whose full-length nature is indicated by its reactivity with antibodies Alz 50, Tau-1 and Tau-46. Immunochemical analyses using phosphorylation-dependent immunoprobes Tau-1 and PHF-1 with the aid of alkaline phosphatase demonstrated that 53-kDa tau was derived from dephosphorylation of 57-kDa tau. Despite its effect on thiol oxidation, menadione treatment did not lead to cytoskeletal changes reminiscent of the neurofibrillary tangles of AD. The data thus indicate that tau dephosphorylation constitutes a major feature of the menadione-induced oxidative injury in these neuronal cells.

Heparan sulfate proteoglycans recognize ghost Pick bodies.

An anti-heparan sulfate proteoglycan (HSPG) monoclonal antibody (3G10) recognized irregular round structures (IRSs) of various sizes adjacent to tau-positive intracellular Pick bodies (PBs) in the granular cell layer of the dentate gyrus and the superficial layers of the parahippocampal and other temporal gyri in Pick's disease. Some intracellular PBs were also weakly immunostained with 3G10. Only part of the IRSs were double-immunostained with 3G10 and anti-tau antibody. Immunoelectron-microscopic examination revealed that IRSs were composed of aggregated fibrillary structures with a diameter of 10-20 nm, corresponding to the appearance of ghost PBs. These findings suggest that 3G10 identifies ghost PBs better than intracellular PBs, and that heparan sulfate proteoglycans are involved in the process of PBs extinction.

Investigation of tau-2 positive microglia-like cells in the subcortical nuclei of human neurodegenerative disorders.

An anti-tau monoclonal antibody tau-2 was demonstrated to react with the cells which characteristically appeared in the subcortical nuclei of certain neurodegenerative disorders. These cells had rod-like cell bodies and elongated processes, whose morphology was consistent with that of reactive microglia (tau-2 positive microglia-like cells; TPMC). TPMC were diffusely scattered in the subcortical nuclei, especially the putamen, irrelevant to focal tissue injury such as infarcts and amyloid deposits. TPMC were positively immunostained with anti-ferritin antibody, but negatively with LN3, anti-GFAP, other kinds of anti-tau and anti-neurofilament antibodies. TPMC were found in some cases of Alzheimer type dementia and diffuse Lewy body disease, but not in the cases of Parkinson's disease, Pick's disease and control without neurological disorder. Similar microglia-like cells were found around infarctic foci and amyloid cores of senile plaques, regardless of the disorder. They were, however, different from TPMC in that they were positively immunostained with LN3.

Hippocampal pathology in diffuse Lewy body disease using ubiquitin immunohistochemistry.

Various ubiquitin-positive structures in the hippocampus in diffuse Lewy body disease (n=12) and non-demented aged subjects (n=3) were investigated immunohistochemically. These structures were composed of ubiquitin-positive granular structures (UPG), ubiquitin-positive neuritic structures (UPN), spheroidal structures, neuritic plaques, neurofibrillary tangles (NFT), Lewy bodies (LB) and ubiquitin-positive neurons. UPG, UPN, spheroidal structures and neuritic plaques were distributed with special reference to the hippocampal pathway assumed in this study. This pathway was thought to run along the stratum oriens, mostly perforating the stratum pyramidale at many sites of the subiculum and CA1-3, and to end partly in the CA2-3 and the subiculum of the uncus (UPG or UPN). After perforating the stratum pyramidale and giving off terminal branches (ubiquitin-positive neurons or neuritic plaques with degenerative neurites), it was thought to run along the stratum radiatum and continue along the stratum moleculare of the dentate gyrus, forming synapses with the apical dendrites from the stratum pyramidale and the stratum granulosum (spheroidal structures or neuritic plaques). These findings suggest that many of the ubiquitin-positive structures may be caused by degeneration of terminal or distal axons of this pathway. NFT and LB also had a somewhat orderly distribution with reference to this pathway.

Age-related ubiquitin-positive granular structures in non-demented subjects and neurodegenerative disorders.

The distribution and nature of age-related ubiquitin-positive granular structures (UPG) were examined in non-demented brains. In addition, their appearance pattern in some neurodegenerative disorders was investigated. In the transentorhinal cortex, they were distributed among cell islands of layer pre-alpha and in layers II and IIIab. In the amygdala, they were preferentially located in the accessory basal and basal nuclei. UPG were first observed in the transentorhinal cortex of non-demented middle-aged brains and increased in frequency and extended to other regions with increasing age. In Alzheimer-type dementia (ATD), they decreased with advance of the clinical stage. In diffuse Lewy body disease (DLBD), they decreased, accompanying linear neuritic structures. With the double-immuno-staining, UPG were frequently overlapped with neurofilament-positive granules. The multipolar cells of layer pre-alpha and pyramidal cells of layers IIIc and V were also immunostained with anti-neurofilament antibody, and the obliquely ascending fibers of these cells were found frequently to continue to these neurofilament-positive granules. Using ubiquitin immunoelectron microscopy, UPG appeared to derive from degenerating terminal axons. These findings suggest that UPG originate mainly from the recurrent collateral ascending axons in layers II-IIIab and from projecting axons in the amygdala. The occurrence of UPG in the limbic system is an important morphological hallmark of aging. In addition, further studies on the appearance pattern of UPG in ATD and DLBD may clarify whether a difference in the degenerative process of both disorders exists.

Regional quantitative analysis of tau-positive neurons in progressive supranuclear palsy: comparison with Alzheimer's disease.

In patients with progressive supranuclear palsy (PSP), various tau-positive abnormal structures are found in the cerebral cortex as well as in the subcortical nuclei. Similar tau-positive abnormalities are also identified in cortico-basal degeneration (CBD). It is therefore questionable as to whether PSP can be neuropathologically differentiated from CBD. It also remains nuclear whether neurofibrillary tangles (NFT) in the cerebral cortex of PSP patients consist of PSP-NFT or concomitant Alzheimer's disease (AD)-NFT, although there have been some reports suggesting that PSP- and AD-NFT are different with respect to distribution pattern and biochemical character. In this study, a regional quantitative analysis of the distribution and antigenicity of tau-positive neurons (TPN) was performed in PSP cases and compared with that in AD cases. TPN consisted of NFT with tangle-formation and pretangle neurons (PN) without tangle-formation. In addition, NFT were subdivided into mature and immature NFT according to the difference of staining properties with anti-tau-related antibodies. The comparison of the TPN of the PSP cases with those of the AD cases revealed that the degree of tangle-formation in the TPN of AD was similar in all of the examined regions, while that in the TPN of PSP varied according to the region and case. Moreover, the NFT in the PSP and AD cases had different distributions according to the cortical layer and subnucleus, even in the common predilection sites of PSP and AD, suggesting that NFT in these regions of the PSP cases consist mainly of PSP-NFT. In addition, the PSP cases could be divided into two groups according to the difference of the tangle-formation of TPN; group I with typical PSP pathology and group II with atypical PSP pathology similar to CBD. This suggests that there is a continuity between PSP and CBD with respect to the distribution and antigenicity of TPN.

Neuropathological evaluation and apolipoprotein E gene polymorphism analysis in diffuse Lewy body disease.

We performed a quantitative neuropathological investigation of senile plaques and neurofibrillary tangles in the brains of 14 Japanese patients with diffuse Lewy body disease (DLBD), and examined apolipoprotein E (APOE) gene polymorphism in these patients. Most DLBD brains had as many senile plaques as those with Alzheimer-type dementia (ATD), but fewer neurofibrillary tangles. The APOE epsilon 4 allele frequency in DLBD was 39.3%, similar to that previously reported in pathologically diagnosed ATD. DLBD and ATD are clinically and pathologically distinct, but may have common mechanisms with regard to the formation of amyloid deposition based on these findings. Future investigation of the pure form of DLBD may clarify the association between Lewy body dementia and APOE.

Ubiquitin-immunohistochemical investigation of atypical Pick's disease without Pick bodies.

Six cases of atypical Pick's disease (PD) without Pick bodies (PB) were examined immunohistochemically. These cases showed severe neuronal loss with gliosis predominantly in the temporal cortices. Ubiquitin immunohistochemistry revealed ubiquitin-positive intraneuronal inclusions in the dentate gyrus and ubiquitin-positive neurites in the cerebral cortex. In the dentate gyrus, the dendrites in the stratum moleculare as well as the intraneuronal inclusions in the granular cells were positively stained. Both structures were composed of ubiquitin-positive ribosome-like granular components and a few filamentous components immunoelectron-microscopically. In the cerebral cortex, ubiquitin-positive neurites were distributed in layers II-IIIab and layers V-VI, and were considered to be the distal dendrites from the small neurons. The dendrites and perikarya of these neurons contained ubiquitin-positive components similar to those in the dentate gyrus. Some ubiquitin-positive neurites were also found in the hippocampal subiculum, amygdala and striatum. The results of this study suggest that the granular cells in the dentate gyrus and the small neurons in the cerebral cortex share common ubiquitin-related and ribosome-associated abnormalities in both the perikarya and dendrites, that the degeneration of the perforant pathway caused by the parahippocampal lesion participates in the ubiquitin related abnormalities in the granular cells, and that PD cases with and without PB have common affected neurons, as shown immunohistochemically.

An autopsied case of juvenile parkinsonism and dementia, with a widespread occurrence of Lewy bodies and spheroids.

An autopsied case of juvenile parkinsonism and dementia is described. The patient is a 48-year-old man who had a ten-year history of parkinsonian syndrome and progressive dementia. Neuropathological examination revealed a widespread occurrence of Lewy bodies and spheroids in the central nervous system. Lewy bodies were found not only in the brain stem and diencephalon, but also in the cerebral cortex. Massive numbers of small spheroids were observed in the globus pallidus, substantia nigra, mamillary bodies and hippocampus. Electron microscopical examination showed that most spheroids were composed of degenerative organelles with only a few neurofilaments, and were different from those of Hallervorden-Spatz disease. There was also marked neuronal loss with gliosis in the CA3-4 of the hippocampus. Some neurofibrillary tangles occurred in the hippocampus, subcortical and brain stem nuclei, but senile plaques were absent. This case may represent an atypical form of pure diffuse Lewy body disease.

[Parkinsonism in Alzheimer's disease].

Parkinsonism occurs frequently in the patients with Alzheimer type dementia (ATD). The frequency ranges from 9% to 100% of ATD patients, depending on samples, clinical instruments and stages of illness. Several studies have described that rigidity and hypokinesia are the most prevalently observed signs of parkinsonism, and that resting tremor is less. The clinical progress of patients with parkinsonism is more rapid than those of patients without parkinsonism. Patients with parkinsonism are frequently associated with psychiatric symptoms such as depression and delusion. The pathogenesis of parkinsonism in ATD remains to be elucidated, but it should be noted that some cases with parkinsonism correlates with Parkinson's disease pathologic condition, and some have diffuse Lewy body disease.

AIDS-related cerebral toxoplasmosis with hyperintense foci on T1-weighted MR images: a case report.

The neuroradiological findings are helpful for the diagnosis of toxoplasmic encephalitis. The T1 hypersignal intensity foci on brain magnetic resonance (MR) images without contrast enhancement are presented and can be a pathognomonic sign of this disease.