Primary age-related tauopathy in a Chinese cohort / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Primary age-related tauopathy (PART) is characterized by the presence of tau neurofibrillary tangles (NFTs) which are typically observed in Alzheimer's disease (AD) brains, with few or without β-amyloid (Aβ) plaques. The diagnosis of PART can be categorized into "definite" or "possible" depending on the amount of Aβ plaques. Definite PART is diagnosed when NFTs are observed and the Braak stage is ≤IV, with Thal Aβ Phase 0 (Crary et al., 2014). According to the neuropathological diagnostic criteria, we reported that PART was frequently observed in the Chinese population according to our findings from specimens in our brain bank, with 47% of brain bank subjects meeting the criteria for PART. There is no consensus on the nature of PART. It remains to be elucidated whether PART is an early form of AD or a novel tauopathy (Duyckaerts et al., 2015; Jellinger et al., 2015).

Alzheimer's Disease Diagnosis Using Misfolding Proteins in Blood

Alzheimer's disease (AD) is pathologically characterized by a long progressive phase of neuronal changes, including accumulation of extracellular amyloid-β (Aβ) and intracellular neurofibrillary tangles, before the onset of observable symptoms. Many efforts have been made to develop a blood-based diagnostic method for AD by incorporating Aβ and tau as plasma biomarkers. As blood tests have the advantages of being highly accessible and low cost, clinical implementation of AD blood tests would provide preventative screening to presymptomatic individuals, facilitating early identification of AD patients and, thus, treatment development in clinical research. However, the low concentration of AD biomarkers in the plasma has posed difficulties for accurate detection, hindering the development of a reliable blood test. In this review, we introduce three AD blood test technologies emerging in South Korea, which have distinctive methods of heightening detection sensitivity of specific plasma biomarkers. We discuss in detail the multimer detection system, the self-standard analysis of Aβ biomarkers quantified by interdigitated microelectrodes, and a biomarker ratio analysis comprising Aβ and tau.

Research progress on the epigenetic mechanisms of inverse relationship between Alzheimer's disease and cancer onset / 生理学报

Alzheimer's disease (AD) is currently the most prevalent neurodegenerative disease in the aging population. It is characterized by massive deposition of extracellular β-amyloid peptide and formation of intracellular neurofibrillary tangles. Cancer is also an age-related disease. Some epidemiological studies have shown an inverse relationship between AD and the onset of various types of cancers, that is, the risk of cancer in patients with AD is reduced, and vice versa. Epigenetic mechanisms play important roles in the development of AD and cancer. In this article, we will review the recent research advances on the epigenetic mechanisms of AD and cancer onset, and provide new ideas for rethinking the relevance of AD and cancer with a "holistic concept".

pathological model of Alzheimer's disease based on neuronal network chip and its real-time dynamic analysis / 生物医学工程学杂志

Alzheimer's disease (AD) is a chronic central neurodegenerative disease. The pathological features of AD are the extracellular deposition of senile plaques formed by amyloid-β oligomers (AβOs) and the intracellular accumulation of neurofibrillary tangles formed by hyperphosphorylated tau protein. In this paper, an in vitro pathological model of AD based on neuronal network chip and its real-time dynamic analysis were presented. The hippocampal neuronal network was cultured on the microelectrode array (MEA) chip and induced by AβOs as an AD model to simultaneously record two firing patterns from the interneurons and pyramidal neurons. The spatial firing patterns mapping and cross-correlation between channels were performed to validate the degeneration of neuronal network connectivity. This biosensor enabled the detection of the AβOs toxicity responses, and the identification of connectivity and interactions between neuronal networks, which can be a novel technique in the research of AD pathological model .

Phosphorylated TDP-43 Staging of Primary Age-Related Tauopathy / 神经科学通报·英文版

Primary age-related tauopathy (PART) is characterized by tau neurofibrillary tangles (NFTs) in the absence of amyloid plaque pathology. In the present study, we analyzed the distribution patterns of phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) in the brains of patients with PART. Immunohistochemistry and immunofluorescence double-labeling in multiple brain regions was performed on brain tissues from PART, Alzheimer's disease (AD), and aging control cases. We examined the regional distribution patterns of pTDP-43 intraneuronal inclusions in PART with Braak NFT stages > 0 and ≤ IV, and a Thal phase of 0 (no beta-amyloid present). We found four stages which indicated potentially sequential dissemination of pTDP-43 in PART. Stage I was characterized by the presence of pTDP-43 lesions in the amygdala, stage II by such lesions in the hippocampus, stage III by spread of pTDP-43 to the neocortex, and stage IV by pTDP-43 lesions in the putamen, pallidum, and insular cortex. In general, the distribution pattern of pTDP-43 pathology in PART cases was similar to the early TDP-43 stages reported in AD, but tended to be more restricted to the limbic system. However, there were some differences in the distribution patterns of pTDP-43 between PART and AD, especially in the dentate gyrus of the hippocampus. Positive correlations were found in PART between the Braak NFT stage and the pTDP-43 stage and density.

Gait Ignition Failure in JNPL3 Human Tau-mutant Mice

Cognitive impairments and motor dysfunction are commonly observed behavioral phenotypes in genetic animal models of neurodegenerative diseases. JNPL3 transgenic mice expressing human P301L-mutant tau display motor disturbances with age- and gene dose-dependent development of neurofibrillary tangles, suggesting that tau pathology causes neurodegeneration associated with motor behavioral abnormalities. Although gait ignition failure (GIF), a syndrome marked by difficulty in initiating locomotion, has been described in patients with certain forms of tauopathies, transgenic mouse models mirroring human GIF syndrome have yet to be reported. Using the open field and balance beam tests, here we discovered that JNPL3 homozygous mice exhibit a marked delay of movement initiation. The elevated plus maze excluded the possibility that hesitation to start in JNPL3 mice was caused by enhanced levels of anxiety. Considering the normal gait ignition in rTg4510 mice expressing the same mutant tau in the forebrain, GIF in JNPL3 mice seems to arise from abnormal tau deposition in the hindbrain areas involved in locomotor initiation. Accordingly, immunohistochemistry revealed highly phosphorylated paired helical filament tau in JNPL3 brainstem areas associated with gait initiation. Together, these findings demonstrate a novel behavioral phenotype of impaired gait initiation in JNPL3 mice and underscore the value of this mouse line as a tool to study the neural mechanisms and potential treatments for human GIF syndrome.

Primary Age-Related Tauopathy: An Elderly Brain Pathology Frequently Encountered during Autopsy

Due to the progressive aging of Korean society and the introduction of brain banks to the Korean medical system, the possibility that pathologists will have access to healthy elderly brains has increased. The histopathological analysis of an elderly brain from a subject with relatively well-preserved cognition is quite different from that of a brain from a demented subject. Additionally, the histology of elderly brains differs from that of young brains. This brief review discusses primary age-related tauopathy; this term was coined to describe elderly brains with Alzheimer’s diseasetype neurofibrillary tangles mainly confined to medial temporal structures, and no β-amyloid pathology.

In vitro pathological model of Alzheimer's disease based on neuronal network chip and its real-time dynamic analysis / 生物医学工程学杂志

Alzheimer's disease (AD) is a chronic central neurodegenerative disease. The pathological features of AD are the extracellular deposition of senile plaques formed by amyloid-β oligomers (AβOs) and the intracellular accumulation of neurofibrillary tangles formed by hyperphosphorylated tau protein. In this paper, an in vitro pathological model of AD based on neuronal network chip and its real-time dynamic analysis were presented. The hippocampal neuronal network was cultured on the microelectrode array (MEA) chip and induced by AβOs as an AD model in vitro to simultaneously record two firing patterns from the interneurons and pyramidal neurons. The spatial firing patterns mapping and cross-correlation between channels were performed to validate the degeneration of neuronal network connectivity. This biosensor enabled the detection of the AβOs toxicity responses, and the identification of connectivity and interactions between neuronal networks, which can be a novel technique in the research of AD pathological model in vitro.

Targeted Downregulation of kdm4a Ameliorates Tau-engendered Defects in Drosophila melanogaster

BACKGROUND: Tauopathies, a class of neurodegenerative diseases that includes Alzheimer's disease (AD), are characterized by the deposition of neurofibrillary tangles composed of hyperphosphorylated tau protein in the human brain. As abnormal alterations in histone acetylation and methylation show a cause and effect relationship with AD, we investigated the role of several Jumonji domain-containing histone demethylase (JHDM) genes, which have yet to be studied in AD pathology. METHODS: To examine alterations of several JHDM genes in AD pathology, we performed bioinformatics analyses of JHDM gene expression profiles in brain tissue samples from deceased AD patients. Furthermore, to investigate the possible relationship between alterations in JHDM gene expression profiles and AD pathology in vivo, we examined whether tissue-specific downregulation of JHDM Drosophila homologs (kdm) can affect tauR406W-induced neurotoxicity using transgenic flies containing the UAS-Gal4 binary system. RESULTS: The expression levels of JHDM1A, JHDM2A/2B, and JHDM3A/3B were significantly higher in postmortem brain tissue from patients with AD than from non-demented controls, whereas JHDM1B mRNA levels were downregulated in the brains of patients with AD. Using transgenic flies, we revealed that knockdown of kdm2 (homolog to human JHDM1), kdm3 (homolog to human JHDM2), kdm4a (homolog to human JHDM3A), or kdm4b (homolog to human JHDM3B) genes in the eye ameliorated the tauR406W-engendered defects, resulting in less severe phenotypes. However, kdm4a knockdown in the central nervous system uniquely ameliorated tauR406W-induced locomotion defects by restoring heterochromatin. CONCLUSION: Our results suggest that downregulation of kdm4a expression may be a potential therapeutic target in AD.

Relationships between ¹⁸F-THK5351 Retention and Language Functions in Primary Progressive Aphasia

BACKGROUND AND PURPOSE: There are three distinct subtypes of primary progressive aphasia (PPA): the nonfluent/agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). We sought to characterize the pattern of [¹⁸F]-THK5351 retention across all three subtypes and determine the topography of [¹⁸F]-THK5351 retention correlated with each neurolinguistic score. METHODS: We enrolled 50 participants, comprising 13 PPA patients (3 nfvPPA, 5 svPPA, and 5 lvPPA) and 37 subjects with normal cognition (NC) who underwent 3.0-tesla magnetic resonance imaging, [¹⁸F]-THK5351 positron-emission tomography scans, and detailed neuropsychological tests. The PPA patients additionally participated in extensive neurolinguistic tests. Voxel-wise and region-of-interest-based analyses were performed to analyze [¹⁸F]-THK5351 retention. RESULTS: The nfvPPA patients exhibited higher [¹⁸F]-THK5351 retention in the the left inferior frontal and precentral gyri. In svPPA patients, [¹⁸F]-THK5351 retention was elevated in the anteroinferior and lateral temporal cortices compared to the NC group (left>right). The lvPPA patients exhibited predominant [¹⁸F]-THK5351 retention in the inferior parietal, lateral temporal, and dorsolateral prefrontal cortices, and the precuneus (left>right). [¹⁸F]-THK5351 retention in the left inferior frontal area was associated with lower fluency scores. Comprehension was correlated with [¹⁸F]-THK5351 retention in the left temporal cortices. Repetition was associated with [¹⁸F]-THK5351 retention in the left inferior parietal and posterior temporal areas, while naming difficulty was correlated with retention in the left fusiform and temporal cortices. CONCLUSIONS: The pattern of [¹⁸F]-THK5351 retention was well matched with clinical and radiological findings for each PPA subtype, in agreement with the anatomical and functional location of each language domain.

¹⁸F-THK5351 PET Imaging in Nonfluent-Agrammatic Variant Primary Progressive Aphasia

BACKGROUND AND PURPOSE: To analyze 18F-THK5351 positron emission tomography (PET) scans of patients with clinically diagnosed nonfluent/agrammatic variant primary progressive aphasia (navPPA). METHODS: Thirty-one participants, including those with Alzheimer's disease (AD, n=13), navPPA (n=3), and those with normal control (NC, n=15) who completed 3 Tesla magnetic resonance imaging, 18F-THK5351 PET scans, and detailed neuropsychological tests, were included. Voxel-based and region of interest (ROI)-based analyses were performed to evaluate retention of 18F-THK5351 in navPPA patients. RESULTS: In ROI-based analysis, patients with navPPA had higher levels of THK retention in the Broca's area, bilateral inferior frontal lobes, bilateral precentral gyri, and bilateral basal ganglia. Patients with navPPA showed higher levels of THK retention in bilateral frontal lobes (mainly left side) compared than NC in voxel-wise analysis. CONCLUSIONS: In our study, THK retention in navPPA patients was mainly distributed at the frontal region which was well correlated with functional-radiological distribution of navPPA. Our results suggest that tau PET imaging could be a supportive tool for diagnosis of navPPA in combination with a clinical history.

Sex Differences in Neuropathology and Cognitive Behavior in APP/PS1/tau Triple-Transgenic Mouse Model of Alzheimer's Disease / 神经科学通报·英文版

Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation in the brain, as well as impaired cognitive behaviors. A sex difference in the prevalence of AD has been noted, while sex differences in the cerebral pathology and relevant molecular mechanisms are not well clarified. In the present study, we systematically investigated the sex differences in pathological characteristics and cognitive behavior in 12-month-old male and female APP/PS1/tau triple-transgenic AD mice (3×Tg-AD mice) and examined the molecular mechanisms. We found that female 3×Tg-AD mice displayed more prominent amyloid plaques, neurofibrillary tangles, neuroinflammation, and spatial cognitive deficits than male 3×Tg-AD mice. Furthermore, the expression levels of hippocampal protein kinase A-cAMP response element-binding protein (PKA-CREB) and p38-mitogen-activated protein kinases (MAPK) also showed sex difference in the AD mice, with a significant increase in the levels of p-PKA/p-CREB and a decrease in the p-p38 in female, but not male, 3×Tg-AD mice. We suggest that an estrogen deficiency-induced PKA-CREB-MAPK signaling disorder in 12-month-old female 3×Tg-AD mice might be involved in the serious pathological and cognitive damage in these mice. Therefore, sex differences should be taken into account in investigating AD biomarkers and related target molecules, and estrogen supplementation or PKA-CREB-MAPK stabilization could be beneficial in relieving the pathological damage in AD and improving the cognitive behavior of reproductively-senescent females.

Tau Positron Emission Tomography Imaging in Degenerative Parkinsonisms

In recent years, several radiotracers that selectively bind to pathological tau proteins have been developed. Evidence is emerging that binding patterns of in vivo tau positron emission tomography (PET) studies in Alzheimer's disease (AD) patients closely resemble the distribution patterns of known neurofibrillary tangle pathology, with the extent of tracer binding reflecting the clinical and pathological progression of AD. In Lewy body diseases (LBD), tau PET imaging has clearly revealed cortical tau burden with a distribution pattern distinct from AD and increased cortical binding within the LBD spectrum. In progressive supranuclear palsy, the globus pallidus and midbrain have shown increased binding most prominently. Tau PET patterns in patients with corticobasal syndrome are characterized by asymmetrical uptake in the motor cortex and underlying white matter, as well as in the basal ganglia. Even in the patients with multiple system atrophy, which is basically a synucleinopathy, ¹⁸F-flortaucipir, a widely used tau PET tracer, also binds to the atrophic posterior putamen, possibly due to off-target binding. These distinct patterns of tau-selective radiotracer binding in the various degenerative parkinsonisms suggest its utility as a potential imaging biomarker for the differential diagnosis of parkinsonisms.

Development of tau PET Imaging Ligands and their Utility in Preclinical and Clinical Studies / 대한핵의학회잡지

The pathological features of Alzheimer's disease are senile plaques which are aggregates of β-amyloid peptides and neurofibrillary tangles in the brain. Neurofibrillary tangles are aggregates of hyperphosphorylated tau proteins, and these induce various other neurodegenerative diseases, such as progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and chronic traumatic encephalopathy. In the case of Alzheimer's disease, the measurement of neurofibrillary tangles associated with cognitive decline is suitable for differential diagnosis, disease progression assessment, and to monitor the effects of therapeutic treatment. This review discusses considerations for the development of tau ligands for imaging and summarizes the results of the first-in-human and preclinical studies of the tau tracers that have been developed thus far. The development of tau ligands for imaging studies will be helpful for differential diagnosis and for the development of therapeutic treatments for tauopathies including Alzheimer's disease.

An Autopsy Proven Child Onset Chronic Traumatic Encephalopathy

Here we present an autopsy case of chronic traumatic encephalopathy (CTE) in a 36-year-old man. He had a history of febrile seizures at the age of four and was severely demented at age 10 when he was admitted to a mental hospital. He had suffered repetitive self-harm, such as frequent banging of the head on the wall in his hospital record, but he had no clear history between the ages of four and ten. Autopsy revealed global cerebral atrophy, including the basal ganglia, thalamus, hippocampus, amygdala, mammilary bodies and lateral geniculate bodies. This case showed typical pathological features of CTE. Phosphorylated tau (p-tau)-positive neurofibrillary tangles (NFTs) and neuropil threads (NT) we are widely distributed in the brain, especially in the depth of the cerebral sulci. NFT and NT were also found in the basal ganglia, thalamus, amygdala and brainstem. Scanty β-amyloid deposits were found in the motor and sensory cortices, but α-synuclein was completely negative in the brain. This example showed that CTE can occur in young ages and that even children can experience CTE dementia.

Mechanisms of Alzheimer's Disease Pathogenesis and Prevention: The Brain, Neural Pathology, N-methyl-D-aspartate Receptors, Tau Protein and Other Risk Factors

The characteristic features of Alzheimer's disease (AD) are the appearance of extracellular amyloid-beta (Aβ) plaques and neurofibrillary tangles in the intracellular environment, neuronal death and the loss of synapses, all of which contribute to cognitive decline in a progressive manner. A number of hypotheses have been advanced to explain AD. Abnormal tau phosphorylation may contribute to the formation of abnormal neurofibrillary structures. Many different structures are susceptible to AD, including the reticular formation, the nuclei in the brain stem (e.g., raphe nucleus), thalamus, hypothalamus, locus ceruleus, amygdala, substantia nigra, striatum, and claustrum. Excitotoxicity results from continuous, low-level activation of N-methyl-D-aspartate (NMDA) receptors. Premature synaptotoxicity, changes in neurotransmitter expression, neurophils loss, accumulation of amyloid β-protein deposits (amyloid/senile plaques), and neuronal loss and brain atrophy are all associated with stages of AD progression. Several recent studies have examined the relationship between Aβ and NMDA receptors. Aβ-induced spine loss is associated with a decrease in glutamate receptors and is dependent upon the calcium-dependent phosphatase calcineurin, which has also been linked to long-term depression.

Metabolism-Centric Overview of the Pathogenesis of Alzheimer's Disease

Alzheimer's disease (AD) is a degenerative brain disease and the most common cause of dementia. AD is characterized by the extracellular amyloid beta (Aβ) plaques and intraneuronal deposits of neurofibrillary tangles (NFTs). Recently, as aging has become a familiar phenomenon around the world, patients with AD are increasing in number. Thus, many researchers are working toward finding effective therapeutics for AD focused on Aβ hypothesis, although there has been no success yet. In this review paper, we suggest that AD is a metabolic disease and that we should focus on metabolites that are affected by metabolic alterations to find effective therapeutics for AD. Aging is associated with not only AD but also obesity and type 2 diabetes (T2DM). AD, obesity, and T2DM share demographic profiles, risk factors, and clinical and biochemical features in common. Considering AD as a kind of metabolic disease, we suggest insulin, adiponectin, and antioxidants as mechanistic links among these diseases and targets for AD therapeutics. Patients with AD show reduced insulin signal transductions in the brain, and intranasal injection of insulin has been found to have an effect on AD treatment. In addition, adiponectin is decreased in the patients with obesity and T2DM. This reduction induces metabolic dysfunction both in the body and the brain, leading to AD pathogenesis. Oxidative stress is known to be induced by Aβ and NFTs, and we suggest that oxidative stress caused by metabolic alterations in the body induce brain metabolic alterations, resulting in AD.

Stem Cell Therapy: A Prospective Treatment for Alzheimer's Disease

Alzheimer's disease (AD) without cure remains as a serious health issue in the modern society. The major neuropathological alterations in AD are characterized by chronic neuroinflammation and neuronal loss due to neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau, plaques of β-amyloid (Aβ) and various metabolic dysfunctions. Due to the multifaceted nature of AD pathology and our limited understanding on its etiology, AD is difficult to be treated with currently available pharmaceuticals. This unmet need, however, could be met with stem cell technology that can be engineered to replace neuronal loss in AD patients. Although stem cell therapy for AD is only in its development stages, it has vast potential uses ranging from replacement therapy to disease modelling and drug development. Current progress with stem cells in animal model studies offers promising results for the new prospective treatment for AD. This review will discuss the characteristics of AD, current progress in stem cell therapy and remaining challenges and promises in its development.

Efeitos do lítio sobre a expressão e atividade das enzimas fosfolipase A2 e glicogênio sintase quinase 3beta e sua relação com o estado de fosforilação da proteína tau / Effects of lithium on the expression of the enzymes activity phospholipase A2 and glycogen synthase kinase 3beta and its relationship with the phosphorylation state of tau protein

O presente estudo comparou o efeito do tratamento crônico com lítio em doses subterapêuticas (0,02mM e 0,2mM) e dose terapêutica (2mM) em cultura primária de neurônios corticais e hipocampais. As amostras foram analisadas e comparadas com o grupo controle (sem tratamento) tanto para os neurônios corticais, como para os neurônios hipocampais. O objetivo do estudo foi: 1) avaliar, nessas culturas celulares, a atividade de diferentes quinases (PKA, CaMKII, AKT e GSK3beta), diferentes sítio de fosforilação da Tau (Ser, 199, 205, 214, 396, C-terminal e seis isoformas), a partir da inibição da PLA2 pelo lítio; 2) Investigar as vias de sinalização envolvidas na modulação do estado de fosforilação da proteína tau a partir da inibição da PLA2 em culturas primárias de neurônios; 3) avaliar, simultaneamente, a expressão de fatores neurotróficos (BDNF) e citocinas (GM-CSF, IL-1b, IL-2, IL-4, IL-5, IL6, IL-10, IL-12, IFN-y e TNF-alfa) mediante o tratamento de neurônios primários com lítio e 4) avaliar expressão gênica por microarray das culturas tratadas com diferentes doses, subterapêuticas e terapêutica, de cloreto de lítio. Nossos resultados sugerem uma dissociação de efeitos em neurônios corticais dos observados em neurônios hipocampais. O lítio aumentou a atividade enzimática da iPLA2 e da cPLA2, tanto em neurônios corticais como em neurônios hipocampais. A atividade da GSK3beta foi inibida pelo tratamento crônico com lítio em neurônios hipocampais e apresentou efeito contrário em neurônios corticais. Observamos comportamentos diferentes das diferentes proteínas analisadas em culturas de neurônios corticais e hipocampais, e não tivemos significância estatística para as alterações na proteína tau. O tratamento nas doses subterapêuticas aumentou a secreção de citocinas pró-inflamatórias tanto em neurônios corticais quanto em neurônios hipocampais.

The present study compared the effect of lithium chronic treatment with subtherapeutic doses (0.02mM and 0.2mM) and therapeutic dose (2mM) in primary cortical and hippocampal neurons cell culture. This samples were analyzed and compared with the control group (no treatment). The study's goal was: 1) to evaluate in these Cell Culture a different activity kinases (PKA, CaMKII, AKT and GSK3beta), different phosphorylation site of the Tau (199, 205, 214, 396, C-terminal and Six isoforms) and PLA2 inhibition; 2) To investigate how signaling pathways involved in modulation of tau phosphorylation from the inhibition of PLA2 in primary cultures of neurons; 3) analyze an expression of neurotrophic factors (BDNF) and cytokines (GM-CSF, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IFNy TNFalfa 4) to evaluate gene expression via microarray with different doses of lithium treatment. Our results suggest a dissociation effects on cortical and hippocampal neurons cell culture. Lithium increased the enzyme activity of iPLA2 and cPLA2, in both cortical and hippocampal neurons. The GSK3beta the activity was inhibited by chronic treatment with lithium in hippocampal neurons and presented contrary effect on cortical neurons. We observe not statistics significance on tau protein. The treatment at subtherapeutic and therapeutic doses increased the secretion of pro and anti-inflammatory cytokines both in cortical and hippocampal neurons.

Clinical Neuropathological Analysis of 10 Cases of Cerebral Amyloid Angiopathy-Related Cerebral Lobar Hemorrhage

OBJECTIVE: The clinical and pathological characteristics of 10 cases of cerebral amyloid angiopathy (CAA)-related cerebral lobar hemorrhage (CLH) that was diagnosed at autopsy were investigated to facilitate the diagnosis of this condition. METHODS: The clinical characteristics of 10 cases of CAA-related CLH were retrospectively reviewed, and a neuropathological examination was performed on autopsy samples. RESULTS: The 10 cases included two with a single lobar hemorrhage and eight with multifocal lobar hemorrhages. In all of the cases, the hemorrhage bled into the subarachnoid space. Pathological examinations of the 10 cases revealed microaneurysms in two, double barrel-like changes in four, multifocal arteriolar clusters in five, obliterative onion skin-like intimal changes in four, fibrinoid necrosis of the vessels in seven, neurofibrillary tangles in eight, and senile plaques in five cases. CONCLUSION: CAA-related CLHs were located primarily in the parietal, temporal, and occipital lobes. These hemorrhages normally consisted of multiple repeated CLHs that frequently bled into the subarachnoid space. CAA-associated microvascular lesions may be the pathological factor underlying CLH.