Novel insights into presenilin 1 mutation associated with a distinctive dementia phenotype and cotton wool plaques.

BACKGROUND: The mutations in the presenilin 1 gene (PSEN1) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production. METHOD: Using the proband's samples, we performed genetic analysis of the PSEN1, APP, MAPT, and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aß production in COS cells transfected with wild-type or mutant PSEN1. RESULTS: The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aß42 in PSEN1 G266S-transfected cells significantly increased. CONCLUSION: Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors.

Association of Plasma Claudin-5 with Age and Alzheimer Disease.

The blood-brain barrier (BBB) plays pivotal roles in synaptic and neuronal functioning by sealing the space between adjacent microvascular endothelial cells. BBB breakdown is present in patients with mild cognitive impairment (MCI) or Alzheimer disease (AD). Claudin-5 (CLDN-5) is a tetra-spanning protein essential for sealing the intercellular space between adjacent endothelial cells in the BBB. In this study, we developed a blood-based assay for CLDN-5 and investigated its diagnostic utility using 100 cognitively normal (control) subjects, 100 patients with MCI, and 100 patients with AD. Plasma CLDN-5 levels were increased in patients with AD (3.08 ng/mL) compared with controls (2.77 ng/mL). Plasma levels of phosphorylated tau (pTau181), a biomarker of pathological tau, were elevated in patients with MCI or AD (2.86 and 4.20 pg/mL, respectively) compared with control subjects (1.81 pg/mL). In patients with MCI or AD, plasma levels of CLDN-5-but not pTau181-decreased with age, suggesting some age-dependent BBB changes in MCI and AD. These findings suggest that plasma CLDN-5 may a potential biochemical marker for the diagnosis of AD.

APOE genotypes modify the obesity paradox in dementia.

BACKGROUND: While obesity in midlife is a risk factor for dementia, several studies suggested that obesity also protected against dementia, hence so-called obesity paradox. The current study aims to address the relationship between apolipoprotein E (APOE) genotype and obesity in dementia. METHODS: Clinical and neuropathological records of the National Alzheimer's Coordinating Center (NACC) in the USA, which longitudinally followed approximately 20 000 subjects with different cognitive statues, APOE genotype and obesity states, were reviewed. RESULTS: Obesity was associated with cognitive decline in early elderly cognitively normal individuals without APOE4, especially those with APOE2. Neuropathological analyses adjusted for dementia status showed that APOE2 carriers tended to have more microinfarcts and haemorrhages due to obesity. On the other hand, obesity was associated with a lower frequency of dementia and less cognitive impairment in individuals with mild cognitive impairment or dementia. Such trends were particularly strong in APOE4 carriers. Obesity was associated with fewer Alzheimer's pathologies in individuals with dementia. CONCLUSIONS: Obesity may accelerate cognitive decline in middle to early elderly cognitive normal individuals without APOE4 likely by provoking vascular impairments. On the other hand, obesity may ease cognitive impairment in both individuals with dementia and individuals at the predementia stage, especially those with APOE4, through protecting against Alzheimer's pathologies. These results support that APOE genotype modifies the obesity paradox in dementia.

Effects of APOEɛ4 genotype on age-associated change in cognitive functions among Japanese middle-aged and older adults: A 20-year follow-up study.

BACKGROUND AND AIMS: Carriers of the apolipoprotein E ε4 allele (APOEɛ4) have an increased risk of developing dementia (e.g., Alzheimer's disease). However, it is less clear whether the APOEɛ4 might also be involved in cognitive aging among the non-clinical population of older adults. While some studies have suggested that the APOEɛ4 is related to accelerated cognitive decline in the normal aging process, others have failed to provide compelling evidence of such an impact. Notably, these discrepancies may depend on methodological shortcomings, including short time spans, few assessments, and small sample sizes. The present study overcomes the above limitations and aims to clarify the impact of the APOEɛ4 genotype on long-term longitudinal changes in cognitive functions in middle-aged and older adults in Japan. METHODS AND RESULTS: The data were retrieved from the National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) survey (N = 1832; 40 to 79 years of age at baseline). The participants were tested over nine waves covering a period of approximately 20 years. Latent Growth Curve (LGC) modeling was employed to test the impact of the interaction between APOEɛ4 status and age on several cognitive functions. Four tests of the WAIS-R were administered: Information, Similarities, Picture completion, and Digit Symbol Substitution Test (DSST). The results showed that the APOEɛ4 carriers experienced a more pronounced decline in the DSST (p = 0.001) and Similarities (p = 0.022) tests. A similar tendency was found in the Information test (p = 0.034). By contrast, no effect was found in the Picture completion test (p = 0.563). CONCLUSIONS: APOEɛ4 carriers seem to exhibit a steeper cognitive decline, which becomes apparent in old age. This effect is more robust in fluid cognitive skills (DSST) than crystallized cognitive skills (Information and Similarities). Overall, the APOEɛ4 genotype may be a significant risk factor in normal (i.e., non-clinical) cognitive aging.

Relationship Between Plasma Neurofilament Light Chain, Gut Microbiota, and Dementia: A Cross-Sectional Study.

BACKGROUND: Previous studies have demonstrated associations between gut microbiota, microbial metabolites, and cognitive decline. However, relationships between these factors and neurofilament light chain (NfL; a disease-nonspecific biomarker of neural damage) remain controversial. OBJECTIVE: To evaluate the associations between plasma NfL, gut microbiota, and cognitive function. METHODS: We performed a cross-sectional sub-analysis of data from our prospective cohort study that was designed to investigate the relationship between gut microbiota and cognitive function. Patients who visited our memory clinic were enrolled and demographics, dementia-related risk factors, cognitive function, brain imaging, gut microbiomes, and microbial metabolites were assessed. We evaluated the relationships between the gut microbiome, microbial metabolites, and plasma NfL. Moreover, the relationships between plasma NfL and cognitive function were assessed using multivariable logistic regression analyses. RESULTS: We analyzed 128 participants (women: 59%, mean age: 74 years). Participants with high (above the median) plasma NfL concentrations tended to be older, women, and hypertensive and have a history of stroke, chronic kidney disease, and dementia. Plasma NfL was also associated with cerebral small vessel disease. However, plasma NfL levels were not significantly correlated with gut microbial metabolites. Multivariable analyses revealed that a higher plasma NfL concentration was independently associated with the presence of dementia (odds ratio: 9.94, 95% confidence interval: 2.75-48.2, p < 0.001). CONCLUSION: High plasma NfL concentration was independently associated with the presence of dementia as previously reported. However, plasma NfL levels were not significantly correlated with gut microbial metabolites in this preliminary study.

Cortical traveling waves reflect state-dependent hierarchical sequencing of local regions in the human connectome network.

Recent human studies using electrocorticography have demonstrated that alpha and theta band oscillations form traveling waves on the cortical surface. According to neural synchronization theories, the cortical traveling waves may group local cortical regions and sequence them by phase synchronization; however these contributions have not yet been assessed. This study aimed to evaluate the functional contributions of traveling waves using connectome-based network modeling. In the simulation, we observed stable traveling waves on the entire cortical surface wherein the topographical pattern of these phases was substantially correlated with the empirically obtained resting-state networks, and local radial waves also appeared within the size of the empirical networks (< 50 mm). Importantly, individual regions in the entire network were instantaneously sequenced by their internal frequencies, and regions with higher intrinsic frequency were seen in the earlier phases of the traveling waves. Based on the communication-through-coherence theory, this phase configuration produced a hierarchical organization of each region by unidirectional communication between the arbitrarily paired regions. In conclusion, cortical traveling waves reflect the intrinsic frequency-dependent hierarchical sequencing of local regions, global traveling waves sequence the set of large-scale cortical networks, and local traveling waves sequence local regions within individual cortical networks.

ELISA Evaluation of Tau Accumulation in the Brains of Patients with Alzheimer Disease.

Despite the routine use of sandwich enzyme-linked immunosorbent assays (ELISAs) for quantifying tau levels in CSF and plasma, tau accumulations in the brains of patients with Alzheimer disease (AD) have rarely been evaluated by this method. Thus, by introducing several tau ELISAs that target different epitopes, we evaluated accumulated tau levels in postmortem brains depending on disease stage, brain areas, and other AD-related changes. Notably, tau levels in insoluble fraction determined by each ELISAs differ depending on the epitopes of antibodies: non-AD control samples yield relatively high signals when an antibody against the N-terminal region of tau is used. On the other hand, ELISAs combining antibodies against the later-middle to C-terminal regions of tau produced substantially increased signals from AD samples, compared to those from non-AD controls. Such ELISAs better distinguish AD and non-AD controls, and the results are more closely associated with Braak neurofibrillary tangles stage, Aß accumulation, and glial markers. Moreover, these ELISAs can reflect the pattern of tau spread across brain regions. In conclusion, Tau ELISAs that combine antibodies against the later-middle to C-terminal regions of tau can better reflect neuropathological tau accumulation, which would enable to evaluate tau accumulation in the brain at a biochemical level.

Interaction Between APOE Genotype and Diabetes in Longevity.

BACKGROUND: While both apolipoprotein E (APOE) genotype and diabetes affect longevity as well as Alzheimer's disease, their relationship remains to be elucidated. OBJECTIVE: The current study investigated the potential interaction between diabetes and APOE for lifespan and their relationship with cognitive status. METHODS: We reviewed the National Alzheimer's Coordinating Center (NACC) dataset, which documents longitudinally clinical records of 24,967 individuals with APOE genotype and diabetic status. RESULTS: Diabetes was associated with shorter lifespan in APOE3 carriers (n = 12,415, HR = 1.29, 95%CI = 1.17-1.42, p < 0.001) and APOE2 carriers (n = 2,390, HR = 1.37, 95%CI = 1.10-1.69, p = 0.016), while such associations were weaker and not significant in APOE4 carriers (n = 9,490, HR = 1.11, 95%CI = 0.99-1.24, p = 0.162). As there is a significant interactive effect of cognitive status and diabetes on lifespan (p < 0.001), we stratified subjects by cognitive status and observed persistent APOE-dependent harmful effects of diabetes in nondemented individuals but not demented individuals. Notably, questionnaire-based activity status, with which we previously observed an association between APOE genotype and longevity, was also significantly affected by diabetes only in non-APOE4 carriers. CONCLUSION: The effects of diabetes on longevity vary among APOE genotype. These effects are observed in nondemented individuals and are potentially associated with activity status during their lifespan.

Upregulated expression of a subset of genes in APP;ob/ob mice: Evidence of an interaction between diabetes-linked obesity and Alzheimer's disease.

Clinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. However, the mechanism by which obesity/diabetes and AD interact with each other and contribute to dementia remains elusive. To obtain insights into their interaction at molecular levels, we performed gene expression analysis of APP;ob/ob mice, which were generated by crossing transgenic AD model mice (APP23 mice) with ob/ob mice, which are obese and mildly diabetic. The Aß level in these mice was reduced compared with that in pure APP mice. However, we identified a cluster of genes (cluster 10) upregulated in APP;ob/ob mice but not in either APP or ob/ob mice. Interestingly, genes upregulated in the human AD brain were enriched in cluster 10. Moreover, genes in cluster 10 formed a network and shared upregulated genes with a cell model of neurodegeneration and other models of neurological disorders such as ischemia and epilepsy. In silico analyses showed that serum response factor (SRF), recently identified in a single-cell analysis of human brains as a transcription factor that can control the conversion from healthy cells to AD cells, might be a common transcriptional regulator for a subset of cluster 10 genes. These data suggest that upregulation of genes uniquely associated with APP;ob/ob mice is an evidence of the interaction between obesity/diabetes and AD.

Frequency-Dependent Cortical Interactions during Semantic Processing: An Electrocorticogram Cross-spectrum Analysis Using a Semantic Space Model.

Convergent evidence has demonstrated that semantics are represented by the interaction between a multimodal semantic hub at the anterior temporal lobe (ATL) and other modality-specific association cortical areas. Electrocorticogram (ECoG) recording with high spatiotemporal resolutions is efficient in evaluating such cortical interactions; however, this has not been a focus of preceding studies. The present study evaluated cortical interactions during picture naming using a novel ECoG cross-spectrum analysis, which was formulated from a computational simulation of neuronal networks and combined with a vector space model of semantics. The results clarified three types of frequency-dependent cortical networks: 1) an earlier-period (0.2-0.8 s from stimulus onset) high-gamma-band (90-150 Hz) network with a hub at the posterior fusiform gyrus, 2) a later-period (0.4-1.0 s) beta-band (15-40 Hz) network with multiple hubs at the ventral ATL and posterior middle temporal gyrus, and 3) a pre-articulation theta-band (4-7 Hz) network distributed over widely located cortical regions. These results suggest that frequency-dependent cortical interactions can characterize the underlying processes of semantic cognition, and the beta-band network with a hub at the ventral ATL is especially associated with the formation of semantic representation.

Deletion of B-cell translocation gene 2 (BTG2) alters the responses of glial cells in white matter to chronic cerebral hypoperfusion.

BACKGROUND: Subcortical ischemic vascular dementia, one of the major subtypes of vascular dementia, is characterized by lacunar infarcts and white matter lesions caused by chronic cerebral hypoperfusion. In this study, we used a mouse model of bilateral common carotid artery stenosis (BCAS) to investigate the role of B-cell translocation gene 2 (BTG2), an antiproliferation gene, in the white matter glial response to chronic cerebral hypoperfusion. METHODS: Btg2-/- mice and littermate wild-type control mice underwent BCAS or sham operation. Behavior phenotypes were assessed by open-field test and Morris water maze test. Brain tissues were analyzed for the degree of white matter lesions and glial changes. To further confirm the effects of Btg2 deletion on proliferation of glial cells in vitro, BrdU incorporation was investigated in mixed glial cells derived from wild-type and Btg2-/- mice. RESULTS: Relative to wild-type mice with or without BCAS, BCAS-treated Btg2-/- mice exhibited elevated spontaneous locomotor activity and poorer spatial learning ability. Although the severities of white matter lesions did not significantly differ between wild-type and Btg2-/- mice after BCAS, the immunoreactivities of GFAP, a marker of astrocytes, and Mac2, a marker of activated microglia and macrophages, in the white matter of the optic tract were higher in BCAS-treated Btg2-/- mice than in BCAS-treated wild-type mice. The expression level of Gfap was also significantly elevated in BCAS-treated Btg2-/- mice. In vitro analysis showed that BrdU incorporation in mixed glial cells in response to inflammatory stimulation associated with cerebral hypoperfusion was higher in Btg2-/- mice than in wild-type mice. CONCLUSION: BTG2 negatively regulates glial cell proliferation in response to cerebral hypoperfusion, resulting in behavioral changes.

Interaction between APOE genotype and diabetes in cognitive decline.

INTRODUCTION: Although diabetes and apolipoprotein E (apoE) are both significant risk factors for dementia, including Alzheimer's disease, it remains to be clarified how they are related to each other in contributing to the risk of dementia. METHODS: By reviewing the National Alzheimer's Coordinating Center (NACC) clinical records, we investigated whether diabetes affects cognitive decline depending on APOE genotype and their potential relationships with neuropathology. RESULTS: A significant interaction between diabetes and APOE genotype exists, where diabetes affected cognitive decline in APOE3 carriers and APOE2 carriers, but not APOE4 carriers. Moreover, the presence of vascular pathology was increased by diabetes in APOE3 carriers, while APOE4 carriers nearly reached plateau levels irrespective of diabetes. DISCUSSION: Diabetes accelerates cognitive decline, in part, through accelerating vascular impairment in non-APOE ε4 carriers, but such effects are negligible in APOE4 carriers, who themselves are already vulnerable to vascular impairment.

Increased levels of Aß42 decrease the lifespan of ob/ob mice with dysregulation of microglia and astrocytes.

Clinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. Although the mechanisms underlying these associations remain elusive, the bidirectional interactions between obesity/diabetes and Alzheimer's disease (AD) may be involved in them. Both obesity/diabetes and AD significantly reduce life expectancy. We generated AppNL-F/wt knock-in; ob/ob mice by crossing AppNL-F/wt knock-in mice and ob/ob mice to investigate whether amyloid-ß (Aß) affects the lifespan of ob/ob mice. AppNL-F/wt knock-in; ob/ob mice displayed the shortest lifespan compared to wild-type mice, AppNL-F/wt knock-in mice, and ob/ob mice. Notably, the Aß42 levels were increased at minimum levels before deposition in AppNL-F/wt knock-in mice and AppNL-F/wt knock-in; ob/ob mice at 18 months of age. No differences in the levels of several neuronal markers were observed between mice at this age. However, we observed increased levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in AppNL-F/wt knock-in; ob/ob mice, while the levels of several microglial markers, including CD11b, TREM2, and DAP12, were decreased in both ob/ob mice and AppNL-F/wt knock-in; ob/ob mice. The increase in GFAP levels was not observed in young AppNL-F/wt knock-in; ob/ob mice. Thus, the increased Aß42 levels may decrease the lifespan of ob/ob mice, which is associated with the dysregulation of microglia and astrocytes in an age-dependent manner. Based on these findings, the imbalance in these neuroinflammatory cells may provide a clue to the mechanisms by which the interaction between obesity/diabetes and early AD reduces life expectancy.

The Roles of Apolipoprotein E, Lipids, and Glucose in the Pathogenesis of Alzheimer's Disease.

Although the mechanisms by which Alzheimer's disease (AD) occurs remains unclear, it is widely accepted that both genetic and nongenetic components contribute to the pathogenesis of AD, especially the sporadic form of the disease. Nongenetic risk factors include diabetes and dyslipidemia, which are associated with impaired glucose and lipid metabolism, respectively. Apolipoprotein E (ApoE), one of the major lipid carriers in the brain, is the strongest genetic risk factor for late-onset AD. Several studies indicate that ApoE isoforms differentially affect not only lipid metabolism but also glucose metabolism or related pathways, suggesting that these risk factors contribute to the pathogenesis of AD through some common mechanisms. In this chapter, we discuss the roles of ApoE, lipids, and glucose in the pathogenesis of AD by considering their potential interactions.

Successful Encoding during Natural Reading Is Associated with Fixation-Related Potentials and Large-Scale Network Deactivation.

Reading literature (e.g., an entire book) is an enriching experience that qualitatively differs from reading a single sentence; however, the brain dynamics of such context-dependent memory remains unclear. This study aimed to elucidate mnemonic neural dynamics during natural reading of literature by performing electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI). Brain activities of human participants recruited on campus were correlated with their subsequent memory, which was quantified by semantic correlation between the read text and reports subsequently written by them based on state of the art natural language processing procedures. The results of the EEG data analysis showed a significant positive relationship between subsequent memory and fixation-related EEG. Sentence-length and paragraph-length mnemonic processes were associated with N1-P2 and P3 fixation-related potential (FRP) components and fixation-related θ-band (4-8 Hz) EEG power, respectively. In contrast, the results of fMRI analysis showed a significant negative relationship between subsequent memory and blood oxygenation level-dependent (BOLD) activation. Sentence-length and paragraph-length mnemonic processes were associated with networks of regions forming part of the salience network and the default mode network (DMN), respectively. Taken together with the EEG results, these memory-related deactivations in the salience network and the DMN were thought to reflect the reading of sentences characterized by low mnemonic load and the suppression of task-irreverent thoughts, respectively. It was suggested that the context-dependent mnemonic process during literature reading requires large-scale network deactivation, which might reflect coordination of a range of voluntary processes during reading.

Bidirectional interactions between diabetes and Alzheimer's disease.

Clinical studies have indicated that diabetes is associated with Alzheimer's disease (AD) and neurodegeneration. However, the mechanisms underlying this association have not been fully elucidated. Diabetes causes neurodegeneration by inducing changes in vascular function and structure, glucose metabolism, and insulin signaling, as well as by modifying ß-amyloid (Aß)/tau metabolisms. In turn, AD influences systemic glucose metabolism by inducing behavioral changes, memory disturbances, hypothalamic dysfunction, frailty and possibly plasma/peripheral Aß level changes. Hypoglycemia, one of the major conditions encountered during the treatment of patients with diabetes, may also contribute to neurodegeneration. Through this vicious circle, diabetes and AD may cooperate to cause neurodegeneration. Various molecular, cellular, inter-organ, physical and clinical factors might contribute to the bidirectional interactions between diabetes and AD. Explorations of a key factor that underlies the bidirectional interactions, "Factor X", could lead to the development of a potential therapeutic target for neurodegeneration. Factor X should fulfill the following equation: neurodegeneration equals Aß levels multiplied by Factor X.

Direction and viewing area-sensitive influence of EOG artifacts revealed in the EEG topographic pattern analysis.

The influence of eye movement-related artifacts on electroencephalography (EEG) signals of human subjects, who were requested to perform a direction or viewing area dependent saccade task, was investigated by using a simultaneous recording with ocular potentials as electro-oculography (EOG). In the past, EOG artifact removals have been studied in tasks with a single fixation point in the screen center, with less attention to the sensitivity of cornea-retinal dipole orientations to the EEG head map. In the present study, we hypothesized the existence of a systematic EOG influence that differs according to coupling conditions of eye-movement directions with viewing areas including different fixation points. The effect was validated in the linear regression analysis by using 12 task conditions combining horizontal/vertical eye-movement direction and three segregated zones of gaze in the screen. In the first place, event-related potential topographic patterns were analyzed to compare the 12 conditions and propagation coefficients of the linear regression analysis were successively calculated in each condition. As a result, the EOG influences were significantly different in a large number of EEG channels, especially in the case of horizontal eye-movements. In the cross validation, the linear regression analysis using the appropriate dataset of the target direction/viewing area combination demonstrated an improved performance compared with the traditional methods using a single fixation at the center. This result may open a potential way to improve artifact correction methods by considering the systematic EOG influence that can be predicted according to the view angle such as using eye-tracker systems.

Aging and dementia.

Is it possible to prevent the onset of dementia by the regulation of aging ? In this review, cognitive changes by aging and modifications of cognitive function by age-related disorders are summarized. Recent evidences of randomized clinical trials are also reviewed to answer the question.

The roles of lipid and glucose metabolism in modulation of ß-amyloid, tau, and neurodegeneration in the pathogenesis of Alzheimer disease.

Diabetes is a risk factor for Alzheimer disease (AD). Apolipoprotein E (ApoE) and several genes related to AD have recently been identified by genome-wide association studies (GWAS) as being closely linked to lipid metabolism. Lipid metabolism and glucose-energy metabolism are closely related. Here, we review the emerging evidence regarding the roles of lipid and glucose metabolism in the modulation of ß-amyloid, tau, and neurodegeneration during the pathogenesis of AD. Disruption of homeostasis of lipid and glucose metabolism affects production and clearance of ß-amyloid and tau phosphorylation, and induces neurodegeneration. A more integrated understanding of the interactions among lipid, glucose, and protein metabolism is required to elucidate the pathogenesis of AD and to develop next-generation therapeutic options.