High Aβ Load Research Articles

Human in vivo evidence of associations between herpes simplex virus and cerebral amyloid-beta load in normal aging

BackgroundMounting data suggests that herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of AD, possibly instigating amyloid-beta (Aβ) accumulation decades before the onset of clinical symptoms. However, human in vivo evidence linking HSV-1 infection to AD pathology is lacking in normal aging, which may contribute to the elucidation of the role of HSV-1 infection as a potential AD risk factor.MethodsTo shed light into this question, serum anti-HSV IgG levels were correlated with 18F-Florbetaben-PET binding to Aβ deposits and blood markers of neurodegeneration (pTau181 and neurofilament light chain) in cognitively normal older adults. Additionally, we investigated whether associations between anti-HSV IgG and AD markers were more evident in APOE4 carriers.ResultsWe showed that increased anti-HSV IgG levels are associated with higher Aβ load in fronto-temporal regions of cognitively normal older adults. Remarkably, these cortical regions exhibited abnormal patterns of resting state-functional connectivity (rs-FC) only in those individuals showing the highest levels of anti-HSV IgG. We further found that positive relationships between anti-HSV IgG levels and Aβ load, particularly in the anterior cingulate cortex, are moderated by the APOE4 genotype, the strongest genetic risk factor for AD. Importantly, anti-HSV IgG levels were unrelated to either subclinical cognitive deficits or to blood markers of neurodegeneration.ConclusionsAll together, these results suggest that HSV infection is selectively related to cortical Aβ deposition in normal aging, supporting the inclusion of cognitively normal older adults in prospective trials of antimicrobial therapy aimed at decreasing the AD risk in the aging population.

The fluorescent ligand bTVBT2 reveals increased p-tau uptake by retinal microglia in Alzheimer's disease patients and AppNL-F/NL-F mice.

Amyloid beta (Aβ) deposits and hyperphosphorylated tau (p-tau) accumulation have been identified in the retina of Alzheimer's disease (AD) patients and transgenic AD mice. Previous studies have shown that retinal microglia engulf Aβ, but this property decreases in AD patients. Whether retinal microglia also take up p-tau and if this event is affected in AD is yet not described. In the current study, we use the p-tau-specific thiophene-based ligand bTVBT2 to investigate the relationship between disease progression and p-tau uptake by microglia in the retina of AD patients and AppNL-F/NL-F knock-in mice, an AD mouse model known to demonstrate extracellular Aβ plaques and dystrophic neurites in the brain from 6months of age. Evaluation of bTVBT2 specificity and its presence within microglia was assessed by immunofluorescent staining of hippocampal sections and flat-mount retina samples from non-demented controls, AD patients, 3-, 9-, and 12-month-old AppNL-F/NL-F knock-in mice and 12- and 18-month-old wild type (WT) mice. We used ImageJ to analyze the amount of bTVBT2 inside Iba1-positive microglia. Co-localization between the ligand and p-tau variant Ser396/Ser404 (PHF-1), Aβ, phosphorylated TAR DNA binding protein 43 (pTDP-43), and islet amyloid polypeptide (IAPP) in the brain and retina was analyzed using confocal imaging. Confocal imaging analysis showed that bTVBT2 binds to PHF-1- and AT8-positive aggregates inside retinal microglia, and not to Aβ, pTDP-43, or IAPP. The density of bTVBT2-positive microglia was higher in cases with a high Aβ load compared to those with a low Aβ load. This density correlated with the neurofibrillary tangle load in the brain, but not with retinal levels of high molecular weight (aggregated) Aβ40 or Aβ42. Analysis of AppNL-F/NL-F knock-in mouse retina further showed that 50% of microglia in 3-month-old AppNL-F/NL-F knock-in mice contained bTVBT2. The percentage significantly increased in 9- and 12-month-old mice. Our study suggests that the microglial capability to uptake p-tau in the retina persists and intensifies with AD progression. These results also highlight bTVBT2 as a ligand of interest in future monitoring of retinal AD pathology.

Amyloid‐beta (Aβ) load in the post‐mortem brain correlates with APOE genotype and ante‐mortem cognitive performance in centenarians

AbstractBackgroundThe prevalence of amyloid‐beta (Aβ) pathology increases at higher ages in non‐demented individuals1. With anti‐amyloid‐beta therapies on the horizon and the growing number of elderly in our population, a clear perception of the association between accumulated Aβ pathology, APOE genotype and cognitive performance in the oldest‐old is warranted.MethodsIn 93 post‐mortem brains donated by participants of the Dutch 100‐plus Study, who self‐reported to be cognitively healthy at inclusion, we evaluated: 1) the spatiotemporal Aβ spread using Thal phases2; and 2) Aβ load in frontal, parietal, temporal and occipital cortices using a quantitative image analysis method. Spread and load of Aβ pathology were compared between different APOE groups (ɛ2/2 and ɛ2/3 (n = 20); ɛ3/3 (n = 65); ɛ2/4 and ɛ3/4 (n = 8)). Post‐mortem Aβ measurements were correlated to ante‐mortem test scores on a comprehensive neuropsychological test battery3 and a composite z‐score for global cognitive performance. Median age at death was 103.3 (interquartile range (IQR): 102.3‐104.9) and median time between neuropsychological assessment and brain donation amounted 0.61 years (IQR: 0.28‐0.93).ResultsNotably, only 10% of the centenarians had not accumulated Aβ pathology. APOE ɛ2/2 and ɛ2/3 carriers had lower Aβ load (median frontal AB load = 0.30%, IQR: 0.02‐6.15), but not spread, compared to APOE ɛ2/4 and ɛ3/4 carriers (median frontal AB load = 5.08%, IQR: 2.13‐30.71) (p = 0.041), but not compared to ɛ3/3 carriers (median frontal AB load = 2.19%, IQR:0.23‐7.54) (p = 0.245). Higher Aβ load in all four analyzed regions associated with lower performance on the Digit Span Backward test (rfrontal = ‐0.29, rparietal = ‐0.29, rtemporal = ‐0.28, roccipital = ‐0.32, FDR corrected p<0.05) and the Clock Drawing test (rfrontal = ‐0.40, rparietal = ‐0.29, rtemporal = ‐0.29, roccipital = ‐0.33, FDR corrected p<0.05), which assess executive‐ and visuospatial‐functioning. Moreover, higher Aβ load in the frontal cortex correlated with lower performance on the Mini Mental State Examination (MMSE) (r = ‐0.24, p = 0.049) and a seperate composite score of global cognitive performance (r = ‐0.28, p = 0.019).ConclusionAlthough Aβ pathology seems nearly inevitable at extreme ages, our results suggest that Aβ load, rather than Aβ spread, affects cognitive performance in the oldest‐old1 https://doi.org/10.1002/alz.12899 2 https://doi.org/10.1212/wnl.58.12.1791 3 https://doi.org/10.1007/s10654-018-0451-3

Elevated gonadotropin levels are associated with increased biomarker risk of Alzheimer's disease in midlife women.

In preclinical studies, menopausal elevations in pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), trigger Alzheimer's disease (AD) pathology and synaptic loss in female animals. Herein, we took a translational approach to test whether gonadotropin elevations are linked to AD pathophysiology in women. We examined 191 women ages 40-65 years, carrying risk factors for late-onset AD, including 45 premenopausal, 67 perimenopausal, and 79 postmenopausal participants with clinical, laboratory, cognitive exams, and volumetric MRI scans. Half of the cohort completed 11C-Pittsburgh Compound B (PiB) amyloid-β (Aβ) PET scans. Associations between serum FSH, LH and biomarkers were examined using voxel-based analysis, overall and stratified by menopause status. Associations with region-of-interest (ROI) hippocampal volume, plasma estradiol levels, APOE-4 status, and cognition were assessed in sensitivity analyses. FSH levels were positively associated with Aβ load in frontal cortex (multivariable adjusted P≤0.05, corrected for family wise type error, FWE), an effect that was driven by the postmenopausal group (multivariable adjusted PFWE ≤ 0.044). LH levels were also associated with Aβ load in frontal cortex, which did not survive multivariable adjustment. FSH and LH were negatively associated with gray matter volume (GMV) in frontal cortex, overall and in each menopausal group (multivariable adjusted PFWE ≤ 0.040), and FSH was marginally associated with ROI hippocampal volume (multivariable adjusted P = 0.058). Associations were independent of age, clinical confounders, menopause type, hormone therapy status, history of depression, APOE-4 status, and regional effects of estradiol. There were no significant associations with cognitive scores. Increasing serum gonadotropin levels, especially FSH, are associated with higher Aβ load and lower GMV in some AD-vulnerable regions of midlife women at risk for AD. These findings are consistent with preclinical work and provide exploratory hormonal targets for precision medicine strategies for AD risk reduction.

The association between sleep restlessness and neuroimaging biomarkers of Alzheimer’s Disease in mid‐life to older adults and patients

AbstractBackgroundRecent research demonstrates a bidirectional relationship between sleep and Alzheimer’s Disease (AD) pathology, with supporting evidence that changes in sleep pattern occurs from the preclinical stage of AD. The cooccurrence of sleep disturbances and amyloid‐beta (Aβ) accumulation suggests the importance of monitoring sleep patterns in adults that are at high‐risk of developing AD later in life. We first investigated whether resting heart rate (RHR) and nocturnal sleep restlessness (NSR) are different in cognitively impaired (CI) and cognitively unimpaired (CU) mid‐life to older adults. We also examined any association of these sleep characteristics with hippocampus volume (HV) and Aβ, as neuroimaging biomarkers of AD, regardless of the cognitive status.Method107 middle to old age (46‐75 years old) adults (age 61.5±6.5, 74 Females, 64 APOE ε4 carriers, and 88 CU) underwent 3T MRI and PET scans as part of the Prospective Imaging Study of Ageing (PISA) study. A ballistocardiograph sleep monitoring device was used to track their RHR and NSR for approximately 5 months after their PET scan. NSR was quantified by total time in bed, total duration and number of bed‐exits, and multi‐episodic sleep. HV was normalised using total intracranial volume, and Aβ load was calculated in Centiloid scale (CL) with Aβ positivity defined as CL>20. Generalised Linear Models were used to examine the relationship between sleep and imaging biomarkers. Age, gender, BMI, APOE, and years of education were used as independent covariates.ResultCIs spent more time in bed (p = 0.002) and had more bed‐exits (p = 0.009) than CUs. However, no significant difference was found on RHR and multi‐episodic sleep between CUs and CIs. Individuals with higher Aβ load, regardless of their cognitive status, had lower RHR (p = 0.04) and more bed‐exits (p = 0.04), and spent more time in bed (p = 0.01). Also, individuals with smaller HV frequently exited the bed during the night (p = 0.03) and spent more time in bed (p = 0.003).ConclusionIndividuals with cognitive impairment experienced higher levels of NSR with frequent bed‐exits and more time in bed. Also, these sleep characteristics were significantly associated with the Centiloid value, Aβ status, and HV, regardless of the cognitive status.

Most dystrophic neurites in the common 5xFAD Alzheimer mouse model originate from axon terminals

How dystrophic neurites form around amyloid plaques is a key aspect of understanding the early pathophysiology of Alzheimer's disease. At present, three hypotheses prevail: (1) dystrophies result from extracellular amyloid-beta (Aβ) toxicity; (2) dystrophies results from accumulation of Aβ into distal neurites; and (3) dystrophies represent blebbing of the somatic membrane of a neuron with high Aβ load. We utilized a unique feature of the common 5xFAD AD mouse model to test these hypotheses. Cortical layer 5 pyramidal neurons show intracellular APP and Aβ accumulation before amyloid plaque formation while dentate granule cells in these mice show no APP accumulation at any age. However, the dentate gyrus shows amyloid plaques by 3 months of age. By a careful confocal microscopic analysis we found no evidence of severe degeneration in amyloid laden layer 5 pyramidal neurons in contrast to hypothesis 3. Using injecting red fluorescent marker into lateral entorhinal projection neurons in 5xFAD mice with endogenous green fluorescent protein (GFP) in dentate granule cells we could demonstrate that all dystrophies is outer molecular layer originate from the axon terminal of entorhinal projection neurons. Immunostaining with vesicular glutamate transporter supported the axonal nature of the dystrophies in the acellular dentate molecular layer. We observed few small dystrophies in the GFP labeled granule cell dendrites. In general GFP labeled dendrites appear normal around the amyloid plaques. These findings favor hypothesis 2 as the most likely mechanism of dystrophic neurite formation.

CSF Synaptic Biomarkers in the Preclinical Stage of Alzheimer Disease and Their Association With MRI and PET: A Cross-sectional Study.

Background and ObjectivesTo determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers.MethodsThis cross-sectional study was performed in the Alzheimer's and Families (ALFA+) cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and growth-associated protein-43 (GAP-43) were measured with immunoassays, and synaptosomal-associated protein-25 (SNAP-25) and synaptotagmin-1 were measured with immunoprecipitation mass spectrometry. AD CSF biomarkers β-amyloid (Aβ)42/40, phosphorylated tau (p-tau), and total tau and the neurodegeneration biomarker neurofilament light chain (NfL) were also measured. Participants underwent structural MRI and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers.ResultsAll CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values), and it is important to note that the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism but lower cortical thickness in AD-related brain regions.DiscussionCSF synaptic biomarkers increase in the early preclinical stages of the Alzheimer continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE ε4, and markers of neurodegeneration.Trial Registration InformationClinicalTrials.gov Identifier NCT02485730.

Variability in the type and layer distribution of cortical Aβ pathology in familial Alzheimer's disease.

Familial Alzheimer's disease (FAD) is caused by autosomal dominant mutations in the PSEN1, PSEN2 or APP genes, giving rise to considerable clinical and pathological heterogeneity in FAD. Here we investigate variability in clinical data and the type and distribution of Aβ pathologies throughout the cortical layers of different FAD mutation cases. Brain tissue from 20 FAD cases [PSEN1 pre‐codon 200 (n = 10), PSEN1 post‐codon 200 (n = 6), APP (n = 4)] were investigated. Frontal cortex sections were stained immunohistochemically for Aβ, and Nissl to define the cortical layers. The frequency of different amyloid‐beta plaque types was graded for each cortical layer and the severity of cerebral amyloid angiopathy (CAA) was determined in cortical and leptomeningeal blood vessels. Comparisons were made between FAD mutations and APOE4 status, with associations between pathology, clinical and genetic data investigated. In this cohort, possession of an APOE4 allele was associated with increased disease duration but not with age at onset, after adjusting for mutation sub‐group and sex. We found Aβ pathology to be heterogeneous between cases although Aβ load was highest in cortical layer 3 for all mutation groups and a higher Aβ load was associated with APOE4. The PSEN1 post‐codon 200 group had a higher Aβ load in lower cortical layers, with a small number of this group having increased cotton wool plaque pathology in lower layers. Cotton wool plaque frequency was positively associated with the severity of CAA in the whole cohort and in the PSEN1 post‐codon 200 group. Carriers of the same PSEN1 mutation can have differing patterns of Aβ deposition, potentially because of differences in risk factors. Our results highlight possible influences of APOE4 genotype, and PSEN1 mutation type on Aβ deposition, which may have effects on the clinical heterogeneity of FAD.

Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using 11C-BU99008 PET and its relationship with amyloid load

11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer’s disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aβ)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer’s brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer’s disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aβ load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.

Aberrant Synaptic PTEN in Symptomatic Alzheimer's Patients May Link Synaptic Depression to Network Failure.

In Alzheimer’s disease (AD), Amyloid β (Aβ) impairs synaptic function by inhibiting long-term potentiation (LTP), and by facilitating long-term depression (LTD). There is now evidence from AD models that Aβ provokes this shift toward synaptic depression by triggering the access to and accumulation of PTEN in the postsynaptic terminal of hippocampal neurons. Here we quantified the PTEN in 196,138 individual excitatory dentate gyrus synapses from AD patients at different stages of the disease and from controls with no neuropathological findings. We detected a gradual increase of synaptic PTEN in AD brains as the disease progresses, in conjunction with a significant decrease in synaptic density. The synapses that remain in symptomatic AD patients are more likely to be smaller and exhibit fewer AMPA receptors (AMPARs). Hence, a high Aβ load appears to strongly compromise human hippocampal synapses, as reflected by an increase in PTEN, inducing a loss of AMPARs that may eventually provoke synaptic failure and loss.

Associations of Salivary Total Antioxidant Capacity With Cortical Amyloid-Beta Burden, Cortical Glucose Uptake, and Cognitive Function in Normal Aging.

Determining susceptibility to Alzheimer's disease (AD) in asymptomatic individuals requires from noninvasive, simple, and inexpensive markers that can be easily obtained in primary care settings. While saliva meets all these requirements, there is a lack of evidence linking salivary constituents to in vivo AD pathology in aging. We examined the potential of salivary total antioxidant capacity (TAC) for identifying global cortical amyloid-beta (Aβ) burden, deficits in regional glucose uptake, and poorer cognition in 71 cognitively normal older adults. We further assessed whether salivary TAC-related cognitive performance was associated with higher Aβ load and lower cortical glucose consumption. Linear regression analyses adjusted by age, sex, years of education, and ApoE4 status showed that salivary TAC was associated with slower processing speed and poorer sustained attention, as well as with higher Aβ load and lower glucose metabolism in cortical regions vulnerable to cognitive aging and AD. Results also revealed that lower scores in processing speed and sustained attention were associated with greater Aβ burden and lower regional glucose consumption, respectively. Together, these findings support the use of salivary TAC for preventive screening and detection of cerebral vulnerability to AD. Further research is needed to evaluate the utility of salivary TAC as a clinical marker.

Amyloid angiopathy may contribute to white‐matter hyperintensities in Alzheimer’s disease

AbstractBackgroundCerebral amyloid angiopathy (CAA) is characterised by the accumulation of amyloid‐b (Aβ) in cerebral vessels and is often coexistent with Alzheimer’s disease (AD). However, the overlap between CAA and AD and the contribution of CAA pathology to cerebrovascular lesions are not well understood. We hypothesize that in subjects with high Aβ load, the presence of imaging markers of CAA would be associated with greater white matter hyperintensities (WMH) burden.MethodData used in the preparation of this article was obtained from the Australian Imaging Biomarkers and Lifestyle flagship study of ageing (AIBL). See www.aibl.csiro.au. We analysed MRI (SWI and FLAIR) and 11C‐PiB‐PET data from 98 cognitively normal (CN), 34 mild‐cognitive impairment (MCI) and 38 AD participants. Subjects were classified as being Aβ+ if their Aβ load was above 20 centiloid.SWI images were manually read for lobar microbleeds (LMB) and superficial siderosis. Subjects were classified as probable‐CAA (PCAA, 2 or more LMB or siderosis), possible‐CAA (SCAA, single LMB or siderosis) or non‐CAA (NCAA) based on the modified Boston criteria. Subjects classified as SCAA (n = 24) were excluded from further analysis since literature shows this group to be heterogenous and having low incidence of CAA pathology. WMH were automatically quantified on FLAIR. Group comparisons of WMH load were made using Kruskal Wallis rank test. A GLM was performed comparing WMH (log10 transformed) and CAA/ Aβ+ classification with age, intracranial volume, gender, APOE‐ε4 genotype and use of anti‐platelet or anticoagulant medication modelled as covariates.ResultSignificantly higher WMH volume was observed in PCAA (n = 17) than NCAA (n = 129) (p‐value = 0.021, d = 0.36). When amyloid status was considered, PCAA/Aβ+ (n = 15) subjects had a significantly higher WMH load than NCAA/Aβ+ (n = 57) subjects (p‐value = 0.012, d = 0.57) and NCAA/Aβ‐ (n = 72) subjects (p‐value = 0.0006, d = 0.76) (Figure 1). PCAA/Aβ‐ (n = 2) were removed from further analysis. GLM results showed a significant association of WMH with PCAA/Aβ+ as compared to NCAA/Aβ+ (p‐value = 0.02, beta = 0.322 [0.056,0.588]).ConclusionOur findings suggest that CAA may contribute to WMH burden in subjects with high Aβ load. Further studies are required to validate our observations and characterise the contributions of CAA compared to small vessel disease associated with traditional risk factors towards the phenotype of AD.

Comorbidity of Cerebrovascular andAlzheimer's Disease in Aging.

Cerebrovascular disease often coexists with Alzheimer's disease (AD). While both diseases share common risk factors, their interrelationship remains unclear. Increasing the understanding of how cerebrovascular changes interact with AD is essential to develop therapeutic strategies and refine biomarkers for early diagnosis. We investigate the prevalence and risk factors for the comorbidity of amyloid-β (Aβ) and cerebrovascular disease in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing, and further examine their cross-sectional association. A total of 598 participants (422 cognitively normal, 89 with mild cognitive impairment, 87 with AD) underwent positron emission tomography and structural magnetic resonance imaging for assessment of Aβ deposition and cerebrovascular disease. Individuals were categorized based on the comorbidity status of Aβ and cerebrovascular disease (V) as Aβ-V-, Aβ-V+, Aβ+V-, or Aβ+V+. Advancing age was associated with greater likelihood of cerebrovascular disease, high Aβ load and their comorbidity. Apolipoprotein E ɛ4 carriage was only associated with Aβ positivity. Greater total and regional WMH burden were observed in participants with AD. However, no association were observed between Aβ and WMH measures after stratification by clinical classification, suggesting that the observed association between AD and cerebrovascular disease was driven by the common risk factor of age. Our observations demonstrate common comorbid condition of Aβ and cerebrovascular disease in later life. While our study did not demonstrate a convincing cross-sectional association between Aβ and WMH burden, future longitudinal studies are required to further confirm this.

Associations among amyloid status, age, and longitudinal regional brain atrophy in cognitively unimpaired older adults

The goal of this study was to compare regional brain atrophy patterns in cognitively unimpaired (CU) older adults with and without brain accumulation of amyloid-β (Aβ) to elucidate contributions of Aβ, age, and other variables to atrophy rates. In 80 CU participants from the Alzheimer's Disease Neuroimaging Initiative, we determined effects of Aβ and age on longitudinal, regional atrophy rates, while accounting for confounding variables including sex, APOE ε4 genotype, white matter lesions, and cerebrospinal fluid total and phosphorylated tau levels. We not only found overlapping patterns of atrophy in Aβ+ versus Aβ− participants but also identified regions where atrophy pattern differed between the 2 groups. Higher Aβ load was associated with increased longitudinal atrophy in the entorhinal cortex, amygdala, and hippocampus, even when accounting for age and other variables. Age was associated with atrophy in insula, fusiform gyrus, and isthmus cingulate, even when accounting for Aβ. We found age by Aβ interactions in the postcentral gyrus and lateral orbitofrontal cortex. These results elucidate the separate and related effects of age, Aβ, and other important variables on longitudinal brain atrophy rates in CU older adults.

High Aβ load may cause microglial cell dysfunction and reduced nuclear repressor element-1 silencing transcription factor (REST) expression which might be ascribed to its degradation by ubiquitination.

This study aimed to investigate the effects of high Aβ load on the microglial function, neuronal activity, and repressor element-1 silencing transcription factor (REST) expression and nuclear localization and further explore the mechanism underlying nuclear REST deficiency and the correlation between pathology and symptoms in Alzheimer's disease (AD). BV2 cells and N2A cells were treated with Aβ at different concentrations, and the viability, apoptosis and autophagy of these cells were further evaluated. The expression of major histocompatibility complex class II (MHC-II, a marker of microglial activation), REST in the neurons and REST specific phosphorylase casein kinase 1 (CK1) were detected. Aβ at a low concentration (2.5 µmol/L) could alter the microglial morphology, and the proportion of amoebic microglia and protein expression of MHC-II increased in a Aβ concentration dependent manner. Aβ at a high concentration (10 µmol/L) was able to reduce REST expression, elevate the expression of pro-apoptotic and pro-autophagic genes, inhibit the expression of anti-apoptotic gene, and reduce the neuronal activity. REST expression reduced, but CK1 increased in neurons, and CK1 inhibitor significantly increased REST expression. there was co-expression of REST and CK1 in the brain of AD mice, which was characterized by reduced nuclear REST expression and elevated CK1 expression. High Aβ load may cause microglial cell dysfunction and loss of REST expression in the neurons, resulting in dementia. The reduced nuclear REST might be ascribed to its degradation by ubiquitination. This supports the hypothesis that high plaque load may increase the risk for dementia.

11C]PIB PET Is Associated with the Brain Biopsy Amyloid-β Load in Subjects Examined for Normal Pressure Hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is frequently associated with concomitant amyloid-β (Aβ) pathology. To compare the [11C]PIB PET uptake in the patients with suspected iNPH to Aβ and hyperphosphorylated-tau (HPτ) in the right frontal cortical biopsy, the cerebrospinal fluid (CSF) Aβ, the response to a CSF shunt, and the final clinical diagnosis of Alzheimer's disease (AD). Patients (n = 21) from Kuopio NPH Registry (http://www.uef.fi/nph) with intraventricular pressure monitoring, immunostaining for Aβ and HPτ in the right frontal cortical biopsies, and a Mini-Mental State Examination and a Clinical Dementia Rating underwent [11C]PIB PET. Aβ, total tau, and Pτ181 were measured by ELISA from the ventricular (n = 15) and the lumbar (n = 9) CSF. Response to the shunt was seen in 13 out of the 15 shunted patients. AD was diagnosed in 8patients during a median follow-up of 6 years (mean 7.3±2.4 years, range 3-1). [11C]PIB uptake in the right frontal cortex (ρ= 0.60, p < 0.01) and the combined neocortical [11C]PIB uptake score (ρ= 0.61, p < 0.01) were associated with a higher Aβ load in the right frontal cortical biopsy. Excluding one (1/15) outlier, [11C]PIB uptake was also associated with the ventricular CSF Aβ (ρ= -0.58, p = 0.03). The findings show that [11C]PIB PET can reliably detect simultaneous amyloid pathology among the iNPH patients. Further studies will show whether amyloid PET could predict a clinical response to the shunt operation. In addition, the presence of Aβ pathology in the patients with iNPH might also warrant treatment with current AD drugs.

Muscarinic M1 Receptor Coupling to G-protein is Intact in Parkinson's Disease Dementia.

Postsynaptic cholinergic deficits, including reduced cortical muscarinic M1 receptor coupling to G-proteins, are neurochemical findings postulated to underlie the limited efficacy of presynaptically-targeted cholinergic replacement therapies in Alzheimer's disease (AD). While the loss of M1-G-protein coupling has been associated with β-amyloid (Aβ) burden in AD, the status of M1 coupling to G-proteins in Parkinson's disease-related or mixed dementias is unclear. To test the hypothesis that M1 receptor uncoupling is correlated with Aβ burden, we aimed to study muscarinic M1 neurochemical parameters in neurodegenerative dementias characterized by low and high Aβ loads. M1 receptors, M1 coupling to G-proteins as well as Aβ were measured in postmortem frontal cortex of a cohort of longitudinally assessed patients with Parkinson's Disease Dementia (PDD, low Aβ load) and AD with significant subcortical cerebrovascular disease (AD + CVD, high Aβ load). We found unchanged levels of M1 receptors in both dementia groups, while M1 coupling was reduced only in AD + CVD (p < 0.01). Furthermore, Aβ concentration was significantly increased only in AD + CVD, and correlated negatively with M1-G-protein coupling in the dementia groups. Our study suggests that loss of M1 coupling to G-proteins may be a neurochemical feature of neurodegenerative dementias with high cortical Aβ burden, and that cholinergic replacement therapies may be more efficacious for PDD due to low Aβ burden.

Distribution and Load of Amyloid-β Pathology in Parkinson Disease and Dementia with Lewy Bodies.

Parkinson disease (PD), Parkinson disease with dementia (PDD), and Dementia with Lewy bodies (DLB) differ clinically with regard to the presence and timing of dementia. In this postmortem study, we evaluated whether the burden and distribution pattern of amyloid-β (Aβ) pathology differs among these disease entities. We assessed Aβ phases and neuritic plaque scores in 133 patients fulfilling clinical diagnostic criteria for PD, PDD, and DLB, and determined the presence and load of Aβ pathology in 5 cortical and 4 subcortical regions in a subset of patients (n = 89) using a multispectral imaging system. Aβ phases and neuritic plaque scores were higher in DLB versus PDD (both p < 0.001) and in PDD vs PD patients (p = 0.020 and 0.022, respectively). Aβ pathology was more often observed in the entorhinal cortex, amygdala and putamen in DLB versus PDD patients; Aβ load was higher in both cortical and subcortical regions. PDD patients had more frequent Aβ pathology in temporal cortex and higher Aβ load in cortical regions and striatum versus PD patients. Our findings suggest that the load and extent of Aβ pathology may contribute to cognitive dysfunction in PDD and the early-stage severe dementia in DLB.

The effect of β-amyloid positivity on cerebral metabolism in cognitively normal seniors

IntroductionWe evaluated the effect of cerebral amyloid-β (Aβ) deposition in cognitively normal (CN) seniors on regional metabolism of specific brain regions known to be affected by p-tau deposition. MethodsFluorodeoxyglucose positron emission tomography (FDG-PET), volumetric magnetic resonance imaging scans, and global amyloid standardized uptake value ratios (SUVr) were obtained for 210 CNs from the Alzheimer's Disease Neuroimaging Initiative-2 (ADNI2). Region of interest (ROI) extraction was used to obtain functional SUVr from six bilateral ROIs: amygdala (AM), entorhinal cortex (EC), hippocampus, lateral orbitofrontal, posterior cingulate (PC), and middle temporal gyrus. Every metabolic SUVr set was averaged and analyzed against the corresponding subject's amyloid SUVr. Correlation analyses were conducted on the full group and between APOE ε4-positive and APOE ε4-negative subgroups. ResultsThe APOE ε4+ group exhibited significantly higher metabolism in the EC (r = 0.270, P = .038) and AM (r = 0.267, P = .041). When a significance of the difference test was conducted between the APOE ε4+ and APOE ε4-groups, these same regions remained significant: P = .012 and P = .016, respectively. By contrast, the APOE ε4 group displayed only the conventionally expected result of reduced regional metabolism in the PC (r = −0.161, P = .048), with higher Aβ load. ConclusionsThe effect of amyloid positivity on brain metabolism is regionally specific, and APOE ε4 status substantially modulates regional glucose uptake in these regions. The APOE ε4 allele may cause earlier emergence of clinical symptoms in AD via a mechanism that influences regional metabolic demand in specifically those regions where p-tau deposition is known to occur earliest.

Phenomenological characterization of memory complaints in preclinical and prodromal Alzheimer's disease.

To explore the subjective experience of memory change in groups at risk of dementia (those with mild cognitive impairment MCI or high β-amyloid (Aβ+) burden) to determine the existence of potential phenomenological typologies. We recruited 123 healthy controls (HC) and individuals with MCI from the Australian Imaging, Biomarker and Lifestyle (AIBL) study. Sixty-7 (HC = 47,MCI = 20) had Aβ scans available for analysis. Semistructured interviews were administered, transcribed, and meaningful phrases extracted from transcripts. Twelve themes were defined and compared across diagnostic status and Aβ status. MCI endorsed more complaints of burdensome coping strategies, increasing frequency, sense of predomination, poor contextualization, progression, dependency, impact on affect, and dismissive attitudes. HCAβ+ acknowledged a progressive memory decline compared to HCAβ-, while MCIAβ+ expressed more burdensome coping strategies, dismissive attitudes, and dependency comparative to either healthy group. Depression was more likely to be related to complaint themes in HCs, while complaint themes were associated with poorer list-learning performance in individuals with MCI. Complaint themes in those with MCI align with the MCI symptom complex, particularly when accompanied with high Aβ load. Healthy Aβ+ individuals acknowledged progressive memory change, suggesting they are aware of memory changes not yet detectable via neuropsychological measures. Depressive symptomatology associated with HC complaints, suggesting certain themes are affect-driven, while complaints in MCI are associated with organically driven functional impairment. Qualitative analysis of SMCs can inform the earliest clinical manifestations of Alzheimer's disease. Our findings can inform diagnostic approaches to the clinical evaluation of memory complaints in the nondemented elderly.