Hypertension and cerebral blood flow in the development of Alzheimer's disease.

INTRODUCTION: We investigated the interactive associations between amyloid and hypertension on the entorhinal cortex (EC) tau and atrophy and the role of cerebral blood flow (CBF) as a shared mechanism by which amyloid and hypertension contribute to EC tau and regional white matter hyperintensities (WMHs). METHODS: We analyzed data from older adults without dementia participating in the Add-Tau study (NCT02958670, n = 138) or Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 523) who had available amyloid-positron emission tomography (PET), tau-PET, fluid-attenuated inversion recovery (FLAIR), and T1-weighted magnetic resonance imaging (MRI). A subsample in both cohorts had available arterial spin labeling (ASL) MRI (Add-Tau: n = 78; ADNI: n = 89). RESULTS: The detrimental effects of hypertension on AD pathology and EC thickness were more pronounced in the Add-Tau cohort. Increased amyloid burden was associated with decreased occipital gray matter CBF in the ADNI cohort. In both cohorts, lower regional gray matter CBF was associated with higher EC tau and posterior WMH burden. DISCUSSION: Reduced cerebral perfusion may be one common mechanism through which hypertension and amyloid are related to increased EC tau and WMH volume. HIGHLIGHTS: Hypertension is associated with increased entorhinal cortex (EC) tau, particularly in the presence of amyloid. Decreased cortical cerebral blood flow (CBF) is associated with higher regional white matter hyperintensity volume. Increasing amyloid burden is associated with decreasing CBF in the occipital lobe. MTL CBF and amyloid are synergistically associated with EC tau.

Lifestyle Affects Amyloid Burden and Cognition Differently in Men and Women.

OBJECTIVE: Evidence on associations of lifestyle factors with Alzheimer's pathology and cognition are ambiguous, potentially because they rarely addressed inter-relationships of factors and sex effects. While considering these aspects, we examined the relationships of lifestyle factors with brain amyloid burden and cognition. METHODS: We studied 178 cognitively normal individuals (women, 49%; 65.0 [7.6] years) and 54 individuals with mild cognitive impairment (women, 35%; 71.3 [8.3] years) enrolled in a prospective study of volunteers who completed 18 F-Flutemetamol amyloid positron emission tomography. Using structural equation modeling, we examined associations between latent constructs representing metabolic/vascular risk, physical activity, and cognitive activity with global amyloid burden and cognitive performance. Furthermore, we investigated the influence of sex in this model. RESULTS: Overall, higher cognitive activity was associated with better cognitive performance and higher physical activity was associated with lower amyloid burden. The latter association was weakened to a nonsignificant level after excluding multivariate outliers. Examination of the moderating effect of sex in the model revealed an inverse association of metabolic/vascular risk with cognition in men, whereas in women metabolic/vascular risk trended toward increased amyloid burden. Furthermore, a significant inverse association between physical activity and amyloid burden was found only in men. Inheritance of an APOE4 allele was associated with higher amyloid burden only in women. INTERPRETATION: Sex modifies effects of certain lifestyle-related factors on amyloid burden and cognition. Notably, our results suggest that the negative impact of metabolic/vascular risk influences the risk of cognitive decline and Alzheimer's disease through distinct paths in women and men. ANN NEUROL 2022;92:451-463.

Explaining variability in early stages of [18F]-flortaucipir tau-PET binding: Focus on sex differences.

INTRODUCTION: Female sex is associated with increased [18F]-flortaucipir signal, which may be affected by amyloid pathology, age, and off-target binding in skull and meninges. METHODS: In this cross-sectional study comprising 52 females and 52 matched males, we examined sex-related differences in regional tau-positron emission tomography (PET) with and without considering off-target binding. We assessed the respective contributions of sex, age, amyloid-PET burden, and off-target binding to tau-PET signal. We explored associations between age at menopause and hormone replacement therapy (HRT) use with regional tau-PET signals. RESULTS: Female sex was associated with increased regional tau both independently and interactively with amyloid, but amyloid-independent associations were largely reduced when controlling for off-target binding. Age but not age*sex interactions explained a small but significant amount of tau-PET signal in temporoparietal regions. Considering the sample size and limited range of amyloid-PET burden, no clear associations between regional tau-PET signals and age at menopause or HRT use could be found. DISCUSSION: Female sex is associated with increased [18F]-flortaucipir signal mainly through its interaction with amyloid.

The links among age, sex, and glutathione: A cross-sectional magnetic resonance spectroscopy study.

Glutathione (GSH) is a brain marker for oxidative stress and has previously been associated with cerebral amyloid deposition and memory decline. However, to date, no study has examined the links among GSH, sex, age, amyloid, and Apolipoprotein E (APOE) genotype in a large non-clinical cohort of older adults. We performed APOE genotyping, magnetic resonance spectroscopy (MRS) as well as simultaneous positron emission tomography with the radiotracer Flutemetamol (Amyloid-PET), in a group of older adults. The final analysis set comprised 140 healthy older adults (mean age: 64.7 years) and 49 participants with mild cognitive impairment (mean age: 71.4 years). We recorded metabolites in the posterior cingulate cortex (PCC) by a GSH-edited MEGAPRESS sequence. Structural equation modeling revealed that higher GSH levels were associated with female sex, but neither APOE- epsilon 4 carrier status nor age showed significant associations with GSH. Conversely, older age and the presence of an APOE4 allele, but not sex, are linked to higher global amyloid load. Our results suggest that the PCC shows sex-specific GSH alterations in older adults.

White matter hyperintensity patterns: associations with comorbidities, amyloid, and cognition.

BACKGROUND: White matter hyperintensities (WMHs) are often measured globally, but spatial patterns of WMHs could underlie different risk factors and neuropathological and clinical correlates. We investigated the spatial heterogeneity of WMHs and their association with comorbidities, Alzheimer's disease (AD) risk factors, and cognition. METHODS: In this cross-sectional study, we studied 171 cognitively unimpaired (CU; median age: 65 years, range: 50 to 89) and 51 mildly cognitively impaired (MCI; median age: 72, range: 53 to 89) individuals with available amyloid (18F-flutementamol) PET and FLAIR-weighted images. Comorbidities were assessed using the Cumulative Illness Rating Scale (CIRS). Each participant's white matter was segmented into 38 parcels, and WMH volume was calculated in each parcel. Correlated principal component analysis was applied to the parceled WMH data to determine patterns of WMH covariation. Adjusted and unadjusted linear regression models were used to investigate associations of component scores with comorbidities and AD-related factors. Using multiple linear regression, we tested whether WMH component scores predicted cognitive performance. RESULTS: Principal component analysis identified four WMH components that broadly describe FLAIR signal hyperintensities in posterior, periventricular, and deep white matter regions, as well as basal ganglia and thalamic structures. In CU individuals, hypertension was associated with all patterns except the periventricular component. MCI individuals showed more diverse associations. The posterior and deep components were associated with renal disorders, the periventricular component was associated with increased amyloid, and the subcortical gray matter structures was associated with sleep disorders, endocrine/metabolic disorders, and increased amyloid. In the combined sample (CU + MCI), the main effects of WMH components were not associated with cognition but predicted poorer episodic memory performance in the presence of increased amyloid. No interaction between hypertension and the number of comorbidities on component scores was observed. CONCLUSION: Our study underscores the significance of understanding the regional distribution patterns of WMHs and the valuable insights that risk factors can offer regarding their underlying causes. Moreover, patterns of hyperintensities in periventricular regions and deep gray matter structures may have more pronounced cognitive implications, especially when amyloid pathology is also present.

Age-, sex-, and pathology-related variability in brain structure and cognition.

This work aimed to investigate potential pathways linking age and imaging measures to early age- and pathology-related changes in cognition. We used [18F]-Flutemetamol (amyloid) and [18F]-Flortaucipir (tau) positron emission tomography (PET), structural MRI, and neuropsychological assessment from 232 elderly individuals aged 50-89 years (46.1% women, 23% APOE-ε4 carrier, 23.3% MCI). Tau-PET was available for a subsample of 93 individuals. Structural equation models were used to evaluate cross-sectional pathways between age, amyloid and tau burden, grey matter thickness and volumes, white matter hyperintensity volume, lateral ventricle volume, and cognition. Our results show that age is associated with worse outcomes in most of the measures examined and had similar negative effects on episodic memory and executive functions. While increased lateral ventricle volume was consistently associated with executive function dysfunction, participants with mild cognitive impairment drove associations between structural measures and episodic memory. Both age and amyloid-PET could be associated with medial temporal lobe tau, depending on whether we used a continuous or a dichotomous amyloid variable. Tau burden in entorhinal cortex was related to worse episodic memory in individuals with increased amyloid burden (Centiloid >12) independently of medial temporal lobe atrophy. Testing models for sex differences revealed that amyloid burden was more strongly associated with regional atrophy in women compared with men. These associations were likely mediated by higher tau burden in women. These results indicate that influences of pathological pathways on cognition and sex-specific vulnerabilities are dissociable already in early stages of neuropathology and cognitive impairment.

Physical activity is associated with lower cerebral beta-amyloid and cognitive function benefits from lifetime experience-a study in exceptional aging.

BACKGROUND: Exceptional agers (85+ years) are characterized by preserved cognition presumably due to high cognitive reserve. In the current study, we examined whether personality, risk and protective factors for dementia as well as quality of life are associated with core features of Alzheimer's disease (amyloid-deposition and hippocampal volume) as well as cognition in exceptional aging. METHODS: We studied 49 exceptional agers (average 87.8 years, range 84-94 years), with preserved activities of daily living and absence of dementia. All participants received a detailed clinical and neuropsychological examination. We used established questionnaires to measure lifetime experience, personality, recent physical and cognitive activity as well as quality of life. Cerebral amyloid-deposition was estimated by 18-[F]-Flutemetamol-PET and manual hippocampal volumetry was performed on 3D T1 MRI images. RESULTS: In this sample of exceptional agers with preserved activities of daily living, we found intact cognitive performance in the subjects with the highest amyloid-load in the brain, but a lower quality of life with respect to autonomy as well as higher neuroticism. Higher self-reported physical activity in the last twelve months went with a lower amyloid load. Higher self-reported leisure-time/ not work-related activity went with better executive functioning at older age. CONCLUSION: Even in exceptional aging, high amyloid load may subtly influence personality and quality of life. Our findings support a close relationship between high physical activity and low amyloid-deposition and underscore the importance of extracurricular activities for executive functions. As executive functions are known to be a central resource for everyday functioning in fostering extracurricular activities may be effective in delaying the onset of dementia.

Reduced uptake of [11C]-ABP688, a PET tracer for metabolic glutamate receptor 5 in hippocampus and amygdala in Alzheimer's dementia.

INTRODUCTION: Metabotropic glutamate receptors play a critical role in the pathogenesis of Alzheimer's disease due to their involvement in processes of memory formation, neuroplasticity, and synaptotoxity. The objective of the current study was to study mGluR5 availability measured by [11 C]-ABP688 (ABP) in patients with clinically diagnosed Alzheimer's dementia (AD). METHODS: A bolus-infusion protocol of [11 C]-ABP688 was applied in 9 subjects with AD and 10 cognitively healthy controls (Controls) to derive distribution volume estimates of mGluR5. Furthermore, we also estimated cerebral perfusion by averaging early frame signal of initial ABP bolus injection. RESULTS: Subjects with Alzheimer's dementia (mean age: 77.3/SD 5.7) were older than controls (mean age: 68.5/SD: 9.6) and scored lower on the MMSE (22.1/SD2.7 vs. 29.0/SD0.8). There were no overall differences in ABP signal. However, distribution volume ratio (DVR) for ABP was reduced in the bilateral hippocampus (AD: 1.34/SD: 0.40 vs. Control: 1.84/SD:0.31, p = .007) and the bilateral amygdala (AD:1.86/SD:0.26 vs. Control:2.33/SD:0.37 p = .006) in AD patients compared to controls. Estimate of cerebral blood flow was reduced in the bilateral hippocampus in AD (AD:0.75/SD:0.10 vs. Control:0.86/SD:0.09 p = .02). CONCLUSION: Our findings demonstrate reduced mGluR5 binding in the hippocampus and amygdala in Alzheimer's dementia. Whether this is due to synaptic loss and/or consecutive reduction of potential binding sites or reflects disease inherent mechanisms remains to be elucidated in future studies.

Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner.

Early uptake of [(11)C]-Pittsburgh Compound B (ePiB, 0-6 minutes) estimates cerebral blood flow. We studied ePiB in 13 PiB-negative and 10 PiB-positive subjects with mild cognitive impairment (MCI, n = 23) and 11 PiB-positive and 74 PiB-negative cognitively healthy elderly control subjects (HCS, n = 85) in 6 bilateral volumes of interest: posterior cingulate cortex (PCC), hippocampus (hipp), temporoparietal region, superior parietal gyrus, parahippocampal gyrus (parahipp), and inferior frontal gyrus (IFG) for the associations with cognitive status, age, amyloid deposition, and apolipoprotein E ε4-allele. We observed no difference in ePiB between PiB-positive and -negative subjects and carriers and noncarriers. EPiB decreased with age in PiB-positive subjects in bilateral superior parietal gyrus, bilateral temporoparietal region, right IFG, right PCC, and left parahippocampal gyrus but not in PiB-negative subjects. MCI had lower ePiB than HCS (left PCC, left IFG, and left and right hipp). Lowest ePiB values were found in MCI of 70 years and older, who also displayed high cortical PiB binding. This suggests that lowered regional cerebral blood flow indicated by ePiB is associated with age in the presence but not in the absence of amyloid pathology.

Cortical Amyloid Beta in Cognitively Normal Elderly Adults is Associated with Decreased Network Efficiency within the Cerebro-Cerebellar System.

BACKGROUND: Deposition of cortical amyloid beta (Aß) is a correlate of aging and a risk factor for Alzheimer disease (AD). While several higher order cognitive processes involve functional interactions between cortex and cerebellum, this study aims to investigate effects of cortical Aß deposition on coupling within the cerebro-cerebellar system. METHODS: We included 15 healthy elderly subjects with normal cognitive performance as assessed by neuropsychological testing. Cortical Aß was quantified using (11)carbon-labeled Pittsburgh compound B positron-emission-tomography late frame signals. Volumes of brain structures were assessed by applying an automated parcelation algorithm to three dimensional magnetization-prepared rapid gradient-echo T1-weighted images. Basal functional network activity within the cerebro-cerebellar system was assessed using blood-oxygen-level dependent resting state functional magnetic resonance imaging at the high field strength of 7 T for measuring coupling between cerebellar seeds and cerebral gray matter. A bivariate regression approach was applied for identification of brain regions with significant effects of individual cortical Aß load on coupling. RESULTS: Consistent with earlier reports, a significant degree of positive and negative coupling could be observed between cerebellar seeds and cerebral voxels. Significant positive effects of cortical Aß load on cerebro-cerebellar coupling resulted for cerebral brain regions located in inferior temporal lobe, prefrontal cortex, hippocampus, parahippocampal gyrus, and thalamus. CONCLUSION: Our findings indicate that brain amyloidosis in cognitively normal elderly subjects is associated with decreased network efficiency within the cerebro-cerebellar system. While the identified cerebral regions are consistent with established patterns of increased sensitivity for Aß-associated neurodegeneration, additional studies are needed to elucidate the relationship between dysfunction of the cerebro-cerebellar system and risk for AD.

Regional Fluid-Attenuated Inversion Recovery (FLAIR) at 7 Tesla correlates with amyloid beta in hippocampus and brainstem of cognitively normal elderly subjects.

BACKGROUND: Accumulation of amyloid beta (Aß) may occur during healthy aging and is a risk factor for Alzheimer Disease (AD). While individual Aß-accumulation can be measured non-invasively using Pittsburgh Compund-B positron emission tomography (PiB-PET), Fluid-attenuated inversion recovery (FLAIR) is a Magnetic Resonance Imaging (MRI) sequence, capable of indicating heterogeneous age-related brain pathologies associated with tissue-edema. In the current study cognitively normal elderly subjects were investigated for regional correlation of PiB- and FLAIR intensity. METHODS: Fourteen healthy elderly subjects without known history of cognitive impairment received 11C-PiB-PET for estimation of regional Aß-load. In addition, whole brain T1-MPRAGE and FLAIR-MRI sequences were acquired at high field strength of 7 Tesla (7T). Volume-normalized intensities of brain regions were assessed by applying an automated subcortical segmentation algorithm for spatial definition of brain structures. Statistical dependence between FLAIR- and PiB-PET intensities was tested using Spearman's rank correlation coefficient (rho), followed by Holm-Bonferroni correction for multiple testing. RESULTS: Neuropsychological testing revealed normal cognitive performance levels in all participants. Mean regional PiB-PET and FLAIR intensities were normally distributed and independent. Significant correlation between volume-normalized PiB-PET signals and FLAIR intensities resulted for Hippocampus (right: rho = 0.86; left: rho = 0.84), Brainstem (rho = 0.85) and left Basal Ganglia vessel region (rho = 0.82). CONCLUSIONS: Our finding of a significant relationship between PiB- and FLAIR intensity mainly observable in the Hippocampus and Brainstem, indicates regional Aß associated tissue-edema in cognitively normal elderly subjects. Further studies including clinical populations are necessary to clarify the relevance of our findings for estimating individual risk for age-related neurodegenerative processes such as AD.