Spatial extent as a sensitive amyloid-PET metric in preclinical Alzheimer's disease.

INTRODUCTION: Spatial extent-based measures of how far amyloid beta (Aß) has spread throughout the neocortex may be more sensitive than traditional Aß-positron emission tomography (PET) measures of Aß level for detecting early Aß deposits in preclinical Alzheimer's disease (AD) and improve understanding of Aß's association with tau proliferation and cognitive decline. METHODS: Pittsburgh Compound-B (PIB)-PET scans from 261 cognitively unimpaired older adults from the Harvard Aging Brain Study were used to measure Aß level (LVL; neocortical PIB DVR) and spatial extent (EXT), calculated as the proportion of the neocortex that is PIB+. RESULTS: EXT enabled earlier detection of Aß deposits longitudinally confirmed to reach a traditional LVL-based threshold for Aß+ within 5 years. EXT improved prediction of cognitive decline (Preclinical Alzheimer Cognitive Composite) and tau proliferation (flortaucipir-PET) over LVL. DISCUSSION: These findings indicate EXT may be more sensitive to Aß's role in preclinical AD than level and improve targeting of individuals for AD prevention trials. HIGHLIGHTS: Aß spatial extent (EXT) was measured as the percentage of the neocortex with elevated Pittsburgh Compound-B. Aß EXT improved detection of Aß below traditional PET thresholds. Early regional Aß deposits were spatially heterogeneous. Cognition and tau were more closely tied to Aß EXT than Aß level. Neocortical tau onset aligned with reaching widespread neocortical Aß.

Lower Locus Coeruleus Integrity Signals Elevated Entorhinal Tau and Clinical Progression in Asymptomatic Older Individuals.

OBJECTIVE: Elevated entorhinal cortex (EC) tau in low beta-amyloid individuals can predict accumulation of pathology and cognitive decline. We compared the accuracy of magnetic resonance imaging (MRI)-derived locus coeruleus integrity, neocortical beta-amyloid burden by positron emission tomography (PET), and hippocampal volume in identifying elevated entorhinal tau signal in asymptomatic individuals who are considered beta-amyloid PET-negative. METHODS: We included 188 asymptomatic individuals (70.78 ± 11.51 years, 58% female) who underwent 3T-MRI of the locus coeruleus, Pittsburgh compound-B (PiB), and Flortaucipir (FTP) PET. Associations between elevated EC tau and neocortical PiB, hippocampal volume, or locus coeruleus integrity were evaluated and compared using logistic regression and receiver operating characteristic analyses in the PiB- sample with a clinical dementia rating (CDR) of 0. Associations with clinical progression (CDR-sum-of-boxes) over a time span of 6 years were evaluated with Cox proportional hazard models. RESULTS: We identified 26 (21%) individuals with high EC FTP in the CDR = 0/PiB- sample. Locus coeruleus integrity was a significantly more sensitive and specific predictor of elevated EC FTP (area under the curve [AUC] = 85%) compared with PiB (AUC = 77%) or hippocampal volume (AUC = 76%). Based on the Youden-index, locus coeruleus integrity obtained a sensitivity of 77% and 85% specificity. Using the resulting locus coeruleus Youden cut-off, lower locus coeruleus integrity was associated with a two-fold increase in clinical progression, including mild cognitive impairment. INTERPRETATION: Locus coeruleus integrity has promise as a low-cost, non-invasive screening instrument to detect early cortical tau deposition and associated clinical progression in asymptomatic, low beta-amyloid individuals. ANN NEUROL 2024.

Amyloid and tau burden relate to longitudinal changes in the performance of complex everyday activities among cognitively unimpaired older adults: results from the performance-based Harvard Automated Phone Task.

Background: Changes in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer's disease. Performance-based assessments of everyday functioning might help uncover these early changes. We aimed to investigate how changes over time in everyday functioning relate to tau and amyloid in cognitively unimpaired older adults. Methods: Seventy-six cognitively unimpaired participants (72 ± 6 years old, 61% female) completed multiple Harvard Automated Phone Task (APT) assessments over 2.0 ± 0.9 years. The Harvard APT consists of three tasks, performed through an automated phone system, in which participants refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and transfer money to pay a bill (APT-Bank). Participants underwent Pittsburgh compound-B and flortaucipir positron emission tomography scans at baseline. We computed distribution volume ratios for a cortical amyloid aggregate and standardized uptake volume ratios for medial temporal and neocortical tau regions. In separate linear mixed models, baseline amyloid by time and tau by time interactions were used to predict longitudinal changes in performance on the Harvard APT tasks. Three-way amyloid by tau by time interactions were also investigated. Lastly, we examined associations between tau and change in Harvard APT scores in exploratory voxel-wise whole-brain analyses. All models were adjusted for age, sex, and education. Results: Amyloid [unstandardized partial regression coefficient estimate (ß) = -0.007, 95% confidence interval (95% CI) = (-0.013, -0.001)], and medial temporal tau [ß = -0.013, 95% CI = (-0.022, -0.004)] were associated with change over time in years on APT-PCP only, i.e., higher baseline amyloid and higher baseline tau were associated with steeper rate of decline of APT-PCP. Voxel-wise analyses showed widespread associations between tau and change in APT-PCP scores over time. Conclusion: Even among cognitively unimpaired older adults, changes over time in the performance of cognitively complex everyday activities relate to cortical amyloid and widespread cerebral tau burden at baseline. These findings support the link between Alzheimer's disease pathology and function and highlight the importance of measuring everyday functioning in preclinical disease stages.

Associations of the Harvard Automated Phone Task and Alzheimer's Disease Pathology in Cognitively Normal Older Adults: Preliminary Findings.

BACKGROUND: Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer's disease (AD) is critical. OBJECTIVE: The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults. METHODS: Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid. RESULTS: Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone. CONCLUSION: Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.

Peak width of skeletonized mean diffusivity and cognitive performance in cerebral amyloid angiopathy.

Background: Cerebral Amyloid Angiopathy (CAA) is a cerebral small vessel disease that can lead to microstructural disruption of white matter (WM), which can be measured by the Peak Width of Skeletonized Mean Diffusivity (PSMD). We hypothesized that PSMD measures would be increased in patients with CAA compared to healthy controls (HC), and increased PSMD is associated with lower cognitive scores in patients with CAA. Methods: Eighty-one probable CAA patients without cognitive impairment who were diagnosed with Boston criteria and 23 HCs were included. All subjects underwent an advanced brain MRI with high-resolution diffusion-weighted imaging (DWI). PSMD scores were quantified from a probabilistic skeleton of the WM tracts in the mean diffusivity (MD) image using a combination of fractional anisotropy (FA) and the FSL Tract-Based Spatial Statistics (TBSS) algorithm (www.psmd-marker.com). Within CAA cohort, standardized z-scores of processing speed, executive functioning and memory were obtained. Results: The mean of age and sex were similar between CAA patients (69.6 ± 7.3, 59.3% male) and HCs (70.6 ± 8.5, 56.5% male) (p = 0.581 and p = 0.814). PSMD was higher in the CAA group [(4.13 ± 0.94) × 10-4 mm2/s] compared to HCs [(3.28 ± 0.51) × 10-4 mm2/s] (p < 0.001). In a linear regression model corrected for relevant variables, diagnosis of CAA was independently associated with increased PSMD compared to HCs (ß = 0.45, 95% CI 0.13-0.76, p = 0.006). Within CAA cohort, higher PSMD was associated with lower scores in processing speed (p < 0.001), executive functioning (p = 0.004), and memory (0.047). Finally, PSMD outperformed all other MRI markers of CAA by explaining most of the variance in models predicting lower scores in each cognitive domain. Discussion: Peak Width of Skeletonized Mean Diffusivity is increased in CAA, and it is associated with worse cognitive scores supporting the view that disruption of white matter has a significant role in cognitive impairment in CAA. As a robust marker, PSMD can be used in clinical trials or practice.

Kinetic evaluation and assessment of longitudinal changes in reference region and extracerebral [18F]MK-6240 PET uptake.

[18F]MK-6240 meningeal/extracerebral off-target binding may impact tau quantification. We examined the kinetics and longitudinal changes of extracerebral and reference regions. [18F]MK-6240 PET was performed in 24 cognitively-normal and eight cognitively-impaired subjects, with arterial samples in 13 subjects. Follow-up scans at 6.1 ± 0.5 (n = 25) and 13.3 ± 0.9 (n = 16) months were acquired. Extracerebral and reference region (cerebellar gray matter (CerGM)-based, cerebral white matter (WM), pons) uptake were evaluated using standardized uptake values (SUV90-110), spectral analysis, and distribution volume. Longitudinal changes in SUV90-110 were examined. The impact of reference region on target region outcomes, partial volume correction (PVC) and regional erosion were evaluated. Eroded WM and pons showed lower variability, lower extracerebral contamination, and lower longitudinal changes than CerGM-based regions. CerGM-based regions resulted larger cross-sectional effect sizes for group differentiation. Extracerebral signal was high in 50% of subjects and exhibited irreversible kinetics and nonsignificant longitudinal changes over one-year but was highly variable at subject-level. PVC resulted in higher variability in reference region uptake and longitudinal changes. Our results suggest that eroded CerGM may be preferred for cross-sectional, whilst eroded WM or pons may be preferred for longitudinal [18F]MK-6240 studies. For CerGM, erosion was necessary (preferred over PVC) to address the heterogenous nature of extracerebral signal.

Effect of vascular amyloid on white matter disease is mediated by vascular dysfunction in cerebral amyloid angiopathy.

We postulated that vascular dysfunction mediates the relationship between amyloid load and white matter hyperintensities (WMH) in cerebral amyloid angiopathy (CAA). Thirty-eight cognitively healthy patients with CAA (mean age 70 ± 7.1) were evaluated. WMH was quantified and expressed as percent of total intracranial volume (pWMH) using structural MRI. Mean global cortical Distribution Volume Ratio representing Pittsburgh Compound B (PiB) uptake (PiB-DVR) was calculated from PET scans. Time-to-peak [TTP] of blood oxygen level-dependent response to visual stimulation was used as an fMRI measure of vascular dysfunction. Higher PiB-DVR correlated with prolonged TTP (r = 0.373, p = 0.021) and higher pWMH (r = 0.337, p = 0.039). Prolonged TTP also correlated with higher pWMH (r = 0.485, p = 0.002). In a multivariate linear regression model, TTP remained independently associated with pWMH (p = 0.006) while PiB-DVR did not (p = 0.225). In a bootstrapping model, TTP had a significant indirect effect (ab = 0.97, 95% CI: 0.137-2.461), supporting that the association between PiB-DVR and pWMH is mediated by TTP response. There was no longer a direct effect independent of the hypothesized pathway. Our study suggests that the effect of vascular amyloid load on white matter disease is mediated by vascular dysfunction in CAA. Amyloid lowering strategies might prevent pathophysiological processes leading to vascular dysfunction, therefore limiting ischemic brain injury.

Comparing PET and MRI Biomarkers Predicting Cognitive Decline in Preclinical Alzheimer Disease.

OBJECTIVE: To compare how structural MRI, Fluorodeoxyglucose (FDG), and Flortaucipir (FTP) PET signal predict cognitive decline in high-amyloid versus low-amyloid participants with the goal of determining which biomarker combination would result in the highest increase of statistical power for prevention trials. METHODS: In this prospective cohort study, we analyzed data from clinically-normal adults from the Harvard Aging Brain Study with MRI, FDG, FTP, and PiB-PET acquired within a year, and prospective cognitive evaluations over a mean three-year follow-up. We focused analyses on pre-defined regions-of-interest: inferior temporal, isthmus cingulate, hippocampus, and entorhinal cortex. Cognition was assessed using the Preclinical Alzheimer's Cognitive Composite (PACC5). We evaluated the association between biomarkers and cognitive decline using linear-mixed-effect models with random intercepts and slopes, adjusting for demographics. We generated power curves simulating prevention trials. RESULTS: Data from 131 participants [52 females, 73.98±8.29 years old] were analyzed in the study. In separate models, most biomarkers had a closer association with cognitive decline in the high-PiB compared to the low-PiB participants. A backward stepwise regression including all biomarkers demonstrated that only neocortical PiB, entorhinal FTP, and entorhinal FDG were independent predictors of subsequent cognitive decline. Power analyses revealed that using both high-PiB and low entorhinal FDG as inclusion criteria reduced 3-fold the number of participants needed in a hypothetical trial compared to using only high-PiB. DISCUSSION: In preclinical Alzheimer's disease, entorhinal hypometabolism is a strong and independent predictor of subsequent cognitive decline, making FDG a potentially useful biomarker to increase power in clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in people with preclinical Alzheimer's disease, entorhinal hypometabolism identified by FDG-PET is predictive of subsequent cognitive decline.

The cortical origin and initial spread of medial temporal tauopathy in Alzheimer's disease assessed with positron emission tomography.

Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer's disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-ß (Aß) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before Aß in a specific area of the medial temporal lobe. Building on recent work that enabled focus of molecular PET measurements on specific TAU-vulnerable convolutional temporal lobe anatomy, we applied an automated anatomic sampling method to quantify TAU PET signal in 443 adult participants from several observational studies of aging and AD, spanning a wide range of ages, Aß burdens, and degrees of clinical impairment. We detected initial cortical emergence of tauopathy near the rhinal sulcus in clinically normal people and, in a subset with longitudinal 2-year follow-up data (n = 104), tracked Aß-associated spread of TAU from this site first to nearby neocortex of the temporal lobe and then to extratemporal regions. Greater rate of TAU spread was associated with baseline measures of both global Aß burden and medial temporal lobe TAU. These findings are consistent with clinicopathological correlation studies of Alzheimer's tauopathy and enable precise tracking of AD-related TAU progression for natural history studies and prevention therapeutic trials.

Longitudinal amyloid and tau accumulation in autosomal dominant Alzheimer's disease: findings from the Colombia-Boston (COLBOS) biomarker study.

BACKGROUND: Neuroimaging studies of autosomal dominant Alzheimer's disease (ADAD) enable characterization of the trajectories of cerebral amyloid-ß (Aß) and tau accumulation in the decades prior to clinical symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD. METHODS: Fourteen ADAD mutation carriers (Presenilin-1 E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2-3 sessions of Aß (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2-4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers. RESULTS: Longitudinal measurements were consistent with a sequence of ADAD-related changes beginning with Aß accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (~ 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers. CONCLUSIONS: Our results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between Aß burden and neocortical tau accumulation in ADAD.

Defining the Lowest Threshold for Amyloid-PET to Predict Future Cognitive Decline and Amyloid Accumulation.

INTRODUCTION: As clinical trials move toward earlier intervention, we sought to redefine the ß-amyloid (Aß)-PET threshold based on the lowest point in a baseline distribution that robustly predicts future Aß accumulation and cognitive decline in 3 independent samples of clinically normal individuals. METHODS: Sequential Aß cutoffs were tested to identify the lowest cutoff associated with future change in cognition (Preclinical Alzheimer Cognitive Composite [PACC]) and Aß-PET in clinically normal participants from the Harvard Aging Brain Study (n = 342), Australian Imaging, Biomarker and Lifestyle study of aging (n = 157), and Alzheimer's Disease Neuroimaging Initiative (n = 356). RESULTS: Within samples, cutoffs derived from future Aß-PET accumulation and PACC decline converged on the same inflection point, beyond which trajectories diverged from normal. Across samples, optimal cutoffs fell within a short range (Centiloid 15-18.5). DISCUSSION: These optimized thresholds can help to inform future research and clinical trials targeting early Aß. Threshold convergence raises the possibility of contemporaneous early changes in Aß and cognition. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among clinically normal individuals a specific Aß-PET threshold is predictive of cognitive decline.

Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study.

IMPORTANCE: Positron emission tomography (PET) imaging now allows in vivo visualization of both neuropathologic hallmarks of Alzheimer disease (AD): amyloid-ß (Aß) plaques and tau neurofibrillary tangles. Observing their progressive accumulation in the brains of clinically normal older adults is critically important to understand the pathophysiologic cascade leading to AD and to inform the choice of outcome measures in prevention trials. OBJECTIVE: To assess the associations among Aß, tau, and cognition, measured during different observation periods for 7 years. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study conducted between 2010 and 2017 at the Harvard Aging Brain Study, Boston, Massachusetts. The study enrolled 279 clinically normal participants. An additional 90 individuals were approached but declined the study or did not meet the inclusion criteria. In this report, we analyzed data from 60 participants who had multiple Aß and tau PET observations available on October 31, 2017. MAIN OUTCOMES AND MEASURES: A median of 3 Pittsburgh compound B-PET (Aß, 2010-2017) and 2 flortaucipir-PET (tau, 2013-2017) images were collected. We used initial PET and slope data, assessing the rates of change in Aß and tau, to measure cognitive changes. Cognition was evaluated annually using the Preclinical Alzheimer Cognitive Composite (2010-2017). Annual consensus meetings evaluated progression to mild cognitive impairment. RESULTS: Of the 60 participants, 35 were women (58%) and 25 were men (42%); median age at inclusion was 73 years (range, 65-85 years). Seventeen participants (28%) exhibited an initial high Aß burden. An antecedent rise in Aß was associated with subsequent changes in tau (1.07 flortaucipir standardized uptake value ratios [SUVr]/PiB-SUVr; 95% CI, 0.13-3.46; P = .02). Tau changes were associated with cognitive changes (-3.28 z scores/SUVR; 95% CI, -6.67 to -0.91; P = .001), covarying baseline Aß and tau. Tau changes were greater in the participants who progressed to mild cognitive impairment (n = 6) than in those who did not (n = 11; 0.05 SUVr per year; 95% CI, 0.03-0.07; P = .001). A serial mediation model demonstrated that the association between initial Aß and final cognition, measured 7 years later, was mediated by successive changes in Aß and tau. CONCLUSIONS AND RELEVANCE: We identified sequential changes in normal older adults, from Aß to tau to cognition, after which the participants with high Aß with greater tau increase met clinical criteria for mild cognitive impairment. These findings highlight the importance of repeated tau-PET observations to track disease progression and the importance of repeated amyloid-PET observations to detect the earliest AD pathologic changes.

Regional Tau Correlates of Instrumental Activities of Daily Living and Apathy in Mild Cognitive Impairment and Alzheimer's Disease Dementia.

BACKGROUND: Instrumental activities of daily living (IADL) impairment and apathy occur in early-stage Alzheimer's disease (AD) and are associated with regional atrophy and hypometabolism in vivo and greater tau burden at autopsy. OBJECTIVE: To explore the association between IADL impairment, apathy, and in vivo regional tau in mild cognitive impairment (MCI) and AD dementia. METHODS: Forty participants (24 MCI, 16 AD dementia) underwent assessments of IADL (Functional Activities Questionnaire, FAQ) and apathy (Apathy Evaluation Scale Informant report, AES-I). Regional tau was assessed using flortaucipir positron emission tomography (PET) and amyloid using Pittsburgh Compound B PET. Regions with unadjusted associations of p≤0.01 were entered into regression models assessing the relationship between tau and FAQ or AES-I, adjusting for age, sex, and cognition, with/without a tau by amyloid interaction. RESULTS: Unadjusted IADL impairment but not apathy was associated with greater tau in multiple regions. After adjusting for covariates, for medial orbitofrontal and entorhinal cortex the interaction between tau and amyloid was associated with IADL impairment and for anterior cingulate it was not but independent associations with both tau and amyloid were retained. With whole brain analyses, similar results were seen for IADL, while for apathy tau in small clusters within the right anterior cingulate and dorsolateral prefrontal cortices were seen, which were more pronounced in individuals with greater amyloid. CONCLUSIONS: This exploratory study suggests that IADL impairment in AD is associated with medial temporal and frontal tau, especially in individuals with elevated amyloid, while apathy may be associated with right frontal tau.

Depressive Symptoms and Tau Accumulation in the Inferior Temporal Lobe and Entorhinal Cortex in Cognitively Normal Older Adults: A Pilot Study.

BACKGROUND: Depressive symptoms are common in older adults and associated with increased morbidity and cognitive decline. These symptoms occur during preclinical and prodromal stages of Alzheimer's disease (AD), but their relationship to tau, one of the main AD proteinopathies, is poorly understood. OBJECTIVE: The objective of this study was to investigate the cross-sectional association between depressive symptoms and cerebral tau [18F T807 (also known as 18F-AV-1451) tau positron emission tomography (PET) imaging] in cognitively normal (CN) older adults. METHODS: We measured depressive symptoms using the Geriatric Depression Scale (GDS), and in vivo cerebral tau using T807 PET in 111 CN older adults. We employed general linear regression models to evaluate the relationship of GDS score regressed on entorhinal cortex (EC) or inferior temporal (IT) tau in separate backward elimination models. Other predictors included age, sex, and in secondary analyses, amyloid (Pittsburgh Compound B PET). RESULTS: Higher GDS was significantly associated with greater IT tau (partial r = 0.188, p = 0.050) and marginally associated with greater EC tau (partial r = 0.183, p = 0.055). In additional analyses including both linear and quadratic age terms, we found a significant U-shaped relation of GDS to age (p = 0.001). CONCLUSIONS: Results suggest that IT and EC tau are modestly associated with depressive symptoms in CN older adults. Findings suggest a link between depressive symptoms and tau-mediated neurodegeneration in a region vulnerable in AD. Future longitudinal studies examining the association of more severe depressive symptoms and cerebral tau accumulation are needed to substantiate this finding and to guide prevention and treatment in AD.

Regional 18F-Fluorodeoxyglucose Hypometabolism is Associated with Higher Apathy Scores Over Time in Early Alzheimer Disease.

OBJECTIVES: Apathy is among the earliest and most pervasive neuropsychiatric symptoms in prodromal and mild Alzheimer disease (AD) dementia that correlates with functional impairment and disease progression. We investigated the association of apathy with regional 18F-fluorodeoxyglucose (FDG) metabolism in cognitively normal, mild cognitive impairment, and AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative database. DESIGN: Cross-sectional and longitudinal studies. SETTING: 57 North American research sites. PARTICIPANTS: 402 community dwelling elders. MEASUREMENTS: Apathy was assessed using the Neuropsychiatric Inventory Questionnaire. Baseline FDG metabolism in five regions implicated in the neurobiology of apathy and AD was investigated in relationship to apathy at baseline (cross-sectional general linear model) and longitudinally (mixed random/fixed effect model). Covariates included age, sex, diagnosis, apolipoprotein E genotype, premorbid intelligence, cognition, and antidepressant use. RESULTS: Cross-sectional analysis revealed that posterior cingulate hypometabolism, diagnosis, male sex, and antidepressant use were associated with higher apathy scores. Longitudinal analysis revealed that the interaction of supramarginal hypometabolism and time, posterior cingulate hypometabolism, and antidepressant use were associated with higher apathy scores across time; only supramarginal hypometabolism was positively related to rate of increase of apathy. CONCLUSIONS: Results support an association of apathy with hypometabolism in parietal regions commonly affected in early stages of AD, rather than medial frontal regions implicated in the neurobiology of apathy in later stages. Further work is needed to substantiate whether this localization is specific to apathy rather than to disease stage, and to investigate the potential role of AD proteinopathies in the pathogenesis of apathy.

Florbetapir-PET to diagnose cerebral amyloid angiopathy: A prospective study.

OBJECTIVE: We hypothesized that florbetapir, a Food and Drug Administration-approved PET tracer, could distinguish cerebral amyloid angiopathy (CAA)-related intracerebral hemorrhage (ICH) from hypertensive ICH (HTN-ICH). METHODS: We prospectively enrolled survivors of primary ICH related to probable CAA (per Boston Criteria, n = 10) and HTN-ICH (n = 9) without dementia. All patients underwent florbetapir-PET and multimodal MRI, and patients with CAA had additional Pittsburgh compound B (PiB) PET. Amyloid burden was assessed quantitatively (standard uptake value ratio [SUVR]) and visually classified as positive or negative. RESULTS: The CAA and HTN-ICH groups had similar age (66.9 vs 67.1), sex, and leukoaraiosis volumes (31 vs 30 mL, all p > 0.8). Florbetapir uptake and PiB retention strongly correlated in patients with CAA both globally within cerebral cortex (r = 0.96, p < 0.001) and regionally in lobar cortices (all r > 0.8, all p ≤ 0.01). Mean global cortical florbetapir uptake was substantially higher in CAA than HTN-ICH (SUVR: 1.41 ± 0.17 vs 1.15 ± 0.08, p = 0.001), as was mean occipital SUVR (1.44 ± 0.12 vs 1.17 ± 0.08, p < 0.001), even after correcting for global SUVR (p = 0.03). Visual rating for positive/negative florbetapir demonstrated perfect interrater agreement (k = 1) and was positive for all 10 patients with CAA vs 1 of 9 HTN-ICH patients (sensitivity 100%, specificity 89%). CONCLUSIONS: Florbetapir appears to label vascular amyloid in patients with CAA-related ICH. The approved florbetapir binary visual reading method can have diagnostic value in appropriate clinical settings. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that florbetapir-PET provides a sensitivity of 100% (95% confidence interval [CI] 66%-100%) and specificity of 89% (95% CI 51%-99%) for determination of probable CAA among cognitively normal patients.

Maternal dementia age at onset in relation to amyloid burden in non-demented elderly offspring.

Family history (FH) of dementia is a major risk factor for Alzheimer's disease, particularly when the FH is maternal and when the age of dementia onset (AO) is younger. This study tested whether brain amyloid-beta deposition, measured in vivo with (11)C-Pittsburgh compound B (PiB), was associated with parental dementia and/or younger parental AO. Detailed FH and positron emission tomography (PiB) data were acquired in 147 nondemented aging individuals (mean age 75 ± 8). No participant had both positive maternal and paternal FH. A series of analyses revealed that those with maternal, but not paternal, FH had greater levels of PiB retention in a global cortical region than those without FH. PiB retention in maternal FH was not significantly greater than paternal FH. Younger maternal dementia AO was related to greater PiB retention in offspring, whereas younger paternal dementia AO was not. Overall, results suggest that not only is amyloid-beta burden greater in individuals with maternal FH, but also that the burden is greater in association with younger maternal AO.

Different partial volume correction methods lead to different conclusions: An (18)F-FDG-PET study of aging.

A cross-sectional group study of the effects of aging on brain metabolism as measured with (18)F-FDG-PET was performed using several different partial volume correction (PVC) methods: no correction (NoPVC), Meltzer (MZ), Müller-Gärtner (MG), and the symmetric geometric transfer matrix (SGTM) using 99 subjects aged 65-87years from the Harvard Aging Brain study. Sensitivity to parameter selection was tested for MZ and MG. The various methods and parameter settings resulted in an extremely wide range of conclusions as to the effects of age on metabolism, from almost no changes to virtually all of cortical regions showing a decrease with age. Simulations showed that NoPVC had significant bias that made the age effect on metabolism appear to be much larger and more significant than it is. MZ was found to be the same as NoPVC for liberal brain masks; for conservative brain masks, MZ showed few areas correlated with age. MG and SGTM were found to be similar; however, MG was sensitive to a thresholding parameter that can result in data loss. CSF uptake was surprisingly high at about 15% of that in gray matter. The exclusion of CSF from SGTM and MG models, which is almost universally done, caused a substantial loss in the power to detect age-related changes. This diversity of results reflects the literature on the metabolism of aging and suggests that extreme care should be taken when applying PVC or interpreting results that have been corrected for partial volume effects. Using the SGTM, significant age-related changes of about 7% per decade were found in frontal and cingulate cortices as well as primary visual and insular cortices.

Tau positron emission tomographic imaging in aging and early Alzheimer disease.

OBJECTIVE: Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer disease (AD), staging and monitoring of disease progression, and development of disease-modifying therapies. METHODS: We acquired tau positron emission tomography (PET) using (18)F T807 (AV1451), and amyloid-ß PET using (11)C Pittsburgh compound B (PiB) in older clinically normal individuals, and symptomatic patients with mild cognitive impairment or mild AD dementia. RESULTS: We found abnormally high cortical (18)F T807 binding in patients with mild cognitive impairment and AD dementia compared to clinically normal controls. Consistent with the neuropathology literature, the presence of elevated neocortical (18)F T807 binding particularly in the inferior temporal gyrus was associated with clinical impairment. The association of cognitive impairment was stronger with inferior temporal (18)F T807 than with mean cortical (11)C PIB. Regional (18)F T807 was correlated with mean cortical (11)C PiB among both impaired and control subjects. INTERPRETATION: These findings suggest that (18)F T807 PET could have value as a biomarker that reflects both the progression of AD tauopathy and the emergence of clinical impairment.

Cognitive activity relates to cognitive performance but not to Alzheimer disease biomarkers.

OBJECTIVE: We aimed to determine whether there was a relationship between lifestyle factors and Alzheimer disease biomarkers. METHODS: In a cross-sectional study, we evaluated self-reported histories of recent and past cognitive activity, self-reported history of recent physical activity, and objective recent walking activity in 186 clinically normal individuals with mean age of 74 ± 6 years. Using backward elimination general linear models, we tested the hypotheses that greater cognitive or physical activity would be associated with lower Pittsburgh compound B-PET retention, greater (18)F-fluorodeoxyglucose-PET metabolism, and larger hippocampal volume, as well as better cognitive performance on neuropsychological testing. RESULTS: Linear regression demonstrated that history of greater cognitive activity was correlated with greater estimated IQ and education, as well as better neuropsychological testing performance. Self-reported recent physical activity was related to objective exercise monitoring. However, contrary to hypotheses, we did not find evidence of an association of Pittsburgh compound B retention, (18)F-fluorodeoxyglucose uptake, or hippocampal volume with past or current levels of cognitive activity, or with current physical activity. CONCLUSIONS: We conclude that a history of lifelong cognitive activity may support better cognitive performance by a mechanism that is independent of brain ß-amyloid burden, brain glucose metabolism, or hippocampal volume.