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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.
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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.
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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.
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Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Carbolinas/metabolismo , Córtex Cerebral/metabolismo , Disfunção Cognitiva/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Biomarcadores/metabolismo , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lobo Temporal/metabolismo , TiazóisRESUMO
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.
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Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Apatia , Disfunção Cognitiva/metabolismo , Lobo Parietal/metabolismo , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Fluordesoxiglucose F18/metabolismo , Neuroimagem Funcional , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/metabolismoRESUMO
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.
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Envelhecimento , Mapeamento Encefálico/métodos , Encéfalo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Feminino , Fluordesoxiglucose F18 , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Tomografia por Emissão de Pósitrons , Reprodutibilidade dos Testes , Processamento de Sinais Assistido por ComputadorRESUMO
Normal aging is often difficult to distinguish from the earliest stages of Alzheimer's disease. Years before clinical memory deficits manifest, amyloid-ß deposits in the cortex in many older individuals. Neuroimaging studies indicate that a set of densely connected neocortical regions, referred to as the default network, is especially vulnerable to amyloid-ß deposition. Yet, the impact of amyloid-ß on age-related changes within the medial temporal lobe (MTL) memory system is less clear. Here we demonstrate that cognitively normal older humans, compared with young adults, show reduced ability to modulate hippocampal activations and entorhinal deactivations during an episodic memory task. Among older adults, amyloid-ß deposition was associated with failure to modulate activity in entorhinal cortex, but not hippocampus. Furthermore, we show that entorhinal regions demonstrating amyloid-ß-related dysfunction are directly connected to the neocortical regions of the default network. Together these findings link neocortical amyloid-ß deposition to neuronal dysfunction specifically in entorhinal cortex, while aging is associated with more widespread functional changes across the MTL.
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Peptídeos beta-Amiloides/metabolismo , Cognição , Córtex Entorrinal/fisiologia , Adulto , Fatores Etários , Idoso , Mapeamento Encefálico , Estudos de Casos e Controles , Córtex Entorrinal/diagnóstico por imagem , Córtex Entorrinal/metabolismo , Feminino , Hipocampo/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Memória , Tomografia por Emissão de PósitronsRESUMO
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.
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Amyloid burden and white matter hyperintensities (WMH) are two common markers of neurodegeneration present in advanced aging. Each represents a potential early indicator of an age-related neurological disorder that impacts cognition. The presence of amyloid is observed in a substantial subset of cognitively normal older adults, but the literature remains equivocal regarding whether amyloid in nondemented populations is deleterious to cognition. Similarly, WMH are detected in many nondemented older adults and there is a body of evidence indicating that WMH are associated with decreased executive function and other cognitive domains. The current study investigated amyloid burden and WMH in clinically normal older adult humans aged 65-86 (N = 168) and examined each biomarker's relation with cognitive domains of episodic memory, executive function, and speed of processing. Factors for each domain were derived from a neuropsychological battery on a theoretical basis without reference to the relation between cognition and the biomarkers. Amyloid burden and WMH were not correlated with one another. Age was associated with lower performance in all cognitive domains, while higher estimated verbal intelligence was associated with higher performance in all domains. Hypothesis-driven tests revealed that amyloid burden and WMH had distinct cognitive profiles, with amyloid burden having a specific influence on episodic memory and WMH primarily associated with executive function but having broad (but lesser) effects on the other domains. These findings suggest that even before clinical impairment, amyloid burden and WMH likely represent neuropathological cascades with distinct etiologies and dissociable influences on cognition.
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Amiloide/metabolismo , Amiloidose/metabolismo , Encéfalo/patologia , Cognição/fisiologia , Idoso , Idoso de 80 Anos ou mais , Amiloidose/diagnóstico por imagem , Anatomia Transversal , Análise Fatorial , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Desempenho Psicomotor/fisiologiaRESUMO
Apathy is the most common neuropsychiatric symptom in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia. The authors sought to determine whether apathy is associated with cortical amyloid burden, as measured by Pittsburgh Compound B (PiB) positron emission tomography (PET), and regional hypometabolism, measured by 18F-fluorodeoxyglocuse (FDG) PET in MCI. The authors found a significant association between increased apathy (lower Apathy Evaluation Scale score) and greater cortical PiB retention independent of age, but no significant association between apathy and regional FDG metabolism. These results suggest that increased apathy is associated with greater amyloid burden but not regional hypometabolism in MCI.
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Amiloide/metabolismo , Apatia , Córtex Cerebral/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina , Córtex Cerebral/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Fluordesoxiglucose F18 , Neuroimagem Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , TiazóisRESUMO
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.
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[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.
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Disfunção Cognitiva , Humanos , Estudos Transversais , Cinética , Tomografia por Emissão de Pósitrons/métodos , Estudos de Casos e ControlesRESUMO
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.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Proteínas tau/metabolismo , Atividades Cotidianas , Disfunção Cognitiva/patologia , Córtex Entorrinal/patologia , Amiloide/metabolismo , Proteínas Amiloidogênicas , Tomografia por Emissão de Pósitrons , Peptídeos beta-Amiloides/metabolismoRESUMO
OBJECTIVE: Both amyloid-ß (Aß) deposition and brain atrophy are associated with Alzheimer's disease (AD) and the disease process likely begins many years before symptoms appear. We sought to determine whether clinically normal (CN) older individuals with Aß deposition revealed by positron emission tomography (PET) imaging using Pittsburgh Compound B (PiB) also have evidence of both cortical thickness and hippocampal volume reductions in a pattern similar to that seen in AD. METHODS: A total of 119 older individuals (87 CN subjects and 32 patients with mild AD) underwent PiB PET and high-resolution structural magnetic resonance imaging (MRI). Regression models were used to relate PiB retention to cortical thickness and hippocampal volume. RESULTS: We found that PiB retention in CN subjects was (1) age-related and (2) associated with cortical thickness reductions, particularly in parietal and posterior cingulate regions extending into the precuneus, in a pattern similar to that observed in mild AD. Hippocampal volume reduction was variably related to Aß deposition. INTERPRETATION: We conclude that Aß deposition is associated with a pattern of cortical thickness reduction consistent with AD prior to the development of cognitive impairment.
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Envelhecimento/patologia , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral/metabolismo , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Análise de Variância , Compostos de Anilina , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Feminino , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Estatística como Assunto , TiazóisRESUMO
Disruption of functional connectivity between brain regions may represent an early functional consequence of ß-amyloid pathology prior to clinical Alzheimer's disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.
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Doença de Alzheimer/complicações , Amiloide/metabolismo , Mapeamento Encefálico , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Transtornos Cognitivos/etiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Compostos de Anilina , Benzotiazóis , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/diagnóstico por imagem , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/patologia , Feminino , Fluordesoxiglucose F18 , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Tomografia por Emissão de Pósitrons/métodos , Estatística como Assunto , TiazóisRESUMO
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.
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Amiloidose , Angiopatia Amiloide Cerebral , Leucoaraiose , Leucoencefalopatias , Substância Branca , Idoso , Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Compostos de Anilina , Angiopatia Amiloide Cerebral/complicações , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismoRESUMO
BACKGROUND/AIMS: Instrumental activities of daily living (IADL) impairment in Alzheimer's disease has been associated with global amyloid deposition in postmortem studies. We sought to determine whether IADL impairment is associated with increased cortical Pittsburgh Compound B (PiB) retention. METHODS: Fifty-five subjects (19 normal older controls, NC, and 36 with mild cognitive impairment, MCI) underwent clinical assessments and dynamic PiB positron emission tomography imaging. RESULTS: A linear multiple regression model showed that greater IADL impairment was associated with greater global PiB retention in all subjects (R(2) = 0.40; unstandardized partial regression coefficient, ß = 5.8; p = 0.0002) and in MCI subjects only (R(2) = 0.28; ß = 6.1; p = 0.003), but not in NC subjects only. CONCLUSION: These results suggest that daily functional impairment is related to greater amyloid burden in MCI.
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Atividades Cotidianas/psicologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Amiloide/metabolismo , Idoso , Idoso de 80 Anos ou mais , Amiloidose/diagnóstico por imagem , Amiloidose/metabolismo , Compostos de Anilina/metabolismo , Carga Corporal (Radioterapia) , Interpretação Estatística de Dados , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Análise de Regressão , Inquéritos e Questionários , Lobo Temporal/fisiologia , Tiazóis/metabolismoRESUMO
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.
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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.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/metabolismo , Tomografia por Emissão de Pósitrons/tendências , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/psicologia , Feminino , Seguimentos , Previsões , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Placa Amiloide/psicologia , Estudos ProspectivosRESUMO
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.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Biomarcadores , Boston , Colômbia , Estudos Transversais , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Proteínas tau/genéticaRESUMO
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.