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1.
Nature ; 581(7806): 71-76, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32376954

RESUMO

Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-ß or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRß7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-ß and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.


Assuntos
Apolipoproteína E4/genética , Barreira Hematoencefálica/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Capilares/patologia , Ciclofilina A/líquido cefalorraquidiano , Ciclofilina A/metabolismo , Feminino , Heterozigoto , Hipocampo/irrigação sanguínea , Humanos , Masculino , Metaloproteinase 9 da Matriz/líquido cefalorraquidiano , Metaloproteinase 9 da Matriz/metabolismo , Giro Para-Hipocampal/irrigação sanguínea , Pericitos/patologia , Tomografia por Emissão de Pósitrons , Receptor beta de Fator de Crescimento Derivado de Plaquetas/líquido cefalorraquidiano , Lobo Temporal/irrigação sanguínea , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/metabolismo
2.
Proc Natl Acad Sci U S A ; 120(7): e2212256120, 2023 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-36745794

RESUMO

The distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta (Aß) deposition in individuals with symptomatic and preclinical Alzheimer disease (AD). Brain AG decreases with age, but the functional significance of this decrease with regard to the development of AD symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption, and glucose utilization-from which we derive AG-we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher than that seen in cognitively unimpaired, amyloid negative adults. Similar findings were not seen for blood flow nor oxygen consumption. Finally, in cognitively unimpaired adults, white matter hyperintensity burden was found to be specifically associated with decreased youthful brain AG. Our results suggest that AG may have a role in the resilience and/or response to early stages of amyloid pathology and that age-related white matter disease may impair this process.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Adulto Jovem , Humanos , Doença de Alzheimer/patologia , Tomografia por Emissão de Pósitrons , Encéfalo/metabolismo , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/patologia , Amiloide/metabolismo , Proteínas Amiloidogênicas , Glicólise
3.
Ann Neurol ; 95(5): 951-965, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38400792

RESUMO

OBJECTIVE: A clock relating amyloid positron emission tomography (PET) to time was used to estimate the timing of biomarker changes in sporadic Alzheimer disease (AD). METHODS: Research participants were included who underwent cerebrospinal fluid (CSF) collection within 2 years of amyloid PET. The ages at amyloid onset and AD symptom onset were estimated for each individual. The timing of change for plasma, CSF, imaging, and cognitive measures was calculated by comparing restricted cubic splines of cross-sectional data from the amyloid PET positive and negative groups. RESULTS: The amyloid PET positive sub-cohort (n = 118) had an average age of 70.4 ± 7.4 years (mean ± standard deviation) and 16% were cognitively impaired. The amyloid PET negative sub-cohort (n = 277) included individuals with low levels of amyloid plaque burden at all scans who were cognitively unimpaired at the time of the scans. Biomarker changes were detected 15-19 years before estimated symptom onset for CSF Aß42/Aß40, plasma Aß42/Aß40, CSF pT217/T217, and amyloid PET; 12-14 years before estimated symptom onset for plasma pT217/T217, CSF neurogranin, CSF SNAP-25, CSF sTREM2, plasma GFAP, and plasma NfL; and 7-9 years before estimated symptom onset for CSF pT205/T205, CSF YKL-40, hippocampal volumes, and cognitive measures. INTERPRETATION: The use of an amyloid clock enabled visualization and analysis of biomarker changes as a function of estimated years from symptom onset in sporadic AD. This study demonstrates that estimated years from symptom onset based on an amyloid clock can be used as a continuous staging measure for sporadic AD and aligns with findings in autosomal dominant AD. ANN NEUROL 2024;95:951-965.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Tomografia por Emissão de Pósitrons , Humanos , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/diagnóstico , Feminino , Masculino , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Idoso de 80 Anos ou mais , Estudos Transversais , Fatores de Tempo , Idade de Início , Estudos de Coortes , Progressão da Doença , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/sangue , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/sangue , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/patologia
4.
Ann Neurol ; 96(3): 453-459, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38963256

RESUMO

The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid-ß plasma biomarker positivity was approximately half the rate in 300 non-MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid-ß pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024;96:453-459.


Assuntos
Peptídeos beta-Amiloides , Esclerose Múltipla , Humanos , Feminino , Masculino , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/sangue , Esclerose Múltipla/patologia , Esclerose Múltipla/sangue , Pessoa de Meia-Idade , Adulto , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/sangue , Biomarcadores/sangue , Idoso
5.
Neuroimage ; 285: 120494, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38086495

RESUMO

White matter hyperintensities (WMH) are nearly ubiquitous in the aging brain, and their topography and overall burden are associated with cognitive decline. Given their numerosity, accurate methods to automatically segment WMH are needed. Recent developments, including the availability of challenge data sets and improved deep learning algorithms, have led to a new promising deep-learning based automated segmentation model called TrUE-Net, which has yet to undergo rigorous independent validation. Here, we compare TrUE-Net to six established automated WMH segmentation tools, including a semi-manual method. We evaluated the techniques at both global and regional level to compare their ability to detect the established relationship between WMH burden and age. We found that TrUE-Net was highly reliable at identifying WMH regions with low false positive rates, when compared to semi-manual segmentation as the reference standard. TrUE-Net performed similarly or favorably when compared to the other automated techniques. Moreover, TrUE-Net was able to detect relationships between WMH and age to a similar degree as the reference standard semi-manual segmentation at both the global and regional level. These results support the use of TrUE-Net for identifying WMH at the global or regional level, including in large, combined datasets.


Assuntos
Leucoaraiose , Substância Branca , Humanos , Substância Branca/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Algoritmos , Envelhecimento
6.
Radiology ; 311(3): e231442, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38860897

RESUMO

Background Visual assessment of amyloid PET scans relies on the availability of radiologist expertise, whereas quantification of amyloid burden typically involves MRI for processing and analysis, which can be computationally expensive. Purpose To develop a deep learning model to classify minimally processed brain PET scans as amyloid positive or negative, evaluate its performance on independent data sets and different tracers, and compare it with human visual reads. Materials and Methods This retrospective study used 8476 PET scans (6722 patients) obtained from late 2004 to early 2023 that were analyzed across five different data sets. A deep learning model, AmyloidPETNet, was trained on 1538 scans from 766 patients, validated on 205 scans from 95 patients, and internally tested on 184 scans from 95 patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) fluorine 18 (18F) florbetapir (FBP) data set. It was tested on ADNI scans using different tracers and scans from independent data sets. Scan amyloid positivity was based on mean cortical standardized uptake value ratio cutoffs. To compare with model performance, each scan from both the Centiloid Project and a subset of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study were visually interpreted with a confidence level (low, intermediate, high) of amyloid positivity/negativity. The area under the receiver operating characteristic curve (AUC) and other performance metrics were calculated, and Cohen κ was used to measure physician-model agreement. Results The model achieved an AUC of 0.97 (95% CI: 0.95, 0.99) on test ADNI 18F-FBP scans, which generalized well to 18F-FBP scans from the Open Access Series of Imaging Studies (AUC, 0.95; 95% CI: 0.93, 0.97) and the A4 study (AUC, 0.98; 95% CI: 0.98, 0.98). Model performance was high when applied to data sets with different tracers (AUC ≥ 0.97). Other performance metrics provided converging evidence. Physician-model agreement ranged from fair (Cohen κ = 0.39; 95% CI: 0.16, 0.60) on a sample of mostly equivocal cases from the A4 study to almost perfect (Cohen κ = 0.93; 95% CI: 0.86, 1.0) on the Centiloid Project. Conclusion The developed model was capable of automatically and accurately classifying brain PET scans as amyloid positive or negative without relying on experienced readers or requiring structural MRI. Clinical trial registration no. NCT00106899 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Bryan and Forghani in this issue.


Assuntos
Doença de Alzheimer , Encéfalo , Aprendizado Profundo , Tomografia por Emissão de Pósitrons , Humanos , Tomografia por Emissão de Pósitrons/métodos , Estudos Retrospectivos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/classificação , Masculino , Feminino , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Amiloide/metabolismo , Idoso de 80 Anos ou mais
7.
Ann Neurol ; 93(6): 1158-1172, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36843330

RESUMO

OBJECTIVE: Identifying cerebrospinal fluid measures of the microtubule binding region of tau (MTBR-tau) species that reflect tau aggregation could provide fluid biomarkers that track Alzheimer's disease related neurofibrillary tau pathological changes. We examined the cerebrospinal fluid (CSF) MTBR-tau species in dominantly inherited Alzheimer's disease (DIAD) mutation carriers to assess the association with Alzheimer's disease (AD) biomarkers and clinical symptoms. METHODS: Cross-sectional and longitudinal CSF from 229 DIAD mutation carriers and 130 mutation non-carriers had sequential characterization of N-terminal/mid-domain phosphorylated tau (p-tau) followed by MTBR-tau species and tau positron emission tomography (tau PET), other soluble tau and amyloid biomarkers, comprehensive clinical and cognitive assessments, and brain magnetic resonance imaging of atrophy. RESULTS: CSF MTBR-tau species located within the putative "border" region and one species corresponding to the "core" region of aggregates in neurofibrillary tangles (NFTs) increased during the presymptomatic stage and decreased during the symptomatic stage. The "border" MTBR-tau species were associated with amyloid pathology and CSF p-tau; whereas the "core" MTBR-tau species were associated stronger with tau PET and CSF measures of neurodegeneration. The ratio of the border to the core species provided a continuous measure of increasing amounts that tracked clinical progression and NFTs. INTERPRETATION: Changes in CSF soluble MTBR-tau species preceded the onset of dementia, tau tangle increase, and atrophy in DIAD. The ratio of 4R-specific MTBR-tau (border) to the NFT (core) MTBR-tau species corresponds to the pathology of NFTs in DIAD and change with disease progression. The dynamics between different MTBR-tau species in the CSF may serve as a marker of tau-related disease progression and target engagement of anti-tau therapeutics. ANN NEUROL 2023;93:1158-1172.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Estudos Transversais , Proteínas tau/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Disfunção Cognitiva/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Atrofia/patologia , Biomarcadores/líquido cefalorraquidiano , Progressão da Doença , Microtúbulos/metabolismo , Microtúbulos/patologia
8.
J Int Neuropsychol Soc ; 30(5): 428-438, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38282413

RESUMO

OBJECTIVE: Maintaining attention underlies many aspects of cognition and becomes compromised early in neurodegenerative diseases like Alzheimer's disease (AD). The consistency of maintaining attention can be measured with reaction time (RT) variability. Previous work has focused on measuring such fluctuations during in-clinic testing, but recent developments in remote, smartphone-based cognitive assessments can allow one to test if these fluctuations in attention are evident in naturalistic settings and if they are sensitive to traditional clinical and cognitive markers of AD. METHOD: Three hundred and seventy older adults (aged 75.8 +/- 5.8 years) completed a week of remote daily testing on the Ambulatory Research in Cognition (ARC) smartphone platform and also completed clinical, genetic, and conventional in-clinic cognitive assessments. RT variability was assessed in a brief (20-40 seconds) processing speed task using two different measures of variability, the Coefficient of Variation (CoV) and the Root Mean Squared Successive Difference (RMSSD) of RTs on correct trials. RESULTS: Symptomatic participants showed greater variability compared to cognitively normal participants. When restricted to cognitively normal participants, APOE ε4 carriers exhibited greater variability than noncarriers. Both CoV and RMSSD showed significant, and similar, correlations with several in-clinic cognitive composites. Finally, both RT variability measures significantly mediated the relationship between APOE ε4 status and several in-clinic cognition composites. CONCLUSIONS: Attentional fluctuations over 20-40 seconds assessed in daily life, are sensitive to clinical status and genetic risk for AD. RT variability appears to be an important predictor of cognitive deficits during the preclinical disease stage.


Assuntos
Doença de Alzheimer , Tempo de Reação , Humanos , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/genética , Idoso , Masculino , Feminino , Tempo de Reação/fisiologia , Idoso de 80 Anos ou mais , Testes Neuropsicológicos , Apolipoproteína E4/genética , Smartphone , Atenção/fisiologia
9.
Alzheimer Dis Assoc Disord ; 38(3): 241-248, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39177169

RESUMO

INTRODUCTION: Alzheimer disease (AD) has a long preclinical phase in which AD pathology is accumulating without detectable clinical symptoms. It is critical to identify participants in this preclinical phase as early as possible since treatment plans may be more effective in this stage. Monitoring for changes in driving behavior, as measured with GPS sensors, has been explored as a low-burden, easy-to-administer method for detecting AD risk. However, driving is a complex, multifaceted process that is likely influenced by other factors, including personality traits, that may change in preclinical AD. METHODS: We examine the moderating influence of neuroticism and conscientiousness on longitudinal changes in driving behavior in a sample of 203 clinically normal older adults who are at varying risk of developing AD. RESULTS: Neuroticism moderated rates of change in the frequency of speeding as well as the number of trips taken at night. Conscientiousness moderated rates of change in typical driving space. CONCLUSIONS: Personality traits change in early AD and also influence driving behaviors. Studies that seek to utilize naturalistic driving behavior to establish AD risk need to accommodate interpersonal differences, of which personality traits are one of many possible factors. Future studies should explicitly establish how much benefit is provided by including personality traits in predictive models of AD progression.


Assuntos
Doença de Alzheimer , Condução de Veículo , Personalidade , Humanos , Doença de Alzheimer/psicologia , Condução de Veículo/psicologia , Masculino , Feminino , Idoso , Personalidade/fisiologia , Estudos Longitudinais , Neuroticismo , Idoso de 80 Anos ou mais
10.
Org Biomol Chem ; 22(26): 5428-5453, 2024 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-38884683

RESUMO

Here we report our design and synthesis of 28 new fluorine-containing compounds as potential F-18 radiotracers for CNS imaging of sphingosine-1-phosphate receptor 1 (S1PR1), and determination of their in vitro binding potency and selectivity toward S1PR1 over other S1PR subtypes. Nine potent and selective compounds, 7c&d, 9a&c, 12b, 15b, and 18a-c with IC50 values ranging from 0.6-12.3 nM for S1PR1 and weak binding toward S1PR2, 3, 4, and 5, were further 18F-radiolabeled to produce [18F]7c&d, [18F]9a&c, [18F]12b, [18F]15b, and [18F]18a-c. Multi-step F-18 radiochemistry procedures were investigated for radiosynthesis of [18F]7c&d and [18F]9a&c, and the presumed intermediates were synthesized and authenticated by analytic HPLC. We then performed nonhuman primate (NHP) PET brain imaging studies for eight radiotracers: [18F]7c&d, [18F]9a, [18F]12b, [18F]15b, and [18F]18a-c. Three radiotracers, [18F]7c, [18F]7d, and [18F]15b, had high NHP brain uptake with standardized uptake values (SUVs) at 2 h post-injection of 2.42, 2.84, and 2.00, respectively, and good brain retention. Our ex vivo biodistribution study in rats confirmed [18F]7d had a high brain uptake with no in vivo defluorination. Radiometabolic analysis of [18F]7c and [18F]7d in rat plasma and brain samples found that [18F]7c has a more favorable metabolic profile than [18F]7d. However, the trend of increased brain uptake precludes [18F]7c as a suitable PET radiotracer for imaging S1PR1 in the brain. Further structural optmization is warranted to identify a highly S1PR1-specific radiotracer with rapid brain uptake kinetics.


Assuntos
Desenho de Fármacos , Radioisótopos de Flúor , Receptores de Esfingosina-1-Fosfato , Animais , Radioisótopos de Flúor/química , Receptores de Esfingosina-1-Fosfato/metabolismo , Ratos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Humanos , Distribuição Tecidual , Masculino , Macaca mulatta
11.
Brain ; 146(7): 2944-2956, 2023 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-36542469

RESUMO

Heterogeneity in progression to Alzheimer's disease (AD) poses challenges for both clinical prognosis and clinical trial implementation. Multiple AD-related subtypes have previously been identified, suggesting differences in receptivity to drug interventions. We identified early differences in preclinical AD biomarkers, assessed patterns for developing preclinical AD across the amyloid-tau-(neurodegeneration) [AT(N)] framework, and considered potential sources of difference by analysing the CSF proteome. Participants (n = 10) enrolled in longitudinal studies at the Knight Alzheimer Disease Research Center completed four or more lumbar punctures. These individuals were cognitively normal at baseline. Cerebrospinal fluid measures of amyloid-ß (Aß)42, phosphorylated tau (pTau181), and neurofilament light chain (NfL) as well as proteomics values were evaluated. Imaging biomarkers, including PET amyloid and tau, and structural MRI, were repeatedly obtained when available. Individuals were staged according to the amyloid-tau-(neurodegeneration) framework. Growth mixture modelling, an unsupervised clustering technique, identified three patterns of biomarker progression as measured by CSF pTau181 and Aß42. Two groups (AD Biomarker Positive and Intermediate AD Biomarker) showed distinct progression from normal biomarker status to having biomarkers consistent with preclinical AD. A third group (AD Biomarker Negative) did not develop abnormal AD biomarkers over time. Participants grouped by CSF trajectories were re-classified using only proteomic profiles (AUCAD Biomarker Positive versus AD Biomarker Negative = 0.857, AUCAD Biomarker Positive versus Intermediate AD Biomarkers = 0.525, AUCIntermediate AD Biomarkers versus AD Biomarker Negative = 0.952). We highlight heterogeneity in the development of AD biomarkers in cognitively normal individuals. We identified some individuals who became amyloid positive before the age of 50 years. A second group, Intermediate AD Biomarkers, developed elevated CSF ptau181 significantly before becoming amyloid positive. A third group were AD Biomarker Negative over repeated testing. Our results could influence the selection of participants for specific treatments (e.g. amyloid-reducing versus other agents) in clinical trials. CSF proteome analysis highlighted additional non-AT(N) biomarkers for potential therapies, including blood-brain barrier-, vascular-, immune-, and neuroinflammatory-related targets.


Assuntos
Doença de Alzheimer , Humanos , Pessoa de Meia-Idade , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Proteoma , Proteômica , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Progressão da Doença
12.
Brain ; 146(7): 2928-2943, 2023 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-36625756

RESUMO

Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer's disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer's disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer's disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer's disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer's disease.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Conectoma , Humanos , Estudos Transversais , Filamentos Intermediários , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Cognição , Rede Nervosa/diagnóstico por imagem
13.
Alzheimers Dement ; 20(3): 2080-2088, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38224146

RESUMO

INTRODUCTION: Reversion, or change in cognitive status from impaired to normal, is common in aging and dementia studies, but it remains unclear what factors predict reversion. METHODS: We investigated whether reverters, defined as those who revert from a Clinical Dementia Rating® (CDR®) scale score of 0.5 to CDR 0) differed on cognition and biomarkers from unimpaired participants (always CDR 0) and impaired participants (converted to CDR > 0 and had no reversion events). Models evaluated relationships between biomarker status, apolipoprotein E (APOE) ε4 status, and cognition. Additional models described predictors of reversion and predictors of eventual progression to CDR > 0. RESULTS: CDR reversion was associated with younger age, better cognition, and negative amyloid biomarker status. Reverters that eventually progressed to CDR > 0 had more visits, were older, and were more likely to have an APOE ε4 allele. DISCUSSION: CDR reversion occupies a transitional phase in disease progression between cognitive normality and overt dementia. Reverters may be ideal candidates for secondary prevention Alzheimer's disease (AD) trials. HIGHLIGHTS: Reverters had more longitudinal cognitive decline than those who remained cognitively normal. Predictors of reversion: younger age, better cognition, and negative amyloid biomarker status. Reverting from CDR 0.5 to 0 is a risk factor for future conversion to CDR > 0. CDR reversion may be a transitional phase in Alzheimer's Disease progression. CDR reverters may be ideal for Alzheimer's disease secondary prevention trials.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/genética , Disfunção Cognitiva/psicologia , Cognição , Testes de Estado Mental e Demência , Biomarcadores , Progressão da Doença
14.
Alzheimers Dement ; 20(1): 421-436, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37667412

RESUMO

INTRODUCTION: Biomarkers remain mostly unavailable for non-Alzheimer's disease neuropathological changes (non-ADNC) such as transactive response DNA-binding protein 43 (TDP-43) proteinopathy, Lewy body disease (LBD), and cerebral amyloid angiopathy (CAA). METHODS: A multilabel non-ADNC classifier using magnetic resonance imaging (MRI) signatures was developed for TDP-43, LBD, and CAA in an autopsy-confirmed cohort (N = 214). RESULTS: A model using demographic, genetic, clinical, MRI, and ADNC variables (amyloid positive [Aß+] and tau+) in autopsy-confirmed participants showed accuracies of 84% for TDP-43, 81% for LBD, and 81% to 93% for CAA, outperforming reference models without MRI and ADNC biomarkers. In an ADNI cohort (296 cognitively unimpaired, 401 mild cognitive impairment, 188 dementia), Aß and tau explained 33% to 43% of variance in cognitive decline; imputed non-ADNC explained an additional 16% to 26%. Accounting for non-ADNC decreased the required sample size to detect a 30% effect on cognitive decline by up to 28%. DISCUSSION: Our results lead to a better understanding of the factors that influence cognitive decline and may lead to improvements in AD clinical trial design.


Assuntos
Doença de Alzheimer , Angiopatia Amiloide Cerebral , Doença por Corpos de Lewy , Humanos , Doença de Alzheimer/patologia , Medicina de Precisão , Doença por Corpos de Lewy/patologia , Proteínas de Ligação a DNA/metabolismo , Biomarcadores
15.
Alzheimers Dement ; 20(9): 6365-6373, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39041391

RESUMO

INTRODUCTION: Cerebrospinal fluid (CSF) tau phosphorylation at multiple sites is associated with cortical amyloid and other pathologic changes in Alzheimer's disease. These relationships can be non-linear. We used an artificial neural network to assess the ability of 10 different CSF tau phosphorylation sites to predict continuous amyloid positron emission tomography (PET) values. METHODS: CSF tau phosphorylation occupancies at 10 sites (including pT181/T181, pT217/T217, pT231/T231 and pT205/T205) were measured by mass spectrometry in 346 individuals (57 cognitively impaired, 289 cognitively unimpaired). We generated synthetic amyloid PET scans using biomarkers and evaluated their performance. RESULTS: Concentration of CSF pT217/T217 had low predictive error (average error: 13%), but also a low predictive range (ceiling 63 Centiloids). CSF pT231/T231 has slightly higher error (average error: 19%) but predicted through a greater range (87 Centiloids). DISCUSSION: Tradeoffs exist in biomarker selection. Some phosphorylation sites offer greater concordance with amyloid PET at lower levels, while others perform better over a greater range. HIGHLIGHTS: Novel pTau isoforms can predict cortical amyloid burden. pT217/T217 accurately predicts cortical amyloid burden in low-amyloid individuals. Traditional CSF biomarkers correspond with higher levels of amyloid.


Assuntos
Doença de Alzheimer , Biomarcadores , Tomografia por Emissão de Pósitrons , Proteínas tau , Humanos , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/metabolismo , Fosforilação , Feminino , Masculino , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Idoso , Biomarcadores/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Pessoa de Meia-Idade , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Redes Neurais de Computação
16.
Alzheimers Dement ; 20(6): 4002-4019, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38683905

RESUMO

INTRODUCTION: Previous approaches pursuing in vivo staging of tau pathology in Alzheimer's disease (AD) have typically relied on neuropathologically defined criteria. In using predefined systems, these studies may miss spatial deposition patterns which are informative of disease progression. METHODS: We selected discovery (n = 418) and replication (n = 132) cohorts with flortaucipir imaging. Non-negative matrix factorization (NMF) was applied to learn tau covariance patterns and develop a tau staging system. Flortaucipir components were also validated by comparison with amyloid burden, gray matter loss, and the expression of AD-related genes. RESULTS: We found eight flortaucipir covariance patterns which were reproducible and overlapped with relevant gene expression maps. Tau stages were associated with AD severity as indexed by dementia status and neuropsychological performance. Comparisons of flortaucipir uptake with amyloid and atrophy also supported our model of tau progression. DISCUSSION: Data-driven decomposition of flortaucipir uptake provides a novel framework for tau staging which complements existing systems. HIGHLIGHTS: NMF reveals patterns of tau deposition in AD. Data-driven staging of flortaucipir tracks AD severity. Learned flortaucipir patterns overlap with AD-related gene expression.


Assuntos
Doença de Alzheimer , Carbolinas , Proteínas tau , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Humanos , Carbolinas/farmacocinética , Feminino , Masculino , Idoso , Proteínas tau/metabolismo , Tomografia por Emissão de Pósitrons , Progressão da Doença , Encéfalo/patologia , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Idoso de 80 Anos ou mais
17.
Alzheimers Dement ; 20(9): 6205-6220, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38970402

RESUMO

INTRODUCTION: We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics. METHODS: Individuals without dementia were classified as A+ (CSF amyloid beta [Aß]42), T+ (CSF phosphorylated tau181), and N+ or N- based on Ng, NfL, or HCV separately. CSF proteomics were generated and compared between groups using analysis of covariance. RESULTS: Only a few individuals were A+T+Ng-. A+T+Ng+ and A+T+NfL+ showed different proteomic profiles compared to A+T+Ng- and A+T+NfL-, respectively. Both Ng+ and NfL+ were associated with neuroplasticity, though in opposite directions. Compared to A+T+HCV-, A+T+HCV+ showed few proteomic changes, associated with oxidative stress. DISCUSSION: Different N markers are associated with distinct neurodegenerative processes and should not be equated. N markers may differentially complement disease staging beyond amyloid and tau. Our findings suggest that Ng may not be an optimal N marker, given its low incongruency with tau pathophysiology. HIGHLIGHTS: In Alzheimer's disease, neurogranin (Ng)+, neurofilament light (NfL)+, and hippocampal volume (HCV)+ showed differential protein expression in cerebrospinal fluid. Ng+ and NfL+ were associated with neuroplasticity, although in opposite directions. HCV+ showed few proteomic changes, related to oxidative stress. Neurodegeneration (N) markers may differentially refine disease staging beyond amyloid and tau. Ng might not be an optimal N marker, as it relates more closely to tau.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Hipocampo , Proteínas de Neurofilamentos , Neurogranina , Proteômica , Proteínas tau , Humanos , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Biomarcadores/líquido cefalorraquidiano , Neurogranina/líquido cefalorraquidiano , Feminino , Masculino , Idoso , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Hipocampo/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano
18.
Alzheimers Dement ; 20(4): 2698-2706, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38400532

RESUMO

INTRODUCTION: Increasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double-blind phase 3 DIAN-TU-001 trial tested clinical and cognitive declines with increasing doses of solanezumab or gantenerumab. METHODS: We used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 trial to test amyloid positron emission tomography (PET) reduction as a potential surrogate biomarker. RESULTS: LC analysis categorized participants into three classes: amyloid no change, amyloid reduction, and amyloid growth, based on longitudinal amyloid Pittsburgh compound B PET standardized uptake value ratio data. The amyloid-no-change class was at an earlier disease stage for amyloid amounts and dementia. Despite similar baseline characteristics, the amyloid-reduction class exhibited reductions in the annual decline rates compared to the amyloid-growth class across multiple biomarker, clinical, and cognitive outcomes. DISCUSSION: LC analysis indicates that amyloid reduction is associated with improved clinical outcomes and supports its use as a surrogate biomarker in clinical trials. HIGHLIGHTS: We used latent class (LC) analysis to test amyloid reduction as a surrogate biomarker. Despite similar baseline characteristics, the amyloid-reduction class exhibited remarkably better outcomes compared to the amyloid-growth class across multiple measures. LC analysis proves valuable in testing amyloid reduction as a surrogate biomarker in clinical trials lacking significant treatment effects.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Amiloide , Peptídeos beta-Amiloides , Proteínas Amiloidogênicas , Biomarcadores , Método Duplo-Cego , Análise de Classes Latentes , Tomografia por Emissão de Pósitrons/métodos
19.
Alzheimers Dement ; 20(1): 47-62, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37740921

RESUMO

INTRODUCTION: Studies suggest distinct differences in the development, presentation, progression, and response to treatment of Alzheimer's disease (AD) between females and males. We investigated sex differences in cognition, neuroimaging, and fluid biomarkers in dominantly inherited AD (DIAD). METHODS: Three hundred twenty-five mutation carriers (55% female) and one hundred eighty-six non-carriers (58% female) of the Dominantly Inherited Alzheimer Network Observational Study were analyzed. Linear mixed models and Spearman's correlation explored cross-sectional sex differences in cognition, cerebrospinal fluid (CSF) biomarkers, Pittsburgh compound B positron emission tomography (11 C-PiB PET) and structural magnetic resonance imaging (MRI). RESULTS: Female carriers performed better than males on delayed recall and processing speed despite similar hippocampal volumes. As the disease progressed, symptomatic females revealed higher increases in MRI markers of neurodegeneration and memory impairment. PiB PET and established CSF AD markers revealed no sex differences. DISCUSSION: Our findings suggest an initial cognitive reserve in female carriers followed by a pronounced increase in neurodegeneration coupled with worse performance on delayed recall at later stages of DIAD.


Assuntos
Doença de Alzheimer , Humanos , Feminino , Masculino , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Estudos Transversais , Caracteres Sexuais , Tomografia por Emissão de Pósitrons , Mutação/genética , Biomarcadores
20.
Hum Brain Mapp ; 44(18): 6375-6387, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37867465

RESUMO

Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (µ) and standard deviation (σ) of standardized image intensities of T1-weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR-µ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1-σ and FLAIR-σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR-µ decreased and T1-σ and FLAIR-σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity-based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/complicações , Peptídeos beta-Amiloides , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons , Biomarcadores , Atrofia , Proteínas tau
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