RESUMEN
BACKGROUND: Biomarker changes that occur in the period between normal cognition and the diagnosis of sporadic Alzheimer's disease have not been extensively investigated in longitudinal studies. METHODS: We conducted a multicenter, nested case-control study of Alzheimer's disease biomarkers in cognitively normal participants who were enrolled in the China Cognition and Aging Study from January 2000 through December 2020. A subgroup of these participants underwent testing of cerebrospinal fluid (CSF), cognitive assessments, and brain imaging at 2-year-to-3-year intervals. A total of 648 participants in whom Alzheimer's disease developed were matched with 648 participants who had normal cognition, and the temporal trajectories of CSF biochemical marker concentrations, cognitive testing, and imaging were analyzed in the two groups. RESULTS: The median follow-up was 19.9 years (interquartile range, 19.5 to 20.2). CSF and imaging biomarkers in the Alzheimer's disease group diverged from those in the cognitively normal group at the following estimated number of years before diagnosis: amyloid-beta (Aß)42, 18 years; the ratio of Aß42 to Aß40, 14 years; phosphorylated tau 181, 11 years; total tau, 10 years; neurofilament light chain, 9 years; hippocampal volume, 8 years; and cognitive decline, 6 years. As cognitive impairment progressed, the changes in CSF biomarker levels in the Alzheimer's disease group initially accelerated and then slowed. CONCLUSIONS: In this study involving Chinese participants during the 20 years preceding clinical diagnosis of sporadic Alzheimer's disease, we observed the time courses of CSF biomarkers, the times before diagnosis at which they diverged from the biomarkers from a matched group of participants who remained cognitively normal, and the temporal order in which the biomarkers became abnormal. (Funded by the Key Project of the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03653156.).
Asunto(s)
Enfermedad de Alzheimer , Biomarcadores , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Proteínas tau/líquido cefalorraquídeo , Estudios de SeguimientoRESUMEN
Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects millions of seniors in the United States. Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to study neurophysiology in AD and its prodromal condition, mild cognitive impairment (MCI). The intrinsic neural timescale (INT), which can be estimated through the magnitude of the autocorrelation of neural signals from rs-fMRI, is thought to quantify the duration that neural information is stored in a local circuit. Such heterogeneity of the timescales forms a basis of the brain functional hierarchy and captures an aspect of circuit dynamics relevant to excitation/inhibition balance, which is broadly relevant for cognitive functions. Given that, we applied rs-fMRI to test whether distinct changes of INT at different hierarchies are present in people with MCI, those progressing to AD (called Converter), and AD patients of both sexes. Linear mixed-effect model was implemented to detect altered hierarchical gradients across populations followed by pairwise comparisons to identify regional differences. High similarities between AD and Converter were observed. Specifically, the inferior temporal, caudate, and pallidum areas exhibit significant alterations in both AD and Converter. Distinct INT-related pathological changes in MCI and AD were found. For AD/Converter, neural information is stored for a longer time in lower hierarchical areas, while higher levels of hierarchy seem to be preferentially impaired in MCI leading to a less pronounced hierarchical gradient. These results inform that the INT holds great potential as an additional measure for AD prediction, even a stable biomarker for clinical diagnosis.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Imagen por Resonancia Magnética , Humanos , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/fisiopatología , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/diagnóstico por imagen , Masculino , Femenino , Anciano , Imagen por Resonancia Magnética/métodos , Encéfalo/fisiopatología , Encéfalo/diagnóstico por imagen , Anciano de 80 o más Años , Persona de Mediana Edad , Progresión de la Enfermedad , Mapeo Encefálico/métodosRESUMEN
Several studies have shown white matter (WM) abnormalities in Alzheimer's disease (AD) using diffusion tensor imaging (DTI). Nonetheless, robust characterization of WM changes has been challenging due to the methodological limitations of DTI. We applied fixel-based analyses (FBA) to examine microscopic differences in fiber density (FD) and macroscopic changes in fiber cross-section (FC) in early stages of AD (N = 393, 212 females). FBA was also compared with DTI, free-water corrected (FW)-DTI and diffusion kurtosis imaging (DKI). We further investigated the correlation of FBA and tensor-derived metrics with AD pathology and cognition. FBA metrics were decreased in the entire cingulum bundle, uncinate fasciculus and anterior thalamic radiations in Aß-positive patients with mild cognitive impairment compared to control groups. Metrics derived from DKI, and FW-DTI showed similar alterations whereas WM degeneration detected by DTI was more widespread. Tau-PET uptake in medial temporal regions was only correlated with reduced FC mainly in the parahippocampal cingulum in Aß-positive individuals. This tau-related WM alteration was also associated with impaired memory. Despite the spatially extensive between-group differences in DTI-metrics, the link between WM and tau aggregation was only revealed using FBA metrics implying high sensitivity but low specificity of DTI-based measures in identifying subtle tau-related WM degeneration. No relationship was found between amyloid load and any diffusion-MRI measures. Our results indicate that early tau-related WM alterations in AD are due to macrostructural changes specifically captured by FBA metrics. Thus, future studies assessing the effects of AD pathology in WM tracts should consider using FBA metrics.
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Enfermedad de Alzheimer , Imagen de Difusión Tensora , Sustancia Blanca , Proteínas tau , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Femenino , Masculino , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Anciano , Proteínas tau/metabolismo , Imagen de Difusión Tensora/métodos , Anciano de 80 o más Años , Persona de Mediana Edad , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patologíaRESUMEN
OBJECTIVE: This study was undertaken to determine whether assessing learning over days reveals Alzheimer disease (AD) biomarker-related declines in memory consolidation that are otherwise undetectable with single time point assessments. METHODS: Thirty-six (21.9%) cognitively unimpaired older adults (aged 60-91 years) were classified with elevated ß-amyloid (Aß+) and 128 (78%) were Aß- using positron emission tomography with 11C Pittsburgh compound B. Participants completed the multiday Boston Remote Assessment for Neurocognitive Health (BRANCH) for 12 min/day on personal devices (ie, smartphones, laptops), which captures the trajectory of daily learning of the same content on 3 repeated tests (Digit Signs, Groceries-Prices, Face-Name). Learning is computed as a composite of accuracy across all 3 measures. Participants also completed standard in-clinic cognitive tests as part of the Preclinical Alzheimer's Cognitive Composite (PACC-5), with 123 participants undergoing PACC-5 follow-up after 1.07 (standard deviation = 0.25) years. RESULTS: At the cross-section, there were no statistically significant differences in performance between Aß+/- participants on any standard in-clinic cognitive tests (eg, PACC-5) or on day 1 of multiday BRANCH. Aß+ participants exhibited diminished 7-day learning curves on multiday BRANCH after 4 days of testing relative to Aß- participants (Cohen d = 0.49, 95% confidence interval = 0.10-0.87). Diminished learning curves were associated with greater annual PACC-5 decline (r = 0.54, p < 0.001). INTERPRETATION: Very early Aß-related memory declines can be revealed by assessing learning over days, suggesting that failures in memory consolidation predate other conventional amnestic deficits in AD. Repeated digital memory assessments, increasingly feasible and uniquely able to assess memory consolidation over short time periods, have the potential to be transformative for detecting the earliest cognitive changes in preclinical AD. ANN NEUROL 2024;95:507-517.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Progresión de la Enfermedad , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/complicaciones , Tomografía de Emisión de Positrones , Trastornos de la Memoria/complicacionesRESUMEN
OBJECTIVE: Biomarkers of Alzheimer disease vary between groups of self-identified Black and White individuals in some studies. This study examined whether the relationships between biomarkers or between biomarkers and cognitive measures varied by racialized groups. METHODS: Cerebrospinal fluid (CSF), amyloid positron emission tomography (PET), and magnetic resonance imaging measures were harmonized across four studies of memory and aging. Spearman correlations between biomarkers and between biomarkers and cognitive measures were calculated within each racialized group, then compared between groups by standard normal tests after Fisher's Z-transformations. RESULTS: The harmonized dataset included at least one biomarker measurement from 495 Black and 2,600 White participants. The mean age was similar between racialized groups. However, Black participants were less likely to have cognitive impairment (28% vs 36%) and had less abnormality of some CSF biomarkers including CSF Aß42/40, total tau, p-tau181, and neurofilament light. CSF Aß42/40 was negatively correlated with total tau and p-tau181 in both groups, but at a smaller magnitude in Black individuals. CSF Aß42/40, total tau, and p-tau181 had weaker correlations with cognitive measures, especially episodic memory, in Black than White participants. Correlations of amyloid measures between CSF (Aß42/40, Aß42) and PET imaging were also weaker in Black than White participants. Importantly, no differences based on race were found in correlations between different imaging biomarkers, or in correlations between imaging biomarkers and cognitive measures. INTERPRETATION: Relationships between CSF biomarkers but not imaging biomarkers varied by racialized groups. Imaging biomarkers performed more consistently across racialized groups in associations with cognitive measures. ANN NEUROL 2024;95:495-506.
Asunto(s)
Enfermedad de Alzheimer , Cognición , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Proteínas tau/líquido cefalorraquídeo , Negro o Afroamericano , BlancoRESUMEN
OBJECTIVE: Subclinical brain infarcts (SBI) increase the risk for stroke and dementia, but whether they should be considered equivalent to symptomatic stroke when determining blood pressure targets remains unclear. We tested whether intensive systolic blood pressure (SBP) treatment reduced the risk of new SBI or stroke and determined the association between SBI and cognitive impairment. METHODS: In this secondary analysis of SPRINT (Systolic Pressure Intervention Trial), participants ≥50 years old, with SBP 130-180mmHg and elevated cardiovascular risk but without known clinical stroke, dementia, or diabetes, were randomized to intensive (<120mmHg) or standard (<140mmHg) SBP treatment. Brain magnetic resonance images collected at baseline and follow-up were read for SBI. The occurrence of mild cognitive impairment (MCI) or probable dementia (PD) was evaluated. RESULTS: For 667 participants at baseline, SBI were identified in 75 (11%). At median 3.9 years follow-up, 12 of 457 had new SBI on magnetic resonance imaging (5 intensive, 7 standard), whereas 8 had clinical stroke (4 per group). Baseline SBI (subhazard ratio [sHR] = 3.90; 95% CI 1.49 to 10.24; p = 0.006), but not treatment group, was associated with new SBI or stroke. For participants with baseline SBI, intensive treatment reduced their risk for recurrent SBI or stroke (sHR = 0.050; 95% CI 0.0031 to 0.79; p = 0.033). Baseline SBI also increased risk for MCI or PD during follow-up (sHR = 2.38; 95% CI 1.23 to 4.61; p = 0.010). INTERPRETATION: New cerebral ischemic events were infrequent, but intensive treatment mitigated the increased risk for participants with baseline SBI, indicating primary prevention SBP goals are still appropriate when SBI are present. ANN NEUROL 2024;95:866-875.
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Antihipertensivos , Infarto Encefálico , Disfunción Cognitiva , Humanos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Antihipertensivos/uso terapéutico , Infarto Encefálico/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Imagen por Resonancia Magnética , Hipertensión/complicaciones , Presión Sanguínea/fisiología , Accidente Cerebrovascular/diagnóstico por imagen , DemenciaRESUMEN
OBJECTIVE: In temporal lobe epilepsy (TLE), a taxonomy classifying patients into 3 cognitive phenotypes has been adopted: minimally, focally, or multidomain cognitively impaired (CI). We examined gray matter (GM) thickness patterns of cognitive phenotypes in drug-resistant TLE and assessed potential use for predicting postsurgical cognitive outcomes. METHODS: TLE patients undergoing presurgical evaluation were categorized into cognitive phenotypes. Network edge weights and distances were calculated using type III analysis of variance F-statistics from comparisons of GM regions within each TLE cognitive phenotype and age- and sex-matched healthy participants. In resected patients, logistic regression models (LRMs) based on network analysis results were used for prediction of postsurgical cognitive outcome. RESULTS: A total of 124 patients (63 females, mean age ± standard deviation [SD] = 36.0 ± 12.0 years) and 117 healthy controls (63 females, mean age ± SD = 36.1 ± 12.0 years) were analyzed. In the multidomain CI group (n = 66, 53.2%), 28 GM regions were significantly thinner compared to healthy controls. Focally impaired patients (n = 37, 29.8%) showed 13 regions, whereas minimally impaired patients (n = 21, 16.9%) had 2 significantly thinner GM regions. Regions affected in both multidomain and focally impaired patients included the anterior cingulate cortex, medial prefrontal cortex, medial temporal, and lateral temporal regions. In 69 (35 females, mean age ± SD = 33.6 ± 18.0 years) patients who underwent surgery, LRMs based on network-identified GM regions predicted postsurgical verbal memory worsening with a receiver operating curve area under the curve of 0.70 ± 0.15. INTERPRETATION: A differential pattern of GM thickness can be found across different cognitive phenotypes in TLE. Including magnetic resonance imaging with clinical measures associated with cognitive profiles has potential in predicting postsurgical cognitive outcomes in drug-resistant TLE. ANN NEUROL 2024;95:984-997.
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Disfunción Cognitiva , Epilepsia Refractaria , Epilepsia del Lóbulo Temporal , Fenotipo , Humanos , Femenino , Masculino , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/cirugía , Epilepsia del Lóbulo Temporal/patología , Adulto , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patología , Persona de Mediana Edad , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/cirugía , Epilepsia Refractaria/patología , Imagen por Resonancia Magnética , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Adulto Joven , Grosor de la Corteza CerebralRESUMEN
OBJECTIVE: Cross-sectional definitions of successful cognitive aging have been widely utilized, but longitudinal measurements can identify people who do not decline. We performed this study to contrast maintenance with declining trajectories, including clinical conversion. METHODS: We included baseline cognitively unimpaired Alzheimer's Disease Neuroimaging Initiative participants with 3 or more cognitive testing sessions (n = 539, follow-up 6.1 ± 3.5 years) and calculated slopes of an episodic memory composite (MEM) to classify them into two groups: maintainers (slope ≥ 0) and decliners (slope < 0). Within decliners, we examined a subgroup of individuals who became clinically impaired during follow-up. These groups were compared on baseline characteristics and cognitive performance, as well as both cross-sectional and longitudinal Alzheimer disease (AD) biomarker measures (beta-amyloid [Aß], tau, and hippocampal volume). RESULTS: Forty-one percent (n = 221) of the cohort were MEM maintainers, and 33% (n = 105) of decliners converted to clinical impairment during follow-up. Compared to those with superior baseline scores, maintainers had lower education and were more likely to be male. Maintainers and decliners did not differ on baseline MEM scores, but maintainers did have higher non-MEM cognitive scores. Maintainers had lower baseline global Aß, lower tau pathology, and larger hippocampal volumes than decliners, even after removing converters. There were no differences in rates of change of any AD biomarkers between any cognitive trajectory groups except for a higher rate of hippocampal atrophy in clinical converters compared to maintainers. INTERPRETATION: Using longitudinal data to define cognitive trajectory groups reduces education and sex bias and reveals the prognostic importance of early onset of accumulation of AD pathology. ANN NEUROL 2024;96:378-389.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Envejecimiento Cognitivo , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Masculino , Femenino , Anciano , Estudios Longitudinales , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Envejecimiento Cognitivo/fisiología , Anciano de 80 o más Años , Proteínas tau/líquido cefalorraquídeo , Progresión de la Enfermedad , Estudios Transversales , Memoria Episódica , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Cognición/fisiología , Pruebas NeuropsicológicasRESUMEN
OBJECTIVE: The aim of this study was to investigate whether, compared to pediatric healthy controls (HCs), the glymphatic system is impaired in pediatric multiple sclerosis (MS) patients according to their cognitive status, and to assess its association with clinical disability and MRI measures of brain structural damage. METHODS: Sixty-five pediatric MS patients (females = 62%; median age = 15.5 [interquartile range, IQR = 14.5;17.0] years) and 23 age- and sex-matched HCs (females = 44%; median age = 14.1 [IQR = 11.8;16.2] years) underwent neurological, neuropsychological and 3.0 Tesla MRI assessment, including conventional and diffusion tensor imaging (DTI). We calculated the diffusion along the perivascular space (DTI-ALPS) index, a proxy of glymphatic function. Cognitive impairment (Co-I) was defined as impairment in at least 2 cognitive domains. RESULTS: No significant differences in DTI-ALPS index were found between HCs and cognitively preserved (Co-P) pediatric MS patients (estimated mean difference [EMD] = -0.002 [95% confidence interval = -0.069; 0.065], FDR-p = 0.956). Compared to HCs and Co-P patients, Co-I pediatric MS patients (n = 20) showed significantly lower DTI-ALPS index (EMD = -0.136 [95% confidence interval = -0.214; -0.058], FDR-p ≤ 0.004). In HCs, no associations were observed between DTI-ALPS index and normalized brain, cortical and thalamic volumes, and normal-appearing white matter (NAWM) fractional anisotropy (FA) and mean diffusivity (MD) (FDR-p ≥ 0.348). In pediatric MS patients, higher brain WM lesion volume (LV), higher NAWM MD, lower normalized thalamic volume, and lower NAWM FA were associated with lower DTI-ALPS index (FDR-p ≤ 0.016). Random Forest selected lower DTI-ALPS index (relative importance [RI] = 100%), higher brain WM LV (RI = 59.5%) NAWM MD (RI = 57.1%) and intelligence quotient (RI = 51.3%) as informative predictors of cognitive impairment (out-of-bag area under the curve = 0.762). INTERPRETATION: Glymphatic system dysfunction occurs in pediatric MS, is associated with brain focal lesions, irreversible tissue loss accumulation and cognitive impairment. ANN NEUROL 2024;95:1080-1092.
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Disfunción Cognitiva , Imagen de Difusión Tensora , Sistema Glinfático , Esclerosis Múltiple , Humanos , Masculino , Femenino , Adolescente , Niño , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple/psicología , Esclerosis Múltiple/complicaciones , Sistema Glinfático/diagnóstico por imagen , Sistema Glinfático/patología , Imagen por Resonancia Magnética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/fisiopatología , Pruebas NeuropsicológicasRESUMEN
OBJECTIVE: We compared the accuracy of amyloid and [18F]Flortaucipir (FTP) tau positron emission tomography (PET) visual reads for distinguishing patients with mild cognitive impairment (MCI) or dementia with fluid biomarker support of Alzheimer's disease (AD). METHODS: Participants with FTP-PET, amyloid-PET, and diagnosis of dementia-AD (n = 102), MCI-AD (n = 41), non-AD diseases (n = 76), and controls (n = 20) were included. AD status was determined independent of PET by cerebrospinal fluid or plasma biomarkers. The mean age was 66.9 years, and 44.8% were women. Three readers interpreted scans blindly and independently. Amyloid-PET was classified as positive/negative using tracer-specific criteria. FTP-PET was classified as positive with medial temporal lobe (MTL) binding as the minimum uptake indicating AD tau (tau-MTL+), positive with posterolateral temporal or extratemporal cortical binding in an AD-like pattern (tau-CTX+), or negative. The majority of scan interpretations were used to calculate diagnostic accuracy of visual reads in detecting MCI/dementia with fluid biomarker support for AD (MCI/dementia-AD). RESULTS: Sensitivity of amyloid-PET for MCI/dementia-AD was 95.8% (95% confidence interval 91.1-98.4%), which was comparable to tau-CTX+ 92.3% (86.7-96.1%, p = 0.67) and tau-MTL+ 97.2% (93.0-99.2%, p = 0.27). Specificity of amyloid-PET for biomarker-negative healthy and disease controls was 84.4% (75.5-91.0%), which was like tau-CTX+ 88.5% (80.4-94.1%, p = 0.34), and trended toward being higher than tau-MTL+ 75.0% (65.1-83.3%, p = 0.08). Tau-CTX+ had higher specificity than tau-MTL+ (p = 0.0002), but sensitivity was lower (p = 0.02), driven by decreased sensitivity for MCI-AD (80.5% [65.1-91.2] vs. 95.1% [83.5-99.4], p = 0.03). INTERPRETATION: Amyloid- and tau-PET visual reads have similar sensitivity/specificity for detecting AD in cognitively impaired patients. Visual tau-PET interpretations requiring cortical binding outside MTL increase specificity, but lower sensitivity for MCI-AD. ANN NEUROL 2024;96:476-487.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Femenino , Tomografía de Emisión de Positrones/métodos , Masculino , Anciano , Proteínas tau/líquido cefalorraquídeo , Diagnóstico Diferencial , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico , Persona de Mediana Edad , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Carbolinas , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/diagnóstico , Péptidos beta-Amiloides/metabolismo , Biomarcadores/sangre , Anciano de 80 o más AñosRESUMEN
Recent longitudinal PET imaging studies have established methods to estimate the age at which amyloid becomes abnormal at the level of the individual. Here we recontextualized amyloid levels into the temporal domain to better understand the downstream Alzheimer's disease processes of tau neurofibrillary tangle (NFT) accumulation and cognitive decline. This cohort study included a total of 601 individuals from the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center that underwent amyloid and tau PET, longitudinal neuropsychological assessments and met clinical criteria for three clinical diagnosis groups: cognitively unimpaired (n = 537); mild cognitive impairment (n = 48); or dementia (n = 16). Cortical 11C-Pittsburgh compound B (PiB) distribution volume ratio (DVR) and sampled iterative local approximation were used to estimate amyloid positive (A+; global PiB DVR > 1.16 equivalent to 17.1 centiloids) onset age and years of A+ duration at tau PET (i.e. amyloid chronicity). Tau PET burden was quantified using 18F-MK-6240 standardized uptake value ratios (70-90â min, inferior cerebellar grey matter reference region). Whole-brain and region-specific approaches were used to examine tau PET binding along the amyloid timeline and across the Alzheimer's disease clinical continuum. Voxel-wise 18F-MK-6240 analyses revealed that with each decade of A+, the spatial extent of measurable tau spread (i.e. progressed) from regions associated with early to late NFT tau stages. Regional analyses indicated that tau burden in the entorhinal cortex was detectable, on average, within 10 years of A+ onset. Additionally, the entorhinal cortex was the region most sensitive to early amyloid pathology and clinical impairment in this predominantly preclinical sample. Among initially cognitively unimpaired (n = 472) individuals with longitudinal cognitive follow-up, mixed effects models showed significant linear and non-linear interactions of A+ duration and entorhinal tau on cognitive decline, suggesting a synergistic effect whereby greater A+ duration, together with a higher entorhinal tau burden, increases the likelihood of cognitive decline beyond their separable effects. Overall, the amyloid time framework enabled a spatiotemporal characterization of tau deposition patterns across the Alzheimer's disease continuum. This approach, which examined cross-sectional tau PET data along the amyloid timeline to make longitudinal disease course inferences, demonstrated that A+ duration explains a considerable amount of variability in the magnitude and topography of tau spread, which largely recapitulated NFT staging observed in human neuropathological studies. By anchoring disease progression to the onset of amyloid, this study provides a temporal disease context, which may help inform disease prognosis and timing windows for anti-amyloid therapies.
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Enfermedad de Alzheimer , Encéfalo , Disfunción Cognitiva , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Anciano , Masculino , Femenino , Proteínas tau/metabolismo , Tomografía de Emisión de Positrones/métodos , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patología , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Anciano de 80 o más Años , Ovillos Neurofibrilares/patología , Ovillos Neurofibrilares/metabolismo , Progresión de la Enfermedad , Compuestos de Anilina , Estudios de Cohortes , Péptidos beta-Amiloides/metabolismo , Persona de Mediana Edad , Estudios Longitudinales , Tiazoles , Pruebas Neuropsicológicas , Amiloide/metabolismoRESUMEN
Mild cognitive impairment (MCI) is the initial phase of Alzheimer's disease (AD). The cognitive decline is linked to abnormal connectivity between different regions of the brain. Most brain network studies fail to consider the changes in brain patterns and do not reflect the dynamic pathological characteristics of patients. Therefore, this paper proposes a method for constructing brain networks based on microstate sequences. It also analyzes the microstate temporal parameters and introduces a new feature, the brain homeostasis coefficient (Bhc), to quantify the stability of patient brain connections. The results showed that microstate class B parameters were higher in the MCI than in the HC group. Additionally, the Bhc values in most channels of the MCI and AD groups were lower than those of the HC group, with the most significant differences observed in the right frontal lobe. These differences were statistically significant (P < 0.05). The findings indicate that connectivity in the right frontal lobe may be most severely disrupted in patients with cognitive impairment. Furthermore, the Montreal Cognitive Assessment score showed a strong positive correlation with Bhc. This suggests that Bhc could be a novel biomarker for evaluating cognitive function in patients with cognitive impairment.
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Enfermedad de Alzheimer , Trastornos del Conocimiento , Disfunción Cognitiva , Humanos , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , CogniciónRESUMEN
Impairments in working memory (WM) are evident in both clinically diagnosed patients with mild cognitive decline and older adults at risk, as indicated by lower scores on neuropsychological tests. Examining the WM-related neural signatures in at-risk older adults becomes essential for timely intervention. WM functioning relies on dynamic brain activities, particularly within the frontoparietal system. However, it remains unclear whether the cognitive decline would be reflected in the decreased dynamic reconfiguration of brain coactivation states during WM tasks. We enrolled 47 older adults and assessed their cognitive function using the Montreal Cognitive Assessment. The temporal dynamics of brain coactivations during a WM task were investigated through graph-based time-frame modularity analysis. Four primary recurring states emerged: two task-positive states with positive activity in the frontoparietal system (dorsal attention and central executive); two task-negative states with positive activity in the default mode network accompanied by negative activity in the frontoparietal networks. Heightened WM load was associated with increased flexibility of the frontoparietal networks, but the cognitive decline was correlated with reduced capacity for neuroplastic changes in response to increased task demands. These findings advance our understanding of aberrant brain reconfiguration linked to cognitive decline, potentially aiding early identification of at-risk individuals.
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Disfunción Cognitiva , Memoria a Corto Plazo , Humanos , Anciano , Memoria a Corto Plazo/fisiología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Cognición/fisiología , Disfunción Cognitiva/diagnóstico por imagen , Mapeo Encefálico , Pruebas Neuropsicológicas , Imagen por Resonancia MagnéticaRESUMEN
Mild cognitive impairment plays a crucial role in predicting the early progression of Alzheimer's disease, and it can be used as an important indicator of the disease progression. Currently, numerous studies have focused on utilizing the functional brain network as a novel biomarker for mild cognitive impairment diagnosis. In this context, we employed a graph convolutional neural network to automatically extract functional brain network features, eliminating the need for manual feature extraction, to improve the mild cognitive impairment diagnosis performance. However, previous graph convolutional neural network approaches have primarily concentrated on single modes of brain connectivity, leading to a failure to leverage the potential complementary information offered by diverse connectivity patterns and limiting their efficacy. To address this limitation, we introduce a novel method called the graph convolutional neural network with multimodel connectivity, which integrates multimode connectivity for the identification of mild cognitive impairment using fMRI data and evaluates the graph convolutional neural network with multimodel connectivity approach through a mild cognitive impairment diagnostic task on the Alzheimer's Disease Neuroimaging Initiative dataset. Overall, our experimental results show the superiority of the proposed graph convolutional neural network with multimodel connectivity approach, achieving an accuracy rate of 92.2% and an area under the Receiver Operating Characteristic (ROC) curve of 0.988.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Imagen por Resonancia Magnética , Enfermedad de Alzheimer/diagnóstico por imagen , Neuroimagen , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagenRESUMEN
Tau pathology is associated with cognitive impairment in both aging and Alzheimer's disease, but the functional and structural bases of this relationship remain unclear. We hypothesized that the integrity of behaviorally meaningful functional networks would help explain the relationship between tau and cognitive performance. Using resting state fMRI, we identified unique networks related to episodic memory and executive function cognitive domains. The episodic memory network was particularly related to tau pathology measured with positron emission tomography in the entorhinal and temporal cortices. Further, episodic memory network strength mediated the relationship between tau pathology and cognitive performance above and beyond neurodegeneration. We replicated the association between these networks and tau pathology in a separate cohort of older adults, including both cognitively unimpaired and mildly impaired individuals. Together, these results suggest that behaviorally meaningful functional brain networks represent a functional mechanism linking tau pathology and cognition.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Cognición , Función Ejecutiva , Disfunción Cognitiva/diagnóstico por imagen , Encéfalo/diagnóstico por imagenRESUMEN
Cognitive decline with aging involves multifactorial processes, including changes in brain structure and function. This study focuses on the role of white matter functional characteristics, as reflected in blood oxygenation level-dependent signals, in age-related cognitive deterioration. Building on previous research confirming the reproducibility and age-dependence of blood oxygenation level-dependent signals acquired via functional magnetic resonance imaging, we here employ mediation analysis to test if aging affects cognition through white matter blood oxygenation level-dependent signal changes, impacting various cognitive domains and specific white matter regions. We used independent component analysis of resting-state blood oxygenation level-dependent signals to segment white matter into coherent hubs, offering a data-driven view of white matter's functional architecture. Through correlation analysis, we constructed a graph network and derived metrics to quantitatively assess regional functional properties based on resting-state blood oxygenation level-dependent fluctuations. Our analysis identified significant mediators in the age-cognition relationship, indicating that aging differentially influences cognitive functions by altering the functional characteristics of distinct white matter regions. These findings enhance our understanding of the neurobiological basis of cognitive aging, highlighting the critical role of white matter in maintaining cognitive integrity and proposing new approaches to assess interventions targeting cognitive decline in older populations.
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Disfunción Cognitiva , Sustancia Blanca , Humanos , Anciano , Sustancia Blanca/diagnóstico por imagen , Reproducibilidad de los Resultados , Mapeo Encefálico , Envejecimiento , Encéfalo/diagnóstico por imagen , Cognición , Imagen por Resonancia Magnética , Disfunción Cognitiva/diagnóstico por imagenRESUMEN
Cerebral small vessel disease is common in most individuals aged 60 years or older, and it is associated with cognitive dysfunction, depression, anxiety disorder, and mobility problems. Currently, many cerebral small vessel disease patients have both cognitive impairment and depressive symptoms, but the relationship between the 2 is unclear. The present research combined static and dynamic functional network connectivity methods to explore the patterns of functional networks in cerebral small vessel disease individuals with cognitive impairment and depression (cerebral small vessel disease-mild cognitive impairment with depression) and their relationship. We found specific functional network patterns in the cerebral small vessel disease-mild cognitive impairment with depression individuals (P < 0.05). The cerebral small vessel disease individuals with depression exhibited unstable dynamic functional network connectivity states (transitions likelihood: P = 0.040). In addition, we found that the connections within the lateral visual network between the sensorimotor network and ventral attention network could mediate white matter hyperintensity-related cognitive impairment (indirect effect: 0.064; 95% CI: 0.003, 0.170) and depression (indirect effect: -0.415; 95% CI: -1.080, -0.011). Cognitive function can negatively regulate white matter hyperintensity-related depression. These findings elucidate the association between cognitive impairment and depression and provide new insights into the underlying mechanism of cerebral small vessel disease-related cognitive dysfunction and depression.
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Enfermedades de los Pequeños Vasos Cerebrales , Disfunción Cognitiva , Sustancia Blanca , Humanos , Encéfalo/diagnóstico por imagen , Depresión/diagnóstico por imagen , Imagen por Resonancia Magnética , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagenRESUMEN
Mild cognitive impairment is considered the prodromal stage of Alzheimer's disease. Accurate diagnosis and the exploration of the pathological mechanism of mild cognitive impairment are extremely valuable for targeted Alzheimer's disease prevention and early intervention. In all, 100 mild cognitive impairment patients and 86 normal controls were recruited in this study. We innovatively constructed the individual morphological brain networks and derived multiple brain connectome features based on 3D-T1 structural magnetic resonance imaging with the Jensen-Shannon divergence similarity estimation method. Our results showed that the most distinguishing morphological brain connectome features in mild cognitive impairment patients were consensus connections and nodal graph metrics, mainly located in the frontal, occipital, limbic lobes, and subcortical gray matter nuclei, corresponding to the default mode network. Topological properties analysis revealed that mild cognitive impairment patients exhibited compensatory changes in the frontal lobe, while abnormal cortical-subcortical circuits associated with cognition were present. Moreover, the combination of multidimensional brain connectome features using multiple kernel-support vector machine achieved the best classification performance in distinguishing mild cognitive impairment patients and normal controls, with an accuracy of 84.21%. Therefore, our findings are of significant importance for developing potential brain imaging biomarkers for early detection of Alzheimer's disease and understanding the neuroimaging mechanisms of the disease.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Conectoma , Humanos , Conectoma/métodos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patología , Imagen por Resonancia Magnética/métodosRESUMEN
Repetitive transcranial magnetic stimulation is used in early-stage Alzheimer's disease to slow progression, but heterogeneity in response results in different treatment outcomes. The mechanisms underlying this heterogeneity are unclear. This study used resting-state neuroimaging to investigate the variability in episodic memory improvement from angular gyrus repetitive transcranial magnetic stimulation and tracked the neural circuits involved. Thirty-four amnestic mild cognitive impairment patients underwent angular gyrus repetitive transcranial magnetic stimulation (4 weeks, 20 Hz, 100% resting motor threshold) and were divided into high-response and low-response groups based on minimal clinically important differences in auditory verbal learning test scores. Baseline and pre/post-treatment neural circuit activities were compared. Results indicated that the orbital middle frontal gyrus in the orbitofrontal cortex network and the precuneus in the default mode network had higher local activity in the low-response group. After treatment, changes in local and remote connectivity within brain regions of the orbitofrontal cortex, default mode network, visual network, and sensorimotor network showed opposite trends and were related to treatment effects. This suggests that the activity states of brain regions within the orbitofrontal cortex and default mode network could serve as imaging markers for early cognitive compensation in amnestic mild cognitive impairment patients and predict the aftereffects of repetitive transcranial magnetic stimulation response.
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Disfunción Cognitiva , Estimulación Magnética Transcraneal , Humanos , Estimulación Magnética Transcraneal/métodos , Masculino , Femenino , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/terapia , Disfunción Cognitiva/diagnóstico por imagen , Anciano , Imagen por Resonancia Magnética , Resultado del Tratamiento , Persona de Mediana Edad , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiopatología , Memoria Episódica , Vías Nerviosas/fisiopatología , Vías Nerviosas/diagnóstico por imagen , Red en Modo Predeterminado/diagnóstico por imagen , Red en Modo Predeterminado/fisiopatología , Encéfalo/fisiopatología , Encéfalo/diagnóstico por imagenRESUMEN
Presbycusis has been reported as related to cognitive decline, but its underlying neurophysiological mechanism is still unclear. This study aimed to investigate the relationship between metabolite levels, cognitive function, and node characteristics in presbycusis based on graph theory methods. Eighty-four elderly individuals with presbycusis and 63 age-matched normal hearing controls underwent magnetic resonance spectroscopy, functional magnetic resonance imaging scans, audiological assessment, and cognitive assessment. Compared with the normal hearing group, presbycusis patients exhibited reduced gamma-aminobutyric acid and glutamate levels in the auditory region, increased nodal characteristics in the temporal lobe and precuneus, as well as decreased nodal characteristics in the superior occipital gyrus and medial orbital. The right gamma-aminobutyric acid levels were negatively correlated with the degree centrality in the right precuneus and the executive function. Degree centrality in the right precuneus exhibited significant correlations with information processing speed and executive function, while degree centrality in the left medial orbital demonstrated a negative association with speech recognition ability. The degree centrality and node efficiency in the superior occipital gyrus exhibited a negative association with hearing loss and speech recognition ability, respectively. These observed changes indicate alterations in metabolite levels and reorganization patterns at the brain network level after auditory deprivation.