RESUMEN
OBJECTIVE: To determine whether memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer disease (AD) biomarkers, we examined associations between performance in 3 memory tasks and CSF ß-amyloid (Aß)42/Aß40 and phosopho-tau181 (p-tau181) in cognitively unimpaired older adults (CU). METHODS: CU enrolled in the Stanford Aging and Memory Study (n = 153; age 68.78 ± 5.81 years; 94 female) completed a lumbar puncture and memory assessments. CSF Aß42, Aß40, and p-tau181 were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied "target" objects, novel "foil" objects, and perceptually similar "lure" objects. Analyses examined cross-sectional relationships among memory performance, age, and CSF measures, controlling for sex and education. RESULTS: Age and lower Aß42/Aß40 were independently associated with elevated p-tau181. Age, Aß42/Aß40, and p-tau181 were each associated with (1) poorer associative memory and (2) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aß42/Aß40 on memory. Relationships between CSF proteins and delayed recall were similar but nonsignificant. CSF Aß42 was not significantly associated with p-tau181 or memory. CONCLUSIONS: Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying CU with preclinical AD pathology.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Hipocampo/fisiopatología , Trastornos de la Memoria/líquido cefalorraquídeo , Trastornos de la Memoria/psicología , Anciano , Anciano de 80 o más Años , Envejecimiento/psicología , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Aprendizaje por Asociación , Estudios Transversales , Señales (Psicología) , Discriminación en Psicología , Femenino , Humanos , Masculino , Memoria , Trastornos de la Memoria/fisiopatología , Memoria Episódica , Recuerdo Mental , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fragmentos de Péptidos/líquido cefalorraquídeo , Desempeño Psicomotor , Proteínas tau/líquido cefalorraquídeoRESUMEN
PURPOSE: In vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer's disease (AD). METHODS: Forty-nine participants were scanned with 18F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (HC) (age range 61 to 86), 11 beta-amyloid+ (Aß+) participants with cognitive impairment (CI; clinical diagnosis of either mild cognitive impairment or AD dementia, age range 57 to 86), and 2 participants with semantic variant primary progressive aphasia (svPPA, age 66 and 78). Group differences in brain regions relevant in AD (medial temporal lobe, posterior cingulate cortex, and lateral parietal cortex) were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum. RESULTS: SUVRs in target regions were relatively stable 60 to 90 min post-injection, with the exception of very high binders who continued to show increases over time. Robust elevations in 18F-PI-2620 were observed between HC and Aß+ CI across all AD regions. Within the HC group, older age was associated with subtle elevations in target regions. Mildly elevated focal uptake was observed in the anterior temporal pole in one svPPA patient. CONCLUSION: Preliminary results suggest strong differences in the medial temporal lobe and cortical regions known to be impacted in AD using 18F-PI-2620 in patients along the AD trajectory. This work confirms that 18F-PI-2620 holds promise as a tool to visualize tau aggregations in AD.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Anciano , Anciano de 80 o más Años , Envejecimiento , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Carbolinas , Humanos , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Proteínas tau/metabolismoRESUMEN
Age-related episodic memory decline is characterized by striking heterogeneity across individuals. Hippocampal pattern completion is a fundamental process supporting episodic memory. Yet, the degree to which this mechanism is impaired with age, and contributes to variability in episodic memory, remains unclear. We combine univariate and multivariate analyses of fMRI data from a large cohort of cognitively normal older adults (N=100) to measure hippocampal activity and cortical reinstatement during retrieval of trial-unique associations. Trial-wise analyses revealed that (a) hippocampal activity scaled with reinstatement strength, (b) cortical reinstatement partially mediated the relationship between hippocampal activity and associative retrieval, (c) older age weakened cortical reinstatement and its relationship to memory behaviour. Moreover, individual differences in the strength of hippocampal activity and cortical reinstatement explained unique variance in performance across multiple assays of episodic memory. These results indicate that fMRI indices of hippocampal pattern completion explain within- and across-individual memory variability in older adults.
Asunto(s)
Envejecimiento/fisiología , Corteza Cerebral/fisiología , Hipocampo/fisiología , Memoria Episódica , Anciano , Anciano de 80 o más Años , Corteza Cerebral/diagnóstico por imagen , Femenino , Hipocampo/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Recuerdo Mental/fisiología , Persona de Mediana EdadRESUMEN
Goal-directed behavior requires the representation of a task-set that defines the task-relevance of stimuli and guides stimulus-action mappings. Past experience provides one source of knowledge about likely task demands in the present, with learning enabling future predictions about anticipated demands. We examine whether spatial contexts serve to cue retrieval of associated task demands (e.g., context A and B probabilistically cue retrieval of task demands X and Y, respectively), and the role of the hippocampus and dorsolateral prefrontal cortex (dlPFC) in mediating such retrieval. Using 3D virtual environments, we induce context-task demand probabilistic associations and find that learned associations affect goal-directed behavior. Concurrent fMRI data reveal that, upon entering a context, differences between hippocampal representations of contexts (i.e., neural pattern separability) predict proactive retrieval of the probabilistically dominant associated task demand, which is reinstated in dlPFC. These findings reveal how hippocampal-prefrontal interactions support memory-guided cognitive control and adaptive behavior.