Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

In perceptual discrimination tasks, a subject’s response time is determined both by sensory and motor processes. Measuring the time consumed by the perceptual evaluation step alone is thus complicated by factors such as motor preparation, task difficulty and speed-accuracy tradeoffs. Here we present a task design that minimizes these confounds and allows us to track a subject’s perceptual performance with unprecedented temporal resolution. We find that monkeys can make accurate color discriminations in less than 30 ms. Furthermore, our simple task design provides a novel tool for elucidating how neuronal activity relates to sensory versus motor processing, as demonstrated with neural data from cortical oculomotor neurons. In these cells, perceptual information acts by accelerating and decelerating the ongoing motor plans associated with correct and incorrect choices, as predicted by a race-to-threshold model, and the time course of these neural events parallels the time course of the subject's choice accuracy.

Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.

There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin.

This study investigates the visuomotor properties of several nuclei within primate central thalamus. These nuclei, which might be considered components of an oculomotor thalamus (OcTh), are found within and at the borders of the internal medullary lamina. These nuclei have extensive anatomical links to numerous cortical and subcortical visuomotor areas including the frontal eye fields, supplementary eye fields, prefrontal cortex, posterior parietal cortex, caudate, and substantia nigra pars reticulata. Previous single-unit recordings have shown that neurons in OcTh respond during self-paced spontaneous saccades and to visual stimuli in the absence of any specific behavioral requirement, but a thorough account of the activity of these areas in association with voluntary, goal-directed movement is lacking. We recorded activity from single neurons in primate central thalamus during performance of a visually guided delayed saccade task. The sample consisted primarily of neurons from the centrolateral and paracentral intralaminar nuclei and paralaminar regions of the ventral anterior and ventral lateral nuclei. Neurons responsive to sensory, delay, and motor phases of the task were observed in each region, with many neurons modulated during multiple task periods. Across the population, variation in the quality and timing of saccade-contingent activity suggested participation in functions ranging from generating a saccade (presaccadic) to registering its consequences (e.g., efference copy). Finally, many neurons were found to carry spatial information during the delay period, suggesting a role for central thalamus in higher-order aspects of visuomotor control.