Brian A. Gordon

Span, crunch, and beyond: Working memory capacity and the aging brain

Neuroimaging data emphasize that older adults often show greater extent of brain activation than younger adults for similar objective levels of difficulty. A possible interpretation of this finding is that older adults need to recruit neuronal resources at lower loads than younger adults, leaving no resources for higher loads, and thus leading to performance decrements [Compensation-Related Utilization of Neural Circuits Hypothesis; e.g., Reuter-Lorenz, P. A., & Cappell, K. A. Neurocognitive aging and the compensation hypothesis. Current Directions in Psychological Science, 17, 177–182, 2008]. The Compensation-Related Utilization of Neural Circuits Hypothesis leads to the prediction that activation differences between younger and older adults should disappear when task difficulty is made subjectively comparable. In a Sternberg memory search task, this can be achieved by assessing brain activity as a function of load relative to the individuals memory span, which declines with age. Specifically, we hypothesized a nonlinear relationship between load and both performance and brain activity and predicted that asymptotes in the brain activation function should correlate with performance asymptotes (corresponding to working memory span). The results suggest that age differences in brain activation can be largely attributed to individual variations in working memory span. Interestingly, the brain activation data show a sigmoid relationship with load. Results are discussed in terms of Cowans [Cowan, N. The magical number 4 in short-term memory: A reconsideration of mental storage capacity. Behavioral and Brain Sciences, 24, 87–114, 2001] model of working memory and theories of impaired inhibitory processes in aging.

Neuroanatomical correlates of aging, cardiopulmonary fitness level, and education.

Fitness and education may protect against cognitive impairments in aging. They may also counteract age-related structural changes within the brain. Here we analyzed volumetric differences in cerebrospinal fluid and gray and white matter, along with neuropsychological data, in adults differing in age, fitness, and education. Cognitive performance was correlated with fitness and education. Voxel-based morphometry was used for a whole-brain analysis of structural magnetic resonance images. We found age-related losses in gray and white matter in medial-temporal, parietal, and frontal areas. As in previous work, fitness within the old correlated with preserved gray matter in the same areas. In contrast, higher education predicted preserved white matter in inferior frontal areas. These data suggest that fitness and education may both be predictive of preserved cognitive function in aging through separable effects on brain structure.

Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease

PET imaging of pathological tau correlates more closely with Alzheimer’s disease–related cognitive impairment than does imaging of β-amyloid. A window into Alzheimer’s disease Alzheimer’s disease is pathologically defined by the accumulation of β-amyloid (Aβ) plaques and tau tangles. The cognitive and pathological correlates of Aβ deposition have been well studied owing to the availability of PET imaging ligands. Using newly available tau imaging agents, Brier et al. now explore relationships among tau pathology and Aβ with PET imaging, cerebrospinal fluid measures of disease, and cognition. Overall, tau imaging provided a more robust predictor of disease status than did Aβ imaging. Thus, whereas Aβ imaging provides a good marker for early disease state, tau imaging is a more robust predictor of disease progression. Alzheimer’s disease (AD) is characterized by two molecular pathologies: cerebral β-amyloidosis in the form of β-amyloid (Aβ) plaques and tauopathy in the form of neurofibrillary tangles, neuritic plaques, and neuropil threads. Until recently, only Aβ could be studied in humans using positron emission tomography (PET) imaging owing to a lack of tau PET imaging agents. Clinical pathological studies have linked tau pathology closely to the onset and progression of cognitive symptoms in patients with AD. We report PET imaging of tau and Aβ in a cohort of cognitively normal older adults and those with mild AD. Multivariate analyses identified unique disease-related stereotypical spatial patterns (topographies) for deposition of tau and Aβ. These PET imaging tau and Aβ topographies were spatially distinct but correlated with disease progression. Cerebrospinal fluid measures of tau, often used to stage preclinical AD, correlated with tau deposition in the temporal lobe. Tau deposition in the temporal lobe more closely tracked dementia status and was a better predictor of cognitive performance than Aβ deposition in any region of the brain. These data support models of AD where tau pathology closely tracks changes in brain function that are responsible for the onset of early symptoms in AD.

Effects of measurement method, wavelength, and source-detector distance on the fast optical signal

Fast optical signals can be used to study the time course of neuronal activity in localized cortical areas. The first report of such signals [Gratton, G., Corballis, P. M., Cho, E., Fabiani, M., Hood, D., 1995a. Shades of gray matter: Noninvasive optical images of human brain responses during visual stimulation. Psychophysiol, 32, 505-509.] was based on photon delay measures. Subsequently, other laboratories have also measured fast optical signals, but a debate still exists about how these signals are generated and optimally recorded. Here we report data from a visual stimulation paradigm in which different parameters (continuous: DC intensity; modulated: AC intensity and photon delay), wavelengths (shorter and longer than the hemoglobin isosbestic point), and source-detector distances (shorter and longer than 22.5 mm) were used to record fast signals. Results indicate that a localized fast signal (peak latency=80 ms) can be detected with both delay and AC intensity measures in visual cortex, but not with unmodulated DC measures. This is likely due to the fact that differential measures (delay and AC intensity) are less sensitive to superficial noise sources, which heavily influence DC intensity. The fast effect had similar sign at wavelengths shorter and longer than the hemoglobin isosbestic point, consistent with light scattering but not rapid deoxygenation accounts of this phenomenon. Finally, the fast signal was only measured at source-detector distances greater than 22.5 mm, consistent with the intracranial origin of the signal, and providing indications about the minimum distance for recording. These data address some of the open questions in the field and provide indications about the optimal recording methods for fast optical signals.

Neurovascular coupling in normal aging: A combined optical, ERP and fMRI study

Brain aging is characterized by changes in both hemodynamic and neuronal responses, which may be influenced by the cardiorespiratory fitness of the individual. To investigate the relationship between neuronal and hemodynamic changes, we studied the brain activity elicited by visual stimulation (checkerboard reversals at different frequencies) in younger adults and in older adults varying in physical fitness. Four functional brain measures were used to compare neuronal and hemodynamic responses obtained from BA17: two reflecting neuronal activity (the event-related optical signal, EROS, and the C1 response of the ERP), and two reflecting functional hemodynamic changes (functional magnetic resonance imaging, fMRI, and near-infrared spectroscopy, NIRS). The results indicated that both younger and older adults exhibited a quadratic relationship between neuronal and hemodynamic effects, with reduced increases of the hemodynamic response at high levels of neuronal activity. Although older adults showed reduced activation, similar neurovascular coupling functions were observed in the two age groups when fMRI and deoxy-hemoglobin measures were used. However, the coupling between oxy- and deoxy-hemoglobin changes decreased with age and increased with increasing fitness. These data indicate that departures from linearity in neurovascular coupling may be present when using hemodynamic measures to study neuronal function.

Structural Correlates of Prospective Memory

Prospective memory (PM) includes the encoding and maintenance of an intention, and the retrieval and execution of this intention at the proper moment in the future. The present study expands upon previous behavioral, electrophysiological, and functional work by examining the association between grey matter volume and PM. Estimates of grey matter volume in theoretically relevant regions of interest (prefrontal, parietal, and medial temporal) were obtained in conjunction with performance on two PM tasks in a sample of 39 cognitively normal and very mildly demented older adults. The first PM task, termed focal in the literature, is supported by spontaneous retrieval of the PM intention whereas the second, termed non-focal, relies on strategic monitoring processes for successful intention retrieval. A positive relationship was observed between medial temporal volume and accuracy on the focal PM task. An examination of medial temporal lobe subregions revealed that this relationship was strongest for the hippocampus, which is considered to support spontaneous memory retrieval. There were no significant structure-behavior associations for the non-focal PM task. These novel results confirm a relationship between behavior and underlying brain structure proposed by the multiprocess theory of PM, and extend findings on cognitive correlates of medial temporal lobe integrity.

The relationship between cerebrospinal fluid markers of Alzheimer pathology and positron emission tomography tau imaging

The two primary molecular pathologies in Alzheimers disease are amyloid-β plaques and tau-immunoreactive neurofibrillary tangles. Investigations into these pathologies have been restricted to cerebrospinal fluid assays, and positron emission tomography tracers that can image amyloid-β plaques. Tau tracers have recently been introduced into the field, although the utility of the tracer and its relationship to other Alzheimer biomarkers are still unknown. Here we examined tau deposition in 41 cognitively normal and 11 cognitively impaired older adults using the radioactive tau ligand (18)F-AV-1451 (previously known as T807) who also underwent a lumbar puncture to assess cerebrospinal fluid levels of total tau (t-tau), phosphorylated tau181 (p-tau181) and amyloid-β42 Voxel-wise statistical analyses examined spatial patterns of tau deposition associated with cognitive impairment. We then related the amount of tau tracer uptake to levels of cerebrospinal fluid biomarkers. All analyses controlled for age and gender and, when appropriate, the time between imaging and lumbar puncture assessments. Symptomatic individuals (Clinical Dementia Rating > 0) demonstrated markedly increased levels of tau tracer uptake. This elevation was most prominent in the temporal lobe and temporoparietal junction, but extended more broadly into parietal and frontal cortices. In the entire cohort, there were significant relationships among all cerebrospinal fluid biomarkers and tracer uptake, notably for tau-related cerebrospinal fluid markers. After controlling for levels of amyloid-β42, the correlations with tau uptake were r = 0.490 (P < 0.001) for t-tau and r = 0.492 (P < 0.001) for p-tau181 Within the cognitively normal cohort, levels of amyloid-β42, but not t-tau or p-tau181, were associated with elevated tracer binding that was confined primarily to the medial temporal lobe and adjacent neocortical regions. AV-1451 tau binding in the medial temporal, parietal, and frontal cortices is correlated with tau-related cerebrospinal fluid measures. In preclinical Alzheimers disease, there is focal tauopathy in the medial temporal lobes and adjacent cortices.

NIA-AA staging of preclinical Alzheimer disease: discordance and concordance of CSF and imaging biomarkers

The National Institute of Aging and Alzheimers Association (NIA-AA) criteria for Alzheimer disease (AD) treat neuroimaging and cerebrospinal fluid (CSF) markers of AD pathology as if they would be interchangeable. We tested this assumption in 212 cognitively normal participants who have both neuroimaging and CSF measures of β-amyloid (CSF Aβ1-42 and positron emission tomography imaging with Pittsburgh Compound B) and neuronal injury (CSF t-tau and p-tau and structural magnetic resonance imaging) with longitudinal clinical follow-up. Participants were classified in preclinical AD stage 1 (β-amyloidosis) or preclinical AD stage 2+ (β-amyloidosis and neuronal injury) using the NIA-AA criteria, or in the normal or suspected non-Alzheimer disease pathophysiology group (neuronal injury without β-amyloidosis). At baseline, 21% of participants had preclinical AD based on CSF and 28% based on neuroimaging. Between modalities, staging was concordant in only 47% of participants. Disagreement resulted from low concordance between biomarkers of neuronal injury. Still, individuals in stage 2+ using either criterion had an increased risk for clinical decline. This highlights the heterogeneity of the definition of neuronal injury and has important implications for clinical trials using biomarkers for enrollment or as surrogate end point measures.

Imaging and cerebrospinal fluid biomarkers in early preclinical alzheimer disease.

Deposition of amyloid β (Aβ)‐containing plaques as evidenced by amyloid imaging and cerebrospinal fluid (CSF) Aβ1–42 (Aβ42) is an early indicator of preclinical Alzheimer disease (AD). To better understand their relationship during the earliest preclinical stages, we investigated baseline CSF markers in cognitively normal individuals at different stages of amyloid deposition defined by longitudinal amyloid imaging with Pittsburgh compound B (PIB): (1) PIB‐negative at baseline and follow‐up (PIB−; normal), (2) PIB‐negative at baseline but PIB‐positive at follow‐up (PIB converters; early preclinical AD), and (3) PIB‐positive at baseline and follow‐up (PIB+; preclinical AD).

Longitudinal β-Amyloid Deposition and Hippocampal Volume in Preclinical Alzheimer Disease and Suspected Non–Alzheimer Disease Pathophysiology

Importance Preclinical Alzheimer disease (AD) can be staged using a 2-factor model denoting the presence or absence of β-amyloid (Aβ+/-) and neurodegeneration (ND+/-). The association of these stages with longitudinal biomarker outcomes is unknown. Objective To examine whether longitudinal Aβ accumulation and hippocampal atrophy differ based on initial preclinical staging. Design, Setting, and Participants This longitudinal population-based cohort study used data collected at the Knight Alzheimer Disease Research Center, Washington University, St Louis, Missouri, from December 1, 2006, to June 31, 2015. Cognitively normal older adults (n = 174) were recruited from the longitudinal Adult Children Study and Healthy Aging and Senile Dementia Study at the Knight Alzheimer Disease Research Center. At baseline, all participants had magnetic resonance imaging (MRI) scans, positron emission tomography (PET) scans with carbon 11-labeled Pittsburgh Compound B (PiB), and cerebrospinal fluid assays of tau and phosphorylated tau (ptau) acquired within 12 months. Using the baseline biomarkers, individuals were classified into preclinical stage 0 (Aβ-/ND-), 1 (Aβ+/ND-), or 2+ (Aβ+/ND+) or suspected non-AD pathophysiology (SNAP; Aβ-/ND+). Main Outcomes and Measures Subsequent longitudinal accumulation of Aβ assessed with PiB PET and loss of hippocampal volume assessed with MRI in each group. Results Among the 174 participants (81 men [46.6%]; 93 women [53.4%]; mean [SD] age, 65.7 [8.9] years), a proportion (14%-17%) of individuals with neurodegeneration alone (SNAP) later demonstrated Aβ+. The rates of Aβ accumulation and loss of hippocampal volume in individuals with SNAP were indistinguishable from those without any pathologic features at baseline (for Aβ accumulation: when hippocampal volume was used to define ND, t = 0.00 [P > .99]; when tau and ptau were used to define ND, t = -0.02 [P = .98]; for loss of hippocampal volume: when hippocampal volume was used to define ND, t = -1.34 [P = .18]; when tau and ptau were used to define ND, t = 0.84 [P = .40]). Later preclinical stages (stages 1 and 2+) had elevated Aβ accumulation. Using hippocampal volume to define ND, individuals with stage 1 had accelerated Aβ accumulation relative to stage 0 (t = 11.06; P < .001), stage 2+ (t = 2.10; P = .04), and SNAP (t = 9.32; P < .001), and those with stage 2+ had accelerated Aβ accumulation relative to stage 0 (t = 4.38; P < .001) and SNAP (t = 4.08; P < .001). When ND was defined using tau and ptau, individuals with stage 2+ had accelerated Aβ accumulation relative to stage 0 (t = 4.96) and SNAP (t = 4.06), and those with stage 1 had accelerated Aβ accumulation relative to stage 0 (t = 8.44) and SNAP (t = 6.61) (P < .001 for all comparisons). When ND was defined using cerebrospinal fluid biomarkers, individuals with stage 2+ had accelerated hippocampal atrophy relative to stage 0 (t = -3.41; P < .001), stage 1 (t = -2.48; P = .03), and SNAP (t = -2.26; P = .03). Conclusions and Relevance More advanced preclinical stages of AD have greater longitudinal Aβ accumulation. SNAP appears most likely to capture inherent individual variability in brain structure or to represent comorbid pathologic features rather than early emerging AD. Low hippocampal volumes or elevated levels of tau or ptau in isolation may not accurately represent ongoing neurodegenerative processes.