Development and decline of memory functions in normal, pathological and healthy successful aging

Abstract

Many neuroimaging studies of age-related memory decline interpret resultant differences in brain activation patterns in the elderly as reflecting a type of compensatory response or regression to a simpler state of brain organization. Here we review a series of our own studies which lead us to an alternative interpretation, and highlights a couple of potential confounds in the aging literature that may act to increase the variability of results within age groups and across laboratories. From our perspective, level of cognitive functioning achieved by a group of elderly is largely determined by the health of individuals within this group. Individuals with a history of hypertension, for example, are likely to have multiple white matter insults which compromise cognitive functioning, independent of aging processes. The health of the elderly group has not been well-documented in most previous studies and elderly participants are rarely excluded, or placed into a separate group, due to health-related problems. In addition, recent results show that white matter tracts within the frontal and temporal lobes, regions critical for higher cognitive functions, continue to mature well into the 4th decade of life. This suggests that a young age group may not be the best control group for understanding aging effects on the brain since development is ongoing within this age range. Therefore, we have added a middle-age group to our studies in order to better understand normal development across the lifespan as well as effects of pathology on cognitive functioning in the aging brain.

Fig. 1

Estimated maturation/degeneration curves for peak volumes of GM (solid line) and WM (dashed line), collapsed across prefrontal and temporal lobe data, as a function of age. Sources Bartzokis et al. (2001), Benes et al. (1994), Giedd et al. (1999), Paus et al. (1999), and Sowell et al. (2003)

Fig. 2

General processing steps for MEG analysis. (a) Averaged evoked responses to words shown superimposed across 275 sensor locations; this 30–900 ms interval of time was analyzed for each subject. MEGAN, a locally developed software package by E. Best, was used for preprocessing the data and formatting it into a netCDF format for CSST source localization analysis. MRIVIEW was used for: (1) segmenting the cortical volume (b); (2) conducting a least squares fit between ~150 points digitized on the head surface and the reconstructed MR surface (c); (3) determining the starting locations (red dots) and best-fitting sphere head model (d); and (4) setting-up the CSST fits and displaying the CSST source localization results (e). The CSST algorithm analyzes thousands of fits to the data, as opposed to a single fit, enhancing the probability of reaching the global minimum and obtaining statistically adequate and accurate solutions (e.g., 20,000–25,000 fits to the data were conducted for 7- and 8-source models with fewer numbers of fits for lower-order models)

Fig. 3

Simulation results for a 4-source model where all sources became synchronous during the later interval. Amplitudes and peak latencies were jittered across each of 128 single trials. Upper left: Actual source locations of the four 20 mm² cortical patches (cross-hairs) for primary visual cortex (V1), inferior lateral occipital gyrus (I.LOG), intraparietal sulcus (IPS), dorsolateral prefrontal cortex (DLPF). Red–orange color on the MRIs reflect segmented cortex which was used to help establish a grid of possible starting points for the CSST algorithm. Left middle: Time-courses of activity supplied to each cortical patch. Lower left: Reveals the averaged waveforms as seen from the 275 sensor locations (VSM/CTF Omega MEG system). Top right: Table of actual source locations, CSST solutions (locations), and resultant location errors. Bottom right: Locations of the CSST solutions and their time-courses (inset). Estimated time-course amplitudes differ somewhat from the current strengths assigned to the cortical patches (left middle plot) due to cancellation/summation between the individual current elements within each patch

Fig. 4

Age-related effects in a DMS task. Top: DMS design. Lower left: Averaged time-courses for six cortical regions. Young (red tracings) and elderly (blue tracings) are shown for the delayed recognition task. Asterisks and plus represent peaks of statistical significance. Lower right: Sample source locations shown for the three conditions of the task (1 sample pattern was shown to participants; 2 participants indicated the probe stimulus did not match the sample; 3 passive control condition where no behavioral responses were required). Note the criterion for a source to be labeled as the same source for each cortical location was determined by examining source locations across subjects and choosing those within 1 cm radius of the average location. MO Medial occipital, LOG lateral occipital gyrus, MP medial parietal, SMG supramarginal gyrus; DLPF dorsolateral prefrontal cortex; AC anterior cingulate. Adapted from Aine et al. (2006)

Fig. 5

Top: GM and WM volumes were calculated and normalized to the whole brain in 11 young, 9 middle-aged and 9 elderly subjects. Asterisks indicate significant differences. The three groups were significantly different in frontal WM volumes: Young versus elderly (P < 0.0001); middle age versus elderly (P < 0.00005) and middle age versus young (P < 0.02). Bottom: WM volumes in the temporal lobe correlated positively with verbal IQ for elderly participants. Adapted from Aine et al. (2006)

Fig. 6

a Performance measures are shown for individuals with moderate to severe abnormalities rated from their MRIs. The solid black line shows the average response of all the elderly control participants (i.e., no or only mild abnormalities on their MRIs). MSE refers to their scores on the mini-mental status exam. In the California Verbal Learning Test, a list of 16 words is presented five times and participants are explicitly instructed to learn these words. Trials T1–T5 records the number of words recalled. The REY complex figure tests for implicit spatial memory; i.e., they are not told in advance to remember the details of the figure they are instructed to copy. After they finish copying the figure the original is taken away and they are asked to draw it from memory (immediate). After 20 min of additional tests they are asked to draw the figure once more (delayed). b Time-courses localized to each cortical region were averaged together for individuals within MRI groups. Parietal (PAR) and anterior temporal lobe (ANT) regions show significantly higher amplitudes compared to the control group and the group with moderate to severe volume loss. The frontal (FRO) region showed a trend in the opposite direction

Fig. 7

Upper left: MRIs show three cortical regions found during source localization that helped to differentiate between the three groups identified in a cluster analysis. Upper right: A cluster analysis performed on the MEG data shows three different activation patterns. The bar graphs show the relative weightings for each area (i.e., the percentage of participants showing activity in these regions by group; 1 = 100%). Bottom: The table shows average group characteristics. Full IQ Full scale IQ on WAIS-R, MSE mini mental status exam score, EDU education level, CVLT California Verbal Learning Test, REYD delayed recall of the REY complex figure test, ANT anterior temporal lobe, FRO frontal, PAR parietal, OCC occipital, PRE premotor, AC anterior cingulate. Asterisks represent statistical significance. Adapted from Aine et al. (2010)

Fig. 8

Working memory task used in our ongoing studies. Spatial and verbal working memory is examined using a variant of the Sternberg task. The stimulus arrays are identical for each condition, only the task instruction differs (i.e., attend to the location of the red digit or the red digit itself). Two other conditions present enhancers or distracters during the delay interval. Spatial enhancers/distracters consist of red highlighted cells of the 16 cell-array that either are the same as the to-be-remembered locations (enhancers) or are different (distracters). Verbal enhancers/distracters consist of single digits presented during the delay interval that are either the same as the to-be-remembered digits (enhancers) or are different (distracters)

Fig. 9

Preliminary behavioral results for 26 participants (young, middle age, elderly) during the spatial and verbal Sternberg tasks. Statistical significance is shown for total correct and reaction times (RTs) for three age groups and two tasks

Fig. 10

Left column and upper middle panel: MEG source locations and time-courses, respectively, were localized for three participants who reported using a spatial strategy during the spatial task (i.e., remember the locations of the red digits). Time-courses for individuals who reported using a spatial strategy were averaged together. Primary/secondary visual cortex is denoted as medial occipital regions (red tracing). Right column and lower middle panel shows source locations and time-courses for four individuals reporting that they used a verbal strategy during the spatial task. White cross-hairs reflect locations of sources. Red–orange color reflects cortex that was segmented during preprocessing to help define the head volume (i.e., search space) for each participant. Time scales do not begin at “0” since visual responses are not evident until after 50 ms (50–500 ms intervals were modeled for each participant)

Fig. 11

a Atlas regions, b the corresponding skeleton and mean FA for that slice, c the part of the skeleton showing a significant negative FA correlation with age. The skeleton corresponding to the body of corpus callosum (BCC), anterior corona radiata (ACR), and the posterior thalamic radiation (PTR) had more than 40% significant voxels

Fig. 12

Preliminary behavioral data for individuals with at least a 5 year history of hypertension during verbal (left column) and spatial (right column) working memory tasks acquired during the MEG exam. Four normal controls (CON) and four hypertensive (HT) subjects are shown