Previous studies have suggested that contingent negative variation (CNV), as recorded by electroencaphalography (EEG), may serve as an index of temporal encoding. The interpretation of these studies is complicated by the fact that in a majority of studies the CNV signal was obtained at a time when subjects were not only registering stimulus duration but also making decisions and preparing to act. Previously, we demonstrated that repetitive transcranial magnetic stimulation (rTMS) of the right supramarginal gyrus (rSMG) in humans lengthened the perceived duration of a visual stimulus (Wiener, et al. 2010a), suggesting the rSMG is involved in basic encoding processes. Here, we report a replication of this effect with simultaneous EEG recordings during the encoding of stimulus duration. Stimulation of the rSMG led to an increase in perceived duration and the amplitude of N1 and CNV components recorded from frontocentral sites. Furthermore, the size of the CNV amplitude, but not N1, positively correlated with the size of the rTMS effect but negatively correlated with bias (the baseline tendency to report a comparison stimulus as shorter), suggesting that the CNV indexes stimulus duration. These results suggest that a feed-forward mechanism from parietal to prefrontal regions mediates temporal encoding, and demonstrate a dissociation between early and late phases of encoding processes.

Different inflammatory and metabolic pathways have been associated with Alzheimeŕs disease (AD). However, only recently multi-analyte panels to study a large number of molecules in well characterized cohorts have been made available. These panels could help identify molecules that point to the affected pathways. We studied the relationship between a panel of plasma biomarkers (Human DiscoveryMAP®) and presence of AD-like brain atrophy patterns defined by a previously published index (SPARE-AD) at baseline in subjects of the ADNI cohort. 818 subjects had MRI-derived SPARE-AD scores, of these subjects 69% had plasma biomarkers and 51% had CSF tau and Aβ measurements. Significant analyte-SPARE-AD and analytes correlations were studied in adjusted models. Plasma cortisol and chromogranin A showed a significant association that did not remain significant in the CSF signature adjusted model. Plasma macrophage inhibitory protein-1α and insulin-like growth factor binding protein 2 showed a significant association with brain atrophy in the adjusted model. Cortisol levels showed an inverse association with tests measuring processing speed. Our results indicate that stress and insulin responses and cytokines associated with recruitment of inflammatory cells in MCI-AD are associated with its characteristic AD-like brain atrophy pattern and correlate with clinical changes or CSF biomarkers.

Objective:

New preclinical Alzheimer disease (AD) diagnostic criteria have been developed using biomarkers in cognitively normal (CN) adults. We implemented these criteria using an MRI biomarker previously associated with AD dementia, testing the hypothesis that individuals at high risk for preclinical AD would be at elevated risk for cognitive decline.

Methods:

The Alzheimer's Disease Neuroimaging Initiative database was interrogated for CN individuals. MRI data were processed using a published set of a priori regions of interest to derive a single measure known as the AD signature (ADsig). Each individual was classified as ADsig-low (≥1 SD below the mean: high risk for preclinical AD), ADsig-average (within 1 SD of mean), or ADsig-high (≥1 SD above mean). A 3-year cognitive decline outcome was defined a priori using change in Clinical Dementia Rating sum of boxes and selected neuropsychological measures.

Results:

Individuals at high risk for preclinical AD were more likely to experience cognitive decline, which developed in 21% compared with 7% of ADsig-average and 0% of ADsig-high groups (p = 0.03). Logistic regression demonstrated that every 1 SD of cortical thinning was associated with a nearly tripled risk of cognitive decline (p = 0.02). Of those for whom baseline CSF data were available, 60% of the high risk for preclinical AD group had CSF characteristics consistent with AD while 36% of the ADsig-average and 19% of the ADsig-high groups had such CSF characteristics (p = 0.1).

Conclusions:

This approach to the detection of individuals at high risk for preclinical AD—identified in single CN individuals using this quantitative ADsig MRI biomarker—may provide investigators with a population enriched for AD pathobiology and with a relatively high likelihood of imminent cognitive decline consistent with prodromal AD.

BACKGROUND

The utility flourodeoxyglucose PET (FDG-PET) imaging in Alzheimer’s Disease (AD) diagnosis is well established. Recently, measurement of cerebral blood flow using arterial spin labeling MRI (ASL-MRI) has shown diagnostic potential in AD, though it has never been directly compared to FDG-PET.

METHODS

We employed a novel imaging protocol to obtain FDG-PET and ASL-MRI images concurrently in 17 AD patients and 19 age-matched controls. Paired FDG-PET and ASL-MRI images from 19 controls and 15 AD patients were included for qualitative analysis, while paired images 18 controls and 13 AD patients were suitable for quantitative analyses.

RESULTS

The combined imaging protocol was well tolerated. Both modalities revealed very similar regional abnormalities in AD, as well as comparable sensitivity and specificity for the detection of AD following visual review by two expert readers. Interobserver agreement was better for FDG-PET (kappa 0.75, SE 0.12) than ASL-MRI (kappa 0.51, SE 0.15), intermodality agreement was moderate to strong (kappa 0.45-0.61), and readers were more confident of FDG-PET reads. Simple quantitative analysis of global cerebral FDG uptake (FDG-PET) or whole brain cerebral blood flow (ASL-MRI) showed excellent diagnostic accuracy for both modalities, with area under ROC curves of 0.90 for FDG-PET (95% CI 0.79-0.99) and 0.91 for ASL-MRI (95% CI 0.80-1.00).

CONCLUSIONS

Our results demonstrate that FDG-PET and ASL-MRI identify similar regional abnormalities and have comparable diagnostic accuracy in a small population of AD patients, and support the further study of ASL-MRI in dementia diagnosis.

Research suggests overlap in brain regions undergoing neurodegeneration in Parkinson's and Alzheimer's disease. To assess the clinical significance of this, we applied a validated Alzheimer's disease-spatial pattern of brain atrophy to patients with Parkinson's disease with a range of cognitive abilities to determine its association with cognitive performance and decline. At baseline, 84 subjects received structural magnetic resonance imaging brain scans and completed the Dementia Rating Scale-2, and new robust and expanded Dementia Rating Scale-2 norms were applied to cognitively classify participants. Fifty-nine non-demented subjects were assessed annually with the Dementia Rating Scale-2 for two additional years. Magnetic resonance imaging scans were quantified using both a region of interest approach and voxel-based morphometry analysis, and a method for quantifying the presence of an Alzheimer's disease spatial pattern of brain atrophy was applied to each scan. In multivariate models, higher Alzheimer's disease pattern of atrophy score was associated with worse global cognitive performance (β = −0.31, P = 0.007), including in non-demented patients (β = −0.28, P = 0.05). In linear mixed model analyses, higher baseline Alzheimer's disease pattern of atrophy score predicted long-term global cognitive decline in non-demented patients [F(1, 110) = 9.72, P = 0.002], remarkably even in those with normal cognition at baseline [F(1, 80) = 4.71, P = 0.03]. In contrast, in cross-sectional and longitudinal analyses there was no association between region of interest brain volumes and cognitive performance in patients with Parkinson's disease with normal cognition. These findings support involvement of the hippocampus and parietal–temporal cortex with cognitive impairment and long-term decline in Parkinson's disease. In addition, an Alzheimer's disease pattern of brain atrophy may be a preclinical biomarker of cognitive decline in Parkinson's disease.

Objective

To assess regions and patterns of brain atrophy in patients with Parkinson disease (PD) with normal cognition (PD-NC), mild cognitive impairment (PD-MCI), and dementia-level cognitive deficits (PDD).

Design

Images were quantified using a region-of-interest approach and voxel-based morphometry analysis. We used a high-dimensional pattern classification approach to delineate brain regions that collectively formed the Spatial Pattern of Abnormalities for Recognition of PDD.

Setting

The Parkinson’s Disease and Movement Disorders Center at the University of Pennsylvania.

Subjects

Eighty-four PD patients (61 PD-NC, 12 PD-MCI, and 11 PDD) and 23 healthy control subjects (HCs) underwent magnetic resonance imaging of the brain.

Results

The PD-NC patients did not demonstrate significant brain atrophy compared with HCs. Compared with PD-NC patients, PD-MCI patients had hippocampal atrophy (β=−0.37; P=.001), and PDD patients demonstrated hippocampal (β=−0.32; P=.004) and additional medial temporal lobe atrophy (β=−0.36; P=.003). The PD-MCI patients had a different pattern of atrophy compared with PD-NC patients (P=.04) and a similar pattern to that of PDD patients (P=.81), characterized by hippocampal, prefrontal cortex gray and white matter, occipital lobe gray and white matter, and parietal lobe white matter atrophy. In nondemented PD patients, there was a correlation between memory-encoding performance and hippocampal volume.

Conclusions

Hippocampal atrophy is a biomarker of initial cognitive decline in PD, including impaired memory encoding and storage, suggesting heterogeneity in the neural substrate of memory impairment. Use of a pattern classification approach may allow identification of diffuse regions of cortical gray and white matter atrophy early in the course of cognitive decline.

The measurement of hippocampal volumes using MRI is a useful in-vivo biomarker for detection and monitoring of early Alzheimer’s Disease (AD), including during the amnestic Mild Cognitive Impairment (a-MCI) stage. The pathology underlying AD has regionally selective effects within the hippocampus. As such, we predict that hippocampal subfields are more sensitive in discriminating prodromal AD (i.e., a-MCI) from cognitively normal controls than whole hippocampal volumes, and attempt to demonstrate this using a semi-automatic method that can accurately segment hippocampal subfields. High-resolution coronal-oblique T2-weighted images of the hippocampal formation were acquired in 45 subjects (28 controls and 17 a-MCI (mean age: 69.5 ± 9.2; 70.2 ± 7.6)). CA1, CA2, CA3, and CA4/DG subfields, along with head and tail regions, were segmented using an automatic algorithm. CA1 and CA4/DG segmentations were manually edited. Whole hippocampal volumes were obtained from the subjects’ T1-weighted anatomical images. Automatic segmentation produced significant group differences in the following subfields: CA1 (left: p=0.001, right: p=0.038), CA4/DG (left: p=0.002, right: p=0.043), head (left: p=0.018, right: p=0.002), and tail (left: p=0.019). After manual correction, differences were increased in CA1 (left: p<0.001, right: p=0.002), and reduced in CA4/DG (left: p=0.029, right: p=0.221). Whole hippocampal volumes significantly differed bilaterally (left: p=0.028, right: p=0.009). This pattern of atrophy in a-MCI is consistent with the topography of AD pathology observed in postmortem studies, and corrected left CA1 provided stronger discrimination than whole hippocampal volume (p=0.03). These results suggest that semi-automatic segmentation of hippocampal subfields is efficient and may provide additional sensitivity beyond whole hippocampal volumes.

Optimal memory retrieval depends not only on the fidelity of stored information, but also on the attentional state of the subject. Factors such as mental preparedness to engage in stimulus processing can facilitate or hinder memory retrieval. The current study used functional magnetic resonance imaging (fMRI) to distinguish preparatory brain activity before episodic and semantic retrieval tasks from activity associated with retrieval itself. A catch-trial imaging paradigm permitted separation of neural responses to preparatory task cues and memory probes. Episodic and semantic task preparation engaged a common set of brain regions, including the bilateral intraparietal sulcus (IPS), left fusiform gyrus (FG), and the pre-supplementary motor area (pre-SMA). In the subsequent retrieval phase, the left IPS was among a set of frontoparietal regions that responded differently to old and new stimuli. In contrast, the right IPS responded to preparatory cues with little modulation during memory retrieval. The findings support a strong left-lateralization of retrieval success effects in left parietal cortex, and further indicate that left IPS performs operations that are common to both task preparation and memory retrieval. Such operations may be related to attentional control, monitoring of stimulus relevance, or retrieval.

Successful memory retrieval depends not only on memory fidelity but also on the mental preparedness on the part of the subject. ERP studies of recognition memory have identified two topographically distinct ERP components, the FN400 old/new effect and the late posterior component (LPC) old/new effect, commonly associated with familiarity and recollection, respectively. Here we used a task-switching paradigm to examine the extent to which adoption of a retrieval task-set influences FN400 and LPC old/new effects, in light of the presumption that recollection, as a control process, relies on the adoption of a retrieval task-set, but that familiarity–based retrieval does not. Behavioral accuracy indicated that source memory (experiment 2), but not item recognition (experiment 1), improved with task-set adoption. ERP data demonstrated a larger LPC on stay trials when a task-set had been adopted even with a simple recognition memory judgment. We conclude that adopting a retrieval task-set impacts recollection memory but not familiarity. These data indicate that attentional state immediately prior to retrieval can influence objective measures of recollection memory.

The aim of this study was to determine the neural correlates of different stages of episodic memory function and their modulation by Alzheimer's Disease (AD). Several decades of work have supported the role of the medial temporal lobes (MTL) in episodic memory function. However, more recent work, derived in part from functional neuroimaging studies, has suggested that other brain structures make up a large-scale network that appear to support successful encoding and retrieval of episodic memories. Furthermore, controversy exists as to whether dissociable MTL regions support qualitatively different aspects of memory (hippocampus: contextual memory or ‘recollection’; perirhinal/lateral entorhinal cortex: item memory or ‘familiarity’). There is limited neuropsychological support for these models and most work in AD only has examined free recall memory measures. We studied the relationship between performance on different stages of the Rey Auditory Verbal Learning Test (AVLT), a 15-item word list learning task, and structural MRI measures in mild AD patients. Structural measures included hippocampal volume and cortical thickness of several ROIs known to undergo atrophy in AD. Correlation and multiple regression analyses, controlling for age, education, and gender, were performed in 146 mild AD patients (MMSE 23.3 ± 2.0). To evaluate the robustness of these relationships, similar analyses were performed with additional standardized verbal memory measures. Early immediate recall trials (e.g. Trial 1 of the AVLT) were not associated with the size of MTL regions, but correlated most strongly with inferior parietal, middle frontal gyrus, and temporal pole ROIs. After repeated exposure (e.g. Trial 5 of the AVLT), immediate recall was correlated with both MTL and a similar distribution of isocortical structures, but most strongly the temporal pole. For delayed recall, only the hippocampus correlated with performance. In contrast, for delayed recognition discrimination, the perirhinal/entorhinal cortex correlated more strongly than hippocampus; no other isocortical regions were strongly associated with performance. Convergent results were found for immediate and delayed trials of the other memory tests. The current results suggest that a richer understanding of the memory deficits in AD can be gained by examining multiple measures, which tap different aspects of memory function. Furthermore, the present findings are consistent with models hypothesizing that different stages of verbal list learning map onto dissociable brain regions. These data have implications for understanding the anatomic basis of processes underlying episodic memory, particularly related to a division of labor within the medial temporal lobes and within the large-scale MTL-cortical memory network.

Objective

To investigate whether some patients with very mild Alzheimer's disease (AD) demonstrate disproportionate executive dysfunction relative to amnesia and how this relates to functional impairment in daily life, future clinical decline, APOE genotype and regional cortical thickness measured from MRI scan data.

Methods

The Alzheimer's Disease Neuroimaging Initiative dataset was interrogated for a primary sample of patients with very mild AD dementia (n=100) and a secondary confirmatory sample of patients with mild cognitive impairment (n=396). An executive predominant subgroup was defined as having executive performance ≥2 SDs worse than memory performance and a memory predominant subgroup was defined conversely. A priori regions of interest from a previous study of an AD patient sample were used to obtain cortical thickness measures.

Results

Despite equivalent global measures of impairment (Mini-Mental State Examination, Clinical Dementia Rating (CDR) Sum of Boxes), executive predominant patients (n=88) were more impaired on other executive measures and in the CDR Judgement and Problem Solving box (p<0.005) while memory predominant patients (n=56) were more impaired on other memory measures (p<0.05). The APOE-ε4 allele was much more frequent in the memory predominant subgroup (p<0.0001). Frontoparietal cortical regions were thinner in the executive predominant group than in the memory predominant group (p<0.05).

Conclusions

A dysexecutive clinical phenotype of very mild AD is not rare and is associated with more problem solving difficulties and possibly more rapid progression compared with patients with a predominant amnesic phenotype. Executive predominant AD may reflect an alternative underlying pathophysiology related to genetic status, reflected in more prominent pathological alterations in frontoparietal regions subserving executive function. These findings, which deserve further investigation, may have implications for diagnosis, prognostication, monitoring and related issues involved in clinical research and care.

Dual process theories of recognition memory posit that recollection and familiarity represent dissociable processes. Animal studies and human functional imaging experiments support an anatomic dissociation of these processes in the medial temporal lobes (MTL). By this hypothesis, recollection may be dependent on the hippocampus; while familiarity appears to rely on extrahippocampal MTL (ehMTL) structures, particularly perirhinal and lateral entorhinal cortices. Despite these findings, the dual process model and these anatomic mappings remain controversial, in part because the study of patients with lesions to the MTL has been limited and has revealed predominantly single dissociations. We examined measures of recollection and familiarity in three groups (normal older adults, amnesic-Mild Cognitive Impairment, Alzheimer’s Disease) in which these memory measures and the relative integrity of MTL structures are variable, thus enhancing our power to detect MTL-memory relationships. Recollection and familiarity and volumes of hippocampus and ehMTL, defined as a region including entorhinal/perirhinal cortices and parahippocampus, were measured. Regression analyses revealed a stronger relationship of recollection with the hippocampus compared to ehMTL, while familiarity was more highly related to ehMTL compared to hippocampus. These results are consistent with a division of labor in the MTL and the dual process model.

This study investigated the relationship between the cognitive status of normal adults and age-related changes in attention to novel and target events. Old, middle-aged, and young subjects, divided into cognitively high and cognitively average performing groups, viewed repetitive standard stimuli, infrequent target stimuli, and unique novel visual stimuli. Subjects controlled viewing duration by a button press that led to the onset of the next stimulus. They also responded to targets by pressing a foot pedal. The amount of time spent looking at different kinds of stimuli served as a measure of visual attention and exploratory activity. Cognitively high performers spent more time viewing novel stimuli than cognitively average performers. The magnitude of the difference between cognitively high and cognitively average performing groups was largest among old subjects. Cognitively average performers had slower and less accurate responses to targets than cognitively high performers. Our results provide strong evidence that the link between engagement by novelty and higher cognitive performance increases with age. Moreover, it supports the notion of there being different patterns of normal cognitive aging and the need to identify the factors that influence them.

Evidence from neuroimaging and neuropsychology suggests that portions of the anterior temporal lobes (ATLs) play a critical role in proper name retrieval. We previously found that anodal transcranial direct current stimulation (tDCS) to the ATLs improved retrieval of proper names in young adults (Ross et al., 2010). Here we extend that finding to older adults who tend to experience greater proper-naming deficits than young adults. The task was to look at pictures of famous faces or landmarks and verbally recall the associated proper name. Our results show a numerical improvement in face naming after left or right ATL stimulation, but a statistically significant effect only after left-lateralized stimulation. The magnitude of the enhancing effect was similar in older and younger adults but the lateralization of the effect differed depending on age. The implications of these findings for the use of tDCS as tool for rehabilitation of age-related loss of name recall are discussed.

Prior work suggests that patients with mild Alzheimer’s disease (AD) often base their recognition memory decisions on familiarity. It has been argued that conceptual fluency may play an important role in the feeling of familiarity. In the present study we measured the effect of conceptual fluency manipulations on recognition judgments of patients with mild AD and older adult controls. “Easy” and “hard” test conditions were created by manipulating encoding depth and list length to yield high and low discrimination, respectively. When the two participant groups performed identical procedures, AD patients displayed lower discrimination and greater reliance on fluency cues than controls. However, when the discrimination of older adult controls was decreased to the level of AD patients by use of a shallow encoding task, we found that controls reliance on fluency did not statistically differ from AD patients. Furthermore, we found that increasing discrimination using shorter study lists resulted in AD patients decreasing their reliance on fluency cues to a similar extent as controls. These findings support the notion that patients with AD are able to attribute conceptual fluency to prior experience. In addition these findings suggest that discrimination and reliance on fluency cues may be inversely related in both AD patients and older adult controls.

Inverse correlations between amyloid-β (Aβ) load measured by Pittsburgh Compound-B (PiB) positron emission tomography (PET) and cerebral metabolism using [18F]fluoro-2-deoxy-D-glucose (FDG) in Alzheimer’s disease (AD) patients, suggest local Aβ-induced metabolic insults. However, this relationship has not been well studied in mild cognitive impairment (MCI) or amyloid-positive controls. Here, we explored associations of Aβ deposition with metabolism via both region-of-interest-based and voxel-based analyses in amyloid-positive control subjects and patients with MCI or AD. Metabolism in parietal and precuneus cortices of AD patients was negatively correlated with PiB retention locally, and more distantly with PiB retention in frontal cortex. In amyloid-positive controls, no clear patterns in correlations were observed. In MCI patients, there were essentially no significant, negative correlations, but there were frequent significant positive correlations between metabolism and PiB retention. Metabolism in anterior cingulate showed positive correlations with PiB in most brain areas in MCI, and metabolism and PiB retention were positively correlated locally in precuneus/parietal cortex. However, there was no significant increase in metabolism in MCI compared to age-matched controls, negating the possibility that Aβ deposition directly caused reactive hypermetabolism. This suggests that, in MCI, higher basal metabolism could either be exacerbating Aβ deposition or increasing the level of Aβ necessary for cognitive impairment sufficient for the clinical diagnosis of AD. Only after extensive Aβ deposition has been present for longer periods of time does Aβ become the driving force for decreased metabolism in clinical AD and, only in more vulnerable brain regions such as parietal and precuneus cortices.

Objective

We utilized the amyloid imaging ligand Pittsburgh Compound-B (PiB) to determine the presence of AD pathology in different MCI subtypes and to relate elevated PiB binding to other markers of early AD and longitudinal outcome.

Methods

Twenty-six patients with MCI – 13 single domain amnestic-MCI (sd a-MCI), 6 multiple domain amnestic-MCI (md a-MCI), and 7 non-amnestic MCI (na-MCI) – underwent PiB imaging. Twenty-three had clinical follow-up [21.2 ± 16.0 (SD) months] subsequent to their PiB scan.

Results

Using cutoffs established from a control cohort, 14 (54%) had elevated levels of PiB retention and were considered “amyloid-positive.” All subtypes were associated with a significant proportion of amyloid-positive patients (6/13 sd a-MCI, 5/6 md a-MCI, 3/7 na-MCI). There were no obvious differences in the distribution of PiB retention in the na-MCI group despite their atypical early AD phenotype. Predictors of conversion to clinical AD in a-MCI, including poorer episodic memory, increased age, and medial temporal atrophy, were found in the amyloid-positive relative to amyloid-negative a-MCI patients. Longitudinal follow-up revealed 5/13 amyloid-positive patients, but 0/10 amyloid-negative patients, converted to clinical AD. Further, 3/10 amyloid-negative patients “reverted to normal” on follow-up.

Interpretation

These data support the notion that amyloid-positive patients are likely to have early AD and that the use of amyloid imaging may have an important role in determining which patients are likely to benefit from disease-specific therapies. In addition, our data is consistent with longitudinal studies suggesting that a significant percentage of all MCI subtypes will develop clinical AD.

We report on the current state of in vivo amyloid imaging. While this technique is less than a decade old, a wealth of information is emerging as the initial clinical studies are reported. Imaging of patients with Alzheimer's Disease (AD) have allowed for quantitative exploration of the natural history of amyloid deposition and it's relationship to neurodegeneration. Amyloid imaging also shows significant promise in differential diagnosis of mild cognitive impairment or atypical dementias. However, amyloid detection may be of greatest utility in healthy elderly in whom amyloid imaging has confirmed prior autopsy reports of a significant percentage of asymptomatic adults with Alzheimer's pathology. Understanding the relationship between this pathology and future cognitive status has significant implications for the application of disease modifying medications in the ‘pre-clinical’ phase of disease. Given the considerable clinical experience compared to other tracers, the current review focuses on the literature involving Pittsburgh Compound-B (PiB) PET.

Decline in episodic memory is a common feature of healthy aging. Event-related potential (ERP) studies in young adults have consistently reported several modulations thought to index memory retrieval processes, but relatively limited work has explored the impact of aging on them. Further, work with functional imaging has demonstrated differential neural recruitment in elderly subjects depending on their level of cognitive performance which may reflect compensatory or, alternatively, inefficient processing. In the present study we examined the effect of aging and level of performance on both early (FN400, LPC) and later [late frontal effect (LFE)] ERP indices of recognition memory. We found that the FN400 and LPC were absent or attenuated in the older group relative to young adults, but that the LFE was actually increased, analogous to findings in the functional imaging literature. Additionally, the latter effect was most prominent in the poorer performing older participants. These findings suggest that weak memory retrieval supported by earlier ERP modulations, may lead to an enhanced LFE in the service of additional retrieval attempts.

Despite memory failures being a central feature of Amnestic Mild Cognitive Impairment (a-MCI), there is limited research into the nature of the memory impairment associated with this condition. A further understanding could lead to refinement of criteria needed to qualify for this designation and aid in prediction of who will progress to development of clinical Alzheimer’s disease. Dual process models posit that recognition memory is supported by the dissociable processes of recollection and familiarity. The present study sought to evaluate recognition memory in a-MCI in the framework of the dual process model. Patients with a-MCI and age- and education-matched controls were tested on three memory paradigms. Two paradigms were modifications of the process-dissociation procedure in which recollection required either memory of word-pair associations (associative) or the font color of words at study (featural). A final paradigm utilized the task-dissociation methodology comparing performance for item and visual spatial source memory. All three tasks revealed that familiarity was impaired to at least the same extent as recollection. As familiarity is thought to be spared in normal aging, its measurement may provide a relatively specific marker for the early pathological changes of Alzheimer’s disease.

Patients with mild Alzheimer’s disease (AD) display a greater tendency to endorse unstudied items as ‘old’ on memory tests than healthy older adults. This liberal response bias may result in mistaken beliefs about the completion of common tasks. This research attempted to determine whether it was possible to shift the response bias of mild AD patients to be more conservative on a recognition memory test through behavioral intervention. Patients with mild AD and matched controls were evaluated with two almost identical paradigms, separated by about one week. For each session, 30 words were studied and 60 words (half studied, half novel) were shown at test. During one session participants were told that 30% of words were old, and at the other session that 70% were old. We found that both groups were able to shift their response bias between the two conditions. That patients with mild AD were able to successfully shift their response bias demonstrates that—despite their overall liberal response bias and poor memory relative to controls—one component of metamemorial ability is preserved in patients with mild AD.

Most cognitive neuroscientific research exploring the nature of age-associated compensatory mechanisms has compared old adults (high vs. average performers) to young adults (not split by performance), leaving ambiguous whether findings are truly age-related or reflect differences between high and average performers throughout the lifespan. Here, we examined differences in neural activity (as measured by ERPs) that were generated by high vs. average performing old, middle-age, and young adults while processing novel and target events to investigate the following three questions: 1) Are differences between cognitively high and average performing subjects in the allocation of processing resources (as indexed by P3 amplitude) specific to old subjects, or found throughout the adult lifespan? 2) Are differences between cognitively high and average performing subjects in speed of processing (as indexed by target P3 latency) of similar magnitude throughout the adult lifespan? 3) Where along the information processing stream does the compensatory neural activity attributed to cognitively high performing old subjects begin to take place? Our results suggest that high performing old adults successfully manage the task by a compensatory neural mechanism associated with the modulation of controlled processing and the allocation of more resources, whereas high performing younger subjects execute the task more efficiently with fewer resources. Differences between cognitively high and average performers in processing speed increase with age. Middle-age seems to be a critical stage in which substantial differences in neural activity between high and average performers emerge. These findings provide strong evidence for different patterns of age-related changes in the processing of salient environmental stimuli, with cognitive status serving as a key mediating variable.