Lindsay R. Clark

Neuropsychological Criteria for Mild Cognitive Impairment Improves Diagnostic Precision, Biomarker Associations, and Progression Rates

We compared two methods of diagnosing mild cognitive impairment (MCI): conventional Petersen/Winblad criteria as operationalized by the Alzheimers Disease Neuroimaging Initiative (ADNI) and an actuarial neuropsychological method put forward by Jak and Bondi designed to balance sensitivity and reliability. 1,150 ADNI participants were diagnosed at baseline as cognitively normal (CN) or MCI via ADNI criteria (MCI: n = 846; CN: n = 304) or Jak/Bondi criteria (MCI: n = 401; CN: n = 749), and the two MCI samples were submitted to cluster and discriminant function analyses. Resulting cluster groups were then compared and further examined for APOE allelic frequencies, cerebrospinal fluid (CSF) Alzheimers disease (AD) biomarker levels, and clinical outcomes. Results revealed that both criteria produced a mildly impaired Amnestic subtype and a more severely impaired Dysexecutive/Mixed subtype. The neuropsychological Jak/Bondi criteria uniquely yielded a third Impaired Language subtype, whereas conventional Petersen/Winblad ADNI criteria produced a third subtype comprising nearly one-third of the sample that performed within normal limits across the cognitive measures, suggesting this methods susceptibility to false positive diagnoses. MCI participants diagnosed via neuropsychological criteria yielded dissociable cognitive phenotypes, significant CSF AD biomarker associations, more stable diagnoses, and identified greater percentages of participants who progressed to dementia than conventional MCI diagnostic criteria. Importantly, the actuarial neuropsychological method did not produce a subtype that performed within normal limits on the cognitive testing, unlike the conventional diagnostic method. Findings support the need for refinement of MCI diagnoses to incorporate more comprehensive neuropsychological methods, with resulting gains in empirical characterization of specific cognitive phenotypes, biomarker associations, stability of diagnoses, and prediction of progression. Refinement of MCI diagnostic methods may also yield gains in biomarker and clinical trial study findings because of improvements in sample compositions of true positive cases and removal of false positive cases.

Are Empirically-Derived Subtypes of Mild Cognitive Impairment Consistent with Conventional Subtypes?

Given the importance of identifying dementia prodromes for future treatment efforts, we examined two methods of diagnosing mild cognitive impairment (MCI) and determined whether empirically-derived MCI subtypes of these diagnostic methods were consistent with one another as well as with conventional MCI subtypes (i.e., amnestic, non-amnestic, single-domain, multi-domain). Participants were diagnosed with MCI using either conventional Petersen/Winblad criteria (n = 134; >1.5 SDs below normal on one test within a cognitive domain) or comprehensive neuropsychological criteria developed by Jak et al. (2009) (n = 80; >1 SD below normal on two tests within a domain), and the resulting samples were examined via hierarchical cluster and discriminant function analyses. Results showed that neuropsychological profiles varied depending on the criteria used to define MCI. Both criteria revealed an Amnestic subtype, consistent with prodromal Alzheimers disease (AD), and a Mixed subtype that may capture individuals in advanced stages of MCI. The comprehensive criteria uniquely yielded Dysexecutive and Visuospatial subtypes, whereas the conventional criteria produced a subtype that performed within normal limits, suggesting its susceptibility to false positive diagnostic errors. Whether these empirically-derived MCI subtypes correspond to dissociable neuropathologic substrates and represent reliable prodromes of dementia will require additional follow-up.

Specific Measures of Executive Function Predict Cognitive Decline in Older Adults

Decline in executive function has been noted in the prodromal stage of Alzheimers disease (AD) and may presage more global cognitive declines. In this prospective longitudinal study, five measures of executive function were used to predict subsequent global cognitive decline in initially nondemented older adults. Of 71 participants, 15 demonstrated significant decline over a 1-year period on the Dementia Rating Scale (Mattis, 1988) and the remaining participants remained stable. In the year before decline, the decline group performed significantly worse than the no-decline group on two measures of executive function: the Color-Word Interference Test (CWIT; inhibition/switching condition) and Verbal Fluency (VF; switching condition). In contrast, decliners and non-decliners performed similarly on measures of spatial fluency (Design Fluency switching condition), spatial planning (Tower Test), and number-letter switching (Trail Making Test switching condition). Furthermore, the CWIT inhibition-switching measure significantly improved the prediction of decline and no-decline group classification beyond that of learning and memory measures. These findings suggest that some executive function measures requiring inhibition and switching provide predictive utility of subsequent global cognitive decline independent of episodic memory and may further facilitate early detection of dementia.

Susceptibility of the conventional criteria for mild cognitive impairment to false-positive diagnostic errors.

We assessed whether mild cognitive impairment (MCI) subtypes could be empirically derived within the Alzheimers Disease Neuroimaging Initiative (ADNI) MCI cohort and examined associated biomarkers and clinical outcomes.

Effect of Mild Cognitive Impairment and APOE Genotype on Resting Cerebral Blood Flow and its Association with Cognition

Using whole-brain pulsed arterial spin labeling magnetic resonance imaging, resting cerebral blood flow (CBF) was measured in 20 mild cognitive impairment (MCI; 11 ε3 and 9 ε4) and 40 demographically matched cognitively normal (CN; 27 ε3 and 13 ε4) participants. An interaction of apolipoprotein (APOE) genotype (ε3 and ε4) and cognitive status (CN and MCI) on quantified gray-matter CBF corrected for partial volume effects was found in the left parahippocampal and fusiform gyri (PHG/FG), right middle frontal gyrus, and left medial frontal gyrus. In the PHG/FG, CBF was elevated for CN ε4 carriers but decreased for MCI ε4 carriers. The opposite pattern was seen in frontal regions: CBF was decreased for CN ε4 carriers but increased for MCI ε4 carriers. Cerebral blood flow in the PHG/FG was positively correlated with verbal memory for CN ε4 adults (r=0.67, P=0.01). Cerebral blood flow in the left medial frontal gyrus was positively correlated with verbal memory for MCI ε4 adults (r=0.70, P=0.05). Findings support dynamic pathophysiologic processes in the brain associated with Alzheimers disease risk and indicate that cognitive status and APOE genotype have interactive effects on CBF. Correlations between CBF and verbal memory suggest a differential neurovascular compensatory response in posterior and anterior cortices with cognitive decline in ε4 adults.

Interaction of Age and APOE Genotype on Cerebral Blood Flow at Rest

We investigated the impact of APOE genotype on cerebral blood flow (CBF) in older and younger adults. Forty cognitively normal older adults (16 ε4 carriers, 24 non-ε4 carriers) and 30 younger adults (15 ε4 carriers, 15 non-ε4 carriers) completed a resting-state whole-brain pulsed arterial spin labeling magnetic resonance scan. Main effects of aging were demonstrated wherein older adults had decreased gray matter CBF corrected for partial volume effects compared to younger adults in widespread brain regions. Main effects of APOE genotype were also observed wherein ε4 carriers displayed greater CBF in the left lingual gyrus and precuneus than non-carriers. An interaction between age and APOE genotype in the left anterior cingulate cortex (ACC) was characterized by reduced CBF in older ε4 carriers and increased CBF in young ε4 carriers. Increased CBF in the left ACC resulting from the interaction of age group and APOE genotype was positively correlated with executive functioning in young ε4 adults (r = 0.61, p = 0.04). Results demonstrate APOE genotype differentially impacts cerebrovascular function across the lifespan and may modify the relationship between CBF and cognition. Findings may partially support suggestions that the gene exerts antagonistic pleiotropic effects.

Interactive effects of vascular risk burden and advanced age on cerebral blood flow

Vascular risk factors and cerebral blood flow (CBF) reduction have been linked to increased risk of cognitive impairment and Alzheimers disease (AD); however the possible moderating effects of age and vascular risk burden on CBF in late life remain understudied. We examined the relationships among elevated vascular risk burden, age, CBF, and cognition. Seventy-one non-demented older adults completed an arterial spin labeling MR scan, neuropsychological assessment, and medical history interview. Relationships among vascular risk burden, age, and CBF were examined in a priori regions of interest (ROIs) previously implicated in aging and AD. Interaction effects indicated that, among older adults with elevated vascular risk burden (i.e., multiple vascular risk factors), advancing age was significantly associated with reduced cortical CBF whereas there was no such relationship for those with low vascular risk burden (i.e., no or one vascular risk factor). This pattern was observed in cortical ROIs including medial temporal (hippocampus, parahippocampal gyrus, uncus), inferior parietal (supramarginal gyrus, inferior parietal lobule, angular gyrus), and frontal (anterior cingulate, middle frontal gyrus, medial frontal gyrus) cortices. Furthermore, among those with elevated vascular risk, reduced CBF was associated with poorer cognitive performance. Such findings suggest that older adults with elevated vascular risk burden may be particularly vulnerable to cognitive change as a function of CBF reductions. Findings support the use of CBF as a potential biomarker in preclinical AD and suggest that vascular risk burden and regionally-specific CBF changes may contribute to differential age-related cognitive declines.

Language and Task Switching in the Bilingual Brain: Bilinguals are Staying, not Switching, Experts

Bilinguals ability to control which language they speak and to switch between languages may rely on neurocognitive mechanisms shared with non-linguistic task switching. However, recent studies also reveal some limitations on the extent control mechanisms are shared across domains, introducing the possibility that some control mechanisms are unique to language. We investigated this hypothesis by directly comparing the neural correlates of task switching and language switching. Nineteen Spanish-English bilingual university students underwent a functional magnetic resonance imaging (fMRI) study employing a hybrid (event-related and blocked) design involving both color-shape switching and language switching paradigms. We compared the two switching tasks using within-subject voxel-wise t-tests for each of three trial types (single trials in single blocks, and stay and switch trials in mixed blocks). Comparing trial types to baseline in each task revealed widespread activation for single, stay, and switch trials in both color-shape and language switching. Direct comparisons of each task for each trial type revealed few differences between tasks on single and switch trials, but large task differences during stay trials, with more widespread activation for the non-linguistic than for the language task. Our results confirm previous suggestions of shared mechanisms of switching across domains, but also reveal bilinguals have greater efficiency for sustaining the inhibition of the non-target language than the non-target task when two responses are available. This efficiency of language control might arise from bilinguals need to control interference from the non-target language specifically when not switching languages, when speaking in single- or mixed-language contexts.

Cortical and Subcortical Cerebrovascular Resistance Index in Mild Cognitive Impairment and Alzheimer's Disease

BACKGROUNDnReduced regional cerebral blood flow (rCBF) is a well-established finding in Alzheimers disease (AD), although fewer studies have examined the role of increased regional cerebrovascular resistance. By calculating the ratio of mean arterial pressure to rCBF, it is possible to estimate an index of regional cerebrovascular resistance (CVRi) that may be a sensitive measure of occult cerebrovascular disease.nnnOBJECTIVEnTo compare probable AD patients to mild cognitive impairment (MCI) and normal control (NC) participants on CVRi, the ratio of mean arterial pressure to rCBF.nnnMETHODSnEighty-one participants (12 AD, 23 MCI, 46 NC) were compared on CVRi using voxel-wise analyses. Region-of-interest analyses examined correlations between subcortical CVRi and both cognition and white matter lesion (WML) volume.nnnRESULTSnVoxel-wise analyses revealed CVRi elevation in AD relative to NCs (subcortical, medial temporal, posterior cingulate, precuneus, inferior parietal, superior temporal) and MCI (subcortical, posterior cingulate). MCI participants exhibited intermediate CVRi values within cortical and medial temporal areas. Significant CVRi clusters were larger and more widespread than those of parallel CBF analyses. Among MCI and AD participants, subcortical CVRi elevation was associated with lower Dementia Rating Scale score (r = -0.52, p = 0.001, for both thalamus and caudate), and caudate CVRi correlated with WML volume (r = 0.45, p = 0.001).nnnCONCLUSIONSnCortical and subcortical CVRi is elevated in AD, particularly within the caudate and thalamus, where it is associated with decreased cognitive performance and increased WMLs. Findings suggest CVRi may play a role in cognitive decline and cerebrovascular disease in MCI and AD.

Yes/No Versus Forced-Choice Recognition Memory in Mild Cognitive Impairment and Alzheimer's Disease: Patterns of Impairment and Associations with Dementia Severity

Memory tests are sensitive to early identification of Alzheimers disease (AD) but less useful as the disease advances. However, assessing particular types of recognition memory may better characterize dementia severity in later stages of AD. We sought to examine patterns of recognition memory deficits in individuals with AD and mild cognitive impairment (MCI). Memory performance and global cognition data were collected from participants with AD (nu2009=u200937), MCI (nu2009=u200937), and cognitively intact older adults (normal controls, NC; nu2009=u200935). One-way analyses of variance (ANOVAs) examined differences between groups on yes/no and forced-choice recognition measures. Individuals with amnestic MCI performed worse than NC and nonamnestic MCI participants on yes/no recognition, but were comparable on forced-choice recognition. AD patients were more impaired across yes/no and forced-choice recognition tasks. Individuals with mild AD (≥120 Dementia Rating Scale, DRS) performed better than those with moderate-to-severe AD (<120 DRS) on forced-choice recognition, but were equally impaired on yes/no recognition. There were differences in the relationships between learning, recall, and recognition performance across groups. Although yes/no recognition testing may be sensitive to MCI, forced-choice procedures may provide utility in assessing severity of anterograde amnesia in later stages of AD. Implications for assessment of insufficient effort and malingering are also discussed.