The emergence of cognitive discrepancies in preclinical Alzheimer's disease: a six-year case study.

We present neuropsychological data from an 81-year-old individual who was followed over a six-year period, initially as a healthy control participant. She performed above age-adjusted cutoff scores for impairment on most neuropsychological tests, including learning and memory measures, until the final assessment when she received a diagnosis of probable Alzheimer's disease (AD). Despite generally normal scores on individual cognitive tests, her cognitive profile revealed increasingly large cognitive discrepancies when contrasting verbal versus visuospatial tasks, and complex versus basic-level tasks. The present case provides intriguing evidence that cognitive-discrepancy measures could improve our ability to detect subtle changes in cognition at the earliest, preclinical stages of AD.

Cognitive discrepancies versus APOE genotype as predictors of cognitive decline in normal-functioning elderly individuals: a longitudinal study.

OBJECTIVES: Cognitive-discrepancy analysis has been shown to be a useful technique for detecting subtle cognitive deficits in normal-functioning elderly individuals who are genetically at-risk for Alzheimer disease (AD). However, studies that have used cognitive-discrepancy measures to date have used retrospective or cross-sectional designs, and the utility of this approach to predict cognitive decline has not been examined in a prospective investigation. DESIGN: Longitudinal study. SETTING: San Diego, CA, Veterans Administration Hospital. PARTICIPANTS: Twenty-four normal-functioning elderly individuals participated in the study, with 16 subjects exhibiting no change in their Dementia Rating Scale (DRS) scores over an 1-year period (Stable Group), and 8 subjects exhibiting a decline in DRS scores over the 1-year period (Decline group). MEASUREMENTS: A cognitive-discrepancy measure isolating cognitive switching was computed that contrasted performance on a new higher-level task of executive functioning (a Stroop/Switching measure) relative to a composite measure of lower-level Stroop conditions. RESULTS: a) In the year before their cognitive changes, the Decline group exhibited a significantly larger cognitive-discrepancy (Stroop/Switching versus lower-level Stroop conditions) score compared with a control (Stable) group; and b) the cognitive-discrepancy measure was superior to APOE genotype in predicting DRS decline. CONCLUSION: Cognitive-discrepancy analysis isolating a component executive function ability not only seems to be a useful tool for identifying individuals at risk for cognitive deficits, but also shows promise in predicting individuals who may show subtle cognitive decline over time.

Cogniform Disorder and Cogniform Condition: proposed diagnoses for excessive cognitive symptoms.

In neuropsychological practice, individuals often present with evidence of excessive cognitive complaints or invalid test performances indicative of symptom exaggeration; however, clinicians often struggle with how to diagnose these cases once they have been identified. Difficulties in subsuming these individuals within existing DSM-IV diagnoses such as Malingering, Factitious Disorder, and Conversion Disorder are discussed, including: (a) lack of a diagnostic category that adequately targets the specific features of this relatively common condition and (b) the use of criteria that require the clinician to make judgments about internal states that are difficult to evaluate in an objective manner (e.g., intentional versus unintentional production of exaggerated symptoms). Two diagnostic categories--Cogniform Disorder and Cogniform Condition--are proposed as new subtypes of the Somatoform Disorders to encompass cases of excessive cognitive complaints and inadequate test-taking effort in the absence of sufficient evidence to diagnose Malingering. Of the two new categories, Cogniform Disorder is defined as a more pervasive form in which the individual tends to exhibit the excessive cognitive symptoms in widespread areas of his or her life, thereby suggesting a conversion-like adoption of the sick role manifested primarily as cognitive dysfunction. Guidelines for improving the evidence-based diagnosis of these cases, particularly with regards to criteria related to intentionality, secondary gain, and sick role factors, are also discussed.

Heterogeneity in verbal memory: a marker of preclinical Alzheimer's disease?

Demonstrations of memory changes in those at risk for Alzheimer's disease by the presence of the APOE e4 allele have been inconsistent to date. The present study went beyond traditional analyses of central tendency (i.e., group differences on mean test scores) and also conducted distribution analyses to search for subtle cognitive differences in subgroups of normal-functioning elderly persons with the APOE e4 genotype. The results of the study revealed that (a) the e4 and non-e4 groups failed to differ in terms of their mean scores on tests of memory and verbal skills; and (b) relative to the non-e4 group, the e4 subjects had significantly greater heterogeneity of variance on the memory measures but not on fundamental verbal skills. Logistic regression analyses indicated that the discrepancy in scores on the memory measures was a significant predictor of genotype group membership (82% correct classification rate). Implications of these findings for the detection of a preclinical phase of AD are discussed.

Olfactory and auditory event-related potentials in Huntington's disease.

The influence of Huntington's disease (HD) on the olfactory event-related potential (OERP), an electrophysiological measure of olfactory information processing, has not been reported to date. In the present study, olfactory and auditory event-related potentials (ERPs) were recorded monopolarly from Fz, Cz, and Pz electrode sites in 8 patients with HD and 8 age- and gender-matched control participants. Results demonstrated that individuals with HD were delayed compared with controls on the P3 component of the OERP (p<.001), with a trend toward a significant delay on the auditory ERP P3 (p<.06). The effect size for OERP P3 latency (pi(2)=.72) was larger than that for the auditory P3 (pi(2)=.24), which has previously been shown to be delayed in HD. Patients performed significantly worse than controls did on all neuropsychological measures. These measures significantly correlated with several components of the OERP. These findings extend the understanding of olfactory deficits in HD.

Asymmetries in global-local processing ability in elderly people with the apolipoprotein e-epsilon4 allele.

Previous studies have identified cognitive asymmetries in elderly people at increased risk for Alzheimer's disease (AD) by comparing standardized neuropsychological tests of verbal and spatial abilities in both preclinical AD and apolipoprotein epsilon4+ elderly groups. This prospective study investigated cognitive asymmetries within a single test by comparing cognitively intact elderly (with and without the epsilon4+ allele) on a learning and memory measure that uses global and local visuospatial stimuli. Both groups demonstrated comparable overall learning and recall. But the epsilon4+ group had a significantly larger discrepancy between their global and local learning scores and had a greater proportion of individuals with more than a one standard deviation difference between their immediate recall of the global and local elements, relative to the epsilon4- group. These findings build on previous studies identifying subgroups of elderly people at greater risk for AD who often demonstrate increased cognitive asymmetries relative to groups without significant risk factors.

A paradigm for measuring the olfactory event-related potential in the clinic.

Recent research on the olfactory event-related potential (OERP) using inter-stimulus intervals (ISIs) of 90 s and shorter has revealed a marked decrease in component amplitude after the first trial, with a leveling off for the remaining trials. Studies manipulating the ISI in olfactory and other modalities demonstrate an association between higher amplitudes and longer ISIs, suggesting that habituation occurs at short time intervals between each stimulus presentation. The present study attempted to reduce the effects of habituation by using a 10-min ISI and fewer trials. OERPs were recorded monopolarly at the Fz, Cz and Pz electrode sites in ten subjects (five males, five females), for three trials using a 10-min ISI. Results demonstrated no significant reduction in component amplitudes across trials and no significant difference in latencies over trials, indicating no habituation effect at this ISI. These results indicate that with a 10-min ISI and three trial recordings, a complete reduction in habituation can be achieved. These findings may prove to be clinically useful to physicians who can implement this technique to assess olfactory functioning in cognitively impaired individuals or to assess malingering.

Olfactory, auditory, and visual ERPs from single trials: no evidence for habituation.

Event-related potentials (ERPs) using olfactory, auditory, and visual stimuli were recorded from young adults to assess possible component habituation across single trials among modalities. A single-stimulus ERP paradigm was used that employed a 10-min inter-stimulus interval (ISI) to minimize possible sensory adaptation and three stimulus trials for each modality to assess initial habituation effects. The present findings were: (1) P3 amplitude does not habituate appreciably over the initial three trials but may increase from the first to second trial. (2) ERPs from a single-stimulus paradigm with a very long ISI produce significantly correlated component amplitudes for the olfactory, auditory, and visual modalities. (3) P3 amplitude from olfactory stimuli demonstrated scalp topography similar to that for auditory and visual ERPs. These findings suggest that the single-stimulus task using a long ISI produces highly comparable and stable P3 components from olfactory, auditory, and visual stimuli. Application of single-stimulus paradigm to olfactory ERP methods is supported.

Comparison of the traditional recall-based versus a new list-based method for computing semantic clustering on the California Verbal Learning Test: evidence from Alzheimer's disease.

For over 50 years, cognitive psychologists and neuropsychologists have relied almost exclusively on a method for computing semantic clustering on list-learning tasks (recall-based formula) that was derived from an outdated assumption about how learning occurs. A new procedure for computing semantic clustering (list-based formula) was developed for the CVLT-II to correct the shortcomings of the traditional method. In the present study we compared the clinical utility of the traditional recall-based method versus the new list-based method using results from the original CVLT administered to 87 patients with Alzheimer's disease and 86 matched normal control participants. Logistic regression and score distribution analyses indicated that the new list-based method enhances the detection of differences in semantic-clustering ability between the groups.

Identifying the "source" of recognition memory deficits in patients with Huntington's disease or Alzheimer's disease: evidence from the CVLT-II.

The present study compared the performance of individuals with Huntington's disease (HD) and Alzheimer's disease (AD) on three types of California Verbal Learning Test-Second Edition (CVLT-II) recognition discriminability indices (RDI): Source, Novel, and Total. The HD and AD groups did not differ significantly on Source RDI (all 16 targets versus the 16 previously presented, List B, distractors). However, HD patients performed significantly better than AD patients on Total RDI (all 16 targets versus all 32 distractors) and Novel RDI (all 16 targets versus 16 new distractors). Implications of these findings on the differentiation of the memory disorders associated with HD and AD are discussed.

Impairments in source memory for olfactory and visual stimuli in preclinical and clinical stages of Huntington's disease.

Individuals in preclinical and clinical stages of Huntington's disease (HD) demonstrate impairments in olfactory functioning. In addition, HD patients are impaired in source memory for verbal stimuli. A task combining both source and odor memory may be particularly sensitive to early changes in HD. The present study examined source and item memory for olfactory and visual stimuli in 10 individuals with HD, 10 asymptomatic HD gene carriers, 8 nongene carriers who had a parent with HD, and 20 normal controls. During the study phase, a male and a female experimenter (sources) presented odors and objects to the participant in an alternating sequence. To assess item memory, a stimulus from the study phase (target) and a novel stimulus (distractor) were presented, and the participant was asked to choose the target. To assess source memory, the experimenter presented a stimulus and asked whether the male or female experimenter had previously presented the stimulus. Results indicate that source memory for both visual and olfactory stimuli was impaired in HD patients compared to normal controls. In asymptomatic gene carriers, however, source memory for olfactory stimuli, but not visual stimuli, was more impaired than in nongene carriers and normal controls. Furthermore, gene carriers and HD patients showed a similar degree of impairment in source memory for olfactory stimuli. The only significant impairment found in item memory was for olfactory stimuli in HD patients. These results suggest that source memory for olfactory stimuli may be particularly sensitive to neuropathological changes in preclinical stages of HD.

Functional implications of ipsilesional motor deficits after unilateral stroke.

OBJECTIVE: To investigate the functional impact of ipsilesional motor deficits after unilateral stroke and the best predictors of those deficits. DESIGN: Observational cohort. SETTING: Primary care Veterans Affairs and private medical center. PARTICIPANTS: Volunteer right-handed sample; stroke patients with left (LHD) or right hemisphere damage (RHD) a mean of 3.9 to 5.2 years poststroke and able-bodied participants who were tested using their left (LAB) or right hand. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The Jebsen-Taylor Hand Function Test (JHFT). RESULTS: Ipsilesional JHFT performance was impaired to the same extent in the LHD and RHD groups. LHD patients with apraxia had poorer scores on the JHFT than LHD patients without apraxia and the LAB group. Regression analyses showed that severity of apraxia was the best predictor of JHFT performance for the LHD group and that right (ipsilesional) motor performance (grip strength, finger tapping) was the best predictor of JHFT performance for the RHD group. CONCLUSIONS: Ipsilesional deficits are present on simulated activities of daily living after LHD or RHD, suggesting that rehabilitation after stroke should include the ipsilesional arm and that ipsilesional limb apraxia is a better predictor of ipsilesional functional motor skills after LHD than aphasia or simple motor skills (grip strength, finger tapping). These findings suggest that limb apraxia should be assessed more routinely after stroke of the left hemisphere.

Response inhibition and set shifting in patients with frontal lobe epilepsy or temporal lobe epilepsy.

Patients with frontal lobe epilepsy (FLE), patients with temporal lobe epilepsy (TLE), and matched controls were administered a test of response inhibition and set shifting (switching) (Color Word Interference Test, CWIT). Patients with FLE were impaired relative to the controls across all conditions of the CWIT, with the FLE patients showing disproportionate impairment in the Inhibition and Inhibition/Switching conditions. In contrast, the TLE patients did not differ from controls. Further analysis of the patient groups revealed that patients with left FLE were impaired relative to those with right FLE, left TLE, and right TLE in the Inhibition condition. In the Inhibition/Switching condition, patients with left FLE and left TLE were impaired relative to their right-sided counterparts. Finally, performance by the TLE group in the Inhibition/Switching condition was correlated with seizure frequency. These data suggest that patients with FLE, but not TLE, show impaired inhibition and set shifting relative to controls. In addition, side of the seizure focus and seizure frequency may contribute to executive dysfunction in patients with epilepsy.

Deficits in inhibition and flexibility are associated with the APOE-E4 allele in nondemented older adults.

This prospective study of nondemented older adults at genetic risk for AD and other types of dementia (i.e., APOE e4 allele) utilized a new Stroop test that includes a dual executive-function condition requiring both response inhibition and cognitive switching. Results indicated that, relative to non-e4 subjects, the e4 group committed more errors, but only on the new Inhibition/Switching condition. In addition, error-rate variance on this task was more heterogeneous for the e4 compared to the non-e4 group, and errors rates correlated significantly with global cognitive status (i.e., DRS scores) for the e4 group but not for the non-e4 group. These findings suggest that vulnerability to errors in response inhibition and cognitive flexibility is present in persons at risk for AD and may signal early emergence of executive dysfunction in preclinical AD. The association between these subtle executive-function deficits and the overall cognitive functioning of at-risk individuals provides further evidence of their utility as a possible preclinical marker of AD.

Recall discriminability: utility of a new CVLT-II measure in the differential diagnosis of dementia.

Memory tests that are in a recall format have almost universally measured accuracy in terms of the number of target items reported by the examinee. However, this traditional scoring method can, in certain cases, result in artificially inflated memory accuracy scores. That is, just as a "yes" response bias and high false-positive rate on recognition testing can artificially inflate a patient's hit rate, so, too, a liberal response bias and high intrusion rate on recall testing can artificially inflate a patient's level of target recall. Recognition tests correct for this problem by using a discriminability measure that provides a single score of hit rate relative to false-positive rate; however, recall tests rarely provide a single score of recall accuracy that corrects for intrusion rate. In the present study, we examined the utility of a new recall discriminability measure that analyzes target recall relative to intrusion rate. Patients with Alzheimer's disease (AD) or Huntington's disease (HD) were administered the CVLT-II, which provides both the traditional measure of target recall and a new measure of recall discriminability. The results indicate that the new recall discriminability measure was superior to the traditional level of target recall measure in distinguishing the recall performance of AD and HD patients. Implications of these results for clinical practice and theories of memory disorder in dementia are discussed.