Eike Wehling

Interactive effects of APOE and CHRNA4 on attention and white matter volume in healthy middle-aged and older adults

In the present study, we investigated age-related changes in interactions between efficiency of neuronal repair mechanisms and efficiency of cholinergic neurotransmission in the context of attentional orienting. In addition, we explored white matter volume changes as possible neuronal underpinnings. A sample of 230 healthy middle-aged (53–64 years) and older (65–75 years) adults was genotyped for polymorphisms of APOE and CHRNA4, a nicotinic receptor subunit gene. Participants were administered a visuospatial attention task involving letter discrimination with location cues of varying validity. Genotype effects on white matter volume were also investigated in a subset of participants who received MRI scans. APOE interacted with CHRNA4, such that APOE-ε4 carriers who were also CHRNA4 TT homozygotes showed disproportionately slowed reaction time (RT) following invalid location cues. The interaction was stronger in the middle-aged participants than in the older participants. There was also a trend for individuals with combined APOE-ε4/CHRNA4 TT genotypes to show both lower white matter volume and slower overall RT on the attention task. The interaction of a neurotransmission gene (CHRNA4) and a susceptibility gene (APOE) suggests that the efficiency of neuronal repair mechanisms may modulate the cholinergic system to influence attentional function.

Hippocampal volumes are important predictors for memory function in elderly women

BackgroundNormal aging involves a decline in cognitive function that has been shown to correlate with volumetric change in the hippocampus, and with genetic variability in the APOE-gene. In the present study we utilize 3D MR imaging, genetic analysis and assessment of verbal memory function to investigate relationships between these factors in a sample of 170 healthy volunteers (age range 46–77 years).MethodsBrain morphometric analysis was performed with the automated segmentation work-flow implemented in FreeSurfer. Genetic analysis of the APOE genotype was determined with polymerase chain reaction (PCR) on DNA from whole-blood. All individuals were subjected to extensive neuropsychological testing, including the California Verbal Learning Test-II (CVLT). To obtain robust and easily interpretable relationships between explanatory variables and verbal memory function we applied the recent method of conditional inference trees in addition to scatterplot matrices and simple pairwise linear least-squares regression analysis.ResultsAPOE genotype had no significant impact on the CVLT results (scores on long delay free recall, CVLT-LD) or the ICV-normalized hippocampal volumes. Hippocampal volumes were found to decrease with age and a right-larger-than-left hippocampal asymmetry was also found. These findings are in accordance with previous studies. CVLT-LD score was shown to correlate with hippocampal volume. Multivariate conditional inference analysis showed that gender and left hippocampal volume largely dominated predictive values for CVLT-LD scores in our sample. Left hippocampal volume dominated predictive values for females but not for males. APOE genotype did not alter the model significantly, and age was only partly influencing the results.ConclusionGender and left hippocampal volumes are main predictors for verbal memory function in normal aging. APOE genotype did not affect the results in any part of our analysis.

Individual variation in a cholinergic receptor gene modulates attention.

Cholinergic influences on attention are well documented and recent evidence indicates that genetic variation in the alpha4beta2 nicotinic receptor affects attentional networks of the brain. Several behavioral and electrophysiological studies have shown that a common polymorphism in the CHRNA4 gene (rs1044396) affects aspects of visual and auditory attentional processing. We examined genetic effects on neuropsychological measures of memory and attention in an adult life-span sample (N=488). TT homozygotes perform speed and attention tasks more slowly than TC or CC allele carriers, with stronger effects on complex attention tasks in participant 70-79 years of age. There are no parallel effects on memory function. The results are consistent with clinical studies indicating that reduction in nicotinic receptor efficiency affects attention and speed, but not memory. Both normal age-related changes in receptor function and incipient pathology may have contributed to the results.

Unawareness of Olfactory Dysfunction and its Association with Cognitive Functioning in Middle Aged and Old Adults

The objective of this study was (a) to investigate the accordance of self-reported and objectively assessed olfactory functioning and (b) to compare performance on cognitive tests of individuals unaware of their olfactory dysfunction with individuals aware of their olfactory status. Two hundred forty participants, constituting two age groups, were evaluated with the Scandinavian Odor Identification Test, a question of self-evaluated olfactory function, tests of cognitive function, and a memory questionnaire. The proportion of individuals being unaware of an olfactory dysfunction was high in both middle aged (86%) and old (78%) participants. Performance on neuropsychological tests showed that persons unaware of their olfactory dysfunction performed poorer on tests of verbal learning and memory and attention/processing speed compared to individuals aware of a normal olfactory status as well as individuals aware of their olfactory dysfunction. The clinical relevance of unawareness of olfactory dysfunction, as suggested earlier, needs further investigation and stresses the need of an extensive multi-modal and longitudinal assessment of unawareness of sensory and cognitive function to learn more about the facets of the concept of unawareness.

Age and sex related changes in episodic memory function in middle aged and older adults

Age-related change in episodic memory function is commonly reported in older adults. When detected on neuropsychological tests, it may still be difficult to distinguish normal from pathological changes. The present study investigates age-and sex-related changes in a group of healthy middle-aged and older adults, participating in a three-wave study on cognitive aging. The California Verbal Learning test (CVLT-II) was used to assess their episodic memory function. A cross-sectional analysis of results from the first wave showed higher performance in females than males, with a steeper age-related decline in males. This was confirmed in a longitudinal analysis using a mixed effects regression model, but with a lower age-related change and smaller difference between the sexes. Information about learning strategies and errors in the third wave turned out to contribute significantly to explain change in episodic memory function across the three waves. We argue that the results from the longitudinal analyses are generalizable to the population of healthy middle-aged and older individuals, and that they could be useful in guiding clinicians when evaluating individuals with respect to cognitive change.

Neuropsychological functioning in a national cohort of severe traumatic brain injury: demographic and acute injury-related predictors

Objectives:To determine the rates of cognitive impairment 1 year after severe traumatic brain injury (TBI) and to examine the influence of demographic, injury severity, rehabilitation, and subacute functional outcomes on cognitive outcomes 1 year after severe TBI. Setting:National multicenter cohort study over 2 years. Participants:Patients (N = 105), aged 16 years or older, with Glasgow Coma Scale score of 3 to 8 and Galveston Orientation and Amnesia Test score of more than 75. Main Measures: Neuropsychological tests representing cognitive domains of Executive Functions, Processing Speed, and Memory. Injury severity included Rotterdam computed tomography score, Glasgow Coma Scale score, and posttraumatic amnesia (PTA) duration, together with length of rehabilitation and Glasgow Outcome Scale–Extended score. Results:In total, 67% of patients with severe TBI had cognitive impairment. Executive Functions, Processing Speed, and Memory were impaired in 41%, 58%, and 57% of patients, respectively. Using multiple regression analysis, Processing Speed was significantly related to PTA duration, Glasgow Outcome Scale–Extended score, and length of inpatient rehabilitation (R2 = 0.30); Memory was significantly related to Glasgow Outcome Scale–Extended score (R2 = 0.15); and Executive Functions to PTA duration (R2 = 0.10). Rotterdam computed tomography and Glasgow Coma Scale scores were not associated with cognitive functioning at 1 year postinjury. Conclusion:Findings highlight cognitive consequences of severe TBI, with nearly two-thirds of patients showing cognitive impairments in at least 1 of 3 cognitive domains. Regarding injury severity predictors, only PTA duration was related to cognitive functioning.

APOE status and its association to learning and memory performance in middle aged and older Norwegians seeking assessment for memory deficits

BackgroundWe examined the hypothesis that deficits in learning, memory, and other cognitive functions are associated with the ε4 allele of the Apolipoprotein E (APOE) gene in a non-demented sample with memory complaints recruited from a population with a high prevalence of this allele.MethodsThe study group comprised 70 consecutively referred patients aged 50–75 seeking assessment due to memory complaints. They were screened for dementia, for neurological and psychiatric disease, and for cerebral infarction using Magnet Resonance Imaging (MRI). Participants were classified as non-demented based on clinical evaluation and results on cognitive tests.ResultsAPOE ε4 carriers (56% of the sample) showed poorer performance than non-carriers on the Mini Mental State Examination, a number of measures of verbal memory function from the California Verbal Learning Test, and visual recall. In 46% of the participants, psychometric criteria for amnestic Mild Cognitive Impairment (aMCI) were satisfied.ConclusionFindings may be partly explained by a significant number of participants being in a preclinical phase of Alzheimers disease. The observed deficits in learning performance and the lack of significant age modulation of the genetic association suggest a more general genetic effect. The findings are consistent with known neurobiological function of APOE ε4, including both increased risk of neurodegenerative disease and reduced synaptic integrity in older age.

Olfactory identification and its relationship to executive functions, memory, and disability one year after severe traumatic brain injury.

OBJECTIVE To explore the frequency of posttraumatic olfactory (dys)function 1 year after severe traumatic brain injury (TBI) and determine whether there is a relationship between olfactory identification and neuropsychological test performance, injury severity and TBI-related disability. METHOD A population-based multicenter study including 129 individuals with severe TBI (99 males; 16 to 85 years of age) that could accomplish neuropsychological examinations. Olfactory (dys)function (anosmia, hyposmia, normosmia) was assessed by the University of Pennsylvania Smell Identification Test (UPSIT) or the Brief Smell Identification Test (B-SIT). Three tests of the Delis-Kaplan Executive Function System (D-KEFS) were used to assess processing speed, verbal fluency, inhibition and set-shifting, and the California Verbal Learning Test-II was used to examine verbal memory. The Glasgow Outcome Scale-Extended (GOSE) was used to measure disability level. RESULTS Employing 2 different smell tests in 2 equal-sized subsamples, the UPSIT sample (n = 65) classified 34% with anosmia and 52% with hyposmia, while the B-SIT sample (n = 64) classified 20% with anosmia and 9% with hyposmia. Individuals classified with anosmia by the B-SIT showed significantly lower scores for set-shifting, category switching fluency and delayed verbal memory compared to hyposmia and normosmia groups. Only the B-SIT scores were significantly correlated with neuropsychological performance and GOSE scores. Brain injury severity (Rotterdam CT score) and subarachnoid hemorrhage were related to anosmia. Individuals classified with anosmia demonstrated similar disability as those with hyposmia/normosmia. CONCLUSIONS Different measures of olfaction may yield different estimates of anosmia. Nevertheless, around 1 third of individuals with severe TBI suffered from anosmia, which may also indicate poorer cognitive outcome.

Epistasis between APOE and nicotinic receptor gene CHRNA4 in age related cognitive function and decline.

Healthy participants (n = 237) aged 45-79 were tested neuropsychologically with tests of memory, speed, and cognitive control and followed up for 3-5 years (mean, 3.4 years). The sample was genotyped for apolipoprotein E (APOE) and CHolinergic Receptor for Nicotine Alpha 4 (CHRNA4), and genetic effects on cognitive function at initial testing and on cognitive decline was studied. We predicted relatively stronger effects of APOE on memory, and of CHRNA4 on speeded tasks. The predictions were partially confirmed, but we found interactive effects of APOE and CHRNA4 in several cognitive domains. Being an APOE epsilon4/CHRNA4 TT carrier was associated with slower and less efficient performance, and with steeper decline in speed tasks and in delayed recall. Age dependent genetic effects were found for both APOE and CHRNA4, where old participants (60-79 years) showed a negative influence of TT carrier status on initial memory performance, but a tendency for steeper memory decline in epsilon4 carriers. Inconsistent and small effects of APOE reported in previous studies of healthy groups may be caused by failure to consider epistasis of APOE with nicotinic receptor and other genes.

Familiarity, Cued and Free Odor Identification and Their Association with Cognitive Functioning in Middle Aged and Older Adults

ABSTRACT The aim of the present study was to examine the association between familiarity of odors, cued and free odor identification performance and cognitive function in elderly adults. It was further investigated how age affects performance on the various odor tasks. A third aim was to investigate the role of familiarity in explaining performance on the free identification task. One hundred and thirty-six participants (aged 45–79 years) with normal olfactory sensitivity were assessed with the Scandinavian Odor Identification Test (SOIT) and standardized tests of cognitive function. Familiarity did not correlate with any measure of cognitive function, while verbal identification performance was associated with several cognitive measures, although correlations were modest. In this sample, free odor identification was affected by increasing age to a marginally larger extent than cued identification performance and familiarity ratings. The results suggest that the different olfactory tasks involve different levels of cognitive processing.