Working memory performance predicts subjective cognitive complaints in HIV infection

The authors examined the contribution of working memory performance to subjective cognitive complaints in HIV infection beyond the influence of depressive symptoms. Thirty-six adults with HIV infection were administered neuropsychological (NP) tests of working memory, complex psychomotor efficiency, verbal learning, delayed recall, and questionnaires measuring depressive symptoms and cognitive complaints. Working memory performance, depression scores, and complex psychomotor efficiency were most strongly associated with self-reported cognitive complaints, whereas verbal learning scores and simple psychomotor efficiency showed more modest associations. Regression analyses revealed working memory performance to be the strongest NP predictor of self-reported cognitive complaints, comparable with depression scores in the amount of variance explained. These results suggest that working memory performance may be well suited to reflect how patients function in their everyday environment.     

Subjective cognitive decline predicts future deterioration in cognitively normal patients with Parkinson's disease

Increasing evidence suggests that subjective cognitive decline (SCD) is a potential predictor of future cognitive decline or dementia. We investigated whether SCD in patients with Parkinson's disease (PD) is a predictor of future cognitive decline. Forty-six cognitively normal patients with PD were selected using comprehensive neuropsychological tests, and classified depending on the presence (PD-SCD⁺, n = 25) or absence of SCD (PD-SCD⁻, n = 21). After a mean follow-up of 2.4 years, we repeated the cognitive assessments with the same subjects. The clinical characteristics and cognitive performance of the 2 groups did not differ at baseline. At the follow-up assessment, 11 patients in the PD-SCD⁺ group (44.0%) and 2 in the PD-SCD⁻ group (9.5%) were diagnosed with mild cognitive impairment (MCI), and the PD-SCD⁺ patients showed more rapid decline in semantic fluency and visuospatial memory tasks than those in the PD-SCD⁻ group. A multivariate logistic regression analysis showed that presence of SCD (odds ratio, 8.378; 95% confidential interval, 1.472–47.683, p = 0.017) and higher Unified PD Rating Scale motor score of 20 or more (odds ratio, 4.539; 95% confidential interval, 1.004–20.528; p = 0.049) were risk factors for incident MCI. Present results demonstrate that SCD in cognitively normal patients with PD is an independent risk factor for incident MCI and acts as a predictor for future cognitive decline.     

Diabetes, aging, and cognitive decline

Type 1 diabetes is associated with cognitive changes in children and adults, but the extent to which cognition declines with increasing age, and increasing duration of diabetes, remains poorly understood. This cross-sectional study assessed neuropsychological performance on 200 diabetic and 175 nondiabetic adults, 18-64 years of age, stratified into five age bands. Similar age-related cognitive declines were seen on measures of problem-solving, learning and memory, and psychomotor speed, but it was only on the latter measure that diabetic and nondiabetic subjects differed significantly. The best predictor of psychomotor slowing was the presence of clinically significant biomedical complications, particularly proliferative retinopathy, peripheral neuropathy, and peripheral vascular disease (PVD). It now appears that psychomotor slowing is the fundamental cognitive deficit associated with diabetes mellitus; why other cognitive skills are relatively unaffected remains poorly understood.     

Predicting memory decline in normal elderly: genetics, MRI, and cognitive reserve

Major predictors of Alzheimer's disease (AD) include apolipoprotein E (APOE)-epsilon4, hippocampal atrophy on magnetic resonance imaging (MRI), and memory dysfunction prior to diagnosis. We examined 159 normal elderly subjects with MRI and the California Verbal Learning Test (CVLT); 84 returned for longitudinal follow-up 5 years later. Analyses at baseline revealed significant variance in hippocampal volume accounted for by cerebral volume and age but not by APOE isoform. However, interactions involving APOE isoform and laterality were observed. As hypothesized, an APOE x time interaction was revealed for CVLT long-delay free recall: APOE-epsilon3/4 subjects had significantly poorer performance than APOE-epsilon3/3 subjects at follow-up. Forward stepwise multiple regression analysis predicting follow-up long-delay free recall selected baseline recall, followed by number of APOE-epsilon4 alleles, followed by left-hippocampal volume. Age and sex did not enter into the model. We conclude that APOE-epsilon4 predicts longitudinal memory decline in healthy controls and that MRI morphometry of hippocampus adds slightly to predictive value.     

Age-related cognitive decline during normal aging: the complex effect of education.

The purpose of this study was to further analyze the effects of education on cognitive decline during normal aging. An 806-subject sample was taken from five different Mexican regions. Participants ranged in age from 16 to 85 years. Subjects were grouped into four educational levels: illiterate, 1-4, 5-9, and 10 or more years of education, and four age ranges: 16-30, 31-50, 51-65, and 66-85 years. A brief neuropsychological test battery (NEUROPSI), standardized and normalized in Spanish, was administered. The NEUROPSI test battery includes assessment of orientation, attention, memory, language, visuoperceptual abilities, motor skills, and executive functions. In general, test scores were strongly associated with level of educational, and differences among age groups were smaller than differences among education groups. However, there was an interaction between age and education such as that among illiterate individuals scores of participants 31-50 years old were higher than scores of participants 16-30 years old for over 50% of the tests. Different patterns of interaction among educational groups were distinguished. It was concluded that: (a) The course of life-span changes in cognition are affected by education. Among individuals with a low level of education, best neuropsychological test performance is observed at an older age than among higher-educated subjects; and (b) there is not a single relationship between age-related cognitive decline and education, but different patterns may be found, depending upon the specific cognitive domain.     

Implicit category learning performance predicts rate of cognitive decline in nondemented patients with Parkinson's disease

Nondemented patients with Parkinson's disease (PD) are impaired in learning to categorize simple perceptual stimuli when category membership is defined by a nonlinear relationship between stimulus dimensions but not when the relationship is linear (J. V. Filoteo, W. T. Maddox, D. P. Salmon, & D. D. Song, 2005). In the present study, the authors examined whether performance in either of these 2 category learning conditions was predictive of global cognitive decline following a mean of 1.6 years since the time patients were 1st seen. Results indicated that final block accuracy in the nonlinear condition, but not the linear condition, predicted global cognitive decline. Performance on the Wisconsin Card Sorting Test (WCST) did not significantly predict global cognitive decline, although there was a trend for this to be the case. In addition, the association between nonlinear category learning and global cognitive decline was not impacted by patients' performance on the WCST. Results suggest that nonlinear category learning predicts cognitive decline in nondemented patients with PD and that nonlinear category learning and WCST performances may provide independent measures of integrity of the posterior and anterior caudate, respectively.     

Structural correlates of cognitive domains in normal aging with diffusion tensor imaging

The involvement of brain structures in specific cognitive functions is not straightforward. In order to characterize the brain micro-structural correlates of cognitive domains, 52 healthy subjects, age 25–82 years, completed a computerized neuropsychological battery and were scanned using magnetic resonance diffusion tensor imaging. Factor analysis of 44 different cognitive scores was performed, isolating three cognitive domains—executive function, information processing speed and memory. Partial correlation was conducted between DTI parameters and each of the three cognitive domains controlling for age and motor function. Regions showing significant correlations with cognitive domains are domain-specific and are consistent with previous knowledge. While executive function was correlated with diffusion tensor imaging (DTI) parameters in frontal white matter and in the superior longitudinal fasciculus, information processing speed was correlated with DTI parameters in the cingulum, corona radiata, inferior longitudinal fasciculus, parietal white matter and in the thalamus. Memory performance was correlated with DTI measures in temporal and frontal gray matter and white matter regions, including the cingulate cortex and the parahippocampus. Thus, inter-subject variability in cognitive performance and tissue morphology, as expressed by diffusion tensor magnetic resonance imaging, can be used to relate tissue microstructure with cognitive performance and to provide information to corroborate other functional localization techniques.     

Memory and cognitive function in normal aging

Memory and cognitive function are known to decline in normal aging. This impairment is due both to inevitable biologic attrition of brain function and to intercurrent disease processes. Memory storage, speed of response, channel capacity, and Performance IQ on the Wechsler Adult Intelligence Scale tend to be most impaired; Verbal IQ and previously learned skills (“crystallized intelligence”) tend to be preserved. Differences between individuals, independent of age, are often more significant than age‐related losses until very advanced age. The biases of cross‐sectional and longitudinal studies may exaggerate or minimize age‐related differences and should be recognized.     

Prediction of longitudinal cognitive decline in normal elderly with subjective complaints using electrophysiological imaging

An extensive literature reports changes in quantitative electroencephalogram (QEEG) with aging and a relationship between magnitude of changes and degree of clinical deterioration in progressive dementia. Longitudinal studies have demonstrated QEEG differences between mild cognitively impaired (MCI) elderly who go on to decline and those who do not. This study focuses on normal elderly with subjective cognitive complaints to assess the utility of QEEG in predicting future decline within 7 years. Forty-four normal elderly received extensive clinical, neurocognitive and QEEG examinations at baseline. All study subjects (N = 44) had only subjective complaints but no objective evidence of cognitive deficit (evaluated using the Global Deterioration Scale [GDS] score, GDS stage = 2) at baseline and were re-evaluated during 7-9 year follow-up. Baseline QEEGs of Decliners differed significantly (p < 0.0001, by MANOVA) from Non-Decliners, characterized by increases in theta power, slowing of mean frequency, and changes in covariance among regions, especially on the right hemisphere. Using logistic regression, an R2 of 0.93 (p < 0.001) was obtained between baseline QEEG features and probability of future decline, with an overall predictive accuracy of 90%. These data indicate high sensitivity and specificity for baseline QEEG as a differential predictor of future cognitive state in normal, subjectively impaired elderly.     

Blood pressure variability predicts cognitive decline in Alzheimer's disease patients

The aim of our study was to evaluate whether blood pressure variability influences the rate of cognitive decline in Alzheimer's disease (AD). Two hundred and forty AD patients were periodically evaluated for a 12-month period. The blood pressure (BP) status of each patient was defined through mean and coefficient of variation for both systolic and diastolic BP. Progression of cognitive decline was investigated using the Mini Mental State Examination administered at entry and at the end of follow-up. Among the considered BP indices, only systolic BP variability explained the decrease in the Mini Mental State Examination score after adjustment for confounding variables (multiple linear regression: R² = 0.603, adjusted R² = 0.513; p < 0.001; logistic regression model: odds ratio = 2.882, 95% confidence interval = 1.772–4.495; p < 0.001). The receiver operating characteristic analysis for evaluating the ability of systolic BP variability to predict a faster cognitive decline presented an area under the curve of 0.913 (95% confidence interval = 0.874–0.953; p < 0.001). Our results suggest that BP variability may be added to the list of the potential vascular risk factors and included in the evaluation of AD patients to better define their risk profile.     

Pupillary cholinergic hypersensitivity predicts cognitive decline in community dwelling elders

Previous research demonstrated that it is possible to distinguish patients with probable Alzheimer's disease from age-matched controls based on an exaggerated pupil dilation response to dilute tropicamide. The research reported here employed a prospective longitudinal design to follow over time (2-4 years) a sample of 55 community dwelling elders with and without an exaggerated pupil response using the pupil assay and a comprehensive battery of neuropsychological tests sensitive to pre-clinical AD. Discrete time survival modeling was used to assess the ability of the assay to predict a pattern of cognitive decline consistent with early AD. Analysis showed that there is an increased risk (odds ratio of 3) with a hypersensitive pupil response (>/=13% increase in pupil diameter over baseline diameter) for developing significant cognitive impairment in areas of memory attention and language in a pattern, consistent with pre-clinical Alzheimer's disease. When controlling for ApoE allele type the odds ratio for pupil response as a risk factor increased to 4. The analysis also found that an exaggerated pupil response was a significant (p=.02) predictor of cognitive decline. This analysis of longitudinal data has shown that over time an exaggerated response on the pupil assay is a significant independent risk factor for developing pre-clinical Alzheimer's disease. The risk for developing pre-clinical Alzheimer's disease is increased four-fold.     

Role of neuroendocrine pathways in cognitive decline during aging

The pineal and pituitary-adrenocortical secretions play an important role in adaptive responses of the organism acting as coordinating signals for both several biological rhythms and multiple neuroendocrine and metabolic functions.The more relevant neuroendocrine changes occurring with ageing affect the secretion of melatonin and of corticosteroids. These changes may be clearly appreciated by the study of their circadian rhythmicity.The circadian profile of plasma melatonin was clearly flattened in elderly subjects and even more in old individuals with dementia. Indeed, the impairment of melatonin signal occurring in aging was related either to age itself or to the cognitive performances of subjects.The biosynthetic dissociation between glucocorticoids and androgen secretion is responsible for the selective impairment of androgens, such as DHEA and DHEA-S, by comparison to cortisol.Due to the opposite effects of the two kinds of corticosteroids either in the periphery and in the CNS, the imbalance between glucocorticoids and androgens, well demonstrated by the evaluation of the cortisol/DHEA-S molar ratio, may be responsible for the occurrence in the CNS of a more neurotoxic steroidal milieu, already present in clinically healthy elderly subjects and especially in patients with dementia. The effects of that steroidal milieu are more prominent at the level of the hippocampal-limbic structure, involved both in the modulation of endocrine structures, such as the HPA axis, and in the control of cognitive, behavioral and affective functions.     

Episodic memory in normal aging and Alzheimer disease: Insights from imaging and behavioral studies

Age-related cognitive changes often include difficulties in retrieving memories, particularly those that rely on personal experiences within their temporal and spatial contexts (i.e., episodic memories). This decline may vary depending on the studied phase (i.e., encoding, storage or retrieval), according to inter-individual differences, and whether we are talking about normal or pathological (e.g., Alzheimer disease; AD) aging. Such cognitive changes are associated with different structural and functional alterations in the human neural network that underpins episodic memory. The prefrontal cortex is the first structure to be affected by age, followed by the medial temporal lobe (MTL), the parietal cortex and the cerebellum. In AD, however, the modifications occur mainly in the MTL (hippocampus and adjacent structures) before spreading to the neocortex. In this review, we will present results that attempt to characterize normal and pathological cognitive aging at multiple levels by integrating structural, behavioral, inter-individual and neuroimaging measures of episodic memory.     

The development of neurobiological models for cognitive decline in aging

Neurobiological models are important for identifying the effects of aging that contribute to cognitive decline and for developing interventions to either prevent those changes or restore more optimal function. As a starting point, this paper considers one type of approach using cholinergic deficiency within the hippocampal system as a model for age-related spatial learning impairment. It is suggested that this approach, based on producing a target lesion in the brain, is inadequate for investigating the aging process. As an alternative, a systems-level approach to the development of more useful and accurate models of neurobiological aging is advocated.     

DNA base excision repair gene polymorphisms modulate human cognitive performance and decline during normal life span

To test the hypothesis that single nucleotide polymorphisms (SNPs) in DNA repair genes are associated with cognitive performance during normal aging, the relationship between SNPs in selected exons in DNA base excision repair (BER) genes and cognitive performance was examined in 712 healthy Norwegian individuals aged 20-75 years. SNPs examined included PolB(Pro242Arg), hOGG1(Ser326Cys), MutYH (Met22Val), MutYH(His324Gln), APE1(Gln51His), APE1(Glu148Asp), XRCC1(Lys298Asn), XRCC1(Arg7Leu), NEIL1(Asp252Asn), and NEIL2(Arg257Leu). XRCC1(Arg7Leu) and PolB(Pro242Arg) were characterized by single nucleotide variations (≤0.1% homozygote SNPs). hOGG1(Ser326Cys) (Ser/Cys 40.8%/Cys/Cys 5.7%), MutYH(His324Gln) (His/Gln37%/Gln/Gln 6.0%) and APE1(Glu148Asp) (Glu/Asp 51.3%/Asp/Asp 23.0%) were characterized by higher SNP frequencies. MutYH(Met22Val), APE1(Gln51His) and NEIL2(Arg257Leu) occurred at intermediate SNP frequencies of 11.5, 7.6 and 5.3%, respectively. Interestingly, hOGG1(Ser326Cys) and APE1(Gln51His) had genotype by age interactions with general cognitive function, reasoning, control and speed of processing in cross-sectional analysis and a significant effect on longitudinal decline. Dispersed association effects involving MutYH(His324Gln), MutYH(Met22Val), PolB(Pro242Arg) and NEIL2(Arg257Leu) were also detected when APOE or CHRNA4, were included in the statistical model, a result consistent with proposed involvement of the latter markers in human cognitive decline and/or function. In summary, the results support the notion that polymorphisms in BER genes modulate cognitive performance in healthy elderly individuals.     

COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome

Although schizophrenia is strongly hereditary, there are limited data regarding biological risk factors and pathophysiological processes. In this longitudinal study of adolescents with 22q11.2 deletion syndrome, we identified the catechol-O-methyltransferase low-activity allele (COMT(L)) as a risk factor for decline in prefrontal cortical volume and cognition, as well as for the consequent development of psychotic symptoms during adolescence. The 22q11.2 deletion syndrome is a promising model for identifying biomarkers related to the development of schizophrenia.     

Changes in cognitive functioning associated with normal aging.

The present study explores age-related changes in cognitive functioning in a cohort of 122 healthy elderly volunteer subjects over a 3-year period. The sample was partitioned into four age groups: 57-65, 66-70, 71-75, 76-85 years. The results suggested high stability of factor structure over three testing probes, as well as selective attrition effect with significantly lower performance in those subjects, who dropped out from the study on the tests of verbal memory and mental speed. The results of repeated measures MANOVA on raw scores and univariate ANOVAs on factor scores comparing four age groups at each testing probe revealed a differential pattern of changes in verbal and nonverbal perception/memory versus mental speed/mental flexibility. Implications of these findings in clinical diagnostics were considered.     

Reduced baroreflex cardiac sensitivity predicts increased cognitive performance

Abstract This study evaluated the relationship between baroreceptor reflex sensitivity and cognitive performance. Twenty normal subjects performed the Uchida-Kraepelin test, a serial arithmetic task. Baroreceptor reflex sensitivity during a 5-min Uchida-Kraepelin test was assessed in minute periods by spectral analysis using the maximum-entropy method. During the task, baroreceptor reflex sensitivity was significantly reduced. There was an inverse between-subjects association between baroreceptor reflex sensitivity and the level of performance (number of additions completed) both at different time periods of the Uchida-Kraepelin test and during the whole task (r=-.51). This finding supports the existence of a pathway mediating mutual cardiovascular-central nervous system influences through the baroreceptors, establishing an essential mechanism facilitating adaptive reactions to stressful conditions.