Patterns of subjective memory impairment in the elderly: association with memory performance

BACKGROUND: The association of subjective memory impairment (SMI) with cognitive performance in healthy elderly subjects is poor because of confounds such as depression. However, SMI is also a predictor for future dementia. Thus, there is a need to identify subtypes of SMI that are particularly related to inferior memory performance and may represent at-risk stages for cognitive decline.METHOD: A total of 2389 unimpaired subjects were recruited from the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe), as part of the German Competence Network on Dementia. Clusters of SMI according to patterns of response to SMI questions were identified. Gender, age, depressive symptoms, apolipoprotein E (apoE) genotype, delayed recall and verbal fluency were included in a Classification and Regression Tree (CART) analysis to identify discriminators between the clusters. RESULTS: We identified three clusters. Cluster 1 contained subjects without memory complaints. Cluster 2 contained subjects with general memory complaints, but mainly without memory complaints on individual tasks of daily living. Cluster 3 contained subjects with general memory complaints and complaints on individual tasks of daily living. Depressive symptoms, as the first-level discriminator, distinguished between clusters 1 and 2 versus cluster 3. In subjects with only a few depressive symptoms, delayed recall discriminated between cluster 1 versus clusters 2 and 3. CONCLUSIONS: In SMI subjects with only a minor number of depressive symptoms, memory complaints are associated with delayed recall. As delayed recall is a sensitive predictor for future cognitive decline, SMI may be the first manifestation of future dementia in elderly subjects without depression.     

Sex differences in the association of the apolipoprotein E epsilon 4 allele with incidence of dementia,cognitive impairment,and decline

We examined longitudinal associations between the apolipoprotein E ε4 allele (ApoE4⁺ status) and several cognitive outcomes and tested effect modification by sex. Data on 644 non-Hispanic Caucasian adults, from the Baltimore Longitudinal Study of Aging (BLSA) were used. Dementia onset, cognitive impairment and decline were assessed longitudinally. After 27.5 years median follow-up, 113 participants developed dementia. ApoE4⁺ predicted dementia significantly (hazard ratio [HR] = 2.89; 95% confidence interval [CI], 1.93–4.33), with nonsignificant sex differences. Taking all time points for predicting cognition, women had significantly stronger positive associations than men between ApoE4⁺ status and impairment or decline on the California Verbal Learning Test (CVLT; delayed recall and List A total recall) and on Verbal Fluency Test-Categories. This ApoE4 × sex interaction remained significant with Bonferroni correction only for CVLT-delayed recall. Taking time points prior to dementia for cognitive predictions, the positive association between impairment in CVLT-delayed recall and ApoE4⁺ status remained stronger among women, though only before Bonferroni correction. While ApoE4+ status appears to be a sex neutral risk factor for dementia, its association with verbal memory and learning decline and impairment was stronger among women.     

Association analysis of NAD(P)H:quinone oxidoreductase gene 609 C/T polymorphism with Alzheimer's disease

Alterations of the NAD(P)H:quinone oxidoreductase (NQO1) activity are associated with Alzheimer's disease (AD). A polymorphism consisting of a single nucleotide (C-->T) change at position 609 of NQO1 influences the NQO1 activity. Therefore the NQO1 C609T polymorphism may confer susceptibility for AD developing. To test the hypothesis, we have performed an association study between the NQO1 gene polymorphism C609T and late-onset Alzheimer's disease (LOAD) in Chinese population. Totally 104 LOAD patients and 128 controls were enrolled in our data set. All subjects were genotyped for NQO1 and Apolipoprotein E (APOE). There were no significant differences in NQO1 genotype or allele frequencies between cases and controls. Likewise, with the stratification of APOE psilon4 status, no statistical difference was observed between cases and controls. Our findings suggested that this polymorphism might not represent additional genetic risk factor for LOAD. However, the present study cannot exclude NQO1 as a possible candidate for LOAD. Further study in a larger population and biological functional analysis of NQO1 gene is required to verify the role of NQO1 in LOAD.     

APOE ε4 differentially influences change in memory performance depending on age. The SMART-MR study

The apolipoprotein E (APOE) gene may act differently in young and old persons, known as antagonistic pleiotropy. We therefore examined the prospective associations between the APOE ε4 allele and cognitive functioning, and the modifying effect of age, in 375 nondemented adults (mean age 57 ± 10 years; follow-up period 3.8 ± 0.2 years) with available data on APOE genotype and cognitive functioning, within the SMART-MR (Second Manifestations of ARTerial disease-Magnetic Resonance) cohort study. Neuropsychological tests assessing memory performance and executive functioning were performed at baseline and follow-up, and composite z-scores were calculated. Age significantly modified the association of APOE ε4 with change in memory performance (p interaction = 0.02). In persons ≤ 57 years (median split), an APOE ε4 allele was associated with an increase in immediate recall (B = 0.42; 95% confidence interval [CI], 0.17 to 0.66) and delayed recall (B = 0.37; 95% CI, 0.09 to 0.64), while in persons > 57 years, an APOE ε4 allele was associated with decline in immediate recall (B = -0.25; 95% CI, -0.52 to 0.01). Our findings suggest that the APOE ε4 allele has a differential effect on change in verbal memory performance depending on age, consistent with the hypothesis of antagonistic pleiotropy.     

Preliminary data on the effect of culture on the assessment of Alzheimer's disease-related verbal memory impairment with the International Shopping List Test

The International Shopping List Test (ISLT) is a measure of verbal learning and memory, developed specifically for use in people from different cultural and linguistic backgrounds. In this report, we describe two studies that examined the ISLT's ability to detect memory impairment and memory decline in patients with mild Alzheimer's disease (AD) from a range of cultural and linguistic backgrounds. In Study 1, the performance of Australian-English-speaking adults with mild AD was compared with that of native Australian-English- and Korean-speaking patients with mild AD. Compared with controls, patients with AD from both language groups showed large but equivalent impairments in total recall, delayed recall, rate of learning, and primacy and retention-weighted recall (RWR) measures on the ISLT. In Study 2, the rate of deterioration in verbal memory over 1 year was examined in groups of native Canadian-English, French, and Korean speakers with mild AD using the total recall, delayed recall, and RWR measures. Rates of change on all three measures were equivalent across the language groups, although the magnitude of deterioration was most pronounced for the total recall and RWR measures. Taken together, these results suggest that the ISLT is valid and reliable for the assessment of verbal learning and memory impairment and decline in patients with mild AD from diverse language groups.     

Effects of aging and dementia upon recent visuospatial memory

In two experiments, a total of 20 young normals, 29 elderly normals, and 76 elderly demented subjects were administered a computerized delayed visuospatial recall task. Subjects were instructed to remember which room of a 25-room house had a light on in the window. A choice reaction time task was interposed during the delay interval (0–120 seconds) between stimulus presentation and recall. The test was designed to be (1) face valid-relevant to the subjects' everyday lives, (2) sensitive and specific to the cognitive decline associated with senile dementia of the Alzheimer's type (SDAT), and (3) comparable to animal memory tests. Immediate recall of the spatial location of a single stimulus was found to be deficient in severely demented subjects only, and all groups exhibited a decline in recall accuracy with increasing delay intervals. This decline in recall accuracy was greatest in severely demented subjects, smaller in less demented subjects, still smaller in aged normals, and smallest in young normals. No significant forgetting of spatial location occurred between 30 and 120 seconds after stimulus presentation. Increasing stimulus number decreased recall accuracy in all groups and the elderly and elderly demented subjects were more sensitive to the increase in stimulus load than the young normals. Choice reaction time also proved sensitive to age and severity of dementia. Correlation analyses demonstrated that delayed spatial recall (as well as choice reaction time) is highly correltated with clinically evaluated global cognitive status, as well as with tests of verbal recall. These results confirm previous reports that spatial recall is impaired by both age and SDAT. It is concluded that this test procedure and others applying similar approaches should be useful in the assessment of age-related cognitive dysfunction and in the evaluation of potential pharmacological treatments for these disorders.     

Effects of aging and dementia upon recent visuospatial memory

In two experiments, a total of 20 young normals, 29 elderly normals, and 76 elderly demented subjects were administered a computerized delayed visuospatial recall task. Subjects were instructed to remember which room of a 25-room house had a light on in the window. A choice reaction time task was interposed during the delay interval (0–120 seconds) between stimulus presentation and recall. The test was designed to be (1) face valid-relevant to the subjects' everyday lives, (2) sensitive and specific to the cognitive decline associated with senile dementia of the Alzheimer's type (SDAT), and (3) comparable to animal memory tests. Immediate recall of the spatial location of a single stimulus was found to be deficient in severely demented subjects only, and all groups exhibited a decline in recall accuracy with increasing delay intervals. This decline in recall accuracy was greatest in severely demented subjects, smaller in less demented subjects, still smaller in aged normals, and smallest in young normals. No significant forgetting of spatial location occurred between 30 and 120 seconds after stimulus presentation. Increasing stimulus number decreased recall accuracy in all groups and the elderly and elderly demented subjects were more sensitive to the increase in stimulus load than the young normals. Choice reaction time also proved sensitive to age and severity of dementia. Correlation analyses demonstrated that delayed spatial recall (as well as choice reaction time) is highly correltated with clinically evaluated global cognitive status, as well as with tests of verbal recall. These results confirm previous reports that spatial recall is impaired by both age and SDAT. It is concluded that this test procedure and others applying similar approaches should be useful in the assessment of age-related cognitive dysfunction and in the evaluation of potential pharmacological treatments for these disorders.     

Recreational use of 3,4-methylenedioxymethamphetamine (MDMA) or 'ecstasy': evidence for cognitive impairment

BACKGROUND: It has recently been shown that 3,4-methylenedioxymethamphetamine (MDMA) or 'ecstasy' causes long-lasting alterations to brain structure and function in animals, and there is mounting evidence that recreational users of the drug show impairments in some aspects of cognitive functioning including memory for verbal information. The present study investigates possible effects on other cognitive functions and explores the temporal course of development and resolution of these impairments by comparing novice, regular and abstaining users with a matched group of non-users. METHODS: Eighty participants categorized as non-users, novice users, regular users or currently abstinent users of MDMA were assessed on tests of verbal IQ, reversed digit span, immediate and delayed recall of a prose passage and of a complex geometric figure and verbal fluency. RESULTS: The four groups were well-matched for verbal IQ and on demographic variables. They differed in frequency of cannabis use over the last month, but this did not correlate with any cognitive test scores. All three groups of MDMA users showed significantly poorer verbal fluency and immediate and delayed prose recall than non-users. Days since last use and total lifetime consumption of MDMA made separate contributions to the variance in recall scores, accounting jointly for almost half of the variance in delayed recall. By contrast, the groups did not differ on either visual recall or reversed digit span. CONCLUSIONS: The observed deficits provide further evidence of impairments of verbal but not visual memory in MDMA users, and indicate that the deficits are not attributable either to differences in general reasoning ability or to impairment of working memory. The data further suggest that the observed impairments may be attributable to a combination of reversible acute effects of MDMA resolving over a period of 2-3 weeks and more long-term changes associated with extent of lifetime consumption.     

ACE genotype and cognitive decline in an African-Caribbean population

The insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme (ACE) gene is believed to influence risk of cerebrovascular disease. However, associations with cognitive outcomes remain controversial. As far as we are aware, all studies to date have been carried out in white American or European populations. African-Caribbean populations have high prevalence rates of hypertension, diabetes and cerebrovascular disease but risk factors for cognitive outcomes remain under-researched. In a UK community sample of 148 African-Caribbean people aged 55–75 years, we investigated the association between ACE genotype and cognitive decline over 3 years using a battery of repeated tests. No direct association was found between ACE genotype and decline. However, the association between increased age and cognitive decline was significantly stronger in people with the ACE DD genotype (odds ratio 3.6 per 5-year increase, 95% CI: 1.9–6.7) compared to those with ID/II genotype (odds ratio 0.7, 95% CI 0.4–1.2). This interaction was particularly strong for decline in verbal memory and was not apparently mediated by vascular risk factors measured at baseline.     

No associations between Parkinson's disease and polymorphisms of the quinone oxidoreductase (NQO1, NQO2) genes

Reactive oxygen species derived from dopamine metabolism can induce oxidative stress and thus may contribute to Parkinson's disease (PD) pathogenesis. The quinone oxidoreductases, nicotinamide adenine dinucleotide (phosphate) (NAD[P]H): quinone oxidoreductase 1 (NQO1) and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 (NQO2) detoxify quinones and quinonoid compounds. We investigated associations of genetic polymorphisms of NQO1 (C609T) and NQO2 (I/D, 29 base pairs) with PD in a population-based case-control study of 190 idiopathic PD cases and 305 unrelated controls matched on age and sex. No associations were detected for either gene variant or for any allele combinations.     

Does aspirin or other NSAIDs reduce the risk of cognitive decline in elderly persons? Results from a population-based study

OBJECTIVE: To investigate the protective effect of NSAIDs and aspirin separately on cognitive decline in elderly subjects, controlling for consistent use of these agents over a prolonged period of time. METHODS: The study sample consisted of 1007 subjects, drawn from a population-based random sample of elderly individuals, 62-85 years old, who participated in a 3-year follow-up study. From this sample subjects were selected, who did use NSAIDs and completed all cognitive tests at both measurements (n=137), and subjects who did not use NSAIDs and completed all cognitive tests (n=475). Cognitive tests included the Mini-Mental State Examination (MMSE), tests for episodic memory (Auditory Verbal Learning Test) and information processing speed (coding task). Cognitive decline was computed using Edwards-Nunnally method. Multiple logistic regression analyses were performed to examine the association between NSAID (with and without aspirin) and decline in cognitive performance. Besides, the interaction of NSAIDs with age on cognitive decline was determined. RESULTS: The relative risk estimates of decline in episodic memory (immediate recall) adjusted for age, gender, education, baseline MMSE, vascular diseases, diabetes mellitus and (rheumatoid) arthritis for aspirin users only was more than three times reduced (OR: 0.30, 95% CI: 0.09-0.82). The odds ratio for decline in memory of NSAID use without aspirin, adjusted for age, gender, education, baseline MMSE, vascular diseases, diabetes mellitus and (rheumatoid) arthritis was not significant (OR: 1.00, 95% CI: 0.39-2.93). The effect of aspirin was significant only in persons of 75 years and over (OR: 0.10, 95% CI: 0.01-0.81), not in subjects younger than 75 years (OR: 0.52, 95% CI: 0.14-1.96). NSAIDs did not have benefit on information processing speed. In 92% of aspirin users a low dose of 100mg daily or less was used. CONCLUSION: Low-dose aspirin might be protective for decline in memory in individuals of 75 years and over. The benefit of a low-dose aspirin does not support an anti-inflammatory effect, but suggests an antiplatelet effect. Therefore, a possible protective effect of low-dose aspirin on cognitive decline is likely only in subjects with aspirin use over a prolonged period of time.     

中国人NAD(P)H:醌氧化还原酶基因多态性与帕金森病遗传易感性的关系

目的　探讨依赖还原型辅酶 / 醌氧化还原酶 [NAD(P) H:quinone oxidoreductase,NQO1]c DNA6 0 9位点 C→ T多态性与帕金森病 (Parkinson'sdisease,PD)遗传易感性的关系。方法　用聚合酶链反应 -变性高效液相技术 (polymerase chain reaction- denaturing high performance liquid chromatog-raphy,PCR- DHPL C)分析了 NQO1基因c DNA6 0 9位点C→T多态性在 PD患者与正常对照之间分布频率的差异。结果　PD组和对照组的 TT基因型频率分别为 2 2 .6 %和 11.8% (P=0 .0 0 4 ) ,TT基因型使患 PD的危险度提高 2 .186倍 (P=0 .0 0 5 ) ;根据发病年龄分组后 ,这种差异主要存在于晚发性 PD和对照组之间 ,TT基因型使患 PD的危险度提高 2 .6 2 7倍 (P=0 .0 0 1)。等位基因在总体 PD组、早发 PD组、晚发 PD组和对照组中的频率分布差异无显著性。结论　NQO1基因c DNA6 0 9位点C→T多态性在对照组和PD患者之间的分布差异有显著性 ,突变基因型 (TT基因型 )频率在 PD组中较高 ,研究结果支持 NQO1基因多态性与 PD相关的假说 ,而且与 PD发病年龄有关。     

Substantial effects of apolipoprotein E ε4 on memory decline in very old age: longitudinal findings from a population-based sample

We examined associations between the apolipoprotein E (APOE) ε4 allele and levels of performance and rates of change in cognition in late life taking incident dementia into account. The sample consisted of 482 nondemented individuals, aged 80 years and older at baseline, drawn from the OCTO twin study. A battery of 10 cognitive tests was administered at 5 occasions with measurements intervals of 2 years. We fitted hierarchical linear models with time specified as time to death and controlled for baseline age, sex, education, stroke, cardiovascular disease, hypertension, diabetes, and incident dementia. The ε4 allele was significantly associated with lower levels of performance or steeper rate of decline in all 7 memory tests. Largest effect sizes were found in tests of delayed recall and recognition memory. The effects of the APOE ε4 allele were, however, reduced to a nonsignificant level in all tests except 1 after accounting for incident dementia. The findings support the notion that the APOE ε4 allele is associated with substantial memory decline in very old age, but as expected, the effect is largely related to incident dementia.     

The TNF-alpha-238G > a single-nucleotide polymorphism protects against memory decline in older adults with type 2 diabetes

Inflammatory markers predict memory dysfunction in elderly patients, but their contribution to memory deficits in adults with Type 2 diabetes mellitus (T2DM) is less well understood. The present study determined whether specific single-nucleotide polymorphisms in the promoter region of tumor necrosis factor-alpha (TNF-alpha) predict verbal memory in older patients with T2DM. Immediate and delayed verbal memory were assessed using word list and paragraph recall tests in a cohort of subjects with T2DM during 2 sessions, separated by 48 weeks. The presence of the TNF-alpha-238A allele, which has been shown to decrease gene expression, consistently predicted better baseline performance and protected against memory decline over a period of 48 weeks. Therefore, inflammatory mediators may be important modulators of memory function in individuals with T2DM.     

Resting EEG theta power correlates with cognitive performance in healthy older adults

We address the degree to which resting EEG bandpower is associated with cognitive performance in 73 healthy older adults (aged 56-70). Relative theta (4-6.5 Hz) power was significantly correlated with immediate and delayed verbal recall, attention, and executive function measures. Relative delta and alpha power and peak alpha frequency did not correlate with any cognitive measures. These data indicate that high resting theta power in healthy older adults is associated with better cognitive function and may be a marker of healthy neurocognitive aging. Comparison of these with previous findings suggests that two forms of theta-frequency oscillations may exist; one indicative of healthy neurocognitive function and the other, EEG/alpha slowing linked to (future) substantial cognitive decline. Future EEG investigations of cognitive aging or decline should analyze both relative theta power and degree of EEG/alpha slowing so as not to confound these.     

No linkage of P187S polymorphism in NAD(P)H: Quinone oxidoreductase (NQO1/DIA4) and type 1 diabetes in the Danish population

Recent genome screening studies have identified novel regions of possible interest for susceptibility to type 1 diabetes. One of these is a 30‐35 cM region mapping to 16q22‐q24 (D16S515‐D16S520), where also the gene encoding NAD(P)H: quinone oxidoreductase (NQO1) maps. Data has suggested association of a polymorphism (P187S) in the NQO1 gene and type 1 diabetes. NQO1 is involved in protection against oxidative stress, which is likely to be involved in β‐cell destruction. By use of the transmission disequilibrium test (TDT), we analyzed the P187S polymorphism for association to type 1 diabetes in a population‐based sample of 247 Danish nuclear type 1 diabetic families. Random transmission patterns were observed to all affected offspring (p_tdt = 0.82), to index cases (p_tdt = 0.77), as well as to unaffected offspring (p_tdt = 0.93). Hence, the NQO1 polymorphism is not likely to be an etiological mutation underlying the reported linkage of the 16q22‐q24 region. Hum Mutat 14:67–70, 1999. © 1999 Wiley‐Liss, Inc.     

Memory after menopause: preliminary considerations of hormone influence on cognitive functioning

Summary Oestrogen has been shown to have a wide variety of organisational and activating effects on brain structure and function. Despite the significant amount of research investigating the relation and effects of oestrogen to cognitive performance in menopausal women over the past two decades, studies have failed to produce consistent findings. This paper reports on evaluations of eighty-one community-based postmenopausal Australian women comparing current, past and never users of hormone therapy (HT) on a wide range of cognitive measures of general, verbal and visual memory, delayed recall, attention, concentration and verbal comprehension. Few significant differences were found among the three groups in the demographic profile, health status or psychological functioning. Although never users had significantly lower scores on verbal memory than past users, the differences were not statistically significant when adjustments were made controlling for age, education level, verbal comprehension, attention and concentration. These findings challenge long-held beliefs regarding the usefulness of oestrogen supplements as a protective factor against cognitive decline in older women’s later years.     

Medial temporal atrophy rather than white matter hyperintensities predict cognitive decline in stroke survivors

Stroke is an important risk factor for dementia, but the exact mechanisms involved in cognitive decline remain unclear. In this study, we related baseline MRI brain measures with later cognitive decline. Seventy-nine stroke survivors aged 75+ years without dementia were recruited 3-month post-stroke. They underwent yearly neuropsychological assessments and had an MRI at baseline and 2 years. Medial temporal lobe atrophy (MTA) was scored and volume of white matter hyperintensities (WMH) was measured at baseline. The rate of ventricular enlargement was measured by comparing the baseline and repeat images. Linear regression indicated that memory loss was related to both baseline memory and MTA (p=0.001; standardized regression coefficient beta=-0.35) but not WMH volume. The only independent predictor of ventricular enlargement was MTA (p=0.003; beta=0.47). However, no baseline MRI variable differed between those who did (18%) and did not (82%) develop dementia. The association of MTA but not WMH with subsequent cognitive decline and increasing brain atrophy suggests a greater role for Alzheimer type than vascular pathology in delayed cognitive impairment after stroke.     

单胺氧化酶B和NAD(P)H醌氧化还原酶基因多态性与帕金森病的关系

目的 探讨参与多巴胺代谢的单胺氧化酶B（monoamine oxidase B,MAO-B)内含子13A／G多态性,NAD（P）H醌氧化还原酶基因[NAD(P)H:quinone oxidoreductase,NQO1]cDNA609C/T多态性与帕金森病（Parkinson's disease,PD)遗传易感性的关系。方法 应用等位基因特异PCR扩增分析MAO－B基因的多态性,用PCR－RFLP分析NQO1基因多态性。结果 MAO－BA／G等位基因频率、各基因型频率PD组与对照组差异无显著性。NQO1基因T等位基因频率PD组（52％）高于正常对照组（43％）带T碱基的NQO1基因型频率PD组显著高于正常对照组（P＜0．05）,其患PD的相对危险度（odds ratio,OR)为3．8。在带有A等位基因MAO－B基因型的个体,带有T碱基因的T等位基因是PD的危险因素。MAO－B基因的A等位基因型与NQO1基因的T等位基因的基因型可相互协同,增加PD发生的风险。