Katie Lane

Use of anticholinergics and the risk of cognitive impairment in an African American population

Background: Anticholinergic properties of certain medications often go unrecognized, and are frequently used by the elderly population. Few studies have yet defined the long-term impact of these medications on the incidence of cognitive impairment. Methods: We report a 6-year longitudinal, observational study, evaluating 1,652 community-dwelling African American subjects over the age of 70 years who were enrolled in the Indianapolis-Ibadan Dementia Project between 2001 and 2007 and who had normal cognitive function at baseline. The exposure group included those who reported the baseline use of possible or definite anticholinergics as determined by the Anticholinergic Cognitive Burden scale. Our main outcome measure was the incidence of cognitive impairment, defined as either dementia or cognitive impairment not dementia, or poor performance on a dementia screening instrument during the follow-up period. Results: At baseline, 53% of the population used a possible anticholinergic, and 11% used a definite anticholinergic. After adjusting for age, gender, educational level, and baseline cognitive performance, the number of definite anticholinergics was associated with an increased risk of cognitive impairment (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.07–1.99; p = 0.02), whereas the number of possible anticholinergics at baseline did not increase the risk (OR 0.96, 95% CI 0.85–1.09; p = 0.55). The risk of cognitive impairment among definite anticholinergic users was increased if they were not carriers of the APOE ε4 allele (OR 1.77, 95% CI 1.03–3.05; p = 0.04). Conclusions: Limiting the clinical use of definite anticholinergics may reduce the incidence of cognitive impairment among African Americans.

Association of statin use with cognitive decline in elderly African Americans

Background: Previously reported associations between statin use and incident dementia or cognitive decline have been inconsistent. We report the results from a 3-year prospective study on the association of statin use on cognitive decline and incident dementia in elderly African Americans. Methods: A community-based cohort of 1,146 African Americans aged 70 and older living in Indianapolis, Indiana, was evaluated in 2001 and 2004. The instrument used for cognitive assessment was the Community Screening Interview for Dementia (CSI-D). Cognitive decline was defined as CSI-D scores measured at 2001 minus scores at 2004. Measurements of low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) were obtained from baseline blood samples. Results: Adjusting for age at baseline, gender, education, and the possession of ApoE ε4 allele, baseline statin use was associated with less cognitive decline (p = 0.0177). There were no significant interactions of statin use when LDL-C and CRP were included. Logistic regression with the four independent variables showed that statin use may be associated with a reduction in incident dementia (OR = 0.32; p = 0.0673). Association with cognitive decline was less clear when investigating statin use over time. Significance remained only for those who discontinued prior to follow-up compared to continuous users or users who started after baseline. Conclusions: The relationship between statin use and cognitive decline is complex and subjected to unknown confounders. This effect may not be associated with the cholesterol lowering or anti-inflammatory action of statins. GLOSSARY: AD = Alzheimer disease; ANCOVA = analysis of covariance; BMI = body mass index; CAMDEX = Cambridge Examination for Mental Disorders of the Elderly informant interview; CERAD = Consortium to Establish a Registry for Alzheimer’s Disease; CHIF = Clinician Home-based Interview to assess Function; CRP = C-reactive protein; CSI-D = Community Screening Instrument for Dementia; HDL = high-density lipoprotein; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A; LDL-C = low-density lipoprotein cholesterol; LLAs = lipid-lowering agents; NSAIDs = nonsteroidal anti-inflammatory drugs.

The development of a semi-structured home interview (CHIF) to directly assess function in cognitively impaired elderly people in two cultures.

BACKGROUND Assessing function is a crucial element in the diagnosis of dementia. This information is usually obtained from key informants. However, reliable informants are not always available. METHODS A 10-item semi-structured home interview (the CHIF, or Clinician Home-based Interview to assess Function) to assess function primarily by measuring instrumental activities of daily living directly was developed and tested for inter-rater reliability and validity as part of the Indianapolis-Ibadan dementia project. The primary validity measurements were correlations between scores on the CHIF and independently gathered scores on the Blessed Dementia Scale (from informants) and the Mini-mental State Examination (MMSE). Sensitivities and specificities of scores on the CHIF and receiver operator characteristic (ROC) curves were constructed with dementia as the dependent variable. RESULTS Inter-rater reliability for the CHIF was high (Pearsons correlation coefficient 0.99 in Indianapolis and 0.87 in Ibadan). Internal consistency, in both samples, was good (Cronbachs alpha 0.95 in Indianapolis and 0.83 in Ibadan). Scores on the CHIF correlated well with the Blessed Dementia scores at both sites (-0.71, p < 0.0001 for Indianapolis and -0.56, p < 0.0001 for Ibadan) and with the MMSE (0.75, p < 0.0001 for Indianapolis and 0.44, p < 0.0001 for Ibadan). For all items at both sites, the subjects without dementia performed significantly better than those with dementia. The area under the ROC curve for dementia diagnosis was 0.965 for Indianapolis and 0.925 for Ibadan. CONCLUSION The CHIF is a useful instrument to assess function directly in elderly participants in international studies, particularly in the absence of reliable informants.

Cognitive impairment in community-dwelling older Nigerians: Clinical correlates and stability of diagnosis

To determine correlates and outcome of cognitive impairment without dementia in community‐dwelling elderly Nigerians. A total of 2487 community residents aged 65 years and over were screened using the Community Screening Interview for Dementia. A subset of 423 individuals received diagnostic clinical evaluation. Participants were diagnosed normal, demented, or cognitive impairment no dementia (CIND). Follow‐up clinical diagnostic evaluation was conducted on CIND subjects approximately 2 years later. One hundred and fifty‐two persons were diagnosed CIND. Eighty‐seven CIND subjects were seen at follow‐up assessment, 14 (16.1%) had converted to dementia, 22 (25.3%) reverted to normal, and 51 (58.6%) remained CIND. No baseline factors predicted later development of dementia amongst the CIND subjects. CIND subjects who reverted to normal tended to be male and to have higher baseline cognitive scores. Apolipoprotein status was not related to diagnosis at follow‐up. CIND is common in community‐dwelling Nigerians. Although the outcome is variable, it does represent a high‐risk group for subsequent dementia.

HYPERTENSION AND INCIDENT DEMENTIA IN COMMUNITY-DWELLING ELDERLY YORUBA NIGERIANS

Ogunniyi A, Lane KA, Baiyewu O, Gao S, Gureje O, Unverzagt FW, Murrell JR, Smith‐Gamble V, Hall KS, Hendrie HC. Hypertension and incident dementia in community‐dwelling elderly Yoruba Nigerians.
Acta Neurol Scand: 2011: 124: 396–402.
© 2011 John Wiley & Sons A/S.

Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians

Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimers disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.

Genome-wide association of plasma homocysteine in the indianapolis-ibadan dementia study cohort

SNPs was related to AD and other neurological disorders. Further filtering for brain eQTL involvement identified 84 SNP candidates suitable for further investigation. A pathway enrichment analysis investigating SNP candidates related to AD is ongoing and we expect a wide distribution of involved biological pathways to quantify pathway specificity. Conclusions: The proposed annotation approach poses a promising filtering mechanism to investigate genetic variants associated with AD. Analyzing pathway specificity of these variants can be a powerful technique to prioritize novel biological targets.

P3-289: Apolipoprotein E and phosphodiesterase 4D variants associated with cognitive decline in elderly African-Americans

Background: The brain is the most cholesterol-rich organ in the human body. The metabolic syndrome, a clustering of several commonly disorders that include hyperlipidemia, may be a risk factor for memory decline in the elderly. Apolipoprotein E (Apo E) is a lipoprotein that transports cholesterol and other lipids. The Cyp46 enzyme is a member of the cytochrome P450 family of proteins. It regulates the elimination of excess cholesterol by adding a hydroxyl group to cholesterol. Previous studies have shown that high serum total cholesterol level is a risk factor for dementia, and may be as well as the clinical hallmark for progressive memory impairment. The aim of this study was to clarify the role of lipid-related gene (APOE, CYP46) in memory performance in middle-aged and elderly adults without dementia. Methods: Using cross-section design, 209 cognitively intact participants were recruited. The mean age (SD) was 67.87 (6.80) years, the mean duration of education was 11.07 (3.91) years, and 49.76% were women. Memory and learning function were measured by logical memory (I) (II), world list (I) (II) and spatial span of the Wechsler Memory Scale-III (WMS-III). Serum levels of total cholesterol, triglyceride, HDL/LDL cholesterol, and gene polymorphisms (APOE and CYP46) were analyzed. Results: After adjustment for age, gender, education and socioeconomic status, participants with moderate high cholesterol levels (200-239mg/dL) performed well in learning ability (p 0.0092). There was no significant association between those with and without APOE 4 genotype on Memory performance. On the contrast, CYP46 gene polymorphisms was significantly associated with logical memory performance (p 0.0006). Conclusions: The CYP46 gene polymorphisms may play an important role in episodic memory performance and SNP4-AA genotype may be a risk factor for memory impairment. The moderate high total cholesterol level, however, is positively associated with learning performance. Finally, Cholesterol level, APOE and CYP46 gene polymorphisms have no interaction effect on memory performance.