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1.  Regional white matter hyperintensity volume, not hippocampal atrophy, predicts incident Alzheimer’s disease in the community 
Archives of neurology  2012;69(12):1621-1627.
Background
New onset Alzheimer’s disease (AD) is often attributed to degenerative changes in the hippocampus. However, the contribution of regionally distributed small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on MRI, remains unclear.
Objective
To determine whether regional WMH and hippocampal volume predict incident AD in an epidemiological study.
Design
A longitudinal community-based epidemiological study of older adults from northern Manhattan.
Setting
The Washington Heights/Inwood Columbia Aging Project
Participants
Between 2005 and 2007, 717 non-demented participants received MRI scans. An average of 40.28 (SD=9.77) months later, 503 returned for follow-up clinical examination and 46 met criteria for incident dementia (45 with AD). Regional WMH and relative hippocampal volumes were derived. Three Cox proportional hazards models were run to predict incident dementia, controlling for relevant variables. The first included all WMH measurements; the second included relative hippocampal volume; and the third combined the two measurements.
Main outcome measures
Incident Alzheimer’s disease.
Results
White matter hyperintensity volume in the parietal lobe predicted time to incident dementia (HR=1.194, p=0.031). Relative hippocampal volume did not predict incident dementia when considered alone (HR=0.419, p=0.768) or with the WMH measures included in the model (HR=0.302, p=0.701). Including hippocampal volume in the model did not notably alter the predictive utility of parietal lobe WMH (HR=1.197, p=0.049).
Conclusion
The findings highlight the regional specificity of the association of WMH with AD. It is not clear whether parietal WMH solely represent a marker for cerebrovascular burden or point to distinct injury compared to other regions. Future work should elucidate pathogenic mechanisms linking WMH and AD pathology.
doi:10.1001/archneurol.2012.1527
PMCID: PMC3597387  PMID: 22945686
Alzheimer’s disease; MRI; cerebrovascular disease; hippocampus
2.  Contribution of vascular risk factors to disease progression in Alzheimer’s Disease 
Archives of neurology  2009;66(3):343-348.
Objective
To determine whether pre-diagnosis vascular risk factors are associated with Alzheimer’s disease progression.
Design
Inception cohort followed longitudinally for a mean of 3.5 (up to 10.2) years.
Setting
Washington Heights Inwood Columbia Aging Project, New York City
Participants
156 incident AD patients (mean age 83 years at diagnosis)
Predictor variables
Vascular factors including medical history (heart disease, stroke, diabetes, hypertension), smoking, and pre-diagnosis blood lipid measurements (total cholesterol, High density lipoproteins (HDL-C), Low density lipoproteins (LDL-C) and triglycerides).
Main Outcome Measure
Change in a composite score of cognitive ability from diagnosis on.
Results
In Generalized Estimating Equation (GEE) models (adjusted for age, race/ethnicity and education), higher cholesterol (total and LDL-C), and diabetes history were associated with faster cognitive decline. Each 10-unit increase in cholesterol and LDL-C was associated with a 10% of a standard deviation decrease in cognitive score per year of follow-up (p<0.001 for total cholesterol, p=0.001 for LDL-C). HDL and triglycerides were not associated with rate of decline. Diabetes history was associated with an additional 50% of a standard deviation decrease in cognitive score per year (p=0.05). History of heart disease and stroke were associated with cognitive decline among APOE-ε4 carriers only. In a final GEE model that included HDL-C, LDL-C and diabetes, only higher LDL-C was independently associated with faster cognitive decline.
Conclusions
Higher pre-diagnosis total cholesterol, LDL-C, and diabetes were associated with faster cognitive decline among incident AD patients, providing further evidence for the role of vascular risk factors in Alzheimer’s disease course.
doi:10.1001/archneur.66.3.343
PMCID: PMC3105324  PMID: 19273753
Alzheimer’s Disease; Natural History; Epidemiology; Cholesterol; Vascular factors
3.  Telephone-based identification of MCI and dementia in a multicultural cohort 
Archives of neurology  2011;68(5):607-614.
Objective
Telephone-based interviews can be used for screening and to obtain key study outcomes when participants in longitudinal studies die or cannot be seen in person, but must be validated among ethnically and educationally diverse people.
Method
The sample consisted of 377 (31% non-Hispanic white, 35% non-Hispanic black, and 34% Caribbean Hispanic) older adults. The validation standard was diagnosis of dementia and mild cognitive impairment (MCI) based on in-person evaluation. The Telephone Interview for Cognitive Status (TICS) and the Dementia Questionnaire (DQ) were administered within the same assessment wave.
Results
The sample included 256 (68%) people with normal cognition, 68 (18%) with MCI, and 53 (14%) with dementia. Validity of the TICS was comparable among non-Hispanic whites, non-Hispanic blacks, and Hispanics, but the DQ had better discrimination of dementia from those without dementia and with MCI among Whites than other groups. Telephone measures discriminated best when used to differentiate demented from nondemented participants (sensitivity/specificity for the TICS = 88%/87%; DQ = 66%/89%) and when used to differentiate cognitively normal participants from those with cognitive impairment (i.e., MCI and demented combined; sensitivity/specificity for the TICS = 73%/77%; DQ = 49%/82%). When demographics and prior memory test performance were used to calculate pre-test probability, consideration of the telephone measures significantly improved diagnostic validity.
Conclusions
The TICS has high diagnostic validity for identification of dementia among ethnically diverse older adults, especially when supported by the DQ and prior visit data. However, telephone interview data were unable to reliably distinguish MCI from normal cognition.
doi:10.1001/archneurol.2011.88
PMCID: PMC3102767  PMID: 21555635
4.  Cognitive Reserve–Mediated Modulation of Positron Emission Tomographic Activations During Memory Tasks in Alzheimer Disease 
Archives of neurology  2004;61(1):73-78.
Background
Cognitive reserve (CR) is the ability of an individual to cope with advancing brain pathological abnormalities so that he or she remains free of symptoms. Epidemiological data and evidence from positron emission tomography suggest that it may be mediated through education or IQ.
Objective
To investigate CR-mediated differential brain activation in Alzheimer disease (AD) subjects compared with healthy elderly persons.
Participants
Using radioactive water positron emission tomography, we scanned 12 AD patients and 17 healthy elderly persons while performing a serial recognition memory task for nonverbalizable shapes under 2 conditions: low demand, in which one shape was presented in each study trial, and titrated demand, in which the study list length was adjusted so that each subject recognized shapes at approximately 75% accuracy. Positron emission tomographic scan acquisition included the encoding and recognition phases. A CR factor score that summarized years of education, National Adult Reading Test estimated IQ, and Wechsler Adult Intelligence Scale–Revised vocabulary subtest score (explaining 71% of the total variance) was used as an index of CR. Voxel-wise, multiple regression analyses were performed with the “activation” difference (titrated demand–low demand) as the dependent variables and the CR factor score as the independent one. Brain regions where regression slopes differed between the 2 groups were identified.
Results
The slopes were significantly more positive for the AD patients in the left precentral gyrus and in the left hippocampus and significantly more negative in the right fusiform, right middle occipital, left superior occipital, and left middle temporal gyri.
Conclusion
Brain regions where systematic relationships (slopes) between subjects’ education-IQ and brain activation differ as a function of disease status may mediate the differential ability to cope with (ie, delay or modify) clinical manifestations of AD.
doi:10.1001/archneur.61.1.73
PMCID: PMC3028435  PMID: 14732623
5.  Association of Life Activities With Cerebral Blood Flow in Alzheimer Disease 
Archives of neurology  2003;60(3):359-365.
Background
Regional cerebral blood flow (CBF), a good indirect index of cerebral pathologic changes in Alzheimer disease (AD), is more severely reduced in patients with higher educational attainment and IQ when controlling for clinical severity. This has been interpreted as suggesting that cognitive reserve allows these patients to cope better with the pathologic changes in AD.
Objective
To evaluate whether premorbid engagement in various activities may also provide cognitive reserve.
Design
We evaluated intellectual, social, and physical activities in 9 patients with early AD and 16 healthy elderly controls who underwent brain H215O positron emission tomography. In voxelwise multiple regression analyses that controlled for age and clinical severity, we investigated the association between education, estimated premorbid IQ, and activities, and CBF.
Results
In accordance with previous findings, we replicated an inverse association between education and CBF and IQ and CBF in patients with AD. In addition, there was a negative correlation between previous reported activity score and CBF in patients with AD. When both education and IQ were added as covariates in the same model, a higher activity score was still associated with more prominent CBF deficits. No significant associations were detected in the controls.
Conclusions
At any given level of clinical disease severity, there is a greater degree of brain pathologic involvement in patients with AD who have more engagement in activities, even when education and IQ are taken into account. This may suggest that interindividual differences in lifestyle may affect cognitive reserve by partially mediating the relationship between brain damage and the clinical manifestation of AD.
PMCID: PMC3028534  PMID: 12633147
6.  Delusions and Hallucinations Are Associated With Worse Outcome in Alzheimer Disease 
Archives of neurology  2005;62(10):1601-1608.
Background
Delusions and hallucinations are common in Alzheimer disease (AD) and there are conflicting reports regarding their ability to predict cognitive decline, functional decline, and institutionalization. According to all previous literature, they are not associated with mortality.
Objective
To examine whether the presence of delusions or hallucinations has predictive value for important outcomes in AD.
Design, Setting, and Participants
A total of 456 patients with AD at early stages (mean Folstein Mini-Mental State Examination [MMSE] score of 21 of 30 at entry) were recruited and followed up semiannually for up to 14 years (mean, 4.5 years) in 5 university-based AD centers in the United States and Europe. Using the Columbia University Scale for Psychopathology in AD (administered every 6 months, for a total of 3266 visit-assessments, average of 7.2 per patient), the presence of delusions and hallucinations was extracted and examined as time-dependent predictors in Cox models. The models controlled for cohort effect, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and baseline functional performance, behavioral symptoms, and use of neuroleptics and cholinesterase inhibitors.
Main Outcome Measures
Cognitive (Columbia MMSE score of ≤20/57 [approximate Folstein MMSE score of ≤10/30]), functional (Blessed Dementia Rating Scale [parts I and II] score of ≥10), institutionalization equivalent index, and death.
Results
During the full course of follow-up, 38% of patients reached the cognitive, 41% the functional, 54% the institutionalization, and 49% the mortality end point. Delusions were noted for 34% of patients at baseline and 70% at any evaluation. Their presence was associated with increased risk for cognitive (risk ratio [RR], 1.50; 95% confidence interval [CI], 1.07-2.08) and functional decline (RR, 1.41; 95% CI, 1.02-1.94). Hallucinations were present in 7% of patients at initial visit and in 33% at any visit. Their presence was associated with increased risk for cognitive decline (RR, 1.62; 95% CI, 1.06-2.47), functional decline (RR, 2.25; 95% CI, 1.54-2.27), institutionalization (RR, 1.60; 95% CI, 1.13-2.28), and death (RR, 1.49; 95% CI, 1.03-2.14).
Conclusions
Delusions and hallucinations are very common in AD and predict cognitive and functional decline. Presence of hallucinations is also associated with institutionalization and mortality.
doi:10.1001/archneur.62.10.1601
PMCID: PMC3028538  PMID: 16216946
7.  Food Combination and Alzheimer Disease Risk 
Archives of neurology  2010;67(6):699-706.
Objective
To assess the association between food combination and Alzheimer disease (AD) risk. Because foods are not consumed in isolation, dietary pattern (DP) analysis of food combination, taking into account the interactions among food components, may offer methodological advantages.
Design
Prospective cohort study.
Setting
Northern Manhattan, New York, New York.
Patients or Other Participants
Two thousand one hundred forty-eight community-based elderly subjects (aged ≥65 years) without dementia in New York provided dietary information and were prospectively evaluated with the same standardized neurological and neuropsychological measures approximately every 1.5 years. Using reduced rank regression, we calculated DPs based on their ability to explain variation in 7 potentially AD-related nutrients: saturated fatty acids, monounsaturated fatty acids, ω-3 polyunsaturated fatty acids, ω-6 poly-unsaturated fatty acids, vitamin E, vitamin B12, and folate. The associations of reduced rank regression–derived DPs with AD risk were then examined using a Cox proportional hazards model.
Main Outcome Measure
Incident AD risk.
Results
Two hundred fifty-three subjects developed AD during a follow-up of 3.9 years. We identified a DP strongly associated with lower AD risk: compared with subjects in the lowest tertile of adherence to this pattern, the AD hazard ratio (95% confidence interval) for subjects in the highest DP tertile was 0.62 (0.43–0.89) after multivariable adjustment (P for trend=.01). This DP was characterized by higher intakes of salad dressing, nuts, fish, tomatoes, poultry, cruciferous vegetables, fruits, and dark and green leafy vegetables and a lower intake of high-fat dairy products, red meat, organ meat, and butter.
Conclusion
Simultaneous consideration of previous knowledge regarding potentially AD-related nutrients and multiple food groups can aid in identifying food combinations that are associated with AD risk.
doi:10.1001/archneurol.2010.84
PMCID: PMC3029147  PMID: 20385883
8.  Mediterranean Diet, Alzheimer Disease, and Vascular Mediation 
Archives of neurology  2006;63(12):1709-1717.
Objectives
To examine the association between the Mediterranean diet (MeDi) and Alzheimer disease (AD) in a different AD population and to investigate possible mediation by vascular pathways.
Design, Setting, Patients, and Main Outcome Measures
A case-control study nested within a community-based cohort in New York, NY. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of AD status (194 patients with AD vs 1790 nondemented subjects) in logistic regression models that were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, medical comorbidity index, and body mass index (calculated as weight in kilograms divided by height in meters squared). We investigated whether there was attenuation of the association between MeDi and AD when vascular variables (stroke, diabetes mellitus, hypertension, heart disease, lipid levels) were simultaneously introduced in the models (which would constitute evidence of mediation).
Results
Higher adherence to the MeDi was associated with lower risk for AD (odds ratio, 0.76; 95% confidence interval, 0.67–0.87; P<.001). Compared with subjects in the lowest MeDi tertile, subjects in the middle MeDi tertile had an odds ratio of 0.47 (95% confidence interval, 0.29–0.76) and those at the highest tertile an odds ratio of 0.32 (95% confidence interval, 0.17–0.59) for AD (P for trend <.001). Introduction of the vascular variables in the model did not change the magnitude of the association.
Conclusions
We note once more that higher adherence to the MeDi is associated with a reduced risk for AD. The association does not seem to be mediated by vascular comorbidity. This could be the result of either other biological mechanisms (oxidative or inflammatory) being implicated or measurement error of the vascular variables.
doi:10.1001/archneur.63.12.noc60109
PMCID: PMC3024906  PMID: 17030648
9.  Extrapyramidal signs before and after the diagnosis of incident Alzheimer disease in a prospective population study 
Archives of neurology  2009;66(9):1120-1126.
Background
Extrapyramidal signs (EPS) are commonly accepted as a feature of Alzheimer’s disease (AD) and may influence both the profile of impairment and prognosis.
Objective
To examine rates of occurrence and risk factors for all types of EPS and to describe the impact of EPS over time on AD clinical course.
Methods
A total of 389 subjects with incident AD (mean age 79 years, 71% females), coming from an urban community (WHICAP), was followed up longitudinally for a mean of 3.6 years (range 0.7 to 13.1 years). EPS were rated using a standardized portion of the Unified Parkinson’s disease Rating scale. Prevalence and incidence rates and cumulative risk for non drug-induced EPS were calculated. Rates of change over time of EPS taking into account potential covariates were also estimated. Predictors of EPS were identified with a Cox model, controlling for age, sex, education and ethnicity.
Results
EPS were detected in 12.3% of patients at first evaluation and 22.6% for the last evaluation. In a multivariate-adjusted generalized estimating equation models of change, total EPS score increased at an annual rate of 1.3%. Women (RR 1.57, p=0.026), subjects with a higher age (RR 1.029, p=0.02) and with EPS (RR 2.07, p=0.001) at baseline had greater rates of cognitive decline.
Conclusion
EPS occur frequently and progress significantly in AD. Subjects with incident AD and concomitant EPS have a faster rate of cognitive decline than subjects with incident AD but without EPS.
doi:10.1001/archneurol.2009.196
PMCID: PMC2896248  PMID: 19752301
10.  Seizures in Alzheimer Disease 
Archives of neurology  2009;66(8):992-997.
Background
Transient symptoms in Alzheimer disease (AD) are frequent and include seizures, syncope, and episodes of inattention or confusion. The incidence of seizures in AD and predictors of which patients with AD might be more predisposed to them is based primarily on retrospective studies and is not well established.
Objective
To determine the incidence and predictors of new-onset unprovoked seizures.
Design
Prospective cohort study.
Setting
Three academic centers.
Patients
Four hundred fifty-three patients with probable AD observed prospectively from mild disease stages since 1992.
Main Outcome Measure
Informant interviews every 6 months included questions about whether the patient had a seizure (convulsion, fainting, or “funny” spell) and whether diagnosis or treatment for epilepsy or seizure was made. Two epileptologists independently retrospectively reviewed all available medical records for 52 patients with positive responses to either of these questions, and using a specific checklist form, events were diagnosed as to whether they were unprovoked seizures (intrarater concordance, κ=0.67). Diagnosis of unprovoked seizures constituted the event in survival analyses. Potential predictors included sex, age, race/ethnicity, educational achievement, duration of illness, baseline cognition and function, depression, medical comorbidities, and time-dependent use of cholinesterase inhibitors and neuroleptic agents, apolipoprotein E genotype, and previous electroencephalographic findings.
Results
Over the course of 3518 visit-assessments (per patient: mean, 7.8; maximum, 27), 7 patients (1.5%) developed seizures. Younger age was associated with higher risk (hazard ratio, 1.23; 95% confidence interval, 1.08–1.41; P=.003 for each additional year of age) of seizure incidence. No other predictor was significant. The overall incidence of seizures was low (418 per 100 000 person-years of observation) although significantly higher than expected for idiopathic unprovoked seizures in similar age ranges of the general population (hazard ratio, 8.06; 95% confidence interval, 3.23–16.61).
Conclusions
Unprovoked seizures are uncommon in AD, but they do occur more frequently than in the general population. Younger age is a risk factor for seizures in AD.
doi:10.1001/archneurol.2009.130
PMCID: PMC2768279  PMID: 19667221
11.  Measuring cerebral atrophy and white matter hyperintensity burden to predict the rate of cognitive decline in Alzheimer disease 
Archives of neurology  2008;65(9):1202-1208.
Objective
Although non-specific, cerebral atrophy and white matter hyperintensities (WMH) are features of the neurodegeneration associated with Alzheimer’s disease (AD). The purpose of the current study was to determine if baseline measurements of cerebral atrophy and WMH predict the rate of future cognitive decline in AD.
Design
Data were drawn from the Predictors Study, a longitudinal study that enrolls mild AD patients and re-asseses them every six months with the Columbia modified Mini Mental State Examination (mMMS; 0–57). MR images were analyzed to determine the severity of WMH (Scheltens Scale) and the degree of atrophy (bicaudate ratio). Generalized estimating equations (GEE) were used to determine whether severity of baseline MRI measurements and their interaction predicted the rate of mMMS decline at subsequent visits.
Setting
Three university-based AD centers in the United States (Predictors Study).
Participants
Eighty-four AD patients from the Predictors Study received structural MRI at baseline and were selected for analysis. They had an average of 6 follow-up evaluations.
Main outcome measure
Cognitive (Columbia modified Mini-Mental State Examination).
Results
Generalized estimating equation models demonstrated that degree of baseline atrophy (β = −0.316, p = 0.036), severity of WMH (β = −0.173, p = 0.028), and their interaction (β = − 6.061, p = 0.018) predicted rate of decline in mMMS scores.
Conclusions
Both degree of cerebral atrophy and severity of WMH are associated with the rapidity of cognitive decline in AD. Atrophy and WMH may interact to have a synergistic effect on future decline, such that AD patients with a high degree of both have a particularly precipitous cognitive course. These findings lend further support to the hypothesis that cerebrovascular pathology contributes to the clinical syndrome of Alzheimer’s disease.
doi:10.1001/archneur.65.9.1202
PMCID: PMC2629007  PMID: 18779424
Alzheimer’s disease; MRI; neuropsychological assessment
12.  Disruptive Behavior as a Predictor in Alzheimer Disease 
Archives of neurology  2007;64(12):1755-1761.
Background
Disruptive behavior is common in Alzheimer disease (AD). There are conflicting reports regarding its ability to predict cognitive decline, functional decline, institutionalization, and mortality.
Objective
To examine whether the presence of disruptive behavior has predictive value for important outcomes in AD.
Design
Using the Columbia University Scale for Psychopathology in Alzheimer Disease (administered every 6 months, for a total of 3438 visit-assessments and an average of 6.9 per patient), the presence of disruptive behavior (wandering, verbal outbursts, physical threats/violence, agitation/restlessness, and sundowning) was extracted and examined as a time-dependent predictor in Cox models. The models controlled for the recruitment cohort, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and functional performance, and neuroleptic use.
Setting
Five university-based AD centers in the United States and Europe (Predictors Study).
Participants
Four hundred ninety-seven patients with early-stage AD (mean Folstein Mini-Mental State Examination score, 20 of 30 at entry) who were recruited and who underwent semiannual follow-up for as long as 14 (mean, 4.4) years.
Main Outcome Measures
Cognitive (Columbia Mini-Mental State Examination score, ≤ 20 of 57 [approximate Folstein Mini-Mental State Examination score, ≤ 10 of 30]) and functional (Blessed Dementia Rating Scale score, parts I and II, ≥ 10) ratings, institutionalization equivalent index, and death.
Results
At least 1 disruptive behavioral symptom was noted in 48% of patients at baseline and in 83% at any evaluation. Their presence was associated with increased risks of cognitive decline (hazard ratio 1.45 [95% confidence interval (CI), 1.03–2.03]), functional decline (1.66 [95% CI, 1.17–2.36]), and institutionalization (1.47 [95% CI, 1.10–1.97]). Sundowning was associated with faster cognitive decline, wandering with faster functional decline and institutionalization, and agitation/restlessness with faster cognitive and functional decline. There was no association between disruptive behavior and mortality (hazard ratio, 0.94 [95% CI, 0.71–1.25]).
Conclusion
Disruptive behavior is very common in AD and predicts cognitive decline, functional decline, and institutionalization but not mortality.
doi:10.1001/archneur.64.12.1755
PMCID: PMC2690610  PMID: 18071039
13.  Mediterranean Diet and Mild Cognitive Impairment 
Archives of neurology  2009;66(2):216-225.
Background
Higher adherence to the Mediterranean diet (MeDi) may protect from Alzheimer’s disease (AD) but its association with Mild Cognitive Impairment (MCI) has not been explored.
Objective
To investigate the association between MeDi and MCI.
Design, Setting, Patients, Outcomes
In a multiethnic community study in New York, we used Cox proportional hazards to investigate the association between adherence to the MeDi (0 – 9 scale; higher scores higher adherence) and (1) incidence of MCI and (2) progression from MCI to AD. All models were adjusted for cohort, age, gender, ethnicity, education, APOE genotype, caloric intake, body mass index and time duration between baseline dietary assessment and baseline diagnosis.
Results
There were 1393 cognitively normal participants, 275 of whom developed MCI during 4.5 (± 2.7, 0.9–16.4) years of follow-up. Compared to subjects in the lowest MeDi adherence tertile, subjects in the middle MeDi tertile had 17 % (HR, 0.83; 95% CI, 0.62 – 1.12; p=0.24) less risk of developing MCI, while those at the highest MeDi adherence tertile had 28 % (HR, 0.72; 95% CI, 0.52 – 1.00; p=0.05) less risk of developing MCI (trend HR, 0.85; 95% CI, 0.72 – 1.00; p for trend= 0.05). There were 482 subjects with MCI, 106 of whom developed AD during 4.3 (± 2.7, 1.0 – 13.8) years of follow-up. Compared to subjects in the lowest MeDi adherence tertile, subjects in the middle MeDi adherence tertile had 45 % (HR, 0.55; 95% CI, 0.34 – 0.90; p=0.01) less risk of developing AD, while those at the highest MeDi adherence tertile had 48 % (HR, 0.52; 95% CI, 0.30 – 0.91; p=0.02) less risk of developing AD (trend HR, 0.71; 95% CI, 0.53 – 0.95; p for trend= 0.02).
Conclusions
Higher adherence to the MeDi is associated with a trend for reduced risk for developing MCI and with reduced risk for MCI conversion to AD.
doi:10.1001/archneurol.2008.536
PMCID: PMC2653223  PMID: 19204158
14.  The Association Between Genetic Variants in SORL1 and Alzheimer’s Disease in an Urban, Multiethnic, Community-Based Cohort 
Archives of neurology  2007;64(4):501-506.
Context
Variants in 3′ and 5′ regions of SORL1, the neuronal sorting protein-related receptor, were recently found to be associated with late onset familial and sporadic Alzheimer’s disease in several datasets that were selected for familial aggregation or were ethnically diverse or clinic-based selected series.
Objective
To investigate the association between Alzheimer’s disease and variant alleles in SORL1 using a series of single nucleotide polymorphisms (SNPs) in an urban, multiethnic community-based population.
Design & Setting
We used a nested case-control analysis in a population-based, prospective study of aging and dementia in Medicare recipients, 65 years and older, residing in northern Manhattan.
Participants
There were 296 patients with probable Alzheimer’s disease and 428 healthy elderly controls. The participants were of African American (34%), Caribbean Hispanic (51%) or non-Hispanic whites (15%).
Main Outcome Measures
We genotyped all 29 SNPs in SORL1 that were examined in the earlier report. We assessed allelic association with AD using standard case-control methods which included APOE genotype as a covariate.
Results
Several individual SNPs and SNP haplotypes were significantly associated with AD in this prospectively collected community-based cohort, confirming the previously reported positive association of SORL1 with Alzheimer’s disease. SNP 12 near the 5′ region was associated with AD in African-Americans and Hispanics. Two SNPs in the 3′ region were also associated with AD in African-Americans (SNP 26) and Whites (SNP 20). A single haplotype in the 3′ region was associated with AD in Hispanics. However, several different haplotypes were associated with AD in the African-Americans and Whites, including the “TTC” haplotypes at SNPs 23–25 (p=0.035) that was significantly associated with AD in the North European Whites in the previous report.
Conclusions
This study confirms the association between genetic variants in SORL1 and AD. While the associations observed in these datasets overlap with those previously reported, the finding of novel SNP and haplotype associations suggest that there may be extensive allelic heterogeneity in SORL1. Broad regions of the SORL1 gene will therefore need to be scrutinized for functional pathogenic variants.
doi:10.1001/archneur.64.4.501
PMCID: PMC2639214  PMID: 17420311
SORL1; Alzheimer’s disease; sporadic; African American; Caribbean Hispanic
15.  Distinct Pools of Aβ in Alzheimer’s Disease Brain: A Clinical-Pathological Study 
Archives of neurology  2008;65(7):906-912.
Objective
Most measures of Aβ are elevated in Alzheimer’s Disease (AD) brain, but correlate inconsistently with disease severity. Since specific forms of Aβ may differentially correlate with clinical features, we segregated Aβ into distinct biochemical pools which may be enriched in biologically-relevant forms of Aβ.
Design
Clinical-pathological correlation
Subjects
27 subjects from a longitudinal study of AD, and 13 age- and gender- matched controls without known history of cognitive impairment or dementia.
Interventions
Temporal and cingulate neocortex were processed using a 4-step extraction, yielding biochemical fractions which are hypothesized to be enriched with proteins from distinct anatomical compartments: Tris (extracellular-soluble), Triton (intracellular), SDS (membrane-associated), Formic Acid (FA) (extracellular-insoluble). Aβ40 and Aβ42 were quantified in each biochemical compartment by ELISA.
Results
Aβ42 from all biochemical compartments was significantly elevated in AD cases vs. controls (p < 0.01). Aβ40 in the Tris and FA fractions were elevated in AD (temporal, p < 0.01; cingulate, p = 0.03), however Triton and SDS Aβ40 were similar in AD and controls. Functional impairment proximal to death correlated with Triton Aβ42 (r = 0.482, p = 0.015) and SDS Aβ42 (r = 0.409, p = 0.042) in temporal cortex. Faster cognitive decline was associated with elevated temporal SDS Aβ42 (p < 0.001) , while slower decline was associated with elevated cingulate FA Aβ42 and SDS Aβ42 (p = 0.02, p = 0.01).
Conclusions
Intracellular and membrane-associated Aβ, especially Aβ42 in temporal neocortex, may be more closely related to AD symptoms than other measured Aβ species.
doi:10.1001/archneur.65.7.906
PMCID: PMC2586606  PMID: 18625856
16.  A Controlled Prospective Study of Neuropsychological Dysfunction Following Carotid Endarterectomy 
Archives of neurology  2002;59(2):217-222.
Background
Although subtle cognitive injury as revealed by neuropsychological testing occurs in a substantial number of patients following carotid endarterectomy (CEA), there is controversy about whether this finding is a result of the surgery or the anesthesia.
Objectives
To examine the changes in neuropsychological test performance in patients following CEA vs a control group of patients older than 60 years following spine surgery, so as to determine whether neuropsychological dysfunction after CEA is a result of surgery or anesthesia.
Methods
Patients undergoing CEA (n=80) and lumbar spine surgery (n=25) were assessed with a battery of neuropsychological tests preoperatively and on postoperative days 1 and 30. The neuropsychological performance of patients in the control group was used to normalize performance for patients in the CEA group, by calculating z scores using the mean and SD of the change scores in the control group. Significant cognitive dysfunction was defined as performance that exceeded 2 SDs above the mean performance of patients in the control group.
Results
Postoperative days 1 and 30 total deficit scores were significantly worse in the CEA group compared with the controls. When individual test results were examined, the CEA group performed significantly worse than the controls on the Rey Complex Figure test and Halstead-Reitan Trails B on day 1, and on the Rey Complex Figure on day 30. Overall, cognitive dysfunction was seen in 22 patients (28%) in the CEA group on day 1 and in 11 (23%) of 48 patients on day 30.
Conclusions
Subtle cognitive decline following CEA occurs and persists for at least several weeks after surgery. This decline was absent in a control group.
PMCID: PMC2435245  PMID: 11843692

Results 1-16 (16)