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1.  Delusions and Hallucinations Are Associated With Worse Outcome in Alzheimer Disease 
Archives of neurology  2005;62(10):1601-1608.
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.
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.
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).
Delusions and hallucinations are very common in AD and predict cognitive and functional decline. Presence of hallucinations is also associated with institutionalization and mortality.
PMCID: PMC3028538  PMID: 16216946
2.  Risk of Parkinson's Disease in Carriers of Parkin mutations: Estimation Using the Kin-Cohort Method 
Archives of neurology  2008;65(4):467-474.
To estimate the risk of Parkinson's disease in individuals with mutations in the Parkin gene.
We assessed point mutations and exon deletions and duplications in the Parkin gene in 247 PD probands with age at onset ≤50 and 104 control probands enrolled in the Genetic Epidemiology of PD study. For each first-degree relative, a consensus diagnosis of PD was established. The probability that each relative carried a mutation was estimated from the proband's Parkin carrier status using Mendelian principles and the relationship of the relative to the proband .
Parkin mutations were identified in 25 PD probands (10.1%), 72% of whom were heterozygotes. One Parkin homozygote reported 2 siblings with PD. The cumulative incidence of PD to age 65 in carrier relatives (age-specific penetrance) was estimated to be 7.0% (95% CI: 0.4-71.9%) compared to 1.7% (95% CI: 0.8-3.4%) in non-carrier relatives of cases (p=0.59) and 1.1% (95% CI: 0.3-3.4%), in relatives of controls ( compared to non-carriers p=0.52).
The cumulative risk of PD to age 65 in a non-carrier relative of a case with AAO ≤50 is not significantly greater than the general population risk among controls. Age specific penetrance among Parkin carriers, in particular heterozygotes, deserves further study.
PMCID: PMC2836931  PMID: 18413468
Parkin; Mutations; Parkinson's disease; Kin-cohort study; Early onset
3.  Seizures in Alzheimer Disease 
Archives of neurology  2009;66(8):992-997.
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.
To determine the incidence and predictors of new-onset unprovoked seizures.
Prospective cohort study.
Three academic centers.
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.
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).
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.
PMCID: PMC2768279  PMID: 19667221
4.  Association of Glucocerebrosidase Mutations With Dementia With Lewy Bodies 
Archives of neurology  2009;66(5):578-583.
Mutations in the glucocerebrosidase (GBA) gene are associated with Lewy body (LB) disorders.
To determine the relationship of GBA mutations and APOE4 genotype to LB and Alzheimer disease (AD) pathological findings.
Case-control study.
Academic research.
The 187 subjects included patients with primary neuropathological diagnoses of LB disorders with or without AD changes (95 cases), randomly selected patients with AD (without significant LB pathological findings; 60 cases), and controls with neither LB nor AD pathological findings (32 cases).
Main Outcome Measures
GBA mutation status, APOE4 genotype, LB pathological findings (assessed according to the third report of the Dementia With Lewy Body Consortium), and Alzheimer plaque and tangle pathological findings (rated by criteria of Braak and Braak, the Consortium to Establish a Registry for Alzheimer Disease, and the National Institute on Aging–Reagan Institute).
GBA mutations were found in 18% (34 of 187) of all subjects, including 28% (27 of 95) of those with primary LB pathological findings compared with 10% (6 of 60) of those with AD pathological findings and 3% (1 of 32) of those without AD or LB pathological findings (P=.001). GBA mutation status was significantly associated with the presence of cortical LBs (odds ratio, 6.48; 95% confidence interval, 2.45–17.16; P<.001), after adjusting for sex, age at death, and presence of APOE4. GBA mutation carriers were significantly less likely to meet AD pathological diagnostic (National Institute on Aging–Reagan Institute intermediate or high likelihood) criteria (odds ratio, 0.35; 95% confidence interval, 0.15–0.79; P=.01) after adjustment for sex, age at death, and APOE4.
GBA mutations may be associated with pathologically “purer” LB disorders, characterized by more extensive (cortical) LB, and less severe AD pathological findings and may be a useful marker for LB disorders.
PMCID: PMC2758782  PMID: 19433657
5.  Quantitative Brain Measures in the Community-Dwelling Elderly with Mild Parkinsonian Signs 
Archives of neurology  2008;65(12):1649-1654.
Mild Parkinsonian signs (MPS) are a marker for incident dementia. MPS have been linked with cerebrovascular disease, which can be evaluated using magnetic resonance imaging (MRI). Also, if MPS are a marker for developing Alzheimer's type changes, hippocampal volume on MRI might be diminished among individuals with MPS.
To examine white matter hyperintensity (WMH) volume and total hippocampal volume in elderly with vs. without MPS.
Community-dwelling elderly in northern Manhattan had a neurological examination and brain MRI. WMH volume (derived on FLAIR-weighted MRI scans using a semi-automated thresholding approach) and total hippocampal volume (manually-derived) were expressed relative to total cranial volume.
MPS were present in 111/666 (16.7%) participants. Relative WMH volume was larger in participants with vs. without MPS (1.70 ± 1.28 vs. 1.17 ± 1.18, p < 0.001) and, in a multivariate logistic regression analysis adjusting for age, gender, years of education, ethnicity, and depression, relative WMH volume was associated with MPS (OR = 1.26, 95% CI = 1.08 − 1.47, p = 0.004). In both unadjusted and adjusted analyses, total relative hippocampal volume was similar in participants with vs. without MPS, regardless of cognitive status.
In this MRI study of the community-dwelling elderly, WMH volume was associated with MPS and total relative hippocampal volume was not. These data raise the possibility that vascular disease could play a role in the development of MPS.
PMCID: PMC2676900  PMID: 19064753
elderly; mild parkinsonian signs; magnetic resonance imaging; hippocampus; Alzheimer's disease; population; epidemiology; white matter hyperintensities

Results 1-5 (5)