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1.  Association of Shorter Leukocyte Telomere Repeat Length with Dementia and Mortality 
Archives of neurology  2012;69(10):1332-1339.
Objective
Shortening of chromosomal telomeres is a consequence of cell division, and is a biological factor related to cellular aging and potentially to more rapid organismal biological aging. We have hypothesized that shorter telomere length, as measured in human blood samples, is associated with the development of Alzheimer disease, and with mortality.
Design/Setting
Using data from a multiethnic community-based study of aging and dementia, we studied 1,983 subjects over age 65 yr, who had available stored leukocyte DNA. Mean age-at-blood-draw was 78.3 ± 6.9 yr. Mean age of death was 86.0 ± 7.4 yr. Median follow-up for mortality was 9.3 yr; 190 (9.6%) developed incident dementia. We used real-time PCR to determine mean telomere length (TL) in a modified telomere-sequence to single-copy-gene-sequence ratio method.
Results
TL was inversely related to age, and shorter in men than women. Persons dying during follow-up had shorter TL compared to survivors (6,218±819 vs. 6,491±881 basepairs, p<0.0001) even after adjustment for age, sex, education, and APOE genotype. Individuals who developed dementia had significantly shorter TL (6,131±798 for prevalent cases, and 6,315±817 for incident cases) compared with those remaining dementia-free (6,431±864). Cox-regression analyses showed that shorter TL was a risk for earlier onset of dementia (p=0.05), but stratified analyses for sex showed that this association of age-at-onset of dementia with shorter TL was significant in women, but not in men.
Conclusions
Our findings suggest that shortened leukocyte TL is associated with risks of dementia and mortality, and may therefore be a marker of biological aging.
doi:10.1001/archneurol.2012.1541
PMCID: PMC3622729  PMID: 22825311
biological aging; Alzheimer's disease; apolipoprotein E; leukocyte; DNA
2.  TRANSLATIONAL RESEARCH IN NEUROLOGY: DEMENTIA 
Archives of neurology  2012;69(8):969-977.
Dementia disorders are characterized by clinicopathological criteria. Molecular understandings of these disorders, based on immunohistochemical studies, biochemical investigations, genetic approaches, and animal models have resulted in advances in diagnosis. Likewise translational research has allowed application of increasing basic scientific knowledge regarding neurodegeneration, to the rational development of new investigational therapies based on current understanding of disease pathogenesis. This review discusses application of translational research to both diagnosis and treatment of dementia disorders. The development of biomarkers has yielded imaging and biochemical methods that more assist in the diagnosis of neurodegenerative dementias, especially Alzheimer’s disease. New diagnostic criteria for disease are based on these molecular-based techniques. And these biomarkers are of potential use in monitoring disease activity during therapeutic trials. Translational investigations likewise have led towards new avenues in targeted dementia research. This is particularly so in the development and testing of disease-modifying treatments that might slow or deter progressive deterioration. Recent clinical trials have not been based on empiric trial of established drugs, but rather upon trial of drugs shown through culture and animal models to interfere with known elements of the pathogenetic cascade of Alzheimer disease.
doi:10.1001/archneurol.2011.2883
PMCID: PMC3644591  PMID: 22473767
3.  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
4.  Reduced Purkinje Cell Number in Essential Tremor 
Archives of neurology  2008;65(1):101-107.
Background
Clinical and functional imaging evidence suggests that cerebellar dysfunction occurs in essential tremor (ET). In recent postmortem studies, we documented increased numbers of torpedoes (Purkinje cell axonal swellings) in ET patients without Lewy bodies. Purkinje cell loss, however, has never been rigorously assessed.
Objective
To quantitatively assess the number of Purkinje cells in brains of ET patients and similarly aged controls.
Methods
Postmortem cerebellar tissue was available in 14 ET cases (6 with Lewy bodies and 8 without Lewy bodies) and 11 controls. Calbindin immunohistochemistry was performed on paraffin sections of the cerebellum. Images were digitally recorded and blinded measurements of the number of Purkinje cells per millimeter of cell layer (linear density) were made.
Results
Purkinje cell linear density was inversely correlated with age (r=-0.53, P=.006) and number of torpedoes (r=-0.42, P=.04). Purkinje cell linear density differed by diagnosis (mean [SD], controls, 3.46 [1.27] cells/mm; ET cases with Lewy bodies, 3.33 [1.06] cells/mm; and ET cases without Lewy bodies, 2.14 [0.82] cells/mm; P=.04), with the most significant difference between ET cases without Lewy bodies and controls, where the reduction was 38.2% (P=.04). In an adjusted linear regression analysis that compared ET cases without Lewy bodies with controls, decreased linear density (outcome variable) was associated with ET (β=.56, P=.03).
Conclusions
We demonstrated a reduction in Purkinje cell number in the brains of patients with ET who do not have Lewy bodies. These data further support the view that the cerebellum is anatomically, as well as functionally, abnormal in these ET cases.
doi:10.1001/archneurol.2007.8
PMCID: PMC2847418  PMID: 18195146
5.  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
6.  Association of Glucocerebrosidase Mutations With Dementia With Lewy Bodies 
Archives of neurology  2009;66(5):578-583.
Background
Mutations in the glucocerebrosidase (GBA) gene are associated with Lewy body (LB) disorders.
Objective
To determine the relationship of GBA mutations and APOE4 genotype to LB and Alzheimer disease (AD) pathological findings.
Design
Case-control study.
Setting
Academic research.
Participants
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).
Results
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.
Conclusion
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.
doi:10.1001/archneurol.2009.54
PMCID: PMC2758782  PMID: 19433657
7.  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

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