Search tips
Search criteria

Results 1-25 (59)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
Document Types
1.  Adjustment for Measurement Error in Evaluating Diagnostic Biomarkers by Using an Internal Reliability Sample 
Statistics in medicine  2013;32(27):10.1002/sim.5878.
Biomarkers are often measured with error due to imperfect lab conditions or temporal variability within subjects. Using an internal reliability sample of the biomarker, we develop a parametric bias-correction approach for estimating a variety of diagnostic performance measures including sensitivity, specificity, the Youden index with its associated optimal cut-point, positive and negative predictive values, and positive and negative diagnostic likelihood ratios when the biomarker is subject to measurement error. We derive the asymptotic properties of the proposed likelihood-based estimators and show that they are consistent and asymptotically normally distributed. We propose confidence intervals for these estimators and confidence bands for the receiver operating characteristic curve. We demonstrate through extensive simulations that the proposed approach removes the bias due to measurement error and outperforms the naïve approach (which ignores the measurement error) in both point and interval estimation. We also derive the asymptotic bias of naïve estimates and discuss conditions in which naïve estimates of the diagnostic measures are biased towards estimates produced when the biomarker is ineffective (i.e., when sensitivity equals 1 – specificity) or are anti-conservatively biased. The proposed method has broad biomedical applications and is illustrated using a biomarker study in Alzheimer's disease. We recommend collecting an internal reliability sample during the biomarker discovery phase in order to adequately evaluate the performance of biomarkers with careful adjustment for measurement error.
PMCID: PMC3808490  PMID: 23765915
biomarkers; diagnostic measures; maximum likelihood; measurement error; replicate data
2.  Differential Longitudinal Decline on the Mini-Mental State Examination in Frontotemporal Lobar Degeneration and Alzheimer's Disease 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e31827bdc6f.
To examine how phenotype affects longitudinal decline on the Mini-Mental State Examination (MMSE) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD)
The MMSE is the most commonly administered assessment for dementia severity; however, the effects of phenotype on longitudinal MMSE performance in FTLD and AD have not been extensively studied.
Data from 185 patients diagnosed with AD (n=106) and three FTLD (n=79) phenotypes (behavioral variant frontotemporal dementia [bvFTD], nonfluent agrammatic variant of primary progressive aphasia [nfaPPA], and semantic variant PPA [svPPA]) were collected for up to 52 months since initial evaluation.
Differential rates of decline were noted in that MMSE scores declined more precipitously for AD and svPPA compared to bvFTD and nfaPPA patients (p=0.001). The absolute 4-year MMSE decline given median baseline MMSE for bvFTD (14.67, 95% confidence interval [CI]: 14.63-14.71) and nfaPPA (11.02, 95% CI: 10.98-11.06) were lower than svPPA (22.32, 95% CI: 22.29-22.34) or AD (22.24, 95% CI: 22.22-22.26).
These data suggest that within-group AD and FTLD phenotypes present distinct patterns of longitudinal decline on the MMSE. MMSE may not be adequately sensitive to track disease progression in some phenotypes of FTLD.
PMCID: PMC3648632  PMID: 23314064
MMSE; Alzheimer's disease; frontotemporal lobe dementia; longitudinal assessment
3.  Building An Integrated Neurodegenerative Disease Database At An Academic Health Center 
It is becoming increasingly important to study common and distinct etiologies, clinical and pathological features, and mechanisms related to neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration (FTLD). These comparative studies rely on powerful database tools to quickly generate data sets which match diverse and complementary criteria set by the studies.
In this paper, we present a novel Integrated NeuroDegenerative Disease (INDD) database developed at the University of Pennsylvania (Penn) through a consortium of Penn investigators. Since these investigators work on AD, PD, ALS and FTLD, this allowed us to achieve the goal of developing an INDD database for these major neurodegenerative disorders. We used Microsoft SQL Server as the platform with built-in “backwards” functionality to provide Access as a front-end client to interface with the database. We used PHP hypertext Preprocessor to create the “front end” web interface and then integrated individual neurodegenerative disease databases using a master lookup table. We also present methods of data entry, database security, database backups, and database audit trails for this INDD database.
We compare the results of a biomarker study using the INDD database to those using an alternative approach by querying individual database separately.
We have demonstrated that the Penn INDD database has the ability to query multiple database tables from a single console with high accuracy and reliability. The INDD database provides a powerful tool for generating data sets in comparative studies across several neurodegenerative diseases.
PMCID: PMC3145967  PMID: 21784346
Database; Neurodegenerative Disease; Microsoft SQL; Relational Neurodegenerative Disease Database
4.  Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier 
Acta neuropathologica  2014;129(1):39-52.
C9orf72 promoter hypermethylation inhibits the accumulation of pathologies which have been postulated to be neurotoxic. We tested here whether C9orf72 hypermethylation is associated with prolonged disease in C9orf72 mutation carriers. C9orf72 methylation was quantified from brain or blood using methylation-sensitive restriction enzyme digest-qPCR in a cross-sectional cohort of 118 C9orf72 repeat expansion carriers and 19 non-carrier family members. Multivariate regression models were used to determine whether C9orf72 hypermethylation was associated with age at onset, disease duration, age at death, or hexanucleotide repeat expansion size. Permutation analysis was performed to determine whether C9orf72 methylation is heritable. We observed a high correlation between C9orf72 methylation across tissues including cerebellum, frontal cortex, spinal cord and peripheral blood. While C9orf72 methylation was not significantly different between ALS and FTD and did not predict age at onset, brain and blood C9orf72 hypermethylation was associated with later age at death in FTD (brain: β = 0.18, p = 0.006; blood: β = 0.15, p < 0.001), and blood C9orf72 hypermethylation was associated with longer disease duration in FTD (β = 0.03, p = 0.007). Furthermore, C9orf72 hypermethylation was associated with smaller hexanucleotide repeat length (β = −16.69, p = 0.033). Finally, analysis of pedigrees with multiple mutation carriers demonstrated a significant association between C9orf72 methylation and family relatedness (p < 0.0001). C9orf72 hypermethylation is associated with prolonged disease in C9orf72 repeat expansion carriers with FTD. The attenuated clinical phenotype associated with C9orf72 hypermethylation suggests that slower clinical progression in FTD is associated with reduced expression of mutant C9orf72. These results support the hypothesis that expression of the hexanucleotide repeat expansion is associated with a toxic gain of function.
PMCID: PMC4282973  PMID: 25388784
Neurodegeneration; Frontotemporal lobar degeneration; Frontotemporal dementia; Amyotrophic lateral sclerosis; Epigenetics
5.  A Randomized Trial of Electro-acupuncture for Arthralgia related to Aromatase Inhibitor Use 
Arthralgia is a common and debilitating side effect experienced by breast cancer patients receiving aromatase inhibitors (AIs) and often results in premature drug discontinuation.
We conducted a randomized controlled trial of electro-acupuncture (EA) as compared to waitlist control (WLC) and sham acupuncture (SA) in postmenopausal women with breast cancer who self-reported arthralgia attributable to AIs. Acupuncturists performed ten EA/SA treatments over eight weeks using a manualized protocol with 2 Hz electro-stimulation delivered by a TENS unit. Acupuncturists administered SA using Streitberger (non-penetrating) needles at non-traditional acupuncture points without electro-stimulation. The primary endpoint was pain severity by Brief Pain Inventory (BPI) between EA and WLC at Week 8; durability of response at Week 12 and comparison of EA to SA were secondary aims.
Of the 67 randomly assigned patients, mean reduction in pain severity was greater in the EA group than in the WLC group at Week 8 (−2.2 vs. −0.2, p=0.0004) and at Week 12 (−2.4 vs. −0.2, p<0.0001). Pain-related interference measured by BPI also improved in the EA group compared to the WLC group at both Week 8 (−2.0 vs. 0.2, p=0.0006) and Week 12 (−2.1 vs. −0.1, p=0.0034). SA produced a magnitude of change in pain severity and pain-related interference at Week 8 (−2.3, −1.5 respectively) and Week 12 (−1.7, −1.3 respectively) similar to that of EA. Participants in both EA and SA groups reported few minor adverse events.
Compared to usual care, EA produced clinically important and durable improvement in arthralgia related to AIs in breast cancer patients, and SA had a similar effect. Both EA and SA were safe.
PMCID: PMC3972040  PMID: 24210070
Acupuncture; breast neoplasm; clinical trial; Aromatase inhibitors/*adverse effects; musculoskeletal; joint pain
6.  A Comparative Survey of the Topographical Distribution of Signature Molecular Lesions in Major Neurodegenerative Diseases 
The Journal of comparative neurology  2013;521(18):10.1002/cne.23430.
An understanding of the anatomic distributions of major neurodegenerative disease lesions is important to appreciate the differential clinical profiles of these disorders and to serve as neuropathological standards for emerging molecular neuroimaging methods. To address these issues, here we present a comparative survey of the topographical distribution of the defining molecular neuropathological lesions among ten neurodegenerative diseases from a large and uniformly assessed brain collection. Ratings of pathological severity in sixteen brain regions from 671 cases with diverse neurodegenerative diseases were summarized and analyzed. These included: a) amyloid-β and tau lesions in Alzheimer’s disease, b) tau lesions in three other tauopathies including Pick’s disease, progressive supranuclear palsy and corticobasal degeneration, c) α-synuclein inclusion ratings in four synucleinopathies including Parkinson’s disease, Parkinson’s disease with dementia, dementia with Lewy bodies and multiple system atrophy, and d) TDP-43 lesions in two TDP-43 proteinopathies, including frontotemporal lobar degeneration associated with TDP-43 and amyotrophic lateral sclerosis. The data presented graphically and topographically confirm and extend previous pathological anatomic descriptions and statistical comparisons highlight the lesion distributions that either overlap or distinguish the diseases in each molecular disease category.
PMCID: PMC3872132  PMID: 23881776
Alzheimer’s disease; Pick’s disease; corticobasal degeneration; progressive supranuclear palsy; Parkinson’s disease; Parkinson’s disease dementia; dementia with Lewy bodies; multiple system atrophy; frontotemporal lobar degeneration - TDP; amyotrophic lateral sclerosis; amyloid-β; Tau α-synuclein; TDP-43
7.  Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI 
Acta neuropathologica  2013;126(5):10.1007/s00401-013-1151-4.
The dynamics of cerebrospinal fluid (CSF) tau and Aβ biomarkers over time in Alzheimer’s disease (AD) patients from prodromal pre-symptomatic to severe stages of dementia have not been clearly defined and recent studies, most of which are cross-sectional, present conflicting findings. To clarify this issue, we analyzed the longitudinal CSF tau and Aβ biomarker data from 142 of the AD Neuroimaging Initiative (ADNI) study subjects [18 AD, 74 mild cognitive impairment (MCI), and 50 cognitively normal subjects (CN)]. Yearly follow-up CSF collections and studies were conducted for up to 48 months (median = 36 months) for CSF Aβ1–42, phosphorylated tau (p-tau181), and total tau (t-tau). An unsupervised analysis of longitudinal measurements revealed that for Aβ1–42 and p-tau181 biomarkers there was a group of subjects with stable longitudinal CSF biomarkers measures and a group of subjects who showed a decrease (Aβ1–42, mean = −9.2 pg/ml/year) or increase (p-tau181, mean = 5.1 pg/ml/year) of these biomarker values. Low baseline Aβ1–42 values were associated with longitudinal increases in p-tau181. Conversely, high baseline p-tau181 values were not associated with changes in Aβ1–42 levels. When the subjects with normal baseline biomarkers and stable concentrations during follow-up were excluded, the expected time to reach abnormal CSF levels and the mean AD values was significantly shortened. Thus, our data demonstrate for the first time that there are distinct populations of ADNI subjects with abnormal longitudinal changes in CSF p-tau181 and Aβ1–42 levels, and our longitudinal results favor the hypothesis that Aβ1–42 changes precede p-tau181 changes.
PMCID: PMC3875373  PMID: 23812320
Alzheimer’s disease; Amyloid beta; Tau; Cerebrospinal fluid; Longitudinal; Dementia; Mild cognitive impairment
8.  Association of Plasma C-Reactive Protein Levels with Diagnosis of Alzheimer’s Disease 
Journal of the neurological sciences  2013;333(0):10.1016/j.jns.2013.05.028.
C-reactive protein (CRP) participates in the systemic response to inflammation. Previous studies report inconsistent findings regarding the relationship between plasma CRP and Alzheimer’s disease (AD). We measured plasma CRP in 203 subjects with AD, 58 subjects with mild cognitive impairment (MCI) and 117 normal aging subjects and administered annual mini-mental state examinations (MMSE) during a three year follow-up period to investigate CRP’s relationship with diagnosis and progression of cognitive decline. Adjusted for age, sex, and education, subjects with AD had significantly lower levels of plasma CRP than subjects with MCI and normal aging. However, there was no significant association between plasma CRP at baseline and subsequent cognitive decline as assessed by longitudinal changes in MMSE score. Our results support previous reports of reduced levels of plasma CRP in AD and indicate its potential utility as a biomarker for the diagnosis of AD.
PMCID: PMC3815534  PMID: 23978419
Alzheimer Disease; Mild Cognitive Impairment; C-Reactive Protein; Inflammation; Biological Markers
9.  Comparative accuracies of two common screening instruments for the classification of Alzheimer’s disease, mild cognitive impairment and healthy aging 
To compare the utility and diagnostic accuracy of the MoCA and MMSE in the diagnosis of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) in a clinical cohort.
321 AD, 126 MCI and 140 older adults with healthy cognition (HC) were evaluated using the the MMSE, MoCA, a standardized neuropsychological battery according to the Consortium to Establish a Registry of Alzheimer’s Disease (CERAD-NB) and an informant based measure of functional impairment, the Dementia Severity Rating Scale (DSRS). Diagnostic accuracy and optimal cut-off scores were calculated for each measure, and a method for converting MoCA to MMSE scores is presented also.
The MMSE and MoCA offer reasonably good diagnostic and classification accuracy as compared to the more detailed CERAD-NB; however, as a brief cognitive screening measure the MoCA was more sensitive and had higher classification accuracy for differentiating MCI from HC. Complementing the MMSE or the MoCA with the DSRS significantly improved diagnostic accuracy.
The current results support recent data indicating that the MoCA is superior to the MMSE as a global assessment tool, particularly in discerning earlier stages of cognitive decline. In addition, we found that overall diagnostic accuracy improves when the MMSE or MoCA is combined with an informant-based functional measure. Finally, we provide a reliable and easy conversion of MoCA to MMSE scores. However, the need for MCI-specific measures is still needed to increase the diagnostic specificity between AD and MCI.
PMCID: PMC4036230  PMID: 23260866
Alzheimer’s disease; Mild Cognitive Impairment; MMSE; MoCA; Diagnostic accuracy
10.  Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre 
Brain  2013;136(9):2697-2706.
Cerebrovascular disease and vascular risk factors are associated with Alzheimer’s disease, but the evidence for their association with other neurodegenerative disorders is limited. Therefore, we compared the prevalence of cerebrovascular disease, vascular pathology and vascular risk factors in a wide range of neurodegenerative diseases and correlate them with dementia severity. Presence of cerebrovascular disease, vascular pathology and vascular risk factors was studied in 5715 cases of the National Alzheimer’s Coordinating Centre database with a single neurodegenerative disease diagnosis (Alzheimer’s disease, frontotemporal lobar degeneration due to tau, and TAR DNA-binding protein 43 immunoreactive deposits, α-synucleinopathies, hippocampal sclerosis and prion disease) based on a neuropathological examination with or without cerebrovascular disease, defined neuropathologically. In addition, 210 ‘unremarkable brain’ cases without cognitive impairment, and 280 cases with pure cerebrovascular disease were included for comparison. Cases with cerebrovascular disease were older than those without cerebrovascular disease in all the groups except for those with hippocampal sclerosis. After controlling for age and gender as fixed effects and centre as a random effect, we observed that α-synucleinopathies, frontotemporal lobar degeneration due to tau and TAR DNA-binding protein 43, and prion disease showed a lower prevalence of coincident cerebrovascular disease than patients with Alzheimer’s disease, and this was more significant in younger subjects. When cerebrovascular disease was also present, patients with Alzheimer’s disease and patients with α-synucleinopathy showed relatively lower burdens of their respective lesions than those without cerebrovascular disease in the context of comparable severity of dementia at time of death. Concurrent cerebrovascular disease is a common neuropathological finding in aged subjects with dementia, is more common in Alzheimer’s disease than in other neurodegenerative disorders, especially in younger subjects, and lowers the threshold for dementia due to Alzheimer’s disease and α-synucleinopathies, which suggests that these disorders should be targeted by treatments for cerebrovascular disease.
PMCID: PMC3858112  PMID: 23842566
Alzheimer’s disease; frontotemporal lobar degeneration; vascular disease; dementia; epidemiology; neuropathology
11.  Plasma Apolipoprotein A1 as a Biomarker for Parkinson's Disease 
Annals of neurology  2013;74(1):119-127.
To identify plasma-based biomarkers for Parkinson's Disease (PD) risk.
In a discovery cohort of 152 PD patients, plasma levels of 96 proteins were measured by multiplex immunoassay; proteins associated with age at PD onset were identified by linear regression. Findings from discovery screening were then assessed in a second cohort of 187 PD patients, using a different technique. Finally, in a third cohort of at-risk, asymptomatic individuals enrolled in the Parkinson's Associated Risk Study (PARS, n=134), plasma levels of the top candidate biomarker were measured, and dopamine transporter (DAT) imaging performed, to evaluate the association of plasma protein levels with dopaminergic system integrity.
One of the best candidate protein biomarkers to emerge from discovery screening was apolipoprotein A1 (ApoA1, p=0.001). Low levels of ApoA1 correlated with earlier PD onset, with a 26% decrease in risk of developing PD associated with each tertile increase in ApoA1 (Cox proportional hazards p<0.001, hazard ratio=0.742). The association between plasma ApoA1 levels and age at PD onset replicated in an independent cohort of PD patients (p<0.001). Finally, in the PARS cohort of high-risk, asymptomatic subjects, lower plasma levels of ApoA1 were associated with greater putaminal DAT deficit (p=0.037).
Lower ApoA1 levels correlate with dopaminergic system vulnerability in symptomatic PD patients and in asymptomatic individuals with physiological reductions in dopamine transporter density consistent with prodromal PD. Plasma ApoA1 may be a new biomarker for PD risk.
PMCID: PMC3773265  PMID: 23447138
12.  Physical activity and telomere length in early stage breast cancer survivors 
Telomere length (TL) is a biomarker of accumulated cellular damage and human aging. Evidence in healthy populations suggests that TL is impacted by a host of psychosocial and lifestyle factors, including physical activity. This is the first study to evaluate the relationship between self-reported physical activity and telomere length in early stage breast cancer survivors.
A cross-sectional sample of 392 postmenopausal women with stage I-III breast cancer at an outpatient oncology clinic of a large university hospital completed questionnaires and provided a blood sample. TL was determined using terminal restriction fragment length analysis of genomic DNA isolated from peripheral blood mononuclear cells. Physical activity was dichotomized into two groups (none versus moderate to vigorous) using the International Physical Activity Questionnaire. Multivariate linear and logistic regression analyses were performed to identify factors associated with mean TL and physical activity.
Among participants, 66 (17%) did not participate in any physical activity. In multivariate model adjusted for age, compared to those who participated in moderate to vigorous physical activity, women who participated in no physical activity had significantly shorter TL (adjusted coefficient β = −0.22; 95% confidence interval (CI), −0.41 to −0.03; P = .03). Non-white race, lower education and depressive symptoms were associated with lack of self-reported physical activity (P < 0.05 for all) but not TL.
Lack of physical activity is associated with shortened TL, warranting prospective investigation of the potential role of physical activity on cellular aging in breast cancer survivors.
PMCID: PMC4303228  PMID: 25074648
13.  Predictors of Emergent Feeding Tubes and Tracheostomies in Amyotrophic Lateral Sclerosis (ALS) 
Predictable decline in ALS makes unplanned gastrostomy and tracheotomy avoidable. We determined whether gastrostomy or tracheostomy insertion during emergent hospitalization is associated with patient or hospital characteristics, changed Medicare policy in 2001, or proximity to specialized ALS care.
We performed a retrospective analysis of hospitalizations and procedures for ALS/MND patients in Pennsylvania between 1996–2009. We identified predictors of gastrotomy/tracheotomy during emergent hospitalization and trends over time.
Patients underwent 1,748 gastrostomies and 373 tracheotomies. 32% of gastrostomies and 67% of tracheostomies were placed emergently. Emergent hospitalizations involving gastrostomy were more expensive with fewer home discharges. Blacks and Medicaid patients had higher odds of emergent gastrostomy placement. Conversely, academic hospital affiliation decreased odds of emergent gastrostomy or tracheostomy placement (AOR 0.49, AOR 0.37, p <0.001). After Medicare policy changes, gastrostomy use increased, while emergent gastrostomies decreased. Surprisingly, proximity to specialized care was associated with increased emergent gastrostomy placement.
Blacks and Medicaid patients were more likely to undergo emergent gastrostomy insertion. Patients receiving gastrostomy during emergent admissions had fewer home discharges and higher costs. Academic hospital affiliation decreased odds of emergent gastrotomy or tracheotomy. After Medicare changes broadening access, while gastrostomy use increased, the proportion of emergent procedures decreased.
PMCID: PMC4104116  PMID: 22533463
gastrostomy; tracheostomy; communication; costs; health policy
14.  A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank 
Neurodegenerative diseases (NDs) are defined by the accumulation of abnormal protein deposits in the central nervous system (CNS), and only neuropathological examination enables a definitive diagnosis. Brain banks and their associated scientific programs have shaped the actual knowledge of NDs, identifying and characterizing the CNS deposits that define new diseases, formulating staging schemes, and establishing correlations between neuropathological changes and clinical features. However, brain banks have evolved to accommodate the banking of biofluids as well as DNA and RNA samples. Moreover, the value of biobanks is greatly enhanced if they link all the multidimensional clinical and laboratory information of each case, which is accomplished, optimally, using systematic and standardized operating procedures, and in the framework of multidisciplinary teams with the support of a flexible and user-friendly database system that facilitates the sharing of information of all the teams in the network. We describe a biobanking system that is a platform for discovery research at the Center for Neurodegenerative Disease Research at the University of Pennsylvania.
PMCID: PMC3933464  PMID: 23978324
Cerebrospinal fluid; Plasma; Serum; Autopsy; Neurodegeneration; Alzheimer’s Disease; Dementia; Genetics; Parkinson’s Disease; Frontotemporal lobar degeneration
15.  Rate of decline in Alzheimer's disease measured by a dementia severity rating scale 
To measure clinically relevant change in Alzheimer's disease (AD) using a family member completed dementia severity rating scale (DSRS) questionnaire.
Measuring rate of change provides important clinical information. Most neuropsychological scores change nonlinearly, complicating their use as a predictor of change throughout the illness.
DSRS and Mini Mental State (MMS) scores were prospectively collected on 702 patients with AD from first evaluation until they became too impaired to return to clinic.
DSRS score increased an average of 4.48 points per year (95% CI 4.14 - 4.82) throughout the entire range of severity. In contrast, the MMS declined an average of 2.15 points per year (95% CI 1.85-2.46) during the first two years, accelerated to 3.83 points per year (95% CI 3.28-4.38) during the subsequent three years and then slowed to an annual decline of 1.63 points during the last two years (95% CI 0.21-3.05). A younger age of symptom onset was associated with an increased rate of DSRS change (p=0.03).
The DSRS provides a clinical measure of functional impairment in AD that increases about 4.48 points per year from the earliest symptomatic stage until patients become too severely impaired to return to clinic.
PMCID: PMC3014643  PMID: 19812470
Dementia severity rating scale; Alzheimer's disease; Rate of decline
16.  Longitudinal Patterns of Semantic and Episodic Memory in Frontotemporal Lobar Degeneration and Alzheimer’s Disease 
The longitudinal assessment of episodic and semantic memory was obtained from 236 patients diagnosed with Alzheimer’s disease (n=128) and with FTLD (n= 108) including patients with a social comportment/ dysexecutive (SOC/ EXEC) disorder; progressive non-fluent aphasia (PNFA); semantic dementia (SemD); and corticobasal syndrome (CBS). At the initial assessment, AD patients obtained a lower score on the delayed free recall test than other patients. Longitudinal analyses for delayed free recall found converging performance, with all patients reaching the same level of impairment as AD patients. On the initial evaluation for delayed recognition, AD patients also obtained lower scores than other groups. Longitudinal analyses for delayed recognition test performance found that AD patients consistently produced lower scores than other groups and no convergence between AD and other dementia groups was seen. For semantic memory, there were no initial between-group differences. However, longitudinal analyses for semantic memory revealed group differences over illness duration, with worse performance for SemD versus AD, PNFA, SOC/ EXEC, and CBS patients. These data suggest the presence of specific longitudinal patterns of impairment for episodic and semantic memory in AD and FTLD patients suggesting that all forms of dementia do not necessarily converge into a single phenotype.
PMCID: PMC2883470  PMID: 20003584
Frontotemporal lobar dementia; longitudinal analysis; neuropsychological assessment; episodic memory; semantic memory; Pick’s disease
17.  Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis 
Disease Models & Mechanisms  2014;7(5):583-592.
A major medical challenge in the elderly is osteoporosis and the high risk of fracture. Telomere dysfunction is a cause of cellular senescence and telomere shortening, which occurs with age in cells from most human tissues, including bone. Telomere defects contribute to the pathogenesis of two progeroid disorders characterized by premature osteoporosis, Werner syndrome and dyskeratosis congenital. It is hypothesized that telomere shortening contributes to bone aging. We evaluated the skeletal phenotypes of mice with disrupted telomere maintenance mechanisms as models for human bone aging, including mutants in Werner helicase (Wrn−/−), telomerase (Terc−/−) and Wrn−/−Terc−/− double mutants. Compared with young wild-type (WT) mice, micro-computerized tomography analysis revealed that young Terc−/− and Wrn−/−Terc−/− mice have decreased trabecular bone volume, trabecular number and trabecular thickness, as well as increased trabecular spacing. In cortical bone, young Terc−/− and Wrn−/−Terc−/− mice have increased cortical thinning, and increased porosity relative to age-matched WT mice. These trabecular and cortical changes were accelerated with age in Terc−/− and Wrn−/−Terc−/− mice compared with older WT mice. Histological quantification of osteoblasts in aged mice showed a similar number of osteoblasts in all genotypes; however, significant decreases in osteoid, mineralization surface, mineral apposition rate and bone formation rate in older Terc−/− and Wrn−/−Terc−/− bone suggest that osteoblast dysfunction is a prominent feature of precocious aging in these mice. Except in the Wrn−/− single mutant, osteoclast number did not increase in any genotype. Significant alterations in mechanical parameters (structure model index, degree of anistrophy and moment of inertia) of the Terc−/− and Wrn−/−Terc−/− femurs compared with WT mice were also observed. Young Wrn−/−Terc−/− mice had a statistically significant increase in bone-marrow fat content compared with young WT mice, which remained elevated in aged double mutants. Taken together, our results suggest that Terc−/− and Wrn−/−Terc−/− mutants recapitulate the human bone aging phenotype and are useful models for studying age-related osteoporosis.
PMCID: PMC4007409  PMID: 24626990
Aging; Bone histomorphometry; Osteoporosis
18.  Development and Validation of Pedigree Classification Criteria for Frontotemporal Lobar Degeneration 
JAMA neurology  2013;70(11):1411-1417.
A significant portion of frontotemporal lobar degeneration (FTLD) is due to inherited gene mutations, and we are unaware of a large sequential series that includes a recently discovered inherited cause of FTLD. There is also great need to develop clinical tools and approaches that will assist clinicians in the identification and counseling of patients with FTLD and their families regarding the likelihood of an identifiable genetic cause.
To ascertain the frequency of inherited FTLD and develop validated pedigree classification criteria for FTLD that provide a standardized means to evaluate pedigree information and insight into the likelihood of mutation-positive genetic test results for C9orf72, MAPT, and GRN.
Information about pedigrees and DNA was collected from 306 serially assessed patients with a clinical diagnosis of FTLD. This information included gene test results for C9orf72, MAPT, and GRN. Pedigree classification criteria were developed based on a literature review of FTLD genetics and pedigree tools and then refined by reviewing mutation-positive and -negative pedigrees to determine differentiating characteristics.
Academic medical center.
Patients with FTLD.
Familial risk.
The rate of C9orf72, MAPT, or GRN mutation–positive FTLD in this series was 15.4%. Categories designating the risk level for hereditary cause were termed high, medium, low, apparent sporadic, and unknown significance. Thirty-nine pedigrees (12.7%)met criteria for high, 31 (10.1%) for medium, 46 (15.0%) for low, 91 (29.7%) for apparent sporadic, and 99 (32.4%) for unknown significance. The mutation-detection rates were as follows: high, 64.1%; medium, 29%; low, 10.9%; apparent sporadic, 1.1%; and unknown significance, 7.1%. Mutation-detection rates differed significantly between the high and other categories.
Mutation rates are high in FTLD spectrum disorders, and the proposed criteria provide a validated standard for the classification of FTLD pedigrees. The combination of pedigree criteria and mutation-detection rates has important implications for genetic counseling and testing in clinical settings.
PMCID: PMC3906581  PMID: 24081456
19.  Prevalence and risk factors for insomnia among breast cancer patients on aromatase inhibitors 
Insomnia is increasingly recognized as a major symptom outcome in breast cancer; however, little is known about its prevalence and risk factors among women receiving aromatase inhibitors (AIs), a standard treatment to increase disease free survival among breast cancer patients.
A cross-sectional survey study was conducted among postmenopausal women with stage 0-III breast cancer receiving adjuvant AI therapy at an outpatient breast oncology clinic of a large university hospital. The Insomnia Severity Index (ISI) was used as the primary outcome. Multivariate logistic regression analyses were performed to evaluate risk factors.
Among 413 participants, 130 (31.5%) had sub-threshold insomnia on the ISI and 77 (18.64%) exceeded the threshold for clinically significant insomnia. In a multivariate logistic regression model, clinically significant insomnia was independently associated with severe joint pain (adjusted odds ratio, 4.84, 95% confidence interval, 1.71–13.69, P=0.003), mild/moderate hot flashes (AOR, 2.28, 95% CI, 1.13–4.60, P=0.02), severe hot flashes (AOR, 2.29, 95% CI, 1.23–6.81, P=0.015), anxiety (AOR, 1.99, 95% CI, 1.08–3.65, P=0.027), and depression (AOR, 3.57, 95% CI, 1.48–8.52, P=0.004). Age (>65 vs. <55 years, AOR, 2.31, 95% CI, 1.11–4.81, p=0.026), and time since breast cancer diagnosis (<2 years vs. 2–5 years, AOR, 1.94, 95% CI, 1.02–3.69, p=0.045) were also found to be significant risk factors. Clinical insomnia was more common among those who used medication for treating insomnia and pain.
Insomnia complaints exceed 50% among AI users. Clinically significant insomnia is highly associated with joint pain, hot flashes, anxiety and depression, age, and time since diagnosis.
PMCID: PMC3600410  PMID: 22584732
Breast cancer; Insomnia; Aromatase Inhibitors
20.  Patient-Physician Communication About Complementary and Alternative Medicine in a Radiation Oncology Setting 
Despite the extensive use of complementary and alternative medicine (CAM) among cancer patients, patient-physician communication regarding CAM therapies remains limited. This study quantified the extent of patient-physician communication about CAM and identified factors associated with its discussion in radiation therapy (RT) settings.
Methods and Materials
We conducted a cross-sectional survey of 305 RT patients at an urban academic cancer center. Patients with different cancer types were recruited in their last week of RT. Participants self-reported their demographic characteristics, health status, CAM use, patient-physician communication regarding CAM, and rationale for/against discussing CAM therapies with physicians. Multivariate logistic regression was used to identify relationships between demographic/clinical variables and patients’ discussion of CAM with radiation oncologists.
Among the 305 participants, 133 (43.6%) reported using CAM, and only 37 (12.1%) reported discussing CAM therapies with their radiation oncologists. In multivariate analyses, female patients (adjusted odds ratio [AOR] 0.45, 95% confidence interval [CI] 0.21-0.98) and patients with full-time employment (AOR 0.32, 95% CI 0.12-0.81) were less likely to discuss CAM with their radiation oncologists. CAM users (AOR 4.28, 95% CI 1.93-9.53) were more likely to discuss CAM with their radiation oncologists than were non-CAM users.
Despite the common use of CAM among oncology patients, discussions regarding these treatments occur rarely in the RT setting, particularly among female and full-time employed patients. Clinicians and patients should incorporate discussions of CAM to guide its appropriate use and to maximize possible benefit while minimizing potential harm.
PMCID: PMC3677204  PMID: 23040545
21.  Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias 
Brain  2012;135(12):3749-3756.
A growing body of evidence demonstrates an association between vascular risk factors and Alzheimer’s disease. This study investigated the frequency and severity of atherosclerotic plaques in the circle of Willis in Alzheimer’s disease and multiple other neurodegenerative diseases. Semi-quantitative data from gross and microscopic neuropathological examinations in 1000 cases were analysed, including 410 with a primary diagnosis of Alzheimer’s disease, 230 with synucleinopathies, 157 with TDP-43 proteinopathies, 144 with tauopathies and 59 with normal ageing. More than 77% of subjects with Alzheimer’s disease had grossly apparent circle of Willis atherosclerosis, a percentage that was significantly higher than normal (47%), or other neurodegenerative diseases (43–67%). Age- and sex-adjusted atherosclerosis ratings were highly correlated with neuritic plaque, paired helical filaments tau neurofibrillary tangle and cerebral amyloid angiopathy ratings in the whole sample and within individual groups. We found no associations between atherosclerosis ratings and α-synuclein or TDP-43 lesion ratings. The association between age-adjusted circle of Willis atherosclerosis and Alzheimer’s disease–type pathology was more robust for female subjects than male subjects. These results provide further confirmation and specificity that vascular disease and Alzheimer’s disease are interrelated and suggest that common aetiologic or reciprocally synergistic pathophysiological mechanisms promote both vascular pathology and plaque and tangle pathology.
PMCID: PMC3577102  PMID: 23204143
atherosclerosis; neuritic plaques; neurofibrillary tangles; synuclein; TDP-43
22.  Integration and relative value of biomarkers for prediction of MCI to AD progression: Spatial patterns of brain atrophy, cognitive scores, APOE genotype and CSF biomarkers☆☆☆ 
NeuroImage : Clinical  2013;4:164-173.
This study evaluates the individual, as well as relative and joint value of indices obtained from magnetic resonance imaging (MRI) patterns of brain atrophy (quantified by the SPARE-AD index), cerebrospinal fluid (CSF) biomarkers, APOE genotype, and cognitive performance (ADAS-Cog) in progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) within a variable follow-up period up to 6 years, using data from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1). SPARE-AD was first established as a highly sensitive and specific MRI-marker of AD vs. cognitively normal (CN) subjects (AUC = 0.98). Baseline predictive values of all aforementioned indices were then compared using survival analysis on 381 MCI subjects. SPARE-AD and ADAS-Cog were found to have similar predictive value, and their combination was significantly better than their individual performance. APOE genotype did not significantly improve prediction, although the combination of SPARE-AD, ADAS-Cog and APOE ε4 provided the highest hazard ratio estimates of 17.8 (last vs. first quartile). In a subset of 192 MCI patients who also had CSF biomarkers, the addition of Aβ1–42, t-tau, and p-tau181p to the previous model did not improve predictive value significantly over SPARE-AD and ADAS-Cog combined. Importantly, in amyloid-negative patients with MCI, SPARE-AD had high predictive power of clinical progression. Our findings suggest that SPARE-AD and ADAS-Cog in combination offer the highest predictive power of conversion from MCI to AD, which is improved, albeit not significantly, by APOE genotype. The finding that SPARE-AD in amyloid-negative MCI patients was predictive of clinical progression is not expected under the amyloid hypothesis and merits further investigation.
•813 ADNI-1 subjects are analyzed using pattern recognition methods.•Combination of SPARE-AD and ADAS-Cog offer high predictive index on MCI progression.•Cox PH models showed predictors were highly associated with time to AD conversion.•SPARE-AD in amyloid-negative MCI patients predicts clinical progression.
PMCID: PMC3871290  PMID: 24371799
Early Alzheimer's disease; Biomarkers of AD; Magnetic resonance imaging; Dementia; Mild cognitive impairment; Cerebrospinal fluid; Amyloid
23.  Neuropathologic substrates of Parkinson’s disease dementia 
Annals of neurology  2012;72(4):587-598.
To examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson’s disease (PD).
140 patients with a clinical diagnosis of PD and either normal cognition or onset of dementia two or more years after motor symptoms (PDD) were studied. Patients with a clinical diagnosis of dementia with Lewy bodies were excluded.
Autopsy records of genetic data and semi-quantitative scores for the burden of neurofibrillary tangles (NFTs), senile plaques (SPs), Lewy body (LB/LN) and other pathologies were used to develop a multivariate logistic regression model to determine the independent association of these variables with dementia. Correlates of co-morbid Alzheimer’s disease (PDD+AD) were also examined.
92 PD patients developed dementia and 48 remained cognitively normal. Severity of cortical LB/LN (CLB/LN) pathology was positively associated with dementia (p<0.001), with an odds-ratio (OR) of 4.06 (CI95%1.87–8.81), as was Apolipoprotein E4 (APOE4) genotype (p=0.018,OR4.19 CI95% 1.28–13.75). 28.6% of all PD cases had sufficient pathology for co-morbid AD, of which 89.5% were demented. The neuropathological diagnosis of PDD+AD correlated with an older age of PD onset (p=0.001,OR1.12 CI95%1.04–1.21), higher CLB/LN burden (p=0.037,OR 2.48 CI95%1.06–5.82), and cerebral amyloid angiopathy severity (p=0.032, OR4.16 CI95%1.13–15.30).
CLB/LN pathology is the most significant correlate of dementia in PD. Additionally, APOE4 genotype may independently influence the risk of dementia in PD. AD pathology was abundant in a subset of patients, and may modify the clinical phenotype. Thus, therapies that target α-synuclein, tau, or Aβ could potentially improve cognitive performance in PD.
PMCID: PMC3484250  PMID: 23037886
24.  Joint pain severity predicts premature discontinuation of aromatase inhibitors in breast cancer survivors 
BMC Cancer  2013;13:401.
Premature discontinuation of aromatase inhibitors (AIs) in breast cancer survivors compromises treatment outcomes. We aimed to evaluate whether patient-reported joint pain predicts premature discontinuation of AIs.
We conducted a retrospective cohort study of postmenopausal women with breast cancer on AIs who had completed a survey about their symptom experience on AIs with specific measurements of joint pain. The primary outcome was premature discontinuation of AIs, defined as stopping the medication prior to the end of prescribed therapy. Multivariate Cox regression modeling was used to identify predictors of premature discontinuation.
Among 437 patients who met eligibility criteria, 47 (11%) prematurely discontinued AIs an average of 29 months after initiation of therapy. In multivariate analyses, patient-reported worst joint pain score of 4 or greater on the Brief Pain Inventory (BPI) (Hazard Ratio [HR] 2.09, 95% Confidence Interval [CI] 1.14-3.80, P = 0.016) and prior use of tamoxifen (HR 2.01, 95% CI 1.09-3.70, P = 0.026) were significant predictors of premature discontinuation of AIs. The most common reason for premature discontinuation was joint pain (57%) followed by other therapy-related side effects (30%). While providers documented joint pain in charts for 82% of patients with clinically important pain, no quantitative pain assessments were noted, and only 43% provided any plan for pain evaluation or management.
Worst joint pain of 4 or greater on the BPI predicts premature discontinuation of AI therapy. Clinicians should monitor pain severity with quantitative assessments and provide timely management to promote optimal adherence to AIs.
PMCID: PMC3847371  PMID: 24004677
Aromatase inhibitor; Joint pain; Adherence; Adverse effects; Musculoskeletal; Breast cancer; Pain diagnosis; Pain management; Survivorship
25.  The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease 
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by intracellular tangles of hyperphosphorylated tau protein distributed throughout the neocortex, basal ganglia, and brainstem. A genome-wide association study identified EIF2AK3 as a risk factor for PSP. EIF2AK3 encodes PERK, part of the endoplasmic reticulum’s (ER) unfolded protein response (UPR). PERK is an ER membrane protein that senses unfolded protein accumulation within the ER lumen. Recently, several groups noted UPR activation in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, multiple system atrophy, and in the hippocampus and substantia nigra of PSP subjects. Here, we evaluate UPR PERK activation in the pons, medulla, midbrain, hippocampus, frontal cortex and cerebellum in subjects with PSP, AD, and in normal controls.
We found UPR activation primarily in disease-affected brain regions in both disorders. In PSP, the UPR was primarily activated in the pons and medulla and to a much lesser extent in the hippocampus. In AD, the UPR was extensively activated in the hippocampus. We also observed UPR activation in the hippocampus of some elderly normal controls, severity of which positively correlated with both age and tau pathology but not with Aβ plaque burden. Finally, we evaluated EIF2AK3 coding variants that influence PERK activation. We show that a haplotype associated with increased PERK activation is genetically associated with increased PSP risk.
The UPR is activated in disease affected regions in PSP and the genetic evidence shows that this activation increases risk for PSP and is not a protective response.
PMCID: PMC3893579  PMID: 24252572
Progressive supranuclear palsy; PERK; Unfolded protein response; EIF2AK3; Alzheimer’s disease

Results 1-25 (59)