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1.  Development and Validation of Pedigree Classification Criteria for Frontotemporal Lobar Degeneration 
JAMA neurology  2013;70(11):1411-1417.
IMPORTANCE
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.
OBJECTIVES
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.
DESIGN
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.
SETTING
Academic medical center.
PARTICIPANTS
Patients with FTLD.
MAIN OUTCOMES AND MEASURES
Familial risk.
RESULTS
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.
CONCLUSIONS AND RELEVANCE
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.
doi:10.1001/jamaneurol.2013.3956
PMCID: PMC3906581  PMID: 24081456
2.  Prevalence and risk factors for insomnia among breast cancer patients on aromatase inhibitors 
Purpose
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s00520-012-1490-z
PMCID: PMC3600410  PMID: 22584732
Breast cancer; Insomnia; Aromatase Inhibitors
3.  Patient-Physician Communication About Complementary and Alternative Medicine in a Radiation Oncology Setting 
Purpose
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.
Results
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.
Conclusions
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.
doi:10.1016/j.ijrobp.2012.08.018
PMCID: PMC3677204  PMID: 23040545
4.  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.
doi:10.1093/brain/aws271
PMCID: PMC3577102  PMID: 23204143
atherosclerosis; neuritic plaques; neurofibrillary tangles; synuclein; TDP-43
5.  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.
Highlights
•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.
doi:10.1016/j.nicl.2013.11.010
PMCID: PMC3871290  PMID: 24371799
Early Alzheimer's disease; Biomarkers of AD; Magnetic resonance imaging; Dementia; Mild cognitive impairment; Cerebrospinal fluid; Amyloid
6.  Neuropathologic substrates of Parkinson’s disease dementia 
Annals of neurology  2012;72(4):587-598.
Objective
To examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson’s disease (PD).
Methods
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.
Results
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).
Interpretation
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.
doi:10.1002/ana.23659
PMCID: PMC3484250  PMID: 23037886
7.  Joint pain severity predicts premature discontinuation of aromatase inhibitors in breast cancer survivors 
BMC Cancer  2013;13:401.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2407-13-401
PMCID: PMC3847371  PMID: 24004677
Aromatase inhibitor; Joint pain; Adherence; Adverse effects; Musculoskeletal; Breast cancer; Pain diagnosis; Pain management; Survivorship
8.  The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease 
Background
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.
Results
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.
Conclusions
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.
doi:10.1186/2051-5960-1-31
PMCID: PMC3893579  PMID: 24252572
Progressive supranuclear palsy; PERK; Unfolded protein response; EIF2AK3; Alzheimer’s disease
9.  Arterial spin labeled MRI in prodromal Alzheimer's disease: A multi-site study☆ 
NeuroImage : Clinical  2013;2:630-636.
We examined differences in cerebral blood flow (CBF) measured by Arterial Spin Labeled perfusion MRI (ASL MRI) across the continuum from cognitively normal (CN) older adults to mild Alzheimer's Disease (AD) using data from the multi-site Alzheimer's Disease Neuroimaging Initiative (ADNI). Measures of CBF, in a predetermined set of regions (meta-ROI), and hippocampal volume were compared between CN (n = 47), patients with early and late Mild Cognitive Impairment [EMCI (n = 32), LMCI (n = 35)], and AD (n = 15). Associations between these measures and disease severity, assessed by Clinical Dementia Rating scale sum of boxes (CDR SB), were also assessed. Mean meta-ROI CBF was associated with group status and significant hypoperfusion was observed in LMCI and AD relative to CN. Hippocampal volume was associated with group status, but only AD patients had significantly smaller volumes than the CN. When examining the relationship between these measures and disease severity, both were significantly associated with CDR SB and appeared to provide independent prediction of status. In light of the tight link between CBF and metabolism, ASL MRI represents a promising functional biomarker for early diagnosis and disease tracking in AD and this study is the first to demonstrate the feasibility in a multi-site context in this population. Combining functional and structural measures, which can be acquired in the same scanning session, appears to provide additional information about disease severity relative to either measure alone.
Highlights
•Arterial Spin Labeled (ASL) MRI is a promising AD biomarker. No prior multi-site study of this modality in AD.•We measured cerebral blood flow (CBF) in a FDG PET defined region.•Reduced CBF was associated with MCI and AD and correlated with disease severity.•Hippocampal volume and ASL provide complementary information.•ASL MRI can be applied to this population in a multi-site context.
doi:10.1016/j.nicl.2013.04.014
PMCID: PMC3777751  PMID: 24179814
10.  Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies 
Brain  2012;135(3):807-818.
The microtubule-binding protein, tau, is the major component of neurofibrillary inclusions characteristic of Alzheimer's disease and related neurodegenerative tauopathies. When tau fibrillizes, it undergoes abnormal post-translational modifications resulting in decreased solubility and altered microtubule-stabilizing properties. Recently, we reported that the abnormal acetylation of tau at lysine residue 280 is a novel, pathological post-translational modification. Here, we performed detailed immunohistochemistry to further examine acetylated-tau expression in Alzheimer's disease and other major tauopathies. Immunohistochemistry using a polyclonal antibody specific for acetylated-tau at lysine 280 was conducted on 30 post-mortem central nervous system regions from patients with Alzheimer's disease (10 patients), corticobasal degeneration (5 patients), and progressive supranuclear palsy (5 patients). Acetylated-tau pathology was compared with the sequential emergence of other tau modifications in the Alzheimer's disease hippocampus using monoclonal antibodies to multiple well-characterized tau epitopes. All cases studied showed significant acetylated-tau pathology in a distribution pattern similar to hyperphosphorylated-tau. Acetylated-tau pathology was largely in intracellular, thioflavin-S-positive tau inclusions in Alzheimer's disease, and also thioflavin-S-negative pathology in corticobasal degeneration and progressive supranuclear palsy. Acetylated-tau was present throughout all stages of Alzheimer's disease pathology, but was more prominently associated with pathological tau epitopes in moderate to severe-stage cases. These temporal and morphological immunohistochemical features suggest acetylation of tau at this epitope is preceded by early modifications, including phosphorylation, and followed by later truncation events and cell death in Alzheimer's disease. Acetylation of tau at lysine 280 is a pathological modification that may contribute to tau-mediated neurodegeneration by both augmenting losses of normal tau properties (reduced solubility and microtubule assembly) as well as toxic gains of function (increased tau fibrillization). Thus, inhibiting tau acetylation could be a disease-modifying target for drug discovery target in tauopathies.
doi:10.1093/brain/aws013
PMCID: PMC3286338  PMID: 22366796
Alzheimer's disease; tauopathy; acetylation; post-translational modification; tau
11.  Frequency and Clinicopathological Characteristics of Presenilin 1 Gly206Ala Mutation in Puerto Rican Hispanics with Dementia 
Journal of Alzheimer's disease : JAD  2013;33(4):1089-1095.
The frequency and clinical and pathological characteristics associated with the Gly206Ala presenilin 1 (PSEN1) mutation in Puerto Rican and non-Puerto Rican Hispanics were evaluated at the University of Pennsylvania’s Alzheimer’s Disease Center. DNAs from all cohort subjects were genotyped for the Gly206Ala PSEN1 mutation. Carriers and non-carriers with neurodegenerative disease dementias were compared for demographic, clinical, psychometric, and biomarker variables. Nineteen (12.6%) of 151 unrelated subjects with dementia were discovered to carry the PSEN1 Gly 206Ala mutation. Microsatellite marker genotyping determined a common ancestral haplotype for all carriers. Carriers were all of Puerto Rican heritage with significantly younger age of onset, but otherwise were clinically and neuropsychologically comparable to those of non-carriers with AD. Three subjects had extensive topographic and biochemical biomarker assessments that were also typical of non-carriers with AD. Neuropathological examination in one subject revealed severe, widespread plaque and tangle pathology without other meaningful disease lesions. The PSEN1 Gly206Ala mutation is notably frequent in unrelated Puerto Rican immigrants with dementia in Philadelphia. Considered together with the increased prevalence and mortality of AD reported in Puerto Rico, these high rates may reflect hereditary risk concentrated in the island which warrants further study.
doi:10.3233/JAD-2012-121570
PMCID: PMC3575080  PMID: 23114514
Age of onset; dementia; haplotype; presenilin
12.  Uncovering the expectancy effect: the validation of Acupuncture Expectancy Scale 
Purpose
Research suggests that expectancy may modulate the response to medical interventions, including acupuncture. However, the paucity of validated tools to measure expectancy limits rigorous evaluation. We sought to validate a previously developed Acupuncture Expectancy Scale (AES) as an instrument to measure patients’ expected responses to acupuncture.
Methods
Participants were patients with stage I to III cancers seen in outpatient medical and radiation oncology clinics. They were drawn from three study cohorts that included 404 participants. We examined the reliability, validity and responsiveness of AES.
Results
The scores of AES had internal consistency (Cronbach’s α coefficient) of 0.95 and test-retest reliability of 0.62 over four weeks without acupuncture treatment. Those who had previously used acupuncture had higher AES compared to those who were acupuncture naïve (12.4 vs. 9.5, p=0.002). AES was higher in those who reported willingness to participate in an acupuncture trial compared to those who did not want to participate in an acupuncture trial (11.5 vs. 8.1, p<0.001). Those patients who enrolled in a pilot trial of acupuncture had higher AES score than the general outpatient population (13.0 vs. 9.8, p=0.02), and expectancy increased during the course of acupuncture treatment (13.0 to 16.5, p<0.017).
Conclusion
The AES is reliable and valid, and scores appear to increase during or after prior therapy. Incorporation of AES in clinical trials and outcome studies can evaluate the role of expectancy on acupuncture outcomes.
PMCID: PMC3569526  PMID: 21280459
13.  Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease–Rating Scale 
Impulse control disorders and related disorders (hobbyism-punding and dopamine dysregulation syndrome) occur in 15% to 20% of Parkinson’s disease (PD) patients. We assessed the validity and reliability of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease–Rating Scale (QUIP-RS), a rating scale designed to measure severity of symptoms and support a diagnosis of impulse control disorders and related disorders in PD. A convenience sample of PD patients at a movement disorders clinic self-completed the QUIP-RS and were administered a semistructured diagnostic interview by a blinded trained rater to assess discriminant validity for impulse control disorders (n = 104) and related disorders (n = 77). Subsets of patients were assessed to determine interrater reliability (n = 104), retest reliability (n = 63), and responsiveness to change (n = 29). Adequate cutoff points (both sensitivity and specificity values >80% plus acceptable likelihood ratios) were established for each impulse control disorder and hobbyism-punding. Interrater and retest reliability (intraclass correlation coefficient r) were >0.60 for all disorders. Participants in an impulse control disorder treatment study who experienced full (t = 3.65, P = .004) or partial (t = 2.98, P = .01) response demonstrated significant improvement on the rating scale over time, while nonresponders did not (t = 0.12, P = .91). The QUIP-RS appears to be valid and reliable as a rating scale for impulse control disorders and related disorders in PD. Preliminary results suggest that it can be used to support a diagnosis of these disorders, as well as to monitor changes in symptom severity over time.
doi:10.1002/mds.24023
PMCID: PMC3537263  PMID: 22134954
dopamine agonists; impulse control disorder; Parkinson’s disease
14.  Alzheimer's disease pattern of brain atrophy predicts cognitive decline in Parkinson's disease 
Brain  2011;135(1):170-180.
Research suggests overlap in brain regions undergoing neurodegeneration in Parkinson's and Alzheimer's disease. To assess the clinical significance of this, we applied a validated Alzheimer's disease-spatial pattern of brain atrophy to patients with Parkinson's disease with a range of cognitive abilities to determine its association with cognitive performance and decline. At baseline, 84 subjects received structural magnetic resonance imaging brain scans and completed the Dementia Rating Scale-2, and new robust and expanded Dementia Rating Scale-2 norms were applied to cognitively classify participants. Fifty-nine non-demented subjects were assessed annually with the Dementia Rating Scale-2 for two additional years. Magnetic resonance imaging scans were quantified using both a region of interest approach and voxel-based morphometry analysis, and a method for quantifying the presence of an Alzheimer's disease spatial pattern of brain atrophy was applied to each scan. In multivariate models, higher Alzheimer's disease pattern of atrophy score was associated with worse global cognitive performance (β = −0.31, P = 0.007), including in non-demented patients (β = −0.28, P = 0.05). In linear mixed model analyses, higher baseline Alzheimer's disease pattern of atrophy score predicted long-term global cognitive decline in non-demented patients [F(1, 110) = 9.72, P = 0.002], remarkably even in those with normal cognition at baseline [F(1, 80) = 4.71, P = 0.03]. In contrast, in cross-sectional and longitudinal analyses there was no association between region of interest brain volumes and cognitive performance in patients with Parkinson's disease with normal cognition. These findings support involvement of the hippocampus and parietal–temporal cortex with cognitive impairment and long-term decline in Parkinson's disease. In addition, an Alzheimer's disease pattern of brain atrophy may be a preclinical biomarker of cognitive decline in Parkinson's disease.
doi:10.1093/brain/awr277
PMCID: PMC3316476  PMID: 22108576
Alzheimer's disease; dementia; mild cognitive impairment; Parkinson's disease; neurodegeneration
15.  Prenatal healthcare providers’ Gaucher disease carrier screening practices 
Purpose
Gaucher disease (GD) carrier screening is controversial in the medical community. The goal of this study was to explore prenatal healthcare providers’ current GD carrier screening practices.
Methods
Prenatal healthcare providers were invited by email to complete an electronic-based survey.
Results
A total of 1454 prenatal healthcare providers, including 209 genetic counselors, 450 midwives, and 795 physicians, completed the study. The majority of genetic counselors (n=208/209, >99%), physicians (n=415/450, 92%), and midwives (n=634/795, 80%) currently offer Jewish ancestry disease carrier screening to couples in whom one or both partners are Jewish. Of providers who offer Jewish ancestry disease screening, the majority of genetic counselors (n=199/208, 96%) and physicians (n=352/415, 85%) always or sometimes offer GD screening whereas the majority of midwives (n=357/634, 56%) never offer GD screening.
Conclusion
This study presents the first report of prenatal healthcare providers’ GD carrier screening practices in North America. Our results indicate that GD carrier screening is being offered at a high rate within the scope of Jewish ancestry-based carrier screening. This may highlight a need to move away from the debate as to whether GD carrier screening should be offered and, instead, focus on how best to provide GD carrier screening services.
doi:10.1038/gim.2012.63
PMCID: PMC3530379  PMID: 22653536
Gaucher disease; prenatal healthcare providers; carrier screening; practices; survey
16.  Neurodegeneration Across Stages of Cognitive Decline in Parkinson Disease 
Archives of Neurology  2011;68(12):1562-1568.
Objective
To assess regions and patterns of brain atrophy in patients with Parkinson disease (PD) with normal cognition (PD-NC), mild cognitive impairment (PD-MCI), and dementia-level cognitive deficits (PDD).
Design
Images were quantified using a region-of-interest approach and voxel-based morphometry analysis. We used a high-dimensional pattern classification approach to delineate brain regions that collectively formed the Spatial Pattern of Abnormalities for Recognition of PDD.
Setting
The Parkinson’s Disease and Movement Disorders Center at the University of Pennsylvania.
Subjects
Eighty-four PD patients (61 PD-NC, 12 PD-MCI, and 11 PDD) and 23 healthy control subjects (HCs) underwent magnetic resonance imaging of the brain.
Results
The PD-NC patients did not demonstrate significant brain atrophy compared with HCs. Compared with PD-NC patients, PD-MCI patients had hippocampal atrophy (β=−0.37; P=.001), and PDD patients demonstrated hippocampal (β=−0.32; P=.004) and additional medial temporal lobe atrophy (β=−0.36; P=.003). The PD-MCI patients had a different pattern of atrophy compared with PD-NC patients (P=.04) and a similar pattern to that of PDD patients (P=.81), characterized by hippocampal, prefrontal cortex gray and white matter, occipital lobe gray and white matter, and parietal lobe white matter atrophy. In nondemented PD patients, there was a correlation between memory-encoding performance and hippocampal volume.
Conclusions
Hippocampal atrophy is a biomarker of initial cognitive decline in PD, including impaired memory encoding and storage, suggesting heterogeneity in the neural substrate of memory impairment. Use of a pattern classification approach may allow identification of diffuse regions of cortical gray and white matter atrophy early in the course of cognitive decline.
doi:10.1001/archneurol.2011.725
PMCID: PMC3290902  PMID: 22159053
17.  The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits and Alzheimer-like pathology in an interventional study with aged tau transgenic mice 
The Journal of Neuroscience  2012;32(11):3601-3611.
Neurodegenerative tauopathies, such as Alzheimer’s disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-stabilizing compound will provide benefit in a Tg model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing.
doi:10.1523/JNEUROSCI.4922-11.2012
PMCID: PMC3321513  PMID: 22423084
18.  Development and Validation of an Instrument for Measuring Attitudes and Beliefs about Complementary and Alternative Medicine (CAM) Use among Cancer Patients 
Despite cancer patients' extensive use of complementary and alternative medicine (CAM), validated instruments to measure attitudes, and beliefs predictive of CAM use are lacking. We aimed at developing and validating an instrument, attitudes and beliefs about CAM (ABCAM). The 15-item instrument was developed using the theory of planned behavior (TPB) as a framework. The literature review, qualitative interviews, expert content review, and cognitive interviews were used to develop the instrument, which was then administered to 317 outpatient oncology patients. The ABCAM was best represented as a 3-factor structure: expected benefits, perceived barriers, and subjective norms related to CAM use by cancer patients. These domains had Eigenvalues of 4.79, 2.37, and 1.43, and together explained over 57.2% of the variance. The 4-item expected benefits, 7-item perceived barriers, and 4-item subjective norms domain scores, each had an acceptable internal consistency (Cronbach's alpha) of 0.91, 0.76, and 0.75, respectively. As expected, CAM users had higher expected benefits, lower perceived barriers, and more positive subjective norms (all P < 0.001) than those who did not use CAM. Our study provides the initial evidence that the ABCAM instrument produced reliable and valid scores that measured attitudes and beliefs related to CAM use among cancer patients.
doi:10.1155/2012/798098
PMCID: PMC3369496  PMID: 22693532
19.  Plasma EGF levels predict cognitive decline in Parkinson's Disease 
Annals of neurology  2010;69(4):655-663.
Objective
Most people with Parkinson's disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma-based biomarkers for CI in PD.
Methods
A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale-2 (DRS) at baseline and on annual follow-up visits, and baseline plasma levels of 102 proteins were determined with a bead-based immunoassay. Using linear regression, we identified biomarkers of CI in PD, i.e. proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow-up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients.
Results
Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, p<0.001); many of the other 10 analytes co-varied with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an eightfold greater risk of cognitive decline to dementia-range DRS scores at follow-up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients.
Interpretation
Our data suggest that plasma EGF may be a biomarker for progression to CI in PD.
doi:10.1002/ana.22271
PMCID: PMC3155276  PMID: 21520231
Epidermal growth factor; EGF; Parkinson's Disease; Parkinson's Disease with Dementia; Biomarker; Plasma
20.  Phosphorylated tau/amyloid beta 1-42 ratio in ventricular cerebrospinal fluid reflects outcome in idiopathic normal pressure hydrocephalus 
Background
Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible cause of dementia and gait disturbance that is typically treated by operative placement of a ventriculoperitoneal shunt. The outcome from shunting is variable, and some evidence suggests that the presence of comorbid Alzheimer's disease (AD) may impact shunt outcome. Evidence also suggests that AD biomarkers in cerebrospinal fluid (CSF) may predict the presence of AD. The aim of this study was to investigate the relationship between the phosphorylated tau/amyloid beta 1-42 (ptau/Aβ1-42) ratio in ventricular CSF and shunt outcome in patients with iNPH.
Methods
We conducted a prospective trial with a cohort of 39 patients with suspected iNPH. Patients were clinically and psychometrically assessed prior to and approximately 4 months after ventriculoperitoneal shunting. Lumbar and ventricular CSF obtained intraoperatively, and tissue from intraoperative cortical biopsies were analyzed for AD biomarkers. Outcome measures included performance on clinical symptom scales, supplementary gait measures, and standard psychometric tests. We investigated relationships between the ptau/Aβ1-42 ratio in ventricular CSF and cortical AD pathology, initial clinical features, shunt outcome, and lumbar CSF ptau/Aβ1-42 ratios in the patients in our cohort.
Results
We found that high ptau/Aβ1-42 ratios in ventricular CSF correlated with the presence of cortical AD pathology. At baseline, iNPH patients with ratio values most suggestive of AD presented with better gait performance but poorer cognitive performance. Patients with high ptau/Aβ1-42 ratios also showed a less robust response to shunting on both gait and cognitive measures. Finally, in a subset of 18 patients who also underwent lumbar puncture, ventricular CSF ratios were significantly correlated with lumbar CSF ratios.
Conclusions
Levels of AD biomarkers in CSF correlate with the presence of cortical AD pathology and predict aspects of clinical presentation in iNPH. Moreover, preliminary evidence suggests that CSF biomarkers of AD may prove useful for stratifying shunt prognosis in patients being evaluated and treated for this condition.
doi:10.1186/2045-8118-9-7
PMCID: PMC3353832  PMID: 22444461
Alzheimer's disease; Normal pressure hydrocephalus; Ventriculoperitoneal shunting; Tau; Amyloid beta 1-42; Cerebrospinal fluid
21.  The Philadelphia Brief Assessment of Cognition (PBAC): A Validated Screening Measure for Dementia 
The Clinical Neuropsychologist  2011;25(8):1314-1330.
The Philadelphia Brief Assessment of the Cognition (PBAC) is a brief dementia-screening instrument. The PBAC assesses five cognitive domains: working memory/executive control; lexical retrieval/language; visuospatial/visuoconstructional operations; verbal/visual episodic memory; and behavior/social comportment. A revised version of the PBAC was administered to 198 participants including patients with Alzheimer’s disease (AD) (n=46) and four groups of patients with frontotemporal dementia (FTD) syndromes: behavioral-variant FTD (bvFTD; n=65), semantic-variant primary progressive aphasia (PPA) (svPPA; n=22), non-fluent/agrammatic-variant PPA (nfaPPA; n=23), and corticobasal syndrome (CBS; n=42), and a group of normal controls (n=15). The total PBAC score was highly correlated with the MMSE. The criterion validity of the PBAC was assessed relative to standard neuropsychological test performance. Using standard neuropsychological test performance as a criterion, the total PBAC score accurately identified the presence and severity of dementia. Intra-class correlations between PBAC subscales and standard neuropsychological tests were highly significant. PBAC subscales demonstrated good clinical utility in distinguishing AD and FTD subtypes using receiver operating characteristic analysis and standard diagnostic performance statistics to determine optimal subscale cut scores. The PBAC is a valid tool and able to assesses differential patterns neuropsychological/behavioral impairment in a broad range of neurodegenerative conditions.
doi:10.1080/13854046.2011.631585
PMCID: PMC3297195  PMID: 22084867
Alzheimer’s disease; Frontotemporal lobar dementia; Frontotemporal dementia; FTD; Philadelphia Brief Assessment of the Cognition; PBAC; Neuropsychological assessment; Philadelphia (repeatable) Verbal Learning Test
22.  Genetic Testing and Parkinson Disease: Assessment of Patient Knowledge, Attitudes, and Interest 
Journal of Genetic Counseling  2011;20(4):384-395.
The most common genetic contributor to late-onset Parkinson disease (PD) is the LRRK2 gene. In order to effectively integrate LRRK2 genetic testing into clinical practice, a strategy tailored to the PD population must be developed. We assessed 168 individuals with PD for baseline knowledge of genetics, perceived risk, and interest and opinions regarding genetic counseling and testing. Most participants felt that they were familiar with general genetics terms but overall knowledge levels were low, with an average score of 55%. The majority of participants thought it was likely they inherited a PD gene (72%), believed genetic testing for PD would be useful (86%), and were interested in genetic testing (59%) and genetic counseling (56%). However, only a few participants had heard of any genetic tests for PD (29%) or LRRK2 (10%). There appears to be a significant level of interest in genetics and genetic testing within the PD population, but a considerable deficit in genetics knowledge and an over-estimation of risk. Genetic education and counseling tools to address these needs were developed to provide patients with the ability to make informed and knowledgeable genetic testing decisions.
doi:10.1007/s10897-011-9362-0
PMCID: PMC3280083  PMID: 21476119
Parkinson disease; Genetic testing; Genetic knowledge; Attitudes; Perceived risk
23.  A memory and organizational aid improves AD research consent capacity: Results of a randomized, controlled trial 
Objectives
AD patients' early and progressive cognitive impairments hinder their capacity to provide informed consent. Unfortunately, the limited research on techniques to improve capacity has shown mixed results. Therefore, we tested whether a memory and organizational aid improves AD patient performance on measures of capacity and competency to give informed consent.
Design, Setting, and Participants
AD patients randomly assigned to standard consent, or standard plus a memory and organizational aid.
Intervention
Memory and organizational aid summarized at a 6th grade reading level the content of information mandated under the Common Rule's informed consent disclosure requirements.
Measurements
Three psychiatrists without access to patient data independently reviewed MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) interview transcripts to judge whether the patient was capable of providing informed consent. The agreement of at least two of three experts defined a participant as capable of providing informed consent. Secondary outcomes are MacCAT-CR measures of understanding, appreciation and reasoning, and comparison to cognitively normal older adult norms.
Results
AD intervention and control groups were similar in terms of age, education, and cognitive status. The intervention group was more likely to be judged competent than control group and had higher scores on MacCAT-CR measure of understanding. The intervention had no effect on measures of appreciation or reasoning.
Conclusions
A consent process that addresses an AD patients' deficits in memory and attention can improve capacity to give informed consent for early phase AD research. The results also validate the MacCAT-CR as an instrument to measure capacity, especially the understanding subscale.
doi:10.1097/JGP.0b013e3181dd1c3b
PMCID: PMC2992096  PMID: 20808101
Alzheimer's disease; informed consent; capacity; research ethics
24.  Odor Identification Deficits are Associated with Increased Risk of Neuropsychiatric Complications in Patients with Parkinson’s Disease 
Olfactory deficits appear early in the course of Parkinson’s disease (PD) but their prognostic significance is not known. The goal of this study was to determine whether the severity of olfactory impairment is associated with subsequent risk of developing complications of PD. One hundred patients with PD self-administered the University of Pennsylvania Smell Identification Test (UPSIT). Testing was done, on average, 3.6 years from the time of initial diagnosis. The incidence of neuropsychiatric features of PD, including cognitive decline and visual hallucinations, was ascertained through chart review after an average of 6.8 years of follow-up. Incidence of motor outcomes including falls and dyskinesias was also obtained. There was a significant trend for increased risk of neuropsychiatric complications across declining quartiles of olfactory test scores. In addition, subjects in the lowest quartile of olfactory performance had a significantly higher adjusted risk of hallucinations (HR = 4.70, 95% CI 1.64, 13.42) and cognitive decline (HR = 3.10, 95% CI 1.05, 9.21) than those in the reference quartile. There was no association between olfactory dysfunction and dyskinesias, and a very modest association with risk of falls. These findings suggest that severity of olfactory impairment early in the disease course may be a useful marker for the risk of neuropsychiatric complications of PD.
doi:10.1002/mds.23234
PMCID: PMC2963102  PMID: 20669288
Parkinson’s disease; olfaction; dementia; visual hallucinations
25.  Building An Integrated Neurodegenerative Disease Database At An Academic Health Center 
Background
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.
Methods
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.
Results
We compare the results of a biomarker study using the INDD database to those using an alternative approach by querying individual database separately.
Conclusions
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.
doi:10.1016/j.jalz.2010.08.233
PMCID: PMC3145967  PMID: 21784346
Database; Neurodegenerative Disease; Microsoft SQL; Relational Neurodegenerative Disease Database

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