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1.  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.
doi:10.1002/cne.23430
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
2.  PROTEOGLYCAN ABNORMALITIES IN OLFACTORY EPITHELIUM TISSUE FROM SUBJECTS DIAGNOSED WITH SCHIZOPHRENIA 
Schizophrenia research  2013;150(0):366-372.
Emerging evidence points to proteoglycans abnormalities in the pathophysiology of schizophrenia (SZ). In particular, markedly abnormal expression of chondroitin sulfate proteoglycans (CSPGs), key components of the extracellular matrix, was observed in the medial temporal lobe. CSPG functions, including regulation of neuronal differentiation and migration, are highly relevant to the pathophysiology of SZ. CSPGs may exert similar functions in the olfactory epithelium (OE), a continuously regenerating neural tissue that shows cell and molecular abnormalities in SZ. We tested the hypothesis that CSPG expression in OE may be altered in SZ. CSPG-positive cells in postmortem OE from nonpsychiatric control (n=9) and SZ (n=10) subjects were counted using computer-assisted light microscopy. ‘Cytoplasmic’ CSPG (c-CSPG) labeling was detected in sustentacular cells and some olfactory receptor neurons (c-CSPG+ORNs), while ‘pericellular’ CSPG (p-CSPG) labeling was found in basal cells and some ORNs (p-CSPG+ORNs). Dual labeling for CSPG and markers for mature and immature ORNs suggests that c-CSPG+ORNs correspond to mature ORNs, and p-CSPG+ORNs to immature ORNs. Previous studies in the same cohort demonstrated that densities of mature ORNs were unaltered (Arnold et al, 2001). In the present study, numerical densities of c-CSPG+ORNs were significantly decreased in SZ (p <0.025; 99.32% decrease), suggesting a reduction of CSPG expression in mature ORNs. Previous studies showed a striking increase in the ratios of immature neurons with respect to basal cells. In this study, we find that the ratio of p-CSPG+ORNs/ CSPG+ basal cells was significantly increased (p=0.03) in SZ, while numerical density changes of p-CSPG+ORNs (110.71% increase) or CSPG+ basal cells (53.71% decrease), did not reach statistical significance. Together, these results indicate that CSPG abnormalities are present in the OE of SZ and specifically point to a reduction of CSPGs expression in mature ORNs in SZ. Given the role CSPG play in OE cell differentiation and axon guidance, we suggest that altered CSPG expression may contribute to ORN lineage dysregulation, and olfactory identification abnormalities, observed in SZ.
doi:10.1016/j.schres.2013.08.013
PMCID: PMC4215560  PMID: 24035561
Schizophrenia; extracellular matrix; chondroitin sulfate proteoglycans; olfactory epitheliu; postmortem
3.  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.
doi:10.1016/j.jns.2013.05.028
PMCID: PMC3815534  PMID: 23978419
Alzheimer Disease; Mild Cognitive Impairment; C-Reactive Protein; Inflammation; Biological Markers
4.  Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer's disease and tauopathies 
Acta neuropathologica  2014;128(5):679-689.
Neuronal insulin signaling abnormalities have been associated with Alzheimer's disease (AD). However, the specificity of this association and its underlying mechanisms have been unclear. This study investigated the expression of abnormal serine phosphorylation of insulin receptor substrate 1 (IRS1) in 157 human brain autopsy cases that included AD, tauopathies, α-synucleinopathies, TDP-43 proteinopathies, and normal aging. IRS1-pS616, IRS1-pS312 and downstream target Akt-pS473 measures were most elevated in AD but were also significantly increased in the tauopathies: Pick's disease, corticobasal degeneration and progressive supranuclear palsy. Double immunofluorescence labeling showed frequent co-expression of IRS1-pS616 with pathologic tau in neurons and dystrophic neurites. To further investigate an association between tau and abnormal serine phosphorylation of IRS1, we examined the presence of abnormal IRS1-pS616 expression in pathological tau-expressing transgenic mice and demonstrated that abnormal IRS1-pS616 frequently co-localizes in tangle-bearing neurons. Conversely, we observed increased levels of hyperphosphorylated tau in the high-fat diet-fed mouse, a model of insulin resistance. These results provide confirmation and specificity that abnormal phosphorylation of IRS1 is a pathological feature of AD and other tauopathies, and provide support for an association between insulin resistance and abnormal tau as well as amyloid-β.
doi:10.1007/s00401-014-1328-5
PMCID: PMC4304658  PMID: 25107476
Alzheimer's disease; Tau; Synuclein; TDP-43; Insulin resistance; Insulin receptor substrate 1
5.  Cognitive and Social Lifestyle: Links with Neuropathology and Cognition in Late Life 
Acta neuropathologica  2013;127(1):137-150.
Many studies report an association of cognitive and social experiential factors and related traits with dementia risk. Further, many clinical-pathologic studies find a poor correspondence between levels of neuropathology and the presence of dementia and level of cognitive impairment. The poor correspondence suggests that other factors contribute to the maintenance or loss of cognitive function, with factors associated with the maintenance of function referred to as neural or cognitive reserve. This has led investigators to examine the associations of cognitive and social experiential factors with neuropathology as a first step in disentangling the complex associations between these experiential risk factors, neuropathology, and cognitive impairment. Despite the consistent associations of a range of cognitive and social lifestyle factors with cognitive decline and dementia risk, the extant clinical pathologic data finds only a single factor from one cohort, linguistic ability, related to AD pathology. Other factors, including education, harm avoidance, and emotional neglect, are associated with cerebrovascular disease. Overall, the associations are weak. Some factors, such as education, social networks, and purpose in life modify the relation of neuropathology to cognition. Finally, some factors such as cognitive activity appear to bypass known pathologies altogether suggesting a more direct association with biologic indices that promote person-specific differences in reserve and resilience. Future work will first need to replicate findings across more studies to ensure the veracity of the existing data. Second, effort is need to identify the molecular substrates of neural reserve as potential mediators of the association of lifestyle factors with cognition.
doi:10.1007/s00401-013-1226-2
PMCID: PMC4054865  PMID: 24356982
Aging; Dementia; Risk Factors; Neuropathology; Neural Reserve; Epidemiology
6.  Resilient Brain Aging: Characterization of Discordance between Alzheimer’s Disease Pathology and Cognition 
Current Alzheimer research  2013;10(8):844-851.
Background
Although it is now evident that normal cognition can occur despite significant AD pathology, few studies have attempted to characterize this discordance, or examine factors that may contribute to resilient brain aging in the setting of AD pathology.
Methods
More than 2,000 older persons underwent annual evaluation as part of participation in the Religious Orders Study or Rush Memory Aging Project. A total of 966 subjects who had brain autopsy and comprehensive cognitive testing proximate to death were analyzed. Resilience was quantified as a continuous measure using linear regression modeling, where global cognition was entered as a dependent variable and global pathology was an independent variable. Studentized residuals generated from the model represented the discordance between cognition and pathology, and served as measure of resilience. The relation of resilience index to known risk factors for AD and related variables was examined.
Results
Multivariate regression models that adjusted for demographic variables revealed significant associations for early life socioeconomic status, reading ability, APOE-ε4 status, and past cognitive activity. A stepwise regression model retained reading level (estimate = 0.10, SE = 0.02; p < 0.0001) and past cognitive activity (estimate = 0.27, SE = 0.09; p = 0.002), suggesting the potential mediating role of these variables for resilience.
Conclusions
The construct of resilient brain aging can provide a framework for quantifying the discordance between cognition and pathology, and help identify factors that may mediate this relationship.
PMCID: PMC4060425  PMID: 23919768
Cognitive activity; Neuropathology; Reading level; Reserve; Resilience
7.  Brainstem Aminergic Nuclei and Late Life Depressive Symptoms 
JAMA psychiatry (Chicago, Ill.)  2013;70(12):10.1001/jamapsychiatry.2013.2224.
Context
The neurobiologic basis of late life depressive symptoms is not well understood.
Objective
To test the hypothesis that neurodegeneration and neuronal density in brainstem aminergic nuclei are related to late life depressive symptoms.
Design
Longitudinal clinical-pathologic cohort study.
Setting
Residences of participants in the Chicago metropolitan area.
Participants
A total of 124 older persons without dementia in the Rush Memory and Aging Project who had annual evaluations for a mean of 5.7 years (SD = 2.8), died, and underwent a neuropathologic examination that provided estimates of the densities of Lewy bodies, neurofibrillary tangles, and aminergic neurons in the locus coeruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area.
Main Outcome Measure
Number of depressive symptoms on the Center for Epidemiological Studies Depression scale averaged across annual evaluations (mean = 1.61, SD = 1.48, range: 0–6, skewness = 0.94).
Results
Brainstem Lewy bodies were associated with depressive symptoms and the association was attenuated in those on antidepressant medication. Brainstem tangles were associated with more depressive symptoms in those without cognitive impairment but fewer symptoms in those with mild cognitive impairment. Lower density of tyrosine-hydroxylase-immunoreactive neurons in the ventral tegmental area was robustly associated with higher level of depressive symptoms (estimate = −0.014, SE = 0.003, p<0.001, increase in adjusted R2 = 16.3%). The association was not modified by medications or cognitive impairment. Neither tyrosine-hydroxlyase-immunoreactive neurons in the locus coeruleus nor tryptophan-hydroxlyase-immunoreactive neurons in the dorsal raphe nucleus were related to depressive symptoms.
Conclusions
The results suggest that the mesolimbic dopamine system, especially the ventral tegemental area, plays an important role in late life depressive symptoms.
doi:10.1001/jamapsychiatry.2013.2224
PMCID: PMC3856195  PMID: 24132763
8.  Neocortical β-amyloid area is associated with dementia and APOE in the oldest-old 
Objective
Apolipoprotein E (APOE) ε2 carriers may be protected from dementia because of reduced levels of cortical β-amyloid. In the oldest-old, however, APOE ε2 carriers have high β-amyloid plaque scores and preserved cognition. We compared different measures of β-amyloid pathology across APOE genotypes in the oldest-old, and their relationship with dementia.
Methods
The study included 96 participants from The 90+ Study. Using all information, dementia diagnoses were made. Neuropathological examination included staging for amyloid plaques and β-amyloid cortical percent area stained by NAB228 antibody.
Results
Both APOE ε2 and APOE ε4 carriers had high Consortium to Establish a Registry for Alzheimer's Disease plaque scores. However, APOE ε2 carriers had low cortical β-amyloid percent areas. β-amyloid percent area was associated with dementia across APOE genotypes.
Conclusions
Lower levels of percent area in APOE ε2 carriers may reflect lower total β-amyloid and may contribute to APOE ε2 carriers' decreased risk of dementia, despite high β-amyloid plaque scores. The relationship between β-amyloid plaques and dementia in the oldest-old may vary by APOE genotype.
doi:10.1016/j.jalz.2012.11.011
PMCID: PMC3971646  PMID: 23474043
Alzheimer; Apolipoprotein E; Beta-amyloid; Dementia; Oldest-old
9.  Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease 
Neurobiology of aging  2012;34(1):157-168.
While neuritic plaques and neurofibrillary tangles in older adults are correlated with cognitive impairment and severity of dementia, it has long been recognized that the relationship is imperfect as some people exhibit normal cognition despite high levels of AD pathology. We compared the cellular, synaptic and biochemical composition of midfrontal cortices in female subjects from the Religious Orders Study who were stratified into three subgroups: 1) pathological AD with normal cognition (“AD-Resilient”), 2) pathological AD with AD-typical dementia (“AD-Dementia)” and 3) pathologically normal with normal cognition (“Normal Comparison”). The AD-Resilient group exhibited preserved densities of synaptophysin-labeled presynaptic terminals and synaptopodin-labeled dendritic spines compared to the AD-Dementia group, and increased densities of GFAP astrocytes compared to both the AD-Dementia and Normal Comparison group. Further, in a discovery antibody microarray protein analysis we identified a number of candidate protein abnormalities that were associated with diagnostic group. These data characterize cellular and synaptic features and identify novel biochemical targets that may be associated with resilient cognitive brain aging in the setting of pathological AD.
doi:10.1016/j.neurobiolaging.2012.03.004
PMCID: PMC3478410  PMID: 22554416
cognitive reserve; synapse; synaptophysin; synaptopodin; glial fibrillary acidic protein; antibody microarray
10.  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
11.  Qualification of a Surrogate Matrix-Based Absolute Quantification Method for Amyloid-β42 in Human Cerebrospinal Fluid Using 2D UPLC-Tandem Mass Spectrometry 
The primary aims of this work were to: 1) establish a calibrator surrogate matrix for quantification of amyloid-β (Aβ)42 in human cerebrospinal fluid (CSF) and preparation of quality control samples for LC-MS-MS methodology, 2) validate analytical performance of the assay, and 3) evaluate its diagnostic utility and compare it with the AlzBio3 immunoassay. The analytical methodology was based on a 2D-UPLC-MS-MS platform. Sample pretreatment used 5 M guanidine hydrochloride and extraction on μElution SPE columns as previously described. A column cleaning procedure involved gradual removal of aqueous solvents by acetonitrile assured consistent long-term chromatography performance. Receiver-operator characteristic (ROC) curve and correlation analyses evaluated the diagnostic utility of UPLC-MS-MS compared to AlzBio3 immunoassay for detection of Alzheimer’s disease (AD). The surrogate matrix, artificial CSF containing 4 mg/mL of BSA, provides linear and reproducible calibration comparable to human pooled CSF as calibration matrix. Appropriate cleaning of the trapping and analytical columns provided every-day, trouble-free runs. Analyses of CSF Aβ42 showed that UPLC-MS-MS distinguished neuropathologically-diagnosed AD subjects from healthy controls with at least equivalent diagnostic utility to AlzBio3. Comparison of ROC curves for these two assays showed no statistically significant difference (p = 0.2229). Linear regression analysis of Aβ42 concentrations measured by this mass spectrometry-based method compared to the AlzBio3 immunoassay showed significantly higher but highly correlated results. In conclusion, the newly established surrogate matrix for 2D-UPLC-MS-MS measurement of Aβ42 provides selective, reproducible, and accurate results. The documented analytical performance and diagnostic performance for AD versus controls supports consideration as a candidate reference method.
doi:10.3233/JAD-132489
PMCID: PMC4159707  PMID: 24625802
Alzheimer’s disease; amyloid-β42; cerebrospinal fluid; mass spectrometry
12.  Comparative accuracies of two common screening instruments for the classification of Alzheimer’s disease, mild cognitive impairment and healthy aging 
Objective
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.
Method
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.
Results
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.
Conclusion
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.
doi:10.1016/j.jalz.2012.10.001
PMCID: PMC4036230  PMID: 23260866
Alzheimer’s disease; Mild Cognitive Impairment; MMSE; MoCA; Diagnostic accuracy
13.  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.
doi:10.1093/brain/awt188
PMCID: PMC3858112  PMID: 23842566
Alzheimer’s disease; frontotemporal lobar degeneration; vascular disease; dementia; epidemiology; neuropathology
14.  Hospitalization and Cognitive Decline: Can the Nature of the Relationship Be Deciphered? 
Background
Evidence for a relationship between hospitalization and incident cognitive decline exists mainly in the literature focusing on critical care hospitalization. Recent studies, however, have also found an association between noncritical care hospitalization and the development of cognitive decline.
Objective
This article will review the literature pertaining to hospitalization and cognitive decline, including hospitalizations for both critical and noncritical care, and in medical and surgical patients. The article will also explore the various factors that have been implicated in the development of cognitive decline and dementia.
Methods
Review of the literature was completed using PubMed and Medline search programs.
Results
Several articles supporting evidence for the association between hospitalization and cognitive decline are available. Evidence for potential mediating factors also does exist.
Conclusions
There is evidence to support an association between hospitalization and development of cognitive decline. Factors that could mediate this association include, but may not be limited to, delirium, medications, stress, and depression. There is a need for further research in this area in order to better understand the underlying pathophysiology involved in the development of cognitive decline and dementia and to determine if preventive measures might be beneficial in decreasing risk for cognitive decline for patients who are hospitalized.
doi:10.1016/j.jagp.2012.08.012
PMCID: PMC4080837  PMID: 23567430
Hospitalization; cognitive impairment; cognitive decline; dementia
15.  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.
doi:10.1016/j.jalz.2013.06.003
PMCID: PMC3933464  PMID: 23978324
Cerebrospinal fluid; Plasma; Serum; Autopsy; Neurodegeneration; Alzheimer’s Disease; Dementia; Genetics; Parkinson’s Disease; Frontotemporal lobar degeneration
16.  Olfaction and Apathy in Alzheimer’s Disease, Mild Cognitive Impairment, and Healthy Older Adults 
Aging & mental health  2013;17(5):564-570.
Objectives
Apathy is a prevalent neuropsychiatric manifestation in individuals with Alzheimer’s disease (AD) that is associated with decreased social functioning and increased caregiver burden. Olfactory deficits are also commonly observed in AD, and prior work has indicated a link between increased apathy and olfactory dysfunction in individuals with Parkinson’s disease. Here, we examined odor identification performance in patients with probable AD (n = 172), individuals with mild cognitive impairment (MCI; n = 112), and neurologically and psychiatrically healthy older adults (n = 132) and its relation to apathy, depression, and overall psychopathology.
Method
Participants were administered the Sniffin’ Sticks odor identification test and measures assessing severity of apathy, depression, and overall neuropsychiatric symptomatology.
Results
Consistent with previous research, AD and MCI patients were significantly worse at identifying odors than healthy older adults. Additionally, a sex by diagnosis interaction was observed. AD patients had significantly higher levels of apathy relative to MCI and control participants. Of note, across the entire sample odor identification deficits were correlated with level of apathy at the level of p < 0.01, but not with depression or neuropsychiatric symptom severity, when controlling for MMSE score.
Conclusion
Collectively, these data suggest that olfactory disturbance and apathy in AD may result from the progression of disease pathology in shared neural substrates.
doi:10.1080/13607863.2013.768208
PMCID: PMC3664659  PMID: 23398350
olfactory; smell; apathy; neuropsychiatry; sex differences
17.  Amphiphysin-1 protein level changes associated with tau-mediated neurodegeneration 
Neuroreport  2012;23(16):942-946.
Tauopathies are a family of neurodegenerative diseases that have the pathological hallmark of intraneuronal accumulation of filaments composed of hyperphosphorylated tau proteins that tend to aggregate in an ultrastructure known as neurofibrillary tangles. The identification of mutations on the tau gene in familial cases of tauopathies underscores the pathological role of the tau protein. However, the molecular process that underlines tau-mediated neurodegeneration is not understood. Here, a proteomics approach was used to identify proteins that may be affected during the course of tau-mediated neurodegeneration in the tauopathy mouse model JNPL3. The JNPL3 mice express human tau proteins bearing a P301L mutation, which mimics the neurodegenerative process observed in humans with tauopathy. The results showed that the protein amphiphysin-1 (AMPH1) is significantly reduced in terminally ill JNPL3 mice. Specifically, the AMPH1 protein level is reduced in brain regions known to accumulate aggregates of hyperphosphorylated tau proteins. The AMPH1 protein reduction was validated in Alzheimer’s disease cases. Taken together, the results suggest that the reduction of the AMPH1 protein level is a molecular event associated with the progression of tau-mediated neurodegeneration.
doi:10.1097/WNR.0b013e32835982ce
PMCID: PMC3696496  PMID: 22975846
Alzheimer’s disease; amphiphysin; calpain; neurodegeneration; tau; tauopathy
18.  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
19.  Familiarity-based memory as an early cognitive marker of preclinical and prodromal AD 
Neuropsychologia  2013;51(6):1094-1102.
There is great interest in the development of cognitive markers that differentiate “normal” age-associated cognitive change from that of Alzheimer's disease (AD) in its prodromal (i.e., mild cognitive impairment; MCI) or even preclinical stages. Dual process models posit that recognition memory is supported by the dissociable processes of recollection and familiarity. Familiarity-based memory has generally been considered to be spared during normal aging, but it remains controversial whether this type of memory is impaired in early AD. Here, we describe findings of estimates of recollection and familiarity in young adults (YA), cognitively normal older adults (CN), and patients with amnestic-MCI (a-MCI). These measures in the CN and a-MCI patients were then related to a structural imaging biomarker of AD that has previously been demonstrated to be sensitive to preclinical and prodromal AD, the Cortical Signature of AD (ADsig). Consistent with much work in the literature, recollection, but not familiarity, was impaired in CN versus YA. Replicating our prior findings, a-MCI patients displayed impairment in both familiarity and recollection. Finally, the familiarity measure was correlated with the ADsig biomarker across the CN and a-MCI group, as well as within the CN adults alone. No other standard psychometric measure was as highly associated with the ADsig, suggesting that familiarity may be a sensitive biomarker of AD-specific brain changes in preclinical and prodromal AD and that it may offer a qualitatively distinct measure of early AD memory impairment relative to normal age-associated change.
doi:10.1016/j.neuropsychologia.2013.02.014
PMCID: PMC3742759  PMID: 23474075
Memory; Recollection; Familiarity; Alzheimer's disease; Medial temporal lobe; Preclinical Alzheimer's disease; Mild cognitive impairment
20.  Neuronal injury biomarkers and prognosis in ADNI subjects with normal cognition 
Introduction
Based on previous studies, a preclinical classification for Alzheimer’s disease (AD) has been proposed. However, 1) specificity of the different neuronal injury (NI) biomarkers has not been studied, 2) subjects with subtle cognitive impairment but normal NI biomarkers (SCINIB) have not been included in the analyses and 3) progression to mild cognitive impairment (MCI) or dementia of the AD type (DAT), referred to here as MCI/DAT, varies between studies. Therefore, we analyzed data from 486 cognitively normal (CN) and 327 DAT subjects in the AD Neuroimaging Initiative (ADNI)-1/GO/2 cohorts.
Results
In the ADNI-1 cohort (median follow-up of 6 years), 6.3% and 17.0% of the CN subjects developed MCI/DAT after 3 and 5 years follow-up, respectively. NI biomarker cutoffs [structural magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET) and cerebrospinal fluid (CSF) tau] were established in DAT patients and memory composite scores were calculated in CN subjects in a cross-sectional sample (n = 160). In the complete longitudinally followed CN ADNI cohort (n = 326, median follow-up of 2 years), CSF and MRI values predicted an increased conversion to MCI/DAT. Different NI biomarkers showed important disagreements for classifying subjects as abnormal NI [kappa = (−0.05)-(0.33)] and into AD preclinical groups. SCINIB subjects (5.0%) were more prevalent than AD preclinical stage 3 subjects (3.4%) and showed a trend for increased progression to MCI/DAT.
Conclusions
Different NI biomarkers lead to different classifications of ADNI subjects, while structural MRI and CSF tau measures showed the strongest predictive value for progression to MCI/DAT. The newly defined SCINIB category of ADNI subjects is more prevalent than AD preclinical stage individuals.
doi:10.1186/2051-5960-2-26
PMCID: PMC4008258  PMID: 24602322
Dementia; Alzheimer’s disease; Magnetic resonance imaging; Cerebrospinal fluid; Amyloid beta; Tau
21.  Neuroticism, Extraversion, and Motor Function in Community-Dwelling Older Persons 
Objective
Personality traits are associated with adverse health outcomes in old age, but their association with motor function is unclear. We tested the hypothesis that neuroticism and extraversion are associated motor decline in older persons.
Design
Prospective, observational cohort study.
Setting
Retirement communities across metropolitan Chicago.
Participants
983 older persons without dementia.
Measurements
At baseline, neuroticism and extraversion were assessed and annual assessment of 18 motor measures were summarized in a composite measure.
Results
Average follow-up was 5 years. Separate linear mixed-effects models controlling for age, sex and education showed that baseline levels of neuroticism and extraversion were associated with the rate of motor decline. For each 7- point (~1SD) higher neuroticism score at baseline, the average annual rate of motor decline was more than 20% faster. This amount of motor decline was associated with a 10% increased risk of death as compared to a participant with an average neuroticism score. Each 6- point (~1SD) lower extraversion score at baseline was associated with an 8% faster rate of motor decline. This amount of motor decline was associated with about 9% increased risk of death as compared to a participant with an average extraversion score. Neuroticism and extraversion were relatively independently associated with motor decline. These associations were unchanged when controlling for depressive symptoms and current health status, but were partially attenuated when controlling for late-life cognitive and social activities.
Conclusions
Higher levels of neuroticism and lower levels of extraversion are associated with more rapid motor decline in old age.
doi:10.1016/j.jagp.2012.10.015
PMCID: PMC3406259  PMID: 23343488
Personality; Neuroticism; Extraversion; Aging; Motor Decline
22.  Cognitive decline and reduced survival in C9orf72 expansion Frontotemporal degeneration and Amyotrophic lateral sclerosis 
Background
Significant heterogeneity in clinical features of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) cases with the pathogenic C9orf72 expansion (C9P) have been described. To clarify this issue, we compared a large C9P cohort with carefully matched non-expansion (C9N) cases with a known or highly-suspected underlying TDP-43 proteinopathy.
Methods
A retrospective-cohort study using available cross-sectional and longitudinal clinical and neuropsychological data, MRI voxel-based morphometry (VBM) and neuropathological assessment from 64 C9P cases (ALS=31, FTLD=33) and 79 C9N cases (ALS=36, FTLD=43).
Results
C9P cases had an earlier age of onset (p=0.047), and in the subset of deceased patients, an earlier age of death (p=0.014) than C9N. C9P had more rapid progression than C9N: C9P ALS cases had a shortened survival (2.6±0.3 years) compared to C9N ALS (3.8±0.4 years; log-rankλ2=4.183,p=0.041), and C9P FTLD showed a significantly greater annualized rate of decline in letter fluency (4.5±1.3words/year) than C9N FTLD (1.4±0.8words/year, p=0.023). VBM revealed greater atrophy in the right fronto-insular, thalamus, cerebellum and bilateral parietal regions for C9P FTLD relative to C9N FTLD, and regression analysis related verbal fluency scores to atrophy in frontal and parietal regions. Neuropathologic analysis found greater neuronal loss in the mid-frontal cortex in C9P FTLD, and mid-frontal cortex TDP-43 inclusion severity correlated with poor letter fluency performance.
Conclusions
C9P cases may have a shorter survival in ALS and more rapid rate of cognitive decline related to frontal and parietal disease in FTLD. C9orf72 genotyping may provide useful prognostic and diagnostic clinical information for ALS and FTLD patients.
doi:10.1136/jnnp-2012-303507
PMCID: PMC3543474  PMID: 23117491
Frontotemporal dementia; Amyotrophic lateral sclerosis; C9orf72; neuropsychological tests; neuroimaging
23.  Vascular Disease and Dementias: Paradigm Shifts to Drive Research in New Directions 
Vascular disease was once considered the principal cause of aging-related dementia. More recently, however, research emphasis has shifted to studies of progressive neurodegenerative disease processes such as those giving rise to neuritic plaques, neurofibrillary tangles, and Lewy bodies. While these studies have led to critical insights and potential therapeutic strategies, interest in the role of systemic and cerebrovascular disease mechanisms waned and has received relatively less attention and research support. Recent studies suggest that vascular disease mechanisms play an important role in the risk for aging-related cognitive decline and disorders. Vascular disease frequently coexists with cognitive decline in aging individuals, shares many risk factors with dementias considered to be of the “Alzheimer-type,” and is observed more frequently than expected in postmortem material from individuals manifesting “specific” disease stigmata such as abundant plaques and tangles. Considerable difficulties have emerged in attempting to classify dementias as being related to vascular vs. neurodegenerative causes, and several systems of criteria have been used. Despite multiple attempts, a lack of consensus remains regarding the optimal means of incorporating vascular disease into clinical diagnostic, neurocognitive, or neuropathologic classification schemes for dementias.
We propose here an integrative, rather than a strictly taxonomic approach to the study and elucidation of how vascular disease mechanisms contribute to the development of dementias. We argue that, instead of discriminating between, e.g., “Alzheimer’s disease,” “vascular dementia,” and other diseases, there is a greater need to focus clinical and research efforts on elucidating specific pathophysiologic mechanisms that contribute to dementia phenotypes and neuropathologic outcomes. We outline a multi-tiered strategy, beginning with clinical and public health interventions that can be implemented immediately; enhancements to ongoing longitudinal studies to increase their informative value; and new initiatives to capitalize on recent advances in systems biology and network medicine. This strategy will require funding from multiple public and private sources to support collaborative and interdisciplinary research efforts in order to take full advantage of these opportunities and realize their societal benefits.
doi:10.1016/j.jalz.2012.02.007
PMCID: PMC3640817  PMID: 23183137
24.  Ethnoracial Differences in the Clinical Characteristics of Alzheimer Disease at Initial Presentation at an Urban Alzheimer’s Disease Center 
Objective
To compare presentation of Alzheimer disease (AD) at the time of initial evaluation at a university specialty clinic across three ethnoracial groups in order to understand similarities and differences in the demographic, clinical, cognitive, psychiatric, and biologic features.
Design
Cross-sectional study.
Participants
A total of 1,341 self-identified African American, Latino (primarily of Caribbean origin), and white non-Hispanic (“WNH”) subjects were recruited from primary care sites or by referral by primary care physicians.
Measurements
Demographic variables and age of onset of AD, as well as cognitive, functional, and mood impairments at the time of initial presentation and frequencies of apolipoprotein E genotypes, were compared across groups.
Results
Differences among ethnoracial groups were found for nearly all variables of interest. In particular, the largely immigrant Puerto Rican Latino group had an earlier age of onset of AD, more cognitive impairment, and greater severity of cognitive impairment at the time of initial evaluation in the setting of low average education and socioeconomic status. There was more depression in the Latinos compared with African Americans and WNHs. Greater severity of symptoms was not accounted for by a difference in lag time between onset of symptoms and initial evaluation. The apolipoprotein E-4 genotype was not associated with AD in the Latino cohort.
Conclusions
Minority groups in Philadelphia, especially Latinos, exhibit a more severe profile of AD at the time of presentation than WNHs. Important potential confounds need to be considered and future research comparing immigrant and nonimmigrant Latino groups will be necessary to elucidate the highly significant differences reported.
doi:10.1097/JGP.0b013e3181f7d881
PMCID: PMC3085004  PMID: 21522051
Alzheimer disease; APOE; dementia; ethnoracial differences
25.  Olfactory Epithelium Amyloid-β and PHFtau Pathology in Alzheimer’s Disease 
Annals of neurology  2010;67(4):462-469.
Objectives
Olfactory dysfunction is common in Alzheimer’s disease (AD) and other neurodegenerative diseases. PHFtau, α-synuclein and amyloid-β lesions occur early and severely in cerebral regions of the olfactory system and they have also been observed in olfactory epithelium (OE). However, their frequency, abundance, disease specificity, and relationships of OE pathology to brain pathology have not been established.
Methods
We investigated the pathological expression of amyloid-β, PHFtau, α-synuclein, and TDP-43 in postmortem OE of 79 cases with AD, 63 cases with various other neurodegenerative diseases, and 45 neuropathologically normal cases.
Results
Amyloid-β was present as punctate and small patchy aggregates in 71% of AD cases compared to 22% of normal cases and 14% of cases with other diseases and in greater amounts in AD than either of the other two diagnostic categories. PHFtau was evident in dystrophic neurites in 55% of cases with AD, 34% with normal brains, and 39% with other neurodegenerative diseases, also at higher densities in AD. α-Synuclein was present in dystrophic neurites in seven cases, six of whom also had cerebral Lewy bodies. Pathological TDP-43 inclusions were not observed in the OE in any cases. Amyloid-β and to a lesser degree, PHFtau ratings in OE significantly correlated with cortical Aβ and PHFtau lesion ratings in the brain.
Interpretation
These data demonstrate that AD pathology in the OE is present in the majority of cases with pathologically verified AD and correlates with brain pathology. Future work may assess the utility of amyloid-β and PHFtau measurement in OE as a biomarker for AD.
doi:10.1002/ana.21910
PMCID: PMC2864948  PMID: 20437581

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