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1.  High Fat Diet Produces Brain Insulin Resistance, Synaptodendritic Abnormalities and Altered Behavior in Mice 
Neurobiology of disease  2014;67:79-87.
Insulin resistance and other features of the metabolic syndrome are increasingly recognized for their effects on cognitive health. To ascertain mechanisms by which this occurs, we fed mice a very high fat diet (60% kcal by fat) for 17 days or a moderate high fat diet (HFD, 45% kcal by fat) for 8 weeks and examined changes in brain insulin signaling responses, hippocampal synaptodendritic protein expression, and spatial working memory. Compared to normal control diet mice, cerebral cortex tissues of HFD mice were insulin-resistant as evidenced by failed activation of Akt, S6 and GSK3β with ex-vivo insulin stimulation. Importantly, we found that expression of brain IPMK, which is necessary for mTOR/Akt signaling, remained decreased in HFD mice upon activation of AMPK. HFD mouse hippocampus exhibited increased expression of serine-phosphorylated insulin receptor substrate 1 (IRS1-pS616), a marker of insulin resistance, as well as decreased expression of PSD-95, a scaffolding protein enriched in post-synaptic densities, and synaptopodin, an actin-associated protein enriched in spine apparatuses. Spatial working memory was impaired as assessed by decreased spontaneous alternation in a T-maze. These findings indicate that HFD is associated with telencephalic insulin resistance and deleterious effects on synaptic integrity and cognitive behaviors.
PMCID: PMC4083060  PMID: 24686304
2.  Repurposing Diabetes Drugs for Brain Insulin Resistance in Alzheimer Disease 
Diabetes  2014;63(7):2253-2261.
A growing body of clinical and epidemiological research suggests that two of the most common diseases of aging, type 2 diabetes (T2DM) and Alzheimer disease (AD), are linked. The nature of the association is not known, but this observation has led to the notion that drugs developed for the treatment of T2DM may be beneficial in modifying the pathophysiology of AD and maintaining cognitive function. Recent advances in the understanding of the biology of T2DM have resulted in a growing number of therapies that are approved or in clinical development for this disease. This review summarizes the evidence that T2DM and AD are linked, with a focus on the cellular and molecular mechanisms in common, and then assesses the various clinical-stage diabetes drugs for their potential activity in AD. At a time when existing therapies for AD offer only limited symptomatic benefit for some patients, additional clinical trials of diabetes drugs are needed to at least advance the care of T2DM patients at risk for or with comorbid AD and also to determine their value for AD in general.
PMCID: PMC4066335  PMID: 24931035
3.  A Comparative Survey of the Topographical Distribution of Signature Molecular Lesions in Major Neurodegenerative Diseases 
The Journal of comparative neurology  2013;521(18):10.1002/cne.23430.
An understanding of the anatomic distributions of major neurodegenerative disease lesions is important to appreciate the differential clinical profiles of these disorders and to serve as neuropathological standards for emerging molecular neuroimaging methods. To address these issues, here we present a comparative survey of the topographical distribution of the defining molecular neuropathological lesions among ten neurodegenerative diseases from a large and uniformly assessed brain collection. Ratings of pathological severity in sixteen brain regions from 671 cases with diverse neurodegenerative diseases were summarized and analyzed. These included: a) amyloid-β and tau lesions in Alzheimer’s disease, b) tau lesions in three other tauopathies including Pick’s disease, progressive supranuclear palsy and corticobasal degeneration, c) α-synuclein inclusion ratings in four synucleinopathies including Parkinson’s disease, Parkinson’s disease with dementia, dementia with Lewy bodies and multiple system atrophy, and d) TDP-43 lesions in two TDP-43 proteinopathies, including frontotemporal lobar degeneration associated with TDP-43 and amyotrophic lateral sclerosis. The data presented graphically and topographically confirm and extend previous pathological anatomic descriptions and statistical comparisons highlight the lesion distributions that either overlap or distinguish the diseases in each molecular disease category.
PMCID: PMC3872132  PMID: 23881776
Alzheimer’s disease; Pick’s disease; corticobasal degeneration; progressive supranuclear palsy; Parkinson’s disease; Parkinson’s disease dementia; dementia with Lewy bodies; multiple system atrophy; frontotemporal lobar degeneration - TDP; amyotrophic lateral sclerosis; amyloid-β; Tau α-synuclein; TDP-43
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.
PMCID: PMC4215560  PMID: 24035561
Schizophrenia; extracellular matrix; chondroitin sulfate proteoglycans; olfactory epitheliu; postmortem
5.  Association of Plasma C-Reactive Protein Levels with Diagnosis of Alzheimer’s Disease 
Journal of the neurological sciences  2013;333(0):10.1016/j.jns.2013.05.028.
C-reactive protein (CRP) participates in the systemic response to inflammation. Previous studies report inconsistent findings regarding the relationship between plasma CRP and Alzheimer’s disease (AD). We measured plasma CRP in 203 subjects with AD, 58 subjects with mild cognitive impairment (MCI) and 117 normal aging subjects and administered annual mini-mental state examinations (MMSE) during a three year follow-up period to investigate CRP’s relationship with diagnosis and progression of cognitive decline. Adjusted for age, sex, and education, subjects with AD had significantly lower levels of plasma CRP than subjects with MCI and normal aging. However, there was no significant association between plasma CRP at baseline and subsequent cognitive decline as assessed by longitudinal changes in MMSE score. Our results support previous reports of reduced levels of plasma CRP in AD and indicate its potential utility as a biomarker for the diagnosis of AD.
PMCID: PMC3815534  PMID: 23978419
Alzheimer Disease; Mild Cognitive Impairment; C-Reactive Protein; Inflammation; Biological Markers
6.  Resilient Brain Aging: Characterization of Discordance between Alzheimer’s Disease Pathology and Cognition 
Current Alzheimer research  2013;10(8):844-851.
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.
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.
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.
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.  PDE-4 Inhibition Rescues Aberrant Synaptic Plasticity in Drosophila and Mouse Models of Fragile X Syndrome 
The Journal of Neuroscience  2015;35(1):396-408.
Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.
PMCID: PMC4287155  PMID: 25568131
cAMP; Drosophila; fragile X; memory; mouse; phosphodiesterase 4
8.  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.
PMCID: PMC3478410  PMID: 22554416
cognitive reserve; synapse; synaptophysin; synaptopodin; glial fibrillary acidic protein; antibody microarray
9.  Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy 
Nature Communications  2015;6:7247.
Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10−12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10−8), and 2p22 at SOS1 (rs963731; P=1.76 × 10−7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10−7) and MAPT H1c (17q21; rs242557; P=7.91 × 10−6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).
Corticobasal degeneration is a rare neurodegenerative disorder that can only be definitively diagnosed by autopsy. Here, Kouri et al. conduct a genome-wide-association study and identify two genetic susceptibility loci 17q21 (MAPT) and 3p12 (MOBP), and a novel susceptibility locus at 8p12.
PMCID: PMC4469997  PMID: 26077951
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.
PMCID: PMC3577102  PMID: 23204143
atherosclerosis; neuritic plaques; neurofibrillary tangles; synuclein; TDP-43
11.  Amyloid imaging in Alzheimer's disease: comparison of Florbetapir and Pittsburgh Compound-B PET 
Amyloid imaging provides in vivo detection of the fibrillar amyloid-β (Aβ) plaques of Alzheimer's Disease (AD). The PET ligand Pittsburgh Compound-B (PiB-C11) is the most well studied amyloid imaging agent, but the short half-life of carbon-11 limits its clinical viability. Florbetapir-F18 recently demonstrated in vivo correlation with post-mortem Aβ histopathology, but has not been directly compared with PiB-C11. Fourteen cognitively normal adults and 12 AD patients underwent PiB-C11 and florbetapir-F18 PET scans within a 28 day period. Both ligands displayed highly significant group discrimination and correlation of regional uptake, supporting the hypothesis that florbetapir-F18 provides comparable information with PiB-C11.
PMCID: PMC4479493  PMID: 22791901
12.  CSF Apo-E levels associate with cognitive decline and MRI changes 
Acta neuropathologica  2014;127(5):621-632.
Apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for Alzheimer’s disease (AD) and it is thought to do so by modulating levels of the its product, apolipoprotein E (Apo-E), and regulating amyloid-β (Aβ) clearance. However, information on clinical and biomarker correlates of Apo-E proteins is scarce. We examined the relationship of cerebrospinal fluid (CSF) and plasma Apo-E protein levels, and APOE genotype to cognition and AD biomarker changes in 311 AD Neuroimaging Initiative (ADNI) subjects with CSF Apo-E measurements and 565 subjects with plasma Apo-E measurements. At baseline, higher CSF Apo-E levels were associated with higher total and phosphorylated CSF tau levels. CSF Apo-E levels were associated with longitudinal cognitive decline, MCI conversion to dementia, and grey matter atrophy rate in total tau/Aβ1–42 ratio and APOE genotype adjusted analyses. In analyses stratified by APOE genotype, our results were only significant in the group without the ε4 allele. Baseline CSF Apo-E levels did not predict longitudinal CSF Aβ or tau changes. Plasma Apo-E levels show a mild correlation with CSF Apo-E levels, but were not associated with longitudinal cognitive and MRI changes. Based on our analyses, we speculate that increased CSF Apo-E2 or -E3 levels might represent a protective response to injury in AD and may have neuroprotective effects by decreasing neuronal damage independent of tau and amyloid deposition in addition to its effects on amyloid clearance.
PMCID: PMC3988233  PMID: 24385135
cerebrospinal fluid; plasma; dementia; beta amyloid; tau; MRI; dementia; neurodegeneration; Alzheimer’s Disease; APOE
13.  A Novel GRN Mutation (GRN c.708+6_+9delTGAG) in Frontotemporal Lobar Degeneration with TDP-43-positive Inclusions: Clinicopathologic Report of 6 Cases 
Understanding of frontotemporal lobar degeneration (FTLD), the underlying pathology that is most often linked to the clinical diagnosis of frontotemporal dementia (FTD), is rapidly increasing. Mutations in 7 known genes (MAPT, GRN, C9orf72, VCP, CHMP2B, and rarely TARDBP and FUS) are associated with FTD and the pathologic classification of FTLD has recently been modified to reflect these discoveries. Mutations in one of these genes (GRN), which encodes progranulin, have been implicated in up to one quarter of FTLD cases with TAR DNA-binding protein 43-positive inclusions (FTLD-TDP); there currently are more than 60 known pathogenic mutations of the gene. We present the clinical, pathologic, and genetic findings of 6 cases from 4 families, 5 of which were shown to have a novel GRN c.708+6_+9delTGAG mutation.
PMCID: PMC4109801  PMID: 24709683
Dementia; Familial FTD; FTLD-TDP; GRN; Mutation; Progranulin
14.  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.
PMCID: PMC3575080  PMID: 23114514
Age of onset; dementia; haplotype; presenilin
15.  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.
PMCID: PMC4304658  PMID: 25107476
Alzheimer's disease; Tau; Synuclein; TDP-43; Insulin resistance; Insulin receptor substrate 1
16.  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.
PMCID: PMC4054865  PMID: 24356982
Aging; Dementia; Risk Factors; Neuropathology; Neural Reserve; Epidemiology
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.
PMCID: PMC3696496  PMID: 22975846
Alzheimer’s disease; amphiphysin; calpain; neurodegeneration; tau; tauopathy
18.  Brainstem Aminergic Nuclei and Late Life Depressive Symptoms 
JAMA psychiatry (Chicago, Ill.)  2013;70(12):10.1001/jamapsychiatry.2013.2224.
The neurobiologic basis of late life depressive symptoms is not well understood.
To test the hypothesis that neurodegeneration and neuronal density in brainstem aminergic nuclei are related to late life depressive symptoms.
Longitudinal clinical-pathologic cohort study.
Residences of participants in the Chicago metropolitan area.
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).
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.
The results suggest that the mesolimbic dopamine system, especially the ventral tegemental area, plays an important role in late life depressive symptoms.
PMCID: PMC3856195  PMID: 24132763
19.  Neocortical β-amyloid area is associated with dementia and APOE in the oldest-old 
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.
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.
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.
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.
PMCID: PMC3971646  PMID: 23474043
Alzheimer; Apolipoprotein E; Beta-amyloid; Dementia; Oldest-old
20.  Ethnoracial Differences in the Clinical Characteristics of Alzheimer Disease at Initial Presentation at an Urban Alzheimer’s Disease Center 
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.
Cross-sectional study.
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.
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.
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.
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.
PMCID: PMC3085004  PMID: 21522051
Alzheimer disease; APOE; dementia; ethnoracial differences
21.  Olfactory Epithelium Amyloid-β and PHFtau Pathology in Alzheimer’s Disease 
Annals of neurology  2010;67(4):462-469.
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.
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.
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.
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.
PMCID: PMC2864948  PMID: 20437581
22.  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.
PMCID: PMC4159707  PMID: 24625802
Alzheimer’s disease; amyloid-β42; cerebrospinal fluid; mass spectrometry
23.  Comparative accuracies of two common screening instruments for the classification of Alzheimer’s disease, mild cognitive impairment and healthy aging 
To compare the utility and diagnostic accuracy of the MoCA and MMSE in the diagnosis of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) in a clinical cohort.
321 AD, 126 MCI and 140 older adults with healthy cognition (HC) were evaluated using the the MMSE, MoCA, a standardized neuropsychological battery according to the Consortium to Establish a Registry of Alzheimer’s Disease (CERAD-NB) and an informant based measure of functional impairment, the Dementia Severity Rating Scale (DSRS). Diagnostic accuracy and optimal cut-off scores were calculated for each measure, and a method for converting MoCA to MMSE scores is presented also.
The MMSE and MoCA offer reasonably good diagnostic and classification accuracy as compared to the more detailed CERAD-NB; however, as a brief cognitive screening measure the MoCA was more sensitive and had higher classification accuracy for differentiating MCI from HC. Complementing the MMSE or the MoCA with the DSRS significantly improved diagnostic accuracy.
The current results support recent data indicating that the MoCA is superior to the MMSE as a global assessment tool, particularly in discerning earlier stages of cognitive decline. In addition, we found that overall diagnostic accuracy improves when the MMSE or MoCA is combined with an informant-based functional measure. Finally, we provide a reliable and easy conversion of MoCA to MMSE scores. However, the need for MCI-specific measures is still needed to increase the diagnostic specificity between AD and MCI.
PMCID: PMC4036230  PMID: 23260866
Alzheimer’s disease; Mild Cognitive Impairment; MMSE; MoCA; Diagnostic accuracy
24.  Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre 
Brain  2013;136(9):2697-2706.
Cerebrovascular disease and vascular risk factors are associated with Alzheimer’s disease, but the evidence for their association with other neurodegenerative disorders is limited. Therefore, we compared the prevalence of cerebrovascular disease, vascular pathology and vascular risk factors in a wide range of neurodegenerative diseases and correlate them with dementia severity. Presence of cerebrovascular disease, vascular pathology and vascular risk factors was studied in 5715 cases of the National Alzheimer’s Coordinating Centre database with a single neurodegenerative disease diagnosis (Alzheimer’s disease, frontotemporal lobar degeneration due to tau, and TAR DNA-binding protein 43 immunoreactive deposits, α-synucleinopathies, hippocampal sclerosis and prion disease) based on a neuropathological examination with or without cerebrovascular disease, defined neuropathologically. In addition, 210 ‘unremarkable brain’ cases without cognitive impairment, and 280 cases with pure cerebrovascular disease were included for comparison. Cases with cerebrovascular disease were older than those without cerebrovascular disease in all the groups except for those with hippocampal sclerosis. After controlling for age and gender as fixed effects and centre as a random effect, we observed that α-synucleinopathies, frontotemporal lobar degeneration due to tau and TAR DNA-binding protein 43, and prion disease showed a lower prevalence of coincident cerebrovascular disease than patients with Alzheimer’s disease, and this was more significant in younger subjects. When cerebrovascular disease was also present, patients with Alzheimer’s disease and patients with α-synucleinopathy showed relatively lower burdens of their respective lesions than those without cerebrovascular disease in the context of comparable severity of dementia at time of death. Concurrent cerebrovascular disease is a common neuropathological finding in aged subjects with dementia, is more common in Alzheimer’s disease than in other neurodegenerative disorders, especially in younger subjects, and lowers the threshold for dementia due to Alzheimer’s disease and α-synucleinopathies, which suggests that these disorders should be targeted by treatments for cerebrovascular disease.
PMCID: PMC3858112  PMID: 23842566
Alzheimer’s disease; frontotemporal lobar degeneration; vascular disease; dementia; epidemiology; neuropathology
25.  Association of Anxiety and Depression With Microtubule-Associated Protein 2– and Synaptopodin-Immunolabeled Dendrite and Spine Densities in Hippocampal CA3 of Older Humans 
Archives of general psychiatry  2010;67(5):448-457.
Chronic psychological distress has deleterious effects on many of the body’s physiological systems. In experimental animal models, chronic stress leads to neuroanatomic changes in the hippocampus, in particular a decrease in the length and branching of dendrites as well as a decrease in the number of dendritic spines.
To examine whether analogous distress-related neuroanatomic changes occur in humans and whether such changes might also be related to cognitive dysfunction observed in older people who report greater psychological distress.
Postmortem study of brain tissues from participants of the Religious Orders Study, an ongoing population-based clinicopathological study of aging and cognition.
The Rush University Religious Orders Study and the University of Pennsylvania Cellular and Molecular Neuropathology Program.
Seventy-two deceased participants of the Religious Orders Study.
Main Outcome Measures
Densities of microtubule-associated protein 2–immunolabeled dendrites and synaptopodin-immunolabeled dendritic spines in the CA3 subfield of the hippocampus, quantified using semiautomated image acquisition and analysis.
Higher levels of trait anxiety and longitudinal depression scores were associated with decreased densities of dendrites and spines in CA3. Dendrite and spine densities did not correlate with an index of global cognition or with densities of common age-related pathological changes.
Regressive neuronal changes occur in humans who experience greater psychological distress. These changes are analogous to neuronal changes in animal models of chronic stress.
PMCID: PMC2926797  PMID: 20439826

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