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1.  Update on the Biomarker Core of the Alzheimer's Disease Neuroimaging Initiative Subjects 
Here we review progress by the Penn Biomarker Core in the Alzheimer's disease Neuroimaging Initiative (ADNI) towards developing a pathological cerebrospinal fluid (CSF) and plasma biomarker signature for mild Alzheimer's disease (AD) as well as a biomarker profile that predicts conversion of mild cognitive impairment (MCI) and/or normal control (NC) subjects to AD. The Penn Biomarker Core also collaborated with other ADNI Cores to integrate data across ADNI to temporally order changes in clinical measures, imaging data and chemical biomarkers that serve as mileposts and predictors of the conversion of NC to MCI as well as MCI to AD, and the progression of AD.
Initial CSF studies by the ADNI Biomarker Core revealed a pathological CSF biomarker signature of AD defined by the combination of Aβ1-42 and total tau (T-tau) that effectively delineates mild AD in the large multisite prospective clinical investigation conducted in ADNI. This signature appears to predict conversion from MCI to AD. Data fusion efforts across ADNI Cores generated a model for the temporal ordering of AD biomarkers which suggests that Aβ amyloid biomarkers become abnormal first, followed by changes in neurodegenerative biomarkers (CSF tau, FDG-PET, MRI) and the onset of clinical symptoms. The timing of these changes varies in individual patients due to genetic and environmental factors that increase or decrease an individual's resilience in response to progressive accumulations of AD pathologies. Further studies in ADNI will refine this model and render the biomarkers studied in ADNI more applicable to routine diagnosis and to clinical trials of disease modifying therapies.
PMCID: PMC2867838  PMID: 20451871
Alzheimer's disease; cerebrospinal fluid; plasma; biomarkers; mild cognitive impairment
2.  Perforant path synaptic loss correlates with cognitive impairment and Alzheimer's disease in the oldest-old 
Brain  2014;137(9):2578-2587.
Cognitive impairment in the oldest-old remains poorly understood. In a study of post-mortem tissue, Robinson et al. find that individuals with cognitive impairment remain pathologically indistinguishable from cognitively intact controls. Tangles, perforant pathway synaptic loss and hippocampal sclerosis are the major pathologies underlying dementia in the oldest-old.
Alzheimer’s disease, which is defined pathologically by abundant amyloid plaques and neurofibrillary tangles concurrent with synaptic and neuronal loss, is the most common underlying cause of dementia in the elderly. Among the oldest-old, those aged 90 and older, other ageing-related brain pathologies are prevalent in addition to Alzheimer’s disease, including cerebrovascular disease and hippocampal sclerosis. Although definite Alzheimer’s disease pathology can distinguish dementia from normal individuals, the pathologies underlying cognitive impairment, especially in the oldest-old, remain poorly understood. We therefore conducted studies to determine the relative contributions of Alzheimer’s disease pathology, cerebrovascular disease, hippocampal sclerosis and the altered expression of three synaptic proteins to cognitive status and global cognitive function. Relative immunohistochemistry intensity measures were obtained for synaptophysin, Synaptic vesicle transporter Sv2 (now known as SV2A) and Vesicular glutamate transporter 1 in the outer molecular layer of the hippocampal dentate gyrus on the first 157 participants of ‘The 90+ Study’ who came to autopsy, including participants with dementia (n = 84), those with cognitive impairment but no dementia (n = 37) and those with normal cognition (n = 36). Thal phase, Braak stage, cerebrovascular disease, hippocampal sclerosis and Pathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) were also analysed. All measures were obtained blind to cognitive diagnosis. Global cognition was tested by the Mini-Mental State Examinaton. Logistic regression analysis explored the association between the pathological measures and the odds of being in the different cognitive groups whereas multiple regression analyses explored the association between pathological measures and global cognition scores. No measure clearly distinguished the control and cognitive impairment groups. Comparing the cognitive impairment and dementia groups, synaptophysin and SV2 were reduced, whereas Braak stage, TDP-43 and hippocampal sclerosis frequency increased. Thal phase and VGLUT1 did not distinguish the cognitive impairment and dementia groups. All measures distinguished the dementia and control groups and all markers associated with the cognitive test scores. When all markers were analysed simultaneously, a reduction in synaptophysin, a high Braak stage and the presence of TDP-43 and hippocampal sclerosis associated with global cognitive function. These findings suggest that tangle pathology, hippocampal sclerosis, TDP-43 and perforant pathway synaptic loss are the major contributors to dementia in the oldest-old. Although an increase in plaque pathology and glutamatergic synaptic loss may be early events associated with cognitive impairment, we conclude that those with cognitive impairment, but no dementia, are indistinguishable from cognitively normal subjects based on the measures reported here.
PMCID: PMC4132652  PMID: 25012223
Alzheimer’s disease; Braak stage; Thal phase; synaptic loss; oldest-old; cognitive impairment
3.  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
4.  Many roads to Parkinson’s disease neurodegeneration: Head trauma- A road more traveled than we know? 
PMCID: PMC4040947  PMID: 23836759
Parkinsons disease; Head trauma; Traumatic Brain injury; Alpha-synuclein; Neurodegeneration
5.  Stages of pTDP-43 pathology in amyotrophic lateral sclerosis 
Annals of neurology  2013;74(1):20-38.
To see if the distribution patterns of phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) intraneuronal inclusions in amyotrophic lateral sclerosis (ALS) permit recognition of neuropathological stages.
pTDP-43 immunohistochemistry was performed on 70 μm sections from ALS autopsy cases (N=76) classified by clinical phenotype and genetic background.
ALS cases with the lowest burden of pTDP-43 pathology were characterized by lesions in the agranular motor cortex, brainstem motor nuclei of cranial nerves XII-X, VII, V, and spinal cord α-motoneurons (stage 1). Increasing burdens of pathology showed involvement of the prefrontal neocortex (middle frontal gyrus), brainstem reticular formation, precerebellar nuclei, and the red nucleus (stage 2). In stage 3, pTDP-43 pathology involved the prefrontal (gyrus rectus and orbital gyri) and then postcentral neocortex and striatum. Cases with the greatest burden of pTDP-43 lesions showed pTDP-43 inclusions in anteromedial portions of the temporal lobe, including the hippocampus (stage 4). At all stages, these lesions were accompanied by pTDP-43 oligodendroglial aggregates. Ten cases with C9orf72 repeat expansion displayed the same sequential spreading pattern as non-expansion cases but a greater regional burden of lesions, indicating a more fulminant dissemination of pTDP-43 pathology.
pTDP-43 pathology in ALS possibly disseminates in a sequential pattern that permits recognition of four neuropathological stages consistent with the hypothesis that pTDP-43 pathology is propagated along axonal pathways. Moreover, the fact that pTDP-43 pathology develops in the prefrontal cortex as part of an ongoing disease process could account for the development of executive cognitive deficits in ALS.
PMCID: PMC3785076  PMID: 23686809
6.  Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies 
Nature reviews. Neuroscience  2013;14(9):626-636.
Dementia is increasingly being recognized in cases of Parkinson's disease (PD); such cases are termed PD dementia (PDD). The spread of fibrillar α-synuclein (α-syn) pathology from the brainstem to limbic and neocortical structures seems to be the strongest neuropathological correlate of emerging dementia in PD. In addition, up to 50% of patients with PDD also develop sufficient amyloid-β plaques and tau-containing neurofibrillary tangles for a secondary diagnosis of Alzheimer's disease (AD), and these pathologies may act synergistically with α-syn pathology to confer a worse prognosis. Understanding the relationships between these three distinct pathologies and their resultant clinical phenotypes are crucial to the development of effective disease-modifying treatments for PD and PDD.
PMCID: PMC4017235  PMID: 23900411
7.  Relationship Between CSF Biomarkers of Alzheimer’s Disease and Rates of Regional Cortical Thinning in ADNI Data 
Previously it was reported that Alzheimer’s disease (AD) patients have reduced amyloid (Aβ1–42) and elevated total tau (t-tau) and phosphorylated tau (p-tau181p) in the cerebro-spinal fluid (CSF), suggesting that these same measures could be used to detect early AD pathology in healthy elderly (CN) and mild cognitive impairment (MCI). In this study, we tested the hypothesis that there would be an association among rates of regional brain atrophy, the CSF biomarkers Aβ1–42, t-tau, and p-tau181p and ApoE ε4 status, and that the pattern of this association would be diagnosis specific. Our findings primarily showed that lower CSF Aβ1–42 and higher tau concentrations were associated with increased rates of regional brain tissue loss and the patterns varied across the clinical groups. Taken together, these findings demonstrate that CSF biomarker concentrations are associated with the characteristic patterns of structural brain changes in CN and MCI that resemble to a large extent the pathology seen in AD. Therefore, the finding of faster progression of brain atrophy in the presence of lower Aβ1–42 levels and higher p-tau levels supports the hypothesis that CSF Aβ1–42 and tau are measures of early AD pathology. Moreover, the relationship among CSF biomarkers, ApoE ε4 status, and brain atrophy rates are regionally varying, supporting the view that the genetic predisposition of the brain to amyloid and tau mediated pathology is regional and disease stage specific.
PMCID: PMC4587763  PMID: 21971452
MRI; Alzheimer’s disease; cerebrospinal fluid; biomarkers; cortical thickness; atrophy; ApoE
8.  Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways 
Science (New York, N.Y.)  2015;347(6229):1436-1441.
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. Here we report the results of a moderate-scale sequencing study aimed at identifying new genes contributing to predisposition for ALS. We performed whole exome sequencing of 2,874 ALS patients and compared them to 6,405 controls. Several known ALS genes were found to be associated, and the non-canonical IκB kinase family TANK-Binding Kinase 1 (TBK1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.
PMCID: PMC4437632  PMID: 25700176
9.  TDP-43 skeins show properties of amyloid in a subset of ALS cases 
Acta neuropathologica  2012;125(1):121-131.
Aggregation of TDP-43 proteins to form intracellular inclusions is the primary pathology in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with TDP-43 inclusions (FTLD-TDP). Histologically, in the cerebral cortex and limbic regions of affected ALS and FTLD-TDP patients, these pathologies occur as a variety of cytoplasmic, neuritic and intranuclear TDP-43 inclusions. In the spinal cord and lower brainstem of ALS patients, the lesions form cytoplasmic dashes or complex filamentous and spherical profiles in addition to skein-like inclusions (SLI). Ultrastructurally, the morphology of TDP-43 inclusions is heterogeneous but mainly composed of loose bundles of 10–20 nm diameter straight filaments associated with electron dense granular material. All of these TDP-43 inclusions are generally described as disordered amorphous aggregations unlike the amyloid fibrils that characterize protein accumulations in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.
We here report that Thioflavin-S positive SLI are present in a subset of ALS cases, while TDP-43 inclusions outside the spinal cord lack the chemical properties of amyloid. Further, we examine the differential enrichment of fibrillar profiles in SLI of ALS cases by TDP-43 immuno-electron microscopy (immuno-EM). The demonstration that pathological TDP-43 can be amyloidogenic in situ suggests the following conclusions: 1) the conformational changes associated with TDP-43 aggregation are more complex than previously thought; 2) Thioflavin-S positive SLI may be composed primarily of filamentous ultrastructures.
PMCID: PMC3536927  PMID: 23124365
TDP-43; amyloid; skein; amyotrophic lateral sclerosis; ALS; frontotemporal lobar degeneration; FTLD-TDP
10.  Potent, Long-Acting Cyclopentane-1,3-Dione Thromboxane (A2)-Receptor Antagonists 
ACS Medicinal Chemistry Letters  2014;5(9):1015-1020.
A series of derivatives of the known thromboxane A2 prostanoid (TP) receptor antagonists, 3-(6-((4-chlorophenyl)sulfonamido)-5,6,7,8-tetrahydronaphthalen-1-yl)propanoic acid and 3-(3-(2-((4-chlorophenyl)sulfonamido)ethyl)phenyl) propanoic acid, were synthesized in which the carboxylic acid functional group was replaced with substituted cyclopentane-1,3-dione (CPD) bioisosteres. Characterization of these molecules led to the discovery of remarkably potent new analogues, some of which were considerably more active than the corresponding parent carboxylic acid compounds. Depending on the choice of the C2 substituent of the CPD unit, these new derivatives can produce either a reversible or an apparent irreversible inhibition of the human TP receptor. Given the potency and the long-lasting inhibition of TP receptor signaling, these novel antagonists may comprise promising leads for the development of antithromboxane therapies.
PMCID: PMC4160754  PMID: 25221659
Cyclopentane-1,3-dione; carboxylic acid bioisostere; thromboxane A2; thromboxane receptor antagonists
11.  Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration 
Acta neuropathologica  2015;130(3):363-372.
We investigated whether chromosome 9 open reading frame 72 hexanucleotide repeat expansion (C9orf72 expansion) size in peripheral DNA was associated with clinical differences in frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) linked to C9orf72 repeat expansion mutations. A novel quantification workflow was developed to measure C9orf72 expansion size by Southern blot densitometry in a cross-sectional cohort of C9orf72 expansion carriers with FTD (n= 39), ALS (n= 33), both (n=35), or who are unaffected (n= 21). Multivariate linear regressions were performed to assess whether C9orf72 expansion size from peripheral DNA was associated with clinical phenotype, age of disease onset, disease duration and age at death. Mode values of C9orf72 expansion size were significantly shorter in FTD compared to ALS (p=0.0001) but were not associated with age at onset in either FTD or ALS. A multivariate regression model correcting for patient’s age at DNA collection and disease phenotype revealed that C9orf72 expansion size is significantly associated with shorter disease duration (p=0.0107) for individuals with FTD, but not with ALS. Despite considerable somatic instability of the C9orf72 expansion, semi-automated expansion size measurements demonstrated an inverse relationship between C9orf72 expansion size and disease duration in patients with FTD. Our finding suggests that C9orf72 repeat size may be a molecular disease modifier in FTD linked to hexanucleotide repeat expansion.
PMCID: PMC4545720  PMID: 26022924
C9orf72; FTD; ALS; Southern blot; Expansion
12.  Neuropathologic substrates of Parkinson’s disease dementia 
Annals of neurology  2012;72(4):587-598.
To examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson’s disease (PD).
140 patients with a clinical diagnosis of PD and either normal cognition or onset of dementia two or more years after motor symptoms (PDD) were studied. Patients with a clinical diagnosis of dementia with Lewy bodies were excluded.
Autopsy records of genetic data and semi-quantitative scores for the burden of neurofibrillary tangles (NFTs), senile plaques (SPs), Lewy body (LB/LN) and other pathologies were used to develop a multivariate logistic regression model to determine the independent association of these variables with dementia. Correlates of co-morbid Alzheimer’s disease (PDD+AD) were also examined.
92 PD patients developed dementia and 48 remained cognitively normal. Severity of cortical LB/LN (CLB/LN) pathology was positively associated with dementia (p<0.001), with an odds-ratio (OR) of 4.06 (CI95%1.87–8.81), as was Apolipoprotein E4 (APOE4) genotype (p=0.018,OR4.19 CI95% 1.28–13.75). 28.6% of all PD cases had sufficient pathology for co-morbid AD, of which 89.5% were demented. The neuropathological diagnosis of PDD+AD correlated with an older age of PD onset (p=0.001,OR1.12 CI95%1.04–1.21), higher CLB/LN burden (p=0.037,OR 2.48 CI95%1.06–5.82), and cerebral amyloid angiopathy severity (p=0.032, OR4.16 CI95%1.13–15.30).
CLB/LN pathology is the most significant correlate of dementia in PD. Additionally, APOE4 genotype may independently influence the risk of dementia in PD. AD pathology was abundant in a subset of patients, and may modify the clinical phenotype. Thus, therapies that target α-synuclein, tau, or Aβ could potentially improve cognitive performance in PD.
PMCID: PMC3484250  PMID: 23037886
13.  BACE1 activity is modulated by cell-associated sphingosine-1-phosphate 
Sphingosine kinases (SphK) 1 and 2 phosphorylate sphingosine to generate sphingosine-1-phosphate (S1P), a pluripotent lipophilic mediator implicated in a variety of cellular events. Here we show that the activity of β-site APP cleaving enzyme-1 (BACE1), the rate limiting enzyme for amyloid-β peptide (Aβ) production, is modulated by S1P in neurons. Treatment by SphK inhibitor, RNAi knockdown of SphK or overexpression of S1P degrading enzymes decreased BACE1 activity to reduce Aβ production. S1P specifically bound to full-length BACE1 and increased its proteolytic activity, suggesting that the cellular S1P directly modulates BACE1 activity. Notably, the relative activity of SphK2 was upregulated in the brains of patients with Alzheimer disease. The unique modulatory effect of cellular S1P on BACE1 activity is a novel potential therapeutic target for Alzheimer disease.
PMCID: PMC4534000  PMID: 21543615
15.  Association between in vivo [18F]-flutemetamol amyloid PET imaging and in vivo cerebral cortical histopathology 
Archives of neurology  2011;68(11):1398-1403.
To determine the correspondence of in vivo quantitative estimates of brain uptake of [18F]-flutemetamol with immunohistochemical estimates of amyloid levels in previously biopsied patients.
Cross-sectional study of [18F]-flutemetamol positron emission tomography (PET) findings in patients with prior cortical biopsy stained for the presence or absence of amyloid plaques.
University Hospital.
Seven patients who previously had a prior right frontal cortical biopsy obtained at the site of ventriculo-peritoneal (VP) placement for presumed Normal Pressure Hydrocephalus (NPH) were recruited. Inclusion criteria included an adequate biopsy for detection and quantification of Aβ pathology and age greater than 50 years.
All patients underwent an [18F]-flutemetamol PET scan.
Main Outcome Measures
Quantitative measures of [18F]-flutemetamol uptake (SUVR – ratio of mean target cortex activity divided by that in a cerabellar reference region) were made at a location contralateral to the biopsy site and compared to estimates of amyloid load based on immunohistochemical and histological staining.
There was complete agreement between visual reads of [18F]-flutemetamol PET scans (three blinded readers with majority rule) and histology. A regression model, including time from biopsy as a covariate, demonstrated a significant relationship (p=0.011) between [18F]-flutemetamol uptake and percent area of amyloid measured by a monoclonal antibody raised against amyloid (NAB228). Similar results were found with the amyloid specific monoclonal antibody 4G8 and Thioflavin S.
These data are the first to demonstrate the concordance of [18F]-flutemetamol PET imaging with histopathology, supporting its sensitivity to detect amyloid and potential use in the study and detection of Alzheimer’s Disease.
PMCID: PMC4532383  PMID: 21747004
16.  Evaluation of Potential Infectivity of Alzheimer and Parkinson Disease Proteins in Recipients of Cadaver-Derived Human Growth Hormone 
JAMA neurology  2013;70(4):462-468.
Growing evidence of cell-to-cell transmission of neurodegenerative disease (ND)–associated proteins (NDAPs) (ie, tau, Aβ, and α-synuclein) suggests possible similarities in the infectious prion protein (PrPsc) in spongiform encephalopathies. There are limited data on the potential human-to-human transmission of NDAPs associated with Alzheimer disease (AD) and other non-PrPsc ND.
To examine evidence for human-to-human transmission of AD, Parkinson disease (PD), and related NDAPs in cadaveric human growth hormone (c-hGH) recipients.
We conducted a detailed immunohistochemical analysis of pathological NDAPs other than PrPsc in human pituitary glands. We also searched for ND in recipients of pituitary-derived c-hGH by reviewing the National Hormone and Pituitary Program (NHPP) cohort database and medical literature.
University-based academic center and agencies of the US Department of Health and Human Services.
Thirty-four routine autopsy subjects (10 non-ND controls and 24 patients with ND) and a US cohort of c-hGH recipients in the NHPP.
Main Outcome Measures
Detectable NDAPs in human pituitary sections and death certificate reports of non-PrPsc ND in the NHPP database.
We found mild amounts of pathological tau, Aβ, and α-synuclein deposits in the adeno/neurohypophysis of patients with ND and control patients. No cases of AD or PD were identified, and 3 deaths attributed to amyotrophic lateral sclerosis (ALS) were found among US NHPP c-hGH recipients, including 2 of the 796 decedents in the originally confirmed NHPP c-hGH cohort database.
Conclusions and Relevance
Despite the likely frequent exposure of c-hGH recipients to NDAPs, and their markedly elevated risk of PrPsc-related disease, this population of NHPP c-hGH recipients does not appear to be at increased risk of AD or PD. We discovered 3 ALS cases of unclear significance among US c-hGH recipients despite the absence of pathological deposits of ALS-associated proteins (TDP-43, FUS, and ubiquilin) in human pituitary glands. In this unique in vivo model of human-to-human transmission, we found no evidence to support concerns that NDAPs underlying AD and PD transmit disease in humans despite evidence of their cell-to-cell transmission in model systems of these disorders. Further monitoring is required to confirm these conclusions.
PMCID: PMC3678373  PMID: 23380910
17.  The Impact of Exercise, Cognitive Activities, and Socialization on Cognitive Function: Results From the National Long-Term Care Survey 
Currently, there are no effective treatments for Alzheimer’s disease and related disorders and age continues to be a robust risk factor. Thus, population aging in the United States may have catastrophic results if interventions are not found and implemented. This study examines possible associations between cognitive impairment and exercise, cognitive activities, and socialization. Cognitive activities, socialization, and exercise were assessed at baseline, and cognitive function was measured at baseline, 5-year, and 10-year follow-up. Controlling for baseline cognitive function, age, sex, education, diabetes, and hypertension, linear regression was performed. Engagement in cognitive activities was inversely associated with the onset of cognitive impairment at 5-year follow-up but was no longer significant at 10-year follow-up. Exercise was associated with a lower risk of cognitive impairment at 10-year follow-up but was not significant at 5-year follow-up. Associations with socialization were not statistically significant at either follow-up.
PMCID: PMC4087091  PMID: 24408752
cognitive impairment; dementia; cognitive activities; exercise; socialization
18.  Common neuropathological features underlie distinct clinical presentations in three siblings with hereditary diffuse leukoencephalopathy with spheroids caused by CSF1R p.Arg782His 
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) presents with a variety of clinical phenotypes including motor impairments such as gait dysfunction, rigidity, tremor and bradykinesia as well as cognitive deficits including personality changes and dementia. In recent years, colony stimulating factor 1 receptor gene (CSF1R) has been identified as the primary genetic cause of HDLS. We describe the clinical and neuropathological features in three siblings with HDLS and the CSF1R p.Arg782His (c.2345G > A) pathogenic mutation. Each case had varied motor symptoms and clinical features, but all included slowed movements, poor balance, memory impairment and frontal deficits. Neuroimaging with magnetic resonance imaging revealed atrophy and increased signal in the deep white matter. Abundant white matter spheroids and CD68-positive macrophages were the predominant pathologies in these cases. Similar to other cases reported in the literature, the three cases described here had varied clinical phenotypes with a pronounced, but heterogeneous distribution of axonal spheroids and distinct microglia morphology. Our findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis of HDLS.
PMCID: PMC4491242  PMID: 26141825
Leukoencephalopathy; Microglia; HDLS; CSF1R; Frontotemporal degeneration; Corticobasal syndrome; Dementia with Lewy bodies
19.  Brain-Penetrant, Orally Bioavailable Microtubule-Stabilizing Small Molecules Are Potential Candidate Therapeutics for Alzheimer’s Disease and Related Tauopathies 
Journal of Medicinal Chemistry  2014;57(14):6116-6127.
Microtubule (MT) stabilizing drugs hold promise as potential treatments for Alzheimer’s disease (AD) and related tauopathies. However, thus far epothilone D has been the only brain-penetrant MT-stabilizer to be evaluated in tau transgenic mice and in AD patients. Furthermore, this natural product exhibits potential deficiencies as a drug candidate, including an intravenous route of administration and the inhibition of the P-glycoprotein (Pgp) transporter. Thus, the identification of alternative CNS-active MT-stabilizing agents that lack these potential limitations is of interest. Toward this objective, we have evaluated representative compounds from known classes of non-naturally occurring MT-stabilizing small molecules. This led to the identification of selected triazolopyrimidines and phenylpyrimidines that are orally bioavailable and brain-penetrant without disruption of Pgp function. Pharmacodynamic studies confirmed that representative compounds from these series enhance MT-stabilization in the brains of wild-type mice. Thus, these classes of MT-stabilizers hold promise for the development of orally active, CNS-directed MT-stabilizing therapies.
PMCID: PMC4111403  PMID: 24992153
20.  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
21.  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.
PMCID: PMC3286338  PMID: 22366796
Alzheimer's disease; tauopathy; acetylation; post-translational modification; tau
22.  High copy wildtype human 1N4R tau expression promotes early pathological tauopathy accompanied by cognitive deficits without progressive neurofibrillary degeneration 
Accumulation of insoluble conformationally altered hyperphosphorylated tau occurs as part of the pathogenic process in Alzheimer’s disease (AD) and other tauopathies. In most AD subjects, wild-type (WT) tau aggregates and accumulates in neurofibrillary tangles and dystrophic neurites in the brain; however, in some familial tauopathy disorders, mutations in the gene encoding tau cause disease.
We generated a mouse model, Tau4RTg2652, that expresses high levels of normal human tau in neurons resulting in the early stages of tau pathology. In this model, over expression of WT human tau drives pre-tangle pathology in young mice resulting in behavioral deficits. These changes occur at a relatively young age and recapitulate early pre-tangle stages of tau pathology associated with AD and mild cognitive impairment. Several features distinguish the Tau4RTg2652 model of tauopathy from previously described tau transgenic mice. Unlike other mouse models where behavioral and neuropathologic changes are induced by transgenic tau harboring MAPT mutations pathogenic for frontotemporal lobar degeneration (FTLD), the mice described here express the normal tau sequence.
Features of Tau4RTg2652 mice distinguishing them from other established wild type tau overexpressing mice include very early phenotypic manifestations, non-progressive tau pathology, abundant pre-tangle and phosphorylated tau, sparse oligomeric tau species, undetectable fibrillar tau pathology, stability of tau transgene copy number/expression, and normal lifespan. These results suggest that Tau4RTg2652 animals may facilitate studies of tauopathy target engagement where WT tau is driving tauopathy phenotypes.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-015-0210-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4453289  PMID: 26041339
Tau; Aggregation; Hyperphosphorylation; Tauopathy
23.  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
24.  Absence of C9ORF72 expanded or intermediate repeats in autopsy confirmed Parkinson Disease 
We have reported that intermediate repeat lengths of the C9ORF72 repeat are a risk factor for Parkinson Disease (PD) in a clinically- diagnosed dataset. As 10-25% of clinically diagnosed PD have different diagnoses upon autopsy, we hypothesized this may reflect phenotypic heterogeneity or concomitant pathology of other neurodegenerative disorders.
We screened 488 autopsy-confirmed PD cases for the expansion haplotype tag, rs3849942T. In 196 identified haplotype carriers, the C9ORF72 repeat was genotyped using the repeat-primed PCR assay.
No larger (intermediate or expanded) repeats were found in these autopsy-confirmed PD samples. This absence of larger repeats is significantly different from the frequency in clinically-diagnosed datasets (p=0.002).
Our results suggest that expanded or intermediate C9ORF72 repeats in clinically-diagnosed PD or Parkinsonism might be an indication of heterogeneity in clinically-diagnosed PD cases. Further studies are needed to elucidate the potential contribution of the C9ORF72 repeat to autopsy-confirmed PD.
PMCID: PMC4022044  PMID: 24573903
autopsy confirmed; Parkinson Disease; C9ORF72 repeat; parkinsonism
25.  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

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