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1.  Neuropsychological assessment in collaborative Parkinson’s disease research 
Cognitive impairment (CI) and behavioral disturbances can be the earliest symptoms of Parkinson’s disease (PD), ultimately afflict the vast majority of PD patients, and increase caregiver burden. Our two Morris K. Udall Centers of Excellence for Parkinson’s Disease Research were supported by the National Institute of Neurological Disorders and Stroke (NINDS) to recommend a comprehensive yet practical approach to cognitive and behavioral assessment to fuel collaborative research. We recommend a step-wise approach with two levels of standardized evaluation to establish a common battery, as well as an alternative testing recommendation for severely impaired subjects, and review supplemental tests that may be useful in specific research settings. Our flexible approach may be applied to studies with varying emphasis on cognition and behavior, does not place undue burden on participants or resources, and has a high degree of compatibility with existing test batteries to promote collaboration.
doi:10.1016/j.jalz.2012.07.006
PMCID: PMC3612566  PMID: 23164549
2.  The Tau Tubulin Kinases TTBK1/2 Promote Accumulation of Pathological TDP-43 
PLoS Genetics  2014;10(12):e1004803.
Pathological aggregates of phosphorylated TDP-43 characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), two devastating groups of neurodegenerative disease. Kinase hyperactivity may be a consistent feature of ALS and FTLD-TDP, as phosphorylated TDP-43 is not observed in the absence of neurodegeneration. By examining changes in TDP-43 phosphorylation state, we have identified kinases controlling TDP-43 phosphorylation in a C. elegans model of ALS. In this kinome-wide survey, we identified homologs of the tau tubulin kinases 1 and 2 (TTBK1 and TTBK2), which were also identified in a prior screen for kinase modifiers of TDP-43 behavioral phenotypes. Using refined methodology, we demonstrate TTBK1 and TTBK2 directly phosphorylate TDP-43 in vitro and promote TDP-43 phosphorylation in mammalian cultured cells. TTBK1/2 overexpression drives phosphorylation and relocalization of TDP-43 from the nucleus to cytoplasmic inclusions reminiscent of neuropathologic changes in disease states. Furthermore, protein levels of TTBK1 and TTBK2 are increased in frontal cortex of FTLD-TDP patients, and TTBK1 and TTBK2 co-localize with TDP-43 inclusions in ALS spinal cord. These kinases may represent attractive targets for therapeutic intervention for TDP-43 proteinopathies such as ALS and FTLD-TDP.
Author Summary
Aggregated proteins are a hallmark of many neurodegenerative diseases. In ALS and FTLD-TDP, these aggregates contain abnormal TDP-43 modified by phosphorylation. Protein phosphorylation normally controls protein activity, stability, or location, but in some neurodegenerative diseases the phosphorylated proteins accumulate in excess. Kinases are the enzymes responsible for protein phosphorylation. We have identified two TDP-43 kinases, TTBK1 and TTBK2, using a novel approach combining reverse genetics and biochemical screening to identify the kinases responsible for changes in TDP-43 phosphorylation. We show TTBK1 and TTBK2 directly phosphorylate TDP-43 in vitro, and control TDP-43 phosphorylation in cellular and simple animal models of ALS. This has uncovered a molecular mechanism by which pathological phosphorylated TDP-43 can occur in disease. To determine whether changes in TTBK1/2 protein are contributing to TDP-43 pathology, we examined diseased brain and spinal cord tissue from patients with ALS or FTLD-TDP. We observed changes in the abundance of TTBK1 and TTBK2 in disease-affected neurons, and the coexistence of TTBK1/2 with phosphorylated TDP-43 aggregates in both FTLD-TDP and ALS. Therefore, increased abundance or activity of TTBK1 or TTBK2 may contribute to the neurodegeneration observed in ALS and FTLD-TDP.
doi:10.1371/journal.pgen.1004803
PMCID: PMC4256087  PMID: 25473830
3.  Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS) 
Human Molecular Genetics  2013;22(16):3259-3268.
We report a novel gene for a parkinsonian disorder. X-linked parkinsonism with spasticity (XPDS) presents either as typical adult onset Parkinson's disease or earlier onset spasticity followed by parkinsonism. We previously mapped the XPDS gene to a 28 Mb region on Xp11.2–X13.3. Exome sequencing of one affected individual identified five rare variants in this region, of which none was missense, nonsense or frame shift. Using patient-derived cells, we tested the effect of these variants on expression/splicing of the relevant genes. A synonymous variant in ATP6AP2, c.345C>T (p.S115S), markedly increased exon 4 skipping, resulting in the overexpression of a minor splice isoform that produces a protein with internal deletion of 32 amino acids in up to 50% of the total pool, with concomitant reduction of isoforms containing exon 4. ATP6AP2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy, a pathway frequently affected in Parkinson's disease. Reduction of the full-size ATP6AP2 transcript in XPDS cells and decreased level of ATP6AP2 protein in XPDS brain may compromise V-ATPase function, as seen with siRNA knockdown in HEK293 cells, and may ultimately be responsible for the pathology. Another synonymous mutation in the same exon, c.321C>T (p.D107D), has a similar molecular defect of exon inclusion and causes X-linked mental retardation Hedera type (MRXSH). Mutations in XPDS and MRXSH alter binding sites for different splicing factors, which may explain the marked differences in age of onset and manifestations.
doi:10.1093/hmg/ddt180
PMCID: PMC3723311  PMID: 23595882
4.  Memory, Mood, and Vitamin D in Persons with Parkinson’s Disease 
Journal of Parkinson's disease  2013;3(4):547-555.
Background
Research in recent years has suggested a role of vitamin D in the central nervous system. The final converting enzyme and the vitamin D receptor are found throughout the human brain. From animal studies vitamin D appears important in neurodevelopment, up-regulation of neurotrophic factors, stabilization of mitochondrial function, and antioxidation.
Objective
To examine the relationship between serum vitamin D and neuropsychiatric function in persons with Parkinson’s disease (PD).
Methods
This is an add-on study to a longitudinal study following neuropsychiatric function in persons with PD. Baseline neuropsychiatric performance and serum 25-hydroxyvitamin D were examined for 286 participants with PD. Measures of global cognitive function (MMSE, MOCA, Mattis Dementia Scale), verbal memory (Hopkins Verbal Learning Test), fluency (animals, vegetables, and FAS words), visuospatial function (Benton Line Orientation), executive function (Trails Making Test and Digit-Symbol Substitution), PD severity (Hoehn & Yahr and Unified Parkinson’s Disease Rating Scale) and depression (Geriatric Depression Scale (GDS)) were administered. Multivariate linear regression assessed the association between vitamin D concentration and neuropsychiatric function, in the entire cohort as well as the non-demented and demented subsets.
Results
Using a multivariate model, higher vitamin concentrations were associated with better performance on numerous neuropsychiatric tests in the non-demented subset of the cohort. Significant associations were specifically found between vitamin D concentration and verbal fluency and verbal memory (t = 4.31, p < 0.001 and t = 3.04, p = 0.0083). Vitamin D concentrations also correlated with depression scores (t =−3.08, p = 0.0083) in the non-demented subset.
Conclusions
Higher plasma vitamin D is associated with better cognition and better mood in this sample of PD patients without dementia. Determination of causation will require a vitamin D intervention study.
doi:10.3233/JPD-130206
PMCID: PMC3966187  PMID: 24081441
Parkinson’s disease; vitamin D; dementia; depression; cognition
5.  MicroRNA in Alzheimer’s disease: an exploratory study in brain, cerebrospinal fluid and plasma 
MicroRNA (miRNA) may be potential biomarkers of Alzheimer’s disease (AD). The objective of this investigation was to demonstrate that miRNAs in human brain or biofluids are differentially expressed according to disease status, tissue type, neuritic plaque score or Braak stage. Post-mortem brain (PMB) miRNA were profiled using arrays and validated using quantitative RT-PCR (qRT-PCR). Five qRT-PCR-validated miRNAs were measured in an independent sample of PMB, cerebrospinal fluid and plasma from the same subjects. Plasma miR-15a was found to be associated with plaque score in the independent sample. In conclusion, miRNA present in human biofluids may offer utility as biomarkers of AD.
doi:10.3109/1354750X.2013.814073
PMCID: PMC3967870  PMID: 23822153
Amyloid; biomarker; Braak stage; miR-15a; miR-370; miR-328; miR-138; miR 132; plaque
6.  Effect of Apolipoprotein E Genotype and Diet on Apolipoprotein E Lipidation and Amyloid Peptides 
JAMA neurology  2013;70(8):10.1001/jamaneurol.2013.396.
Importance
Sporadic Alzheimer disease (AD) is caused in part by decreased clearance of the β-amyloid (Aβ) peptide breakdown products. Lipid-depleted (LD) apolipoproteins are less effective at binding and clearing Aβ, and LD Aβ peptides are more toxic to neurons. However, not much is known about the lipid states of these proteins in human cerebrospinal fluid.
Objective
To characterize the lipidation states of Aβ peptides and apolipoprotein E in the cerebrospinal fluid in adults with respect to cognitive diagnosis and APOE ε4 allele carrier status and after a dietary intervention.
Design
Randomized clinical trial.
Setting
Veterans Affairs Medical Center clinical research unit.
Participants
Twenty older adults with normal cognition (mean [SD] age, 69 [7] years) and 27 with amnestic mild cognitive impairment (67 [6] years).
Interventions
Randomization to a diet high in saturated fat content and with a high glycemic index (High diet;45% of energy from fat [>25% saturated fat], 35%-40%fromcarbohydrates with a mean glycemic index >70, and15%-20% from protein) or a diet low in saturated fat content and with a low glycemic index (Low diet; 25% of energy from fat [<7% saturated fat], 55%-60% from carbohydrates with a mean glycemic index <55, and 15%-20% from protein).
Main Outcomes and Measures
Lipid-depleted Aβ42 and Aβ40 and apolipoprotein E in cerebrospinal fluid.
Results
Baseline levels of LD Aβ were greater for adults with mild cognitive impairment compared with adults with normal cognition (LD Aβ42, P=.05; LD Aβ40, P=.01).These findings were magnified in adults with mild cognitive impairment and the ε4 allele, who had higher LD apolipoprotein E levels irrespective of cognitive diagnosis (P<.001). The Low diet tended to decrease LD Aβ levels, whereas the High diet increased these fractions (LD Aβ42, P=.01; LD Aβ40, P=.15). Changes in LD Aβ levels with the Low diet negatively correlated with changes in cerebrospinal fluid levels of insulin (LD Aβ42 and insulin, r= −0.68 [P=.01]; LD Aβ40 and insulin, r= −0.78 [P=.002]).
Conclusions and Relevance
The lipidation states of apolipoproteins and Aβ peptides in the brain differ depending on APOE genotype and cognitive diagnosis. Concentrations can be modulated by diet. These findings may provide insight into the mechanisms through which apolipoprotein E4 and unhealthy diets impart risk for developing AD.
doi:10.1001/jamaneurol.2013.396
PMCID: PMC3859238  PMID: 23779114
7.  CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration 
Annals of neurology  2013;74(1):39-52.
Objective
Kinase hyperactivity occurs in both neurodegenerative disease and cancer. Lesions containing hyperphosphorylated aggregated TDP-43 characterize amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 inclusions. Dual phosphorylation of TDP-43 at serines 409/410 drives neurotoxicity in disease models; therefore, TDP-43 specific kinases are candidate targets for intervention.
Methods
To find therapeutic targets for the prevention of TDP-43 phosphorylation, we assembled and screened a comprehensive RNA interference library targeting kinases in TDP-43 transgenic C. elegans.
Results
We show CDC7 robustly phosphorylates TDP-43 at pathological residues S409/410 in C. elegans, in vitro, and in human cell culture. In FTLD-TDP cases, CDC7 immunostaining overlaps with the phospho-TDP-43 pathology found in frontal cortex. Furthermore PHA767491, a small molecule inhibitor of CDC7, reduces TDP-43 phosphorylation and prevents TDP-43 dependent neurodegeneration in TDP-43 transgenic animals.
Interpretation
Taken together these data support CDC7 as a novel therapeutic target for TDP-43 proteinopathies including FTLD-TDP and ALS.
doi:10.1002/ana.23870
PMCID: PMC3775949  PMID: 23424178
amyotrophic lateral sclerosis (ALS); frontotemporal lobar degeneration (FTLD); TDP-43; Tardbp; neurodegeneration; neurotoxicity; neuroprotection; CDC7; TTBK1; TTBK2; kinase; phosphorylation; PHA767491
8.  Pacific Northwest Udall Center of Excellence Clinical Consortium: Study Design and Baseline Cohort Characteristics 
Journal of Parkinson's disease  2013;3(2):205-214.
Background
The substantial proportion of individuals with Parkinson’s disease (PD) who have or are expected to develop concomitant cognitive impairment emphasizes the need for large, well-characterized participant cohorts to serve as a basis for research into the causes, manifestations, and potential treatments of cognitive decline in those with PD.
Objective
To establish a multi-site clinical core that cognitively and clinically characterizes patients with PD by obtaining quality longitudinal clinical, neuropsychological, and validated biomarker data.
Methods
Six hundred nineteen participants with idiopathic PD (68.0 ± 9.1 years, 7.1 ± 6.2 years since diagnosis, 70% males) were enrolled in the Pacific Northwest Udall Center (PANUC), one of the Morris K. Udall Centers of Excellence for Parkinson’s Research, Clinical Consortium and underwent comprehensive clinical and neuropsychological assessment. Participants were diagnosed with no cognitive impairment (PD-NCI), mild cognitive impairment (PD-MCI), or dementia (PDD) at a diagnostic consensus conference.
Results
A substantial proportion of the overall sample was diagnosed with cognitive impairment at baseline: 22% with PDD and 59% with PD-MCI. A higher rate of cognitive impairment was observed in men than women (87% vs. 68%, p<0.0001), despite a higher level of education. Most patients older than 50 years at the time of diagnosis and with disease duration greater than 10 years were cognitively impaired or demented.
Conclusions
The PANUC Clinical Consortium is a clinically and cognitively well-characterized cohort of patients with PD. Baseline cohort characteristics demonstrate a high rate of cognitive impairment in the sample, as well as potential sex differences with regard to cognitive diagnosis. The PANUC Clinical Consortium, with its access to biomarker, genetic, and autopsy data, provides an excellent foundation for detailed research related to cognitive impairment in PD.
doi:10.3233/JPD-130189
PMCID: PMC3779428  PMID: 23938350
cognition; cohort studies; dementia; mild cognitive impairment; movement disorders; Parkinson disease
9.  Clinicopathological concordance and discordance in three monozygotic twin pairs with familial Alzheimer's disease 
Aim
Neuropathological examination of both individuals in a monozygotic (MZ) twin pair with Alzheimer's disease (AD) is rare, especially in the molecular genetic era. We had the opportunity to assess the concordance and discordance of clinical presentation and neuropathology in three MZ twin pairs with AD.
Methods
The MZ twins were identified and characterised by the University of Washington Alzheimer's Disease Research Center. We reviewed the available clinical and neuropathological records for all six cases looking specifically for concordance and discordance of clinical phenotype, neuritic amyloid plaques (NP), neurofibrillary tangles (NFT) and Lewy related pathology (LRP).
Results
Discordance in age of onset for developing AD in the MZ twins varied from 4 to 18 years. Clinical presentations also differed between twins. One twin presented with a dementia with Lewy Body clinical syndrome while the other presented with typical clinical AD. Neuropathology within the MZ twin pairs was concordant for NP and NFT, regardless of duration of disease, and was discordant for LRP. This difference was most marked in the late onset AD twin pair. One pair was found to have a mutation in presenilin‐1 (PS1) (A79V) with remarkably late onset in a family member.
Conclusions
MZ twins with AD can vary considerably in age of onset, presentation and disease duration. The concordance of NP and NFT pathological change and the discordance of LRP support the concept that, in AD, the former are primarily under genetic control whereas the latter (LRP) is more influenced by disease duration and environmental factors. The A79V mutation in PS1 can be associated with very late onset of dementia.
doi:10.1136/jnnp.2006.113803
PMCID: PMC2117553  PMID: 17615170
10.  APOE ε4 Increases Risk for Dementia in Pure Synucleinopathies 
JAMA neurology  2013;70(2):223-228.
Objective
To test for an association between the apolipoprotein E (APOE) ε4 allele and dementias with synucleinopathy.
Design
Genetic case-control association study.
Setting
Academic research.
Patients
Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n=244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n=224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n=91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n=81), and control group (n=269).
Main Outcome Measure
The APOE allele frequencies.
Results
The APOE ε4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall χ42=185.25; P=5.56×10−39), and it was higher in the pDLB group than the PDD group (P=.01). In an age-adjusted and sex-adjusted dominant model, ε4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4–15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1–19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5–10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7–5.6).
Conclusions
The APOE ε4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that ε4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated ε4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.
doi:10.1001/jamaneurol.2013.600
PMCID: PMC3580799  PMID: 23407718
11.  GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology 
Neurology  2012;79(19):1944-1950.
Objectives:
Mutations in the GBA gene occur in 7% of patients with Parkinson disease (PD) and are a well-established susceptibility factor for PD, which is characterized by Lewy body disease (LBD) neuropathologic changes (LBDNCs). We sought to determine whether GBA influences risk of dementia with LBDNCs, Alzheimer disease (AD) neuropathologic changes (ADNCs), or both.
Methods:
We screened the entire GBA coding region for mutations in controls and in subjects with dementia and LBDNCs and no or low levels of ADNCs (pure dementia with Lewy bodies [pDLB]), LBDNCs and high-level ADNCs (LBD-AD), and high-level ADNCs but without LBDNCs (AD).
Results:
Among white subjects, pathogenic GBA mutations were identified in 6 of 79 pDLB cases (7.6%), 8 of 222 LBD-AD cases (3.6%), 2 of 243 AD cases (0.8%), and 3 of 381 controls (0.8%). Subjects with pDLB and LBD-AD were more likely to carry mutations than controls (pDLB: odds ratio [OR] = 7.6; 95% confidence interval [CI] = 1.8–31.9; p = 0.006; LBD-AD: OR = 4.6; CI = 1.2–17.6; p = 0.025), but there was no significant difference in frequencies between the AD and control groups (OR = 1.1; CI = 0.2–6.6; p = 0.92). There was a highly significant trend test across groups (χ2(1) = 19.3; p = 1.1 × 10−5), with the likelihood of carrying a GBA mutation increasing in the following direction: control/AD < LBD-AD < pDLB.
Conclusions:
GBA is a susceptibility gene across the LBD spectrum, but not in AD, and appears to convey a higher risk for PD and pDLB than for LBD-AD. PD and pDLB might be more similar to one another in genetic determinants and pathophysiology than either disease is to LBD-AD.
doi:10.1212/WNL.0b013e3182735e9a
PMCID: PMC3484986  PMID: 23035075
12.  Neuropathologic substrates of Parkinson’s disease dementia 
Annals of neurology  2012;72(4):587-598.
Objective
To examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson’s disease (PD).
Methods
140 patients with a clinical diagnosis of PD and either normal cognition or onset of dementia two or more years after motor symptoms (PDD) were studied. Patients with a clinical diagnosis of dementia with Lewy bodies were excluded.
Autopsy records of genetic data and semi-quantitative scores for the burden of neurofibrillary tangles (NFTs), senile plaques (SPs), Lewy body (LB/LN) and other pathologies were used to develop a multivariate logistic regression model to determine the independent association of these variables with dementia. Correlates of co-morbid Alzheimer’s disease (PDD+AD) were also examined.
Results
92 PD patients developed dementia and 48 remained cognitively normal. Severity of cortical LB/LN (CLB/LN) pathology was positively associated with dementia (p<0.001), with an odds-ratio (OR) of 4.06 (CI95%1.87–8.81), as was Apolipoprotein E4 (APOE4) genotype (p=0.018,OR4.19 CI95% 1.28–13.75). 28.6% of all PD cases had sufficient pathology for co-morbid AD, of which 89.5% were demented. The neuropathological diagnosis of PDD+AD correlated with an older age of PD onset (p=0.001,OR1.12 CI95%1.04–1.21), higher CLB/LN burden (p=0.037,OR 2.48 CI95%1.06–5.82), and cerebral amyloid angiopathy severity (p=0.032, OR4.16 CI95%1.13–15.30).
Interpretation
CLB/LN pathology is the most significant correlate of dementia in PD. Additionally, APOE4 genotype may independently influence the risk of dementia in PD. AD pathology was abundant in a subset of patients, and may modify the clinical phenotype. Thus, therapies that target α-synuclein, tau, or Aβ could potentially improve cognitive performance in PD.
doi:10.1002/ana.23659
PMCID: PMC3484250  PMID: 23037886
13.  Profile of Cognitive Impairment in Parkinson Disease 
Cognitive impairment (CI) is a common non-motor complication of Parkinson disease (PD) and is associated with significant disability for patients and burden for caregivers. Similar to motor symptoms, the characteristics of CI in PD can be quite variable, both in terms of what cognitive domains are impaired and the timing of onset and rate of progression. This review will examine the profile of cognitive domain impairments observed in PD, with a focus on early CI (without dementia). We will also discuss possible relationships between specific cognitive domain impairments in PD and pathologic processes such as Lewy related pathology and Alzheimer’s disease. It is our hypothesis that the specific characteristics of CI observed in individual PD patients provides clues to the underlying pathologic processes and that understanding the biologic basis of this clinical phenomenon will assist in directing disease-specific treatments. Given the high lifetime risk for CI in PD it is imperative that we improve our understanding and treatments for this common and disabling problem in PD.
doi:10.1111/j.1750-3639.2010.00373.x
PMCID: PMC3049172  PMID: 20522089
14.  Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis 
Whitcomb, David C. | LaRusch, Jessica | Krasinskas, Alyssa M. | Klei, Lambertus | Smith, Jill P. | Brand, Randall E. | Neoptolemos, John P. | Lerch, Markus M. | Tector, Matt | Sandhu, Bimaljit S. | Guda, Nalini M. | Orlichenko, Lidiya | Alkaade, Samer | Amann, Stephen T. | Anderson, Michelle A. | Baillie, John | Banks, Peter A. | Conwell, Darwin | Coté, Gregory A. | Cotton, Peter B. | DiSario, James | Farrer, Lindsay A. | Forsmark, Chris E. | Johnstone, Marianne | Gardner, Timothy B. | Gelrud, Andres | Greenhalf, William | Haines, Jonathan L. | Hartman, Douglas J. | Hawes, Robert A. | Lawrence, Christopher | Lewis, Michele | Mayerle, Julia | Mayeux, Richard | Melhem, Nadine M. | Money, Mary E. | Muniraj, Thiruvengadam | Papachristou, Georgios I. | Pericak-Vance, Margaret A. | Romagnuolo, Joseph | Schellenberg, Gerard D. | Sherman, Stuart | Simon, Peter | Singh, Vijay K. | Slivka, Adam | Stolz, Donna | Sutton, Robert | Weiss, Frank Ulrich | Wilcox, C. Mel | Zarnescu, Narcis Octavian | Wisniewski, Stephen R. | O'Connell, Michael R. | Kienholz, Michelle L. | Roeder, Kathryn | Barmada, M. Michael | Yadav, Dhiraj | Devlin, Bernie | Albert, Marilyn S. | Albin, Roger L. | Apostolova, Liana G. | Arnold, Steven E. | Baldwin, Clinton T. | Barber, Robert | Barnes, Lisa L. | Beach, Thomas G. | Beecham, Gary W. | Beekly, Duane | Bennett, David A. | Bigio, Eileen H. | Bird, Thomas D. | Blacker, Deborah | Boxer, Adam | Burke, James R. | Buxbaum, Joseph D. | Cairns, Nigel J. | Cantwell, Laura B. | Cao, Chuanhai | Carney, Regina M. | Carroll, Steven L. | Chui, Helena C. | Clark, David G. | Cribbs, David H. | Crocco, Elizabeth A. | Cruchaga, Carlos | DeCarli, Charles | Demirci, F. Yesim | Dick, Malcolm | Dickson, Dennis W. | Duara, Ranjan | Ertekin-Taner, Nilufer | Faber, Kelley M. | Fallon, Kenneth B. | Farlow, Martin R. | Ferris, Steven | Foroud, Tatiana M. | Frosch, Matthew P. | Galasko, Douglas R. | Ganguli, Mary | Gearing, Marla | Geschwind, Daniel H. | Ghetti, Bernardino | Gilbert, John R. | Gilman, Sid | Glass, Jonathan D. | Goate, Alison M. | Graff-Radford, Neill R. | Green, Robert C. | Growdon, John H. | Hakonarson, Hakon | Hamilton-Nelson, Kara L. | Hamilton, Ronald L. | Harrell, Lindy E. | Head, Elizabeth | Honig, Lawrence S. | Hulette, Christine M. | Hyman, Bradley T. | Jicha, Gregory A. | Jin, Lee-Way | Jun, Gyungah | Kamboh, M. Ilyas | Karydas, Anna | Kaye, Jeffrey A. | Kim, Ronald | Koo, Edward H. | Kowall, Neil W. | Kramer, Joel H. | Kramer, Patricia | Kukull, Walter A. | LaFerla, Frank M. | Lah, James J. | Leverenz, James B. | Levey, Allan I. | Li, Ge | Lin, Chiao-Feng | Lieberman, Andrew P. | Lopez, Oscar L. | Lunetta, Kathryn L. | Lyketsos, Constantine G. | Mack, Wendy J. | Marson, Daniel C. | Martin, Eden R. | Martiniuk, Frank | Mash, Deborah C. | Masliah, Eliezer | McKee, Ann C. | Mesulam, Marsel | Miller, Bruce L. | Miller, Carol A. | Miller, Joshua W. | Montine, Thomas J. | Morris, John C. | Murrell, Jill R. | Naj, Adam C. | Olichney, John M. | Parisi, Joseph E. | Peskind, Elaine | Petersen, Ronald C. | Pierce, Aimee | Poon, Wayne W. | Potter, Huntington | Quinn, Joseph F. | Raj, Ashok | Raskind, Murray | Reiman, Eric M. | Reisberg, Barry | Reitz, Christiane | Ringman, John M. | Roberson, Erik D. | Rosen, Howard J. | Rosenberg, Roger N. | Sano, Mary | Saykin, Andrew J. | Schneider, Julie A. | Schneider, Lon S. | Seeley, William W. | Smith, Amanda G. | Sonnen, Joshua A. | Spina, Salvatore | Stern, Robert A. | Tanzi, Rudolph E. | Trojanowski, John Q. | Troncoso, Juan C. | Tsuang, Debby W. | Valladares, Otto | Van Deerlin, Vivianna M. | Van Eldik, Linda J. | Vardarajan, Badri N. | Vinters, Harry V. | Vonsattel, Jean Paul | Wang, Li-San | Weintraub, Sandra | Welsh-Bohmer, Kathleen A. | Williamson, Jennifer | Woltjer, Randall L. | Wright, Clinton B. | Younkin, Steven G. | Yu, Chang-En | Yu, Lei
Nature genetics  2012;44(12):1349-1354.
Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07.
doi:10.1038/ng.2466
PMCID: PMC3510344  PMID: 23143602
15.  Tau Phosphorylation Pathway Genes and Cerebrospinal Fluid Tau Levels in Alzheimer’s Disease 
Alzheimer’s disease (AD) is characterized by the presence in the brain of amyloid plaques, consisting predominately of the amyloid β peptide (Aβ), and neurofibrillary tangles, consisting primarily of tau. Hyper-phosphorylated-tau (p-tau) contributes to neuronal damage, and both p-tau and total-tau (t-tau) levels are elevated in AD cerebrospinal fluid (CSF) compared to cognitively normal controls. Our hypothesis was that increased ratios of CSF phosphorylated-tau levels relative to total-tau levels correlate with regulatory region genetic variation of kinase or phosphatase genes biologically associated with the phosphorylation status of tau. Eighteen SNPs located within 5′ and 3′ regions of 5 kinase and 4 phosphatase genes, as well as two SNPs within regulatory regions of the MAPT gene were chosen for this analysis. The study sample consisted of 101 AD patients and 169 cognitively normal controls. Rs7768046 in the FYN kinase gene and rs913275 in the PPP2R4 phosphatase gene were both associated with CSF p-tau and t-tau levels in AD. These SNPs were also differentially associated with either CSF t-tau (rs7768046) or CSF p-tau (rs913275) relative to t-tau levels in AD compared to controls. These results suggest that rs7768046 and rs913275 both influence CSF tau levels in an AD-associated manner.
doi:10.1002/ajmg.b.32094
PMCID: PMC3626266  PMID: 22927204
FYN; PPP2R4; MAPT; AD; CSF
16.  Differential response of the central noradrenergic nervous system to the loss of locus coeruleus neurons in Parkinson's disease and Alzheimer's disease 
Brain research  2010;1373:240-252.
In Parkinson's disease (PD), there is a significant loss of noradrenergic neurons in the locus coeruleus (LC) in addition to the loss of dopaminergic neurons in the substantia nigra (SN). The goal of this study was to determine if the surviving LC noradrenergic neurons in PD demonstrate compensatory changes in response to the neuronal loss, as observed in Alzheimer's disease (AD). Tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) mRNA expression in postmortem LC tissue of control and age-matched PD subjects demonstrated a significant reduction in the number of noradrenergic neurons in the LC of PD subjects. TH mRNA expression/neuron did not differ between control and PD subjects, but DBH mRNA expression/neuron was significantly elevated in PD subjects compared to control. This increase in DBH mRNA expression in PD subjects is not a response to neuronal loss because the amount of DBH mRNA expression/neuron in AD subjects was not significantly different from control. Norepinephrine transporter (NET) binding site concentration in the LC of PD subjects was significantly reduced over the cell body region as well as the peri-LC dendritic zone. In PD subjects, the loss of dendrites from surviving noradrenergic neurons was also apparent with TH-immunoreactivity (IR). This loss of LC dendritic innervation in PD subjects as measured by TH-IR was not due to LC neuronal loss because TH-IR in AD subjects was robust, despite a similar loss of LC neurons. These data suggest that there is a differential response of the noradrenergic nervous system in PD compared to AD in response to the loss of LC neurons.
doi:10.1016/j.brainres.2010.12.015
PMCID: PMC3038670  PMID: 21147074
Parkinson's disease; Alzheimer's disease; locus coeruleus; tyrosine hydroxylase; dopamine β-hydroxylase; norepinephrine transporter; mRNA; immunohistochemistry
17.  DJ-1 and αSYN in LRRK2 CSF do not correlate with striatal dopaminergic function 
Neurobiology of Aging  2011;33(4):836.e5-836.e7.
Previous studies demonstrated decreased levels of DJ-1 and α-synuclein (αSYN) in human cerebrospinal fluid (CSF) in patients with Parkinson’s disease (PD), but neither marker correlated with PD severity, raising the possibility that they may be excellent progression markers during early or preclinical phases of PD. Individuals carrying the leucine-rich repeat kinase 2 (LRRK2) gene mutation are at increased risk for PD, and the phenotype of LRRK2 patients is almost identical to sporadic PD. To determine whether dopaminergic dysfunction in the basal ganglia, as determined by positron emission tomography (PET) scans, correlates with CSF levels of DJ-1 and αSYN during preclinical stages, Luminex assays were used to analyze CSF samples from asymptomatic LRRK2 mutation carriers, along with carriers who presented with a clinical diagnosis of PD. The data revealed no statistically significant relationship between PET scan evidence of loss of striatal dopaminergic function and the CSF biomarkers DJ-1 and αSYN, except for a weak correlation between DJ-1 and MP binding, suggesting that the use of these potential biomarkers on their own to screen LRRK2 gene mutation carriers for PD is not appropriate.
doi:10.1016/j.neurobiolaging.2011.09.015
PMCID: PMC3279603  PMID: 22019052
Parkinson’s Disease; LRRK2; gene mutation; biomarker; DJ-1; α-synuclein
18.  Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature 
Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.
doi:10.1097/NEN.0b013e31825018f7
PMCID: PMC3560290  PMID: 22487856
Aging; Alzheimer disease; Amyloid; Dementia; Epidemiology; Neuropathology; MAPT; Neurofibrillary tangles
19.  TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis 
Lancet neurology  2008;7(5):409-416.
SUMMARY
BACKGROUND
TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1).
METHODS
TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identifi ed variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families.
FINDINGS
We identified two variants, p.Gly290Ala and p.Gly298Ser, in TARDBP in two familial ALS kindreds and we observed TDP-43 neuropathology in the CNS tissue available from one family. The variants are considered pathogenic mutations because they co-segregate with disease in both families, are absent in ethnically-matched controls, and are associated with TDP-43 neuropathology in several family members.
INTERPRETATION
The p.Gly290Ala and p.Gly298Ser mutations are located in the glycine-rich domain that regulates gene expression and mediates protein-protein interactions; in particular TDP-43 binds to heterogeneous ribonucleoproteins (hnRNPs) via this domain. We postulate that due to the varied and important cellular functions of TDP-43, these mutations may cause neurodegeneration through both gains and losses of function. The finding of TARDBP mutations implicates TDP-43 as an active mediator of neurodegeneration in a novel class of disorders, TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U.
doi:10.1016/S1474-4422(08)70071-1
PMCID: PMC3546119  PMID: 18396105
20.  Empiric Refinement of the Pathologic Assessment of Lewy Related Pathology in the Dementia Patient 
Lewy related pathology (LRP) is a common pathologic finding at autopsy in dementia patients. Recently criteria for categorizing types of LRP in dementia patients were published, though these criteria have yet to be systematically applied to large dementia samples. We examined a large (N = 208) referral-based autopsy sample for LRP, and applied the published criteria for LRP categorization to these cases. We found almost half (49%) of LRP positive cases from this sample were not classifiable. However, modifying the published criteria by reducing the number of regions requiring examination, allowing more variability in LRP severity scores within specific brain regions, and adding an amygdala predominant category permitted classification of 97% of LRP positive cases from the referral-based sample. Application of the modified criteria to an unrelated community-based autopsy sample (N = 226) allowed classification of 96% of LRP positive cases. Modest modifications in the published criteria permit a significantly greater number of dementia cases with LRP to be classified. In addition, this modification allows for more limited sampling of brain regions for classification of LRP. We propose that these modified criteria for the categorization of LRP be utilized in patients with a history of dementia.
doi:10.1111/j.1750-3639.2007.00117.x
PMCID: PMC2689097  PMID: 18241240
Lewy bodies; dementia; α-synuclein
21.  High-Intensity Physical Activity Modulates Diet Effects on Cerebrospinal β-Amyloid Levels in Normal Aging and Mild Cognitive Impairment 
Journal of Alzheimer's Disease  2012;28(1):137-146.
We previously showed that amyloid-β 1-42 (Aβ42) levels in cerebrospinal fluid (CSF) were markedly altered in response to a 4-wk dietary intervention in normal aging and mild cognitive impairment (MCI). Here, we re-examined the data to assess whether diet-induced effects on CSF Aβ42 were modulated by high intensity physical activity (hi–PA). Normal older adults (n=18, mean age=68.6±7.4yrs) and adults with amnestic MCI (n=23, mean age=68.0±6.5yrs) received a low saturated fat/low glycemic index (LOW) diet or a high saturated fat/high glycemic index (HIGH) diet, and CSF levels of Aβ42, tau, and IL-8 were measured at baseline and week 4. Pre-study activity levels were assessed using a 7-d questionnaire, and weekly duration of hi–PA was quantified. At baseline, increased hi–PA in normals predicted lower CSF levels of tau (r=−0.54, p=0.020) and IL-8 (r=−0.70, p=0.025). Diet-induced effects on CSF Aβ42 during the intervention study were modulated by hi–PA, and the nature of this effect differed for normals and MCI (ANOVA, p=0.039). That is, for normal adults, increased hi–PA attenuated the effects of the HIGH diet on CSF Aβ42 whereas in MCI, increased hi–PA potentiated the effects of the LOW diet. Our results suggest that normal adults who engage in hi–PA are less vulnerable to the pathological effects of an unhealthy diet, while in MCI, the benefit of a healthy diet on Aβ modulation is greatest when paired with hi–PA. Exercise may thus interact with diet to alter pathological processes that ultimately modify AD risk.
doi:10.3233/JAD-2011-111076
PMCID: PMC3280092  PMID: 21971406
exercise; diet; biomarker; amyloid; brain; Alzheimer; mild cognitive impairment; aging; tau; interleukin
22.  DJ-1 isoforms in whole blood as potential biomarkers of Parkinson disease 
Scientific Reports  2012;2:954.
DJ-1 is a multifunctional protein that plays an important role in oxidative stress, cell death, and synucleinopathies, including Parkinson disease. Previous studies have demonstrated that total DJ-1 levels decrease in the cerebrospinal fluid, but do not change significantly in human plasma from patients with Parkinson disease when compared with controls. In this study, we measured total DJ-1 and its isoforms in whole blood of patients with Parkinson disease at various stages, Alzheimer disease, and healthy controls to identify potential peripheral biomarkers of PD. In an initial discovery study of 119 subjects, 7 DJ-1 isoforms were reliably detected, and blood levels of those with 4-hydroxy-2-nonenal modifications were discovered to be altered in late-stage Parkinson disease. This result was further confirmed in a validation study of another 114 participants, suggesting that, unlike total DJ-1 levels, post-translationally modified isoforms of DJ-1 from whole blood are candidate biomarkers of late-stage Parkinson disease.
doi:10.1038/srep00954
PMCID: PMC3518819  PMID: 23233873
23.  Truncation of tau at E391 Promotes Early Pathological Changes in Transgenic Mice 
Proteolytic cleavage of tau at glutamic acid 391 (E391) is linked to the pathogenesis of Alzheimer disease (AD). This C-terminal truncated tau species exists in neurofibrillary tangles and abnormal neurites in the brains of AD patients and may potentiate tau polymerization. We generated a mouse model that expresses human tau truncated at E391 to begin to elucidate the role of this C-terminal truncated tau species in the development of tau pathology. Our results show that truncated but otherwise wild type human tau is sufficient to drive pre-tangle pathological changes in tau, including accumulation of insoluble tau, somatodendritic redistribution, formation of pathological conformations, and dual phosphorylation of tau at sites associated with AD pathology. In addition, these mice exhibit atypical neuritic tau immunoreactivity, including abnormal neuritic processes and dystrophic neurites. These results suggest that changes in tau proteolysis can initiate tauopathy.
doi:10.1097/NEN.0b013e31823557fb
PMCID: PMC3237612  PMID: 22002427
Aggregation; Alzheimer disease; tau; Transgenic mice; Truncation
24.  Familial Dementia With Lewy Bodies With an Atypical Clinical Presentation 
The authors report a case of a 64-year-old male with Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) pathology at autopsy who did not manifest the core symptoms of DLB until very late in his clinical course. His initial presentation of early executive and language dysfunction suggested a cortical dementia similar to frontotemporal lobar degeneration (FTLD). Core symptoms of DLB including dementia, hallucination, and parkinsonian symptoms were not apparent until late in the course of his illness. Autopsy revealed both brainstem and cortical Lewy bodies and AD pathology. Family history revealed 7 relatives with a history of dementia including 4 with possible or probable DLB. This case is unique because of the FTLD-like presentation, positive family history of dementia, and autopsy confirmation of DLB.
doi:10.1177/0891988702250585
PMCID: PMC1482838  PMID: 12641375
Lewy bodies; familial dementia; Alzheimer’s disease
25.  Phosphorylated α-Synuclein in Parkinson’s Disease 
Science Translational Medicine  2012;4(121):121ra20.
Phosphorylated α-synuclein (PS-129), a protein implicated in the pathogenesis of Parkinson’s disease (PD), was identified by mass spectrometry in human cerebrospinal fluid (CSF). A highly sensitive and specific assay was established and used to measure PS-129, along withtotal α-synuclein, in the CSF of patients with PD, other parkinsonian disorders such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), and healthy individuals (a total of ~600 samples). PS-129 CSF concentrations correlated weakly with PD severity and, when combined with total α-synuclein CSF concentrations, contributed to distinguishing PD from MSA and PSP. Further rigorous validation in independent cohorts of patients, especially those where samples have been collected longitudinally, will determine whether PS-129 CSF concentrations will be useful for diagnosing PD and for monitoring PD severity and progression.
doi:10.1126/scitranslmed.3002566
PMCID: PMC3302662  PMID: 22344688

Results 1-25 (60)