Precision Medicine
2015; Elsevier BV; Volume: 186; Issue: 3 Linguagem: Inglês
10.1016/j.ajpath.2015.12.001
ISSN1525-2191
AutoresBrenna Cholerton, Eric B. Larson, Joseph F. Quinn, Cyrus P. Zabetian, Ignácio F. Mata, C. Dirk Keene, Margaret E. Flanagan, Paul K. Crane, Thomas J. Grabowski, Kathleen S. Montine, Thomas J. Montine,
Tópico(s)Dementia and Cognitive Impairment Research
ResumoThree key elements to precision medicine are stratification by risk, detection of pathophysiological processes as early as possible (even before clinical presentation), and alignment of mechanism of action of intervention(s) with an individual's molecular driver(s) of disease. Used for decades in the management of some rare diseases and now gaining broad currency in cancer care, a precision medicine approach is beginning to be adapted to cognitive impairment and dementia. This review focuses on the application of precision medicine to address the clinical and biological complexity of two common neurodegenerative causes of dementia: Alzheimer disease and Parkinson disease. Three key elements to precision medicine are stratification by risk, detection of pathophysiological processes as early as possible (even before clinical presentation), and alignment of mechanism of action of intervention(s) with an individual's molecular driver(s) of disease. Used for decades in the management of some rare diseases and now gaining broad currency in cancer care, a precision medicine approach is beginning to be adapted to cognitive impairment and dementia. This review focuses on the application of precision medicine to address the clinical and biological complexity of two common neurodegenerative causes of dementia: Alzheimer disease and Parkinson disease. The goal of precision medicine is to harness new knowledge and technology to optimize the timing and targeting of interventions for maximal therapeutic benefit. There are three key elements to precision medicine: stratification by risk, detection of pathophysiological processes as early as possible and preferably before clinical presentation, and alignment of mechanism of action of intervention(s) with an individual's molecular driver(s) of disease.1Montine T.J. Montine K.S. Precision medicine: clarity for the clinical and biological complexity of Alzheimer's and Parkinson's diseases.J Exp Med. 2015; 212: 601-605Crossref PubMed Scopus (25) Google Scholar Ideally, precision medicine contrasts with the traditional approach in graded surveillance on the basis of level of risk, and intervention to suppress pathophysiologic processes while still latent (Figure 1). The approach of precision medicine, applied for decades to rare diseases like phenylketonuria and, more recently, to cystic fibrosis,2Wainwright C.E. Elborn J.S. Ramsey B.W. Marigowda G. Huang X. Cipolli M. Colombo C. Davies J.C. De Boeck K. Flume P.A. Konstan M.W. McColley S.A. McCoy K. McKone E.F. Munck A. Ratjen F. Rowe S.M. Waltz D. Boyle M.P. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR.N Engl J Med. 2015; 373: 220-231Crossref PubMed Scopus (955) Google Scholar now has broad currency in cancer care and is the focus of a recent White House initiative to transform medical practice (Precision Medicine Cohort Program, https://www.nih.gov/research-training/precision-medicine-initiative, last accessed December 3, 2015). Herein, we review how the key elements of precision medicine are beginning to bring clarity to the clinical and biological complexity of dementia. Dementia is a major public health threat that causes untold suffering to patients and caregivers, and is poised to overwhelm health care systems in the coming decades.3Global Burden of Disease Study 2013 CollaboratorsGlobal, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.Lancet. 2015; 386: 743-800Abstract Full Text Full Text PDF PubMed Scopus (4445) Google Scholar, 4GBD 2013 Mortality and Causes of Death CollaboratorsGlobal, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.Lancet. 2015; 385: 117-171Abstract Full Text Full Text PDF PubMed Scopus (5381) Google Scholar Population- or community-based studies of brain aging and incident dementia from around the world have repeatedly identified three common pathological correlates of dementia. These include Alzheimer disease (AD) neuropathologic changes, including senile plaques (SPs) and neurofibrillary tangles (NFTs); vascular brain injury (VBI), especially caused by small-vessel disease; and Lewy body disease (LBD; vide infra), with recognition that other neuropathologic changes, including cerebral amyloid angiopathy and hippocampal sclerosis, are found in older adults and associated with cognitive impairment.5Sonnen J.A. Santa Cruz K. Hemmy L.S. Woltjer R. Leverenz J.B. Montine K.S. Jack C.R. Kaye J. Lim K. Larson E.B. White L. Montine T.J. Ecology of the aging human brain.Arch Neurol. 2011; 68: 1049-1056Crossref PubMed Scopus (131) Google Scholar, 6Sonnen J.A. Larson E.B. Haneuse S. Woltjer R. Li G. Crane P.K. Craft S. Montine T.J. Neuropathology in the adult changes in thought study: a review.J Alzheimers Dis. 2009; 18: 703-711Crossref PubMed Scopus (50) Google Scholar, 7Haroutunian V. Serby M. Purohit D.P. Perl D.P. Marin D. Lantz M. Mohs R.C. Davis K.L. Contribution of Lewy body inclusions to dementia in patients with and without Alzheimer disease neuropathological conditions.Arch Neurol. 2000; 57: 1145-1150Crossref PubMed Scopus (65) Google Scholar, 8EClipSE Collaborative MembersCohort profile: epidemiological clinicopathological studies in Europe (EClipSE).J Alzheimers Dis. 2009; 18: 659-663PubMed Google Scholar, 9Brayne C. Richardson K. Matthews F.E. Fleming J. Hunter S. Xuereb J.H. Paykel E. Mukaetova-Ladinska E.B. Huppert F.A. O'Sullivan A. Dening T. Neuropathological correlates of dementia in over-80-year-old brain donors from the population-based Cambridge city over-75s cohort (CC75C) study.J Alzheimers Dis. 2009; 18: 645-658Crossref PubMed Scopus (134) Google Scholar, 10O'Brien R.J. Resnick S.M. Zonderman A.B. Ferrucci L. Crain B.J. Pletnikova O. Rudow G. Iacono D. Riudavets M.A. Driscoll I. Price D.L. Martin L.J. Troncoso J.C. Neuropathologic studies of the Baltimore Longitudinal Study of Aging (BLSA).J Alzheimers Dis. 2009; 18: 665-675Crossref PubMed Scopus (94) Google Scholar, 11Yu L. Boyle P.A. Leurgans S. Schneider J.A. Kryscio R.J. Wilson R.S. Bennett D.A. Effect of common neuropathologies on progression of late life cognitive impairment.Neurobiol Aging. 2015; 36: 2225-2231Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 12Nelson P.T. Abner E.L. Schmitt F.A. Kryscio R.J. Jicha G.A. Smith C.D. Davis D.G. Poduska J.W. Patel E. Mendiondo M.S. Markesbery W.R. Modeling the association between 43 different clinical and pathological variables and the severity of cognitive impairment in a large autopsy cohort of elderly persons.Brain Pathol. 2010; 20: 66-79Crossref PubMed Scopus (161) Google Scholar In the Seattle-based Adult Changes in Thought study, a population-based study of brain aging and incident dementia in individuals 65 years or older, the population attributable risk for dementia from these diseases is 45% for AD, 33% for VBI, and 10% for LBD.13Sonnen J.A. Larson E.B. Crane P.K. Haneuse S. Li G. Schellenberg G.D. Craft S. Leverenz J.B. Montine T.J. Pathological correlates of dementia in a longitudinal, population-based sample of aging.Ann Neurol. 2007; 62: 406-413Crossref PubMed Scopus (345) Google Scholar In a collaborative study that pooled data from 1672 brain autopsies from multiple population- and community-based studies, the most common neuropathologic finding was some combination of these diseases, leaving open the extent to which each disease may have contributed to cognitive decline.5Sonnen J.A. Santa Cruz K. Hemmy L.S. Woltjer R. Leverenz J.B. Montine K.S. Jack C.R. Kaye J. Lim K. Larson E.B. White L. Montine T.J. Ecology of the aging human brain.Arch Neurol. 2011; 68: 1049-1056Crossref PubMed Scopus (131) Google Scholar More important, 424 cognitively nonimpaired individuals in the same research studies, who died proximate to extensive neuropsychological evaluation, also showed neuropathologic evidence for the same diseases but at generally lower levels, although some individuals died with advanced neuropathologic changes despite relatively preserved function. Figure 2 presents updated results from 405 brain autopsies from the Adult Changes in Thought study as of December 2014, following exactly the same approach as our earlier publication.5Sonnen J.A. Santa Cruz K. Hemmy L.S. Woltjer R. Leverenz J.B. Montine K.S. Jack C.R. Kaye J. Lim K. Larson E.B. White L. Montine T.J. Ecology of the aging human brain.Arch Neurol. 2011; 68: 1049-1056Crossref PubMed Scopus (131) Google Scholar Results are separated by cognitive status into high cognitive performers (Figure 2A), low cognitive performers (Figure 2B), early dementia (Figure 2C), and late dementia (Figure 2D). Figure 2E shows average values for each group. The proportion of individuals with any pathological evidence of the two neurodegenerative diseases did not change substantially across the four groups; AD pathological change was present in 97% to 100%, and LBD was present in 12% to 20%. The proportion of individuals with VBI ranged from 32% in high cognitive performers to 64% in late dementia. These results from a typical US urban and suburban population demonstrate that the aging brain is a complex environment in which AD, VBI, and LBD each have a latent phase, are variably mixed in older patients with and without dementia, and the overall burden of disease(s) increases in severity with increasing cognitive impairment. LBD is especially complex because this pathological change is associated with clinical diagnoses of dementia with Lewy bodies (DLB) or Parkinson disease (PD) with or without mild cognitive impairment (PD-MCI) or dementia (PDD).14Montine T.J. Koroshetz W.J. Babcock D. Dickson D.W. Galpern W.R. Glymour M.M. Greenberg S.M. Hutton M.L. Knopman D.S. Kuzmichev A.N. Manly J.J. Marder K.S. Miller B.L. Phelps C.H. Seeley W.W. Sieber B.A. Silverberg N.B. Sutherland M. Torborg C.L. Waddy S.P. Zlokovic B.V. Corriveau R.A. Recommendations of the Alzheimer's disease-related dementias conference.Neurology. 2014; 83: 851-860Crossref PubMed Scopus (73) Google Scholar, 15Geurtsen G.J. Hoogland J. Goldman J.G. Schmand B.A. Troster A.I. Burn D.J. Litvan I. Parkinson's disease mild cognitive impairment: application and validation of the criteria.J Parkinsons Dis. 2014; 4: 131-137PubMed Google Scholar, 16Lippa C.F. Duda J.E. Grossman M. Hurtig H.I. Aarsland D. Boeve B.F. Brooks D.J. Dickson D.W. Dubois B. Emre M. Fahn S. Farmer J.M. Galasko D. Galvin J.E. Goetz C.G. Growdon J.H. Gwinn-Hardy K.A. Hardy J. Heutink P. Iwatsubo T. Kosaka K. Lee V.M. Leverenz J.B. Masliah E. McKeith I.G. Nussbaum R.L. Olanow C.W. Ravina B.M. Singleton A.B. Tanner C.M. Trojanowski J.Q. Wszolek Z.K. DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers.Neurology. 2007; 68: 812-819Crossref PubMed Scopus (439) Google Scholar DLB most commonly is associated with a combination of the pathological features of AD and LBD, and less commonly with widespread LBD in the absence of AD neuropathologic changes.17Hyman B.T. Phelps C.H. Beach T.G. Bigio E.H. Cairns N.J. Carrillo M.C. Dickson D.W. Duyckaerts C. Frosch M.P. Masliah E. Mirra S.S. Nelson P.T. Schneider J.A. Thal D.R. Thies B. Trojanowski J.Q. Vinters H.V. Montine T.J. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease.Alzheimers Dement. 2012; 8: 1-13Abstract Full Text Full Text PDF PubMed Scopus (1513) Google Scholar, 18Montine T.J. Phelps C.H. Beach T.G. Bigio E.H. Cairns N.J. Dickson D.W. Duyckaerts C. Frosch M.P. Masliah E. Mirra S.S. Nelson P.T. Schneider J.A. Thal D.R. Trojanowski J.Q. Vinters H.V. Hyman B.T. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach.Acta Neuropathol. 2012; 123: 1-11Crossref PubMed Scopus (1513) Google Scholar Although recognized as a disorder of motor control and characterized by brainstem Lewy bodies (LBs), PD also is accompanied by cognitive impairment or dementia in a large fraction of patients, approximately one-quarter even at the time of initial diagnosis.19Stefanova E. Ziropadja L. Stojkovic T. Stankovic I. Tomic A. Jecmenica-Lukic M. Petrovic I. Kostic V. Mild cognitive impairment in early Parkinson's disease using the Movement Disorder Society Task Force criteria: cross-sectional study in Hoehn and Yahr stage 1.Dement Geriatr Cogn Disord. 2015; 40: 199-209Crossref PubMed Scopus (29) Google Scholar, 20Mayeux R. Denaro J. Hemenegildo N. Marder K. Tang M.X. Cote L.J. Stern Y. A population-based investigation of Parkinson's disease with and without dementia: relationship to age and gender.Arch Neurol. 1992; 49: 492-497Crossref PubMed Scopus (364) Google Scholar, 21Aarsland D. Tandberg E. Larsen J.P. Cummings J.L. Frequency of dementia in Parkinson disease.Arch Neurol. 1996; 53: 538-542Crossref PubMed Scopus (269) Google Scholar, 22Hobson P. Meara J. Risk and incidence of dementia in a cohort of older subjects with Parkinson's disease in the United Kingdom.Mov Disord. 2004; 19: 1043-1049Crossref PubMed Scopus (264) Google Scholar, 23Buter T.C. van den Hout A. Matthews F.E. Larsen J.P. Brayne C. Aarsland D. Dementia and survival in Parkinson disease: a 12-year population study.Neurology. 2008; 70: 1017-1022Crossref PubMed Scopus (346) Google Scholar, 24Domellof M.E. Ekman U. Forsgren L. Elgh E. Cognitive function in the early phase of Parkinson's disease, a five-year follow-up.Acta Neurol Scand. 2015; 132: 79-88Crossref PubMed Scopus (85) Google Scholar, 25Hobson P. Meara J. Mild cognitive impairment in Parkinson's disease and its progression onto dementia: a 16-year outcome evaluation of the Denbighshire cohort.Int J Geriatr Psychiatry. 2015; 30: 1048-1055Crossref PubMed Scopus (96) Google Scholar Results from the Pacific Northwest Udall Center widely replicate the experience of research cohorts from around the globe showing that MCI and dementia are common in PD.26Cholerton B.A. Zabetian C.P. Quinn J.F. Chung K.A. Peterson A. Espay A.J. Revilla F.J. Devoto J. Watson G.S. Hu S.C. Edwards K.L. Montine T.J. Leverenz J.B. Pacific Northwest Udall Center of excellence clinical consortium: study design and baseline cohort characteristics.J Parkinsons Dis. 2013; 3: 205-214Crossref PubMed Scopus (52) Google Scholar Indeed, approximately 80% of the initial 603 research volunteers to the Pacific Northwest Udall Center with PD also were diagnosed with MCI or dementia on intake evaluation, although, admittedly, this estimate from a research cohort may be higher than in community settings. Figure 3 shows basic characteristics of these 491 individuals with PD-MCI or PDD. MCI and dementia occurred much more commonly with shorter duration of PD in older individuals, and more commonly with longer disease duration in younger individuals (Fischer's exact test, P < 0.0001).26Cholerton B.A. Zabetian C.P. Quinn J.F. Chung K.A. Peterson A. Espay A.J. Revilla F.J. Devoto J. Watson G.S. Hu S.C. Edwards K.L. Montine T.J. Leverenz J.B. Pacific Northwest Udall Center of excellence clinical consortium: study design and baseline cohort characteristics.J Parkinsons Dis. 2013; 3: 205-214Crossref PubMed Scopus (52) Google Scholar The pathological bases of PDD, and its distinction from DLB, remain unclear. Hence, the extent to which the pathophysiologic processes that lead to brain regional SP, NFT, or LB formation contribute to cognitive impairment and dementia in an individual with DLB, PD-MCI, or PDD remains impossible to determine. Increased knowledge of molecular drivers and accurate biomarkers of pathophysiologic processes from advances in precision medicine will help bring greater clarity to this complex clinical situation. On the basis of abundant genetic, experimental, pathologic, and biomarker data, two key molecular drivers of AD appear to be Aβ42 and pathological forms of tau.27Raskin J. Cummings J. Hardy J. Schuh K. Dean R.A. Neurobiology of Alzheimer's disease: integrated molecular, physiological, anatomical, biomarker, and cognitive dimensions.Curr Alzheimer Res. 2015; 12: 712-722Crossref PubMed Scopus (106) Google Scholar We quantified Aβ42 and paired helical filament (PHF)-tau in the cerebral cortex from 325 consecutive Adult Changes in Thought participants and observed a generally positive, but complex, relationship.28Postupna N. Keene C.D. Crane P.K. Gonzalez-Cuyar L.F. Sonnen J.A. Hewitt J. Rice S. Howard K. Montine K.S. Larson E.B. Montine T.J. Cerebral cortical Abeta42 and PHF-tau in 325 consecutive brain autopsies stratified by diagnosis, location, and APOE.J Neuropathol Exp Neurol. 2015; 74: 100-109Crossref PubMed Scopus (17) Google Scholar Given the comprehensiveness of brain autopsy, herein, we reanalyzed these published data28Postupna N. Keene C.D. Crane P.K. Gonzalez-Cuyar L.F. Sonnen J.A. Hewitt J. Rice S. Howard K. Montine K.S. Larson E.B. Montine T.J. Cerebral cortical Abeta42 and PHF-tau in 325 consecutive brain autopsies stratified by diagnosis, location, and APOE.J Neuropathol Exp Neurol. 2015; 74: 100-109Crossref PubMed Scopus (17) Google Scholar to test whether isolating AD from common comorbid conditions might bring greater clarity to the quantitative relationship between cerebral cortical Aβ42 and PHF-tauamong individuals without dementia who were last evaluated within 2 years of death (Figure 4). Indeed, exclusion of cases with LBD or VBI and focusing on those whose APOE genotype varied by only one allele revealed a strong positive correlation between cerebral cortical concentrations of Aβ42 and PHF-tau in temporal lobe that approximated a line (P < 0.0001). In contrast, cerebral cortical concentrations of Aβ42 and PHF-tau were weakly correlated in the frontal lobe (P < 0.05). The concentration of Aβ42 was strongly related to APOE genotype regardless of cerebral cortical region, whereas the concentration of PHF-tau was significantly related to APOE genotype only in the temporal, and not in the frontal, lobe. These novel results provide insight into the molecular underpinnings of AD, and will help guide molecular neuroimagers as they now are beginning to compare results of imaging ligands for cerebral amyloid and pathological tau. One approach to identification of additional molecular drivers of disease is determining disease risk. Comprehensive risk assessment requires evaluation of environment, lifestyle, and inherited risk; herein, we focus on recent advances in understanding inherited risk. Recent genome-wide association studies have linked genetic variants across the human genome with a clinical diagnosis of AD dementia. In 2013, the International Genomics of Alzheimer's Project reported results from >74,000 individuals that brought to 21 the total number of genetic susceptibility loci for a clinical diagnosis of AD dementia,30Lambert J.C. Ibrahim-Verbaas C.A. Harold D. Naj A.C. Sims R. Bellenguez C. et al.Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.Nat Genet. 2013; 45: 1452-1458Crossref PubMed Scopus (2702) Google Scholar and more have been discovered since.31Escott-Price V. Bellenguez C. Wang L.S. Choi S.H. Harold D. Jones L. et al.Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.PLoS One. 2014; 9: e94661Crossref PubMed Scopus (88) Google Scholar, 32Jun G. Ibrahim-Verbaas C.A. Vronskaya M. Lambert J.C. Chung J. Naj A.C. et al.A novel Alzheimer disease locus located near the gene encoding tau protein.Mol Psychiatry 2015. 2016; 21: 108-117Crossref Scopus (161) Google Scholar It is important to recognize that these genomic studies have linked genetic variants with the clinical diagnosis of AD dementia. Recognizing that the clinical expression of AD dementia is the culmination of stress and injury, response to injury, consumption of reserve, and compensation, we sought to clarify the mechanisms underlying genetic susceptibility for AD dementia by determining their association with SPs and NFTs. As part of a large multisite collaboration, we assembled neuropathologic data from 4914 brain autopsies, largely from research cohorts, and performed a genome-wide association study as well as analysis of the then known 21 International Genomics of Alzheimer's Project genetic risk loci for AD dementia.30Lambert J.C. Ibrahim-Verbaas C.A. Harold D. Naj A.C. Sims R. Bellenguez C. et al.Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.Nat Genet. 2013; 45: 1452-1458Crossref PubMed Scopus (2702) Google Scholar Genome-wide significance was observed for the following: i) neuritic plaques (a subset of SPs that had been assessed in all cases), NFTs, cerebral amyloid angiopathy, and LBD, with several variants in and around the apolipoprotein E gene (APOE); ii) neuritic plaques with GalNAc transferase 7 gene (GALNT7), ATP-binding cassette, subfamily G, member 1 gene (ABCG1), and an intergenic region on chromosome 9; and iii) hippocampal sclerosis with potassium large conductance calcium-activated channel, subfamily M, β member 2 (KCNMB2). Of the 21 International Genomics of Alzheimer's Project genetic risk loci for clinically defined AD dementia, 12 were confirmed in our smaller clinicopathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4. Of these 12 loci, 9 showed a larger odds ratio in the clinicopathologic sample than in the clinical sample. As anticipated, comparison of effect sizes for risk of AD dementia (function) with effect size for NFTs or neuritic plaques (structure) showed a significant positive correlation. Although limited by relatively low sample size and design characteristics, such that only data from people with late-onset AD dementia and cognitively normal elderly controls were considered, the same approach showed no association with comorbid LBD and perhaps ominously showed a moderate negative correlation with comorbid VBI. Like AD dementia, large consortia have pursued genetic variants associated with PD (defined by motor symptoms) using genomic approaches and have identified a similar number of risk loci.33Nalls M.A. Plagnol V. Hernandez D.G. Sharma M. Sheerin U.M. Saad M. Simon-Sanchez J. Schulte C. Lesage S. Sveinbjornsdottir S. Stefansson K. Martinez M. Hardy J. Heutink P. Brice A. Gasser T. Singleton A.B. Wood N.W. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies.Lancet. 2011; 377: 641-649Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar, 34Lill C.M. Roehr J.T. McQueen M.B. Kavvoura F.K. Bagade S. Schjeide B.M. et al.Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: the PDGene database.PLoS Genet. 2012; 8: e1002548Crossref PubMed Scopus (433) Google Scholar Furthermore, autopsy-based genome-wide association studies for PD also have contributed to novel insights into the genetic risk architecture for PD.35Beecham G.W. Dickson D.W. Scott W.K. Martin E.R. Schellenberg G. Nuytemans K. Larson E.B. Buxbaum J.D. Trojanowski J.Q. Van Deerlin V.M. Hurtig H.I. Mash D.C. Beach T.G. Troncoso J.C. Pletnikova O. Frosch M.P. Ghetti B. Foroud T.M. Honig L.S. Marder K. Vonsattel J.P. Goldman S.M. Vinters H.V. Ross O.A. Wszolek Z.K. Wang L. Dykxhoorn D.M. Pericak-Vance M.A. Montine T.J. Leverenz J.B. Dawson T.M. Vance J.M. PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease.Neurology. 2015; 84: 972-980Crossref PubMed Scopus (42) Google Scholar The Pacific Northwest Udall Center has organized the PD Cognitive Genetics Consortium to investigate the genetic risk for dementia in the context of PD. Initially using a candidate gene approach, this multisite collaborative effort has built on knowledge gained from prior case-control studies and identified genetic variants that increase risk for PD motor symptoms and PDD together, PD motor symptoms alone, and PDD alone (Table 1).36Mata I.F. Leverenz J.B. Weintraub D. Trojanowski J.Q. Hurtig H.I. Van Deerlin V.M. Ritz B. Rausch R. Rhodes S.L. Factor S.A. Wood-Siverio C. Quinn J.F. Chung K.A. Peterson A.L. Espay A.J. Revilla F.J. Devoto J. Hu S.C. Cholerton B.A. Wan J.Y. Montine T.J. Edwards K.L. Zabetian C.P. APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease.JAMA Neurol. 2014; 71: 1405-1412Crossref PubMed Scopus (144) Google Scholar, 37Srivatsal S. Cholerton B. Leverenz J.B. Wszolek Z.K. Uitti R.J. Dickson D.W. Weintraub D. Trojanowski J.Q. Van Deerlin V.M. Quinn J.F. Chung K.A. Peterson A.L. Factor S.A. Wood-Siverio C. Goldman J.G. Stebbins G.T. Bernard B. Ritz B. Rausch R. Espay A.J. Revilla F.J. Devoto J. Rosenthal L.S. Dawson T.M. Albert M.S. Mata I.F. Hu S.C. Montine K.S. Johnson C. Montine T.J. Edwards K.L. Zhang J. Zabetian C.P. Cognitive profile of LRRK2-related Parkinson's disease.Mov Disord. 2015; 30: 728-733Crossref PubMed Scopus (45) Google Scholar, 38Mata IF, Leverenz JB, Weintraub D, Trojanowski JQ, Chen-Plotkin A, Van Deerlin VM, Ritz B, Rausch R, Factor SA, Wood-Siverio C, Quinn JF, Chung KA, Peterson-Hiller AL, Goldman JG, Stebbins GT, Bernard B, Espay AJ, Revilla FJ, Devoto J, Rosenthal LS, Dawson TM, Albert MS, Tsuang D, Huston H, Yearout D, Hu SC, Cholerton BA, Montine TJ, Edwards KL, Zabetian CP: GBA variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord 2015, [Epub ahead of print]. doi:10.1002/mds.26359.Google Scholar Current efforts by the PD Cognitive Genetics Consortium are using genomic approaches to accelerate discovery of novel genetic susceptibility loci for cognitive impairment in PD.Table 1Risk from Candidate Genes for PD When Compared with Unaffected Individuals, or for PDD When Compared with Nondemented Individuals with PDCandidate genePD riskPDD riskSNCA↑—MAPT↑—APOE ε4—↑GBA↑↑LRRK2↑↓—, no significant association; ↑, statistically increased risk; ↓, statistically decreased risk; PD, Parkinson disease; PDD, PD with dementia. Open table in a new tab —, no significant association; ↑, statistically increased risk; ↓, statistically decreased risk; PD, Parkinson disease; PDD, PD with dementia. In precision medicine, because greater knowledge about genetic risk fuels development of interventions tailored to specific molecular drivers, there will be growing need for the third component, detection of pathophysiologic processes as early as possible, ideally during latency. There has been strong progress in this area of research, with many groups around the world pursuing a variety of technologies. Notable successes in AD are positron emission tomography imaging for cerebral amyloid39Klunk W.E. Engler H. Nordberg A. Wang Y. Blomqvist G. Holt D.P. Bergstrom M. Savitcheva I. Huang G.F. Estrada S. Ausen B. Debnath M.L. Barletta J. Price J.C. Sandell J. Lopresti B.J. Wall A. Koivisto P. Antoni G. Mathis C.A. Langstrom B. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B.Ann Neurol. 2004; 55: 306-319Crossref PubMed Scopus (3519) Google Scholar and, more recently, pathological tau,40Villemagne V.L. Fodero-Tavoletti M.T. Masters C.L. Rowe C.C. Tau imaging: early progress and future directions.Lancet Neurol. 2015; 14: 114-124Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar and cerebrospinal fluid concentrations of Aβ42 (a major component of SPs) and tau species (a major component of NFTs).41Motter R. Vigo-Pelfrey C. Kholodenko D. Barbour R. Johnson-Wood K. Galasko D. Chang L. Miller B. Clark C. Green R. Olson D. Southwick P. Wolfert R. Munroe B. Lieberburg I. Seubert P. Schenk D. Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease.Ann Neurol. 1995; 38: 643-648Crossref PubMed Scopus (639) Google Scholar, 42Galasko D. Clark C. Chang L. Miller B. Green R.C. Motter R. Seubert P. Assessment of CSF levels of tau protein in mildly demented patients with Alzheimer's disease.Neurology. 1997; 48: 632-635Crossref PubMed Scopus (135) Google Scholar, 43Arai H. Morikawa Y. Higuchi M. Matsui T. Clark C.M. Miura M. Machida N. Lee V.M. Trojanowski J.Q. Sasaki H. Cerebrospinal fluid tau levels in neurodegenerative diseases with distinct tau-related pathology.Biochem Biophys Res Commun. 1997; 236: 262-264Crossref PubMed Scopus (139) Google Scholar, 44Weiner M.W. Veitch D.P. Aisen P.S. Beckett L.A. Cairns N.J. Cedarbaum J. Donohue M.C. Green R.C. Harvey D. Jack Jr., C.R. Jagust W. Morris J.C. Petersen R.C. Saykin A.J. Shaw L. Thompson P.M. Toga A.W. Trojanowski J.Q. Impact of the Alzheimer's Disease Neuroimaging Initiative, 2004 to 2014.Alzheimers Dement. 2015; 11: 865-884Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 45Skillback T. Farahmand B.Y. Rosen C. Mattsson N. Nagga K. Kilander L. Religa D. Wimo A. Winblad B. Schott J.M. Blennow K. Eriksdotter M. Zetterberg H. Cerebrospinal fluid tau and amyloid-beta1-42 in patients with dementia.Brain. 2015; 138: 2716-2731Crossref PubMed Scopus (119) Google Scholar Although early, experience with imaging of pathological tau suggests that the regional distribution may be critically important, a possibility reinforced by our quantification of PHF-tau. A similar approach and outcomes have been achieved in PD with neuroimaging and measurement of cerebrospinal fluid biomarkers.45Skillback T. Farahmand B.Y. Rosen C. Mattsson N. Nagga K. Kilander L. Religa D. Wimo A. Winblad B. Schott J.M. Blennow K. Eriksdotter M. Zetterberg H. Cerebrospinal fluid tau and amyloid-beta1-42 in patients with dementia.Brain. 2015; 138: 2716-2731Crossref PubMed Scopus (119) Google Scholar, 46Kang J.H. Irwin D.J. Chen-Plotkin A.S. Siderowf A. Caspell C. Coffey C.S. Waligorska T. Taylor P. Pan S. Frasier M. Marek K. Kieburtz K. Jennings D. Simuni T. Tanner C.M. Singleton A. Toga A.W. Chowdhury S. Mollenhauer B. Trojanowski J.Q. Shaw L.M. Association of cerebrospinal fluid beta-amyloid 1-42, T-tau, P-tau181, and alpha-synuclein levels with clinical features of drug-naive patients with early Parkinson disease.JAMA Neurol. 2013; 70: 1277-1287PubMed Google Scholar, 47The Parkinson Progression Marker Initiative (PPMI).Prog Neurobiol. 2011; 95: 629-635Crossref PubMed Scopus (894) Google Scholar, 48Niethammer M. Tang C.C. Ma Y. Mattis P.J. Ko J.H. Dhawan V. Eidelberg D. Parkinson's disease cognitive network correlates with caudate dopamine.Neuroimage. 2013; 78: 204-209Crossref PubMed Scopus (70) Google Scholar, 49Brooks D.J. Imaging dopamine transporters in Parkinson's disease.Biomark Med. 2010; 4: 651-660Crossref PubMed Scopus (31) Google Scholar, 50Backstrom D.C. Eriksson Domellof M. Linder J. Olsson B. Ohrfelt A. Trupp M. Zetterberg H. Blennow K. Forsgren L. Cerebrospinal fluid patterns and the risk of future dementia in early, incident Parkinson disease.JAMA Neurol. 2015; 72: 1175-1182Crossref PubMed Scopus (103) Google Scholar Interestingly, cerebrospinal fluid α-synuclein concentration (a major component of LB) may not only aid in diagnosis of LBD, but also improve the diagnostic accuracy of AD biomarkers.51Toledo J.B. Korff A. Shaw L.M. Trojanowski J.Q. Zhang J. CSF alpha-synuclein improves diagnostic and prognostic performance of CSF tau and Abeta in Alzheimer's disease.Acta Neuropathol. 2013; 126: 683-697Crossref PubMed Scopus (80) Google Scholar Molecular neuroimaging for pathological α-synuclein is a high priority for development.52Sieber B.A. Landis S. Koroshetz W. Bateman R. Siderowf A. Galpern W.R. Dunlop J. Finkbeiner S. Sutherland M. Wang H. Lee V.M. Orr H.T. Gwinn K. Ludwig K. Taylor A. Torborg C. Montine T.J. Prioritized research recommendations from the National Institute of Neurological Disorders and Stroke Parkinson's Disease 2014 conference.Ann Neurol. 2014; 76: 469-472Crossref PubMed Scopus (53) Google Scholar Although envisioned primarily as diagnostic aides or potential surrogates for pharmacological activity,53Kang J.H. Ryoo N.Y. Shin D.W. Trojanowski J.Q. Shaw L.M. Role of cerebrospinal fluid biomarkers in clinical trials for Alzheimer's disease modifying therapies.Korean J Physiol Pharmacol. 2014; 18: 447-456Crossref PubMed Scopus (11) Google Scholar results suggest that biomarkers may also serve to group patients by underlying pathophysiologic processes that apparently can cross classic diagnostic boundaries. From this perspective, neuroimaging and biofluid biomarkers might, in the future, serve as evidence for selection of therapeutics in addition to assignment to a clinical diagnostic category. Success in precision medicine for diseases that cause dementia will require much more work to fill gaps in our knowledge regarding risk stratification, surveillance for preclinical pathophysiologic processes, and development of new interventions that are tailored to key molecular drivers of disease. Of these, we are having the most success in identifying genetic risk and developing tools to detect pathophysiologic processes; major advances in the repertoire of disease-modifying therapies are needed. Despite our incomplete knowledge, several groups are now beginning to incorporate the approach of precision medicine into clinical trials for AD and PD. Indeed, determination of genetic risk as a partial window into molecular drivers of disease, coupled with neuroimaging and biomarkers of underlying pathophysiologic processes, has been incorporated into the design of several clinical trials. These include the Dominantly Inherited Alzheimer Network Trials Unit,54Mills S.M. Mallmann J. Santacruz A.M. Fuqua A. Carril M. Aisen P.S. et al.Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial.Rev Neurol (Paris). 2013; 169: 737-743Crossref PubMed Scopus (113) Google Scholar the Alzheimer's Prevention Initiative,55Reiman E.M. Langbaum J.B. Fleisher A.S. Caselli R.J. Chen K. Ayutyanont N. Quiroz Y.T. Kosik K.S. Lopera F. Tariot P.N. Alzheimer's Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments.J Alzheimers Dis. 2011; 26 Suppl 3: 321-329Crossref PubMed Scopus (269) Google Scholar and Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease56Sperling R.A. Rentz D.M. Johnson K.A. Karlawish J. Donohue M. Salmon D.P. Aisen P. The A4 study: stopping AD before symptoms begin?.Sci Transl Med. 2014; 6: 228fs13Crossref PubMed Scopus (498) Google Scholar trial, which all focus on subgroups of individuals with known genetic risk for AD, and biofluid biomarkers or neuroimaging to detect onset of disease. In addition, major research initiatives are underway to advance therapeutics that oppose the functional outcomes of mutations in LRRK2 or GBA that increase risk of PD. We expect this is only the beginning for a precision medicine approach to clinical and biological complexity of AD and PD.
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