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1.  Role of β-amyloidosis and Neurodegeneration in Subsequent Imaging Changes in Mild Cognitive Impairment 
JAMA neurology  2015;72(12):1475-1483.
To understand how a model of Alzheimer disease pathophysiology based on β-amyloidosis and neurodegeneration predicts the regional anatomic expansion of hypometabolism and atrophy in persons with mild cognitive impairment (MCI).
To define the role of β-amyloidosis and neurodegeneration in the subsequent progression of topographic cortical structural and metabolic changes in MCI.
Longitudinal, observational study with serial brain imaging.
Population-based cohort.
Ninety six MCI participants (all >70 years) with serial imaging biomarkers from the Mayo Clinic Study of Aging or Mayo Alzheimer Disease Research Center. Participants were characterized initially as having elevated or not elevated brain β-amyloidosis (“A+” or “A−“) based on 11C-Pittsburgh compound B positron emission tomography (PET). They were further characterized initially by the presence or absence of neurodegeneration (“N+” or “N−“), where presence of neurodegeneration was defined by abnormally low hippocampal volume or hypometabolism in an Alzheimer Disease (AD)-like pattern on 18fluoro-deoxyglucose (FDG) PET.
Main Outcome Measures
Regional FDG Standardized Uptake Value ratio (SUVR) and grey matter volumes in medial temporal, lateral temporal, lateral parietal and medial parietal regions.
In the primary regions of interest, the A+N+ group had lower FDG SUVR and grey matter volumes at baseline, and showed large declines in FDG SUVR and grey matter volumes compared to the A−N+ and A−N−, but not the A+N− group. The A+N− group exhibited declines in FDG SUVR over time, which were not significantly different from the A−N+ or A−N− groups. The A−N+ group did not show declines in FDG SUVR or grey matter volume compared to A+N− or A−N− groups.
Conclusions and Relevance
Persons with MCI who were A+N+ demonstrated volumetric and metabolic worsening in temporal and parietal association areas, consistent with the expectation that the MCI stage in the Alzheimer pathway heralds incipient isocortical involvement. The A−N+ group, those with suspected non-Alzheimer pathophysiology, lacked a distinctive longitudinal volumetric or metabolic profile.
PMCID: PMC4735877  PMID: 26437123
2.  Multimorbidity and Risk of Mild Cognitive Impairment. 
To determine the association of multiple chronic conditions with risk of incident mild cognitive impairment (MCI)/dementia.
Prospective cohort study
Olmsted County, Minnesota.
Cognitively normal individuals (N=2,176) enrolled in the Mayo Clinic Study of Aging (MCSA).
Participants were randomly selected from the community and evaluated by a study coordinator, a physician, and underwent neuropsychometric testing at baseline and at 15-month intervals to assess diagnoses of MCI and dementia. We electronically captured information on International Classification of Diseases, ninth revision (ICD-9) codes for chronic conditions in the five years prior to enrollment using the Rochester Epidemiology Project medical records linkage system. We defined multimorbidity as having two or more chronic conditions and examined the association of multimorbidity with MCI/dementia using Cox proportional hazards models.
Among 2,176 cognitively normal participants (mean [±SD] age 78.5 [±5.2] years; 50.6% men), 1,884 (86.6%) had multimorbidity. The risk of MCI/dementia was elevated in persons with multimorbidity (hazard ratio [HR]: 1.38; 95% confidence interval [CI], 1.05–1.82). The HR was stronger in persons with ≥4 conditions (HR: 1.61; 95%CI, 1.21–2.13) compared to persons with only 0 or 1 conditions, and for men (HR: 1.53, 95% CI, 1.01– 2.31) than for women (HR: 1.20, 95% CI, 0.83– 1.74).
In older adults, having multiple chronic conditions is associated with an increased risk of MCI/dementia. This is consistent with the hypothesis that multiple etiologies may contribute to MCI and late-life dementia. Preventing chronic diseases may be beneficial in delaying or preventing MCI or dementia.
PMCID: PMC4607039  PMID: 26311270
mild cognitive impairment; dementia; multimorbidity
3.  Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk for Lewy body disorders 
Neurology  2015;85(23):2016-2025.
To assess the role of CHCHD2 variants in patients with Parkinson disease (PD) and Lewy body disease (LBD) in Caucasian populations.
All exons of the CHCHD2 gene were sequenced in a US Caucasian patient-control series (878 PD, 610 LBD, and 717 controls). Subsequently, exons 1 and 2 were sequenced in an Irish series (355 PD and 365 controls) and a Polish series (394 PD and 350 controls). Immunohistochemistry and immunofluorescence studies were performed on pathologic LBD cases with rare CHCHD2 variants.
We identified 9 rare exonic variants of unknown significance. These variants were more frequent in the combined group of PD and LBD patients compared to controls (0.6% vs 0.1%, p = 0.013). In addition, the presence of any rare variant was more common in patients with LBD (2.5% vs 1.0%, p = 0.050) compared to controls. Eight of these 9 variants were located within the gene's mitochondrial targeting sequence.
Although the role of variants of the CHCHD2 gene in PD and LBD remains to be further elucidated, the rare variants in the mitochondrial targeting sequence may be a risk factor for Lewy body disorders, which may link CHCHD2 to other genetic forms of parkinsonism with mitochondrial dysfunction.
PMCID: PMC4676755  PMID: 26561290
4.  APOE effect on Alzheimer’s biomarkers in older adults with significant memory concern 
This study assessed APOE ε4 carrier status effects on Alzheimer’s disease (AD) imaging and cerebrospinal fluid (CSF) biomarkers in cognitively normal older adults with significant memory concerns (SMC).
Cognitively normal, SMC, and early mild cognitive impairment participants from ADNI were divided by APOE ε4 carrier status. Diagnostic and APOE effects were evaluated with emphasis on SMC. Additional analyses in SMC evaluated the effect of the interaction between APOE and [18F]Florbetapir amyloid positivity on CSF biomarkers.
SMC ε4+ showed greater amyloid deposition than SMC ε4−, but no hypometabolism or MTL atrophy. SMC ε4+ showed lower Aβ1–42 and higher tau/p-tau than ε4−, which were most abnormal in APOE ε4+ and cerebral amyloid positive SMC.
SMC APOE ε4+ show abnormal changes in amyloid and tau biomarkers, but no hypometabolism or MTL neurodegeneration, reflecting the at-risk nature of the SMC group and the importance of APOE in mediating this risk.
PMCID: PMC4637003  PMID: 25960448
significant memory concern (SMC)/subjective cognitive decline (SCD); apolipoprotein E (APOE); neuroimaging; [18F]Florbetapir PET; [18F]Fluorodeoxyglucose (FDGb) PET; structural magnetic resonance imaging (MRI); cerebrospinal fluid (CSF); Alzheimer’s Disease Neuroimaging Initiative (ADNI)
5.  Novel clinical associations with specific C9ORF72 transcripts in patients with repeat expansions in C9ORF72 
Acta neuropathologica  2015;130(6):863-876.
The loss of chromosome 9 open reading frame 72 (C9ORF72) expression, associated with C9ORF72 repeat expansions, has not been examined systematically. Three C9ORF72 transcript variants have been described thus far; the GGGGCC repeat is located between two non-coding exons (exon 1a and exon 1b) in the promoter region of transcript variant 2 (NM_018325.4) or in the first intron of variant 1 (NM_145005.6) and variant 3 (NM_001256054.2). We studied C9ORF72 expression in expansion carriers (n = 56) for whom cerebellum and/or frontal cortex was available. Using quantitative real-time PCR and digital molecular barcoding techniques, we assessed total C9ORF72 transcripts, variant 1, variant 2, variant 3, and intron containing transcripts [upstream of the expansion (intron 1a) and downstream of the expansion (intron 1b)]; the latter were correlated with levels of poly(GP) and poly(GA) proteins aberrantly translated from the expansion as measured by immunoassay (n = 50). We detected a decrease in expansion carriers as compared to controls for total C9ORF72 transcripts, variant 1, and variant 2: the strongest association was observed for variant 2 (quantitative real-time PCR cerebellum: median 43 %, p = 1.26e-06, and frontal cortex: median 58 %, p = 1.11e-05; digital molecular barcoding cerebellum: median 31 %, p = 5.23e-10, and frontal cortex: median 53 %, p = 5.07e-10). Importantly, we revealed that variant 1 levels greater than the 25th percentile conferred a survival advantage [digital molecular barcoding cerebellum: hazard ratio (HR) 0.31, p = 0.003, and frontal cortex: HR 0.23, p = 0.0001]. When focusing on intron containing transcripts, analysis of the frontal cortex revealed an increase of potentially truncated transcripts in expansion carriers as compared to controls [digital molecular barcoding frontal cortex (intron 1a): median 272 %, p = 0.003], with the highest levels in patients pathologically diagnosed with frontotemporal lobar degeneration. In the cerebellum, our analysis suggested that transcripts were less likely to be truncated and, excitingly, we discovered that intron containing transcripts were associated with poly(GP) levels [digital molecular barcoding cerebellum (intron 1a): r = 0.33, p = 0.02, and (intron 1b): r = 0.49, p = 0.0004] and poly(GA) levels [digital molecular barcoding cerebellum (intron 1a): r = 0.34, p = 0.02, and (intron 1b): r = 0.38, p = 0.007]. In summary, we report decreased expression of specific C9ORF72 transcripts and provide support for the presence of truncated transcripts as well as pre-mRNAs that may serve as templates for RAN translation. We further show that higher C9ORF72 levels may have beneficial effects, which warrants caution in the development of new therapeutic approaches.
PMCID: PMC4655160  PMID: 26437865
C9ORF72; Frontotemporal dementia; Frontotemporal lobar degeneration; Motor neuron disease; Amyotrophic lateral sclerosis; Disease modifier
6.  The Alzheimer’s Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans 
We describe Alzheimer’s Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Aβ1–42), t-tau, and p-tau181 analytical performance, definition of Alzheimer’s disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids.
Review publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSF Aβ1–42, t-tau, and p-tau181 data.
CSFAD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies.
Further studies will refine this model and enable the use of biomarkers studied in ADNI clinically and in disease-modifying therapeutic trials.
PMCID: PMC5127404  PMID: 26194312
Alzheimer’s disease; Mild cognitive impairment; Cerebrospinal fluid; Plasma; Biomarkers; Immunoassay; ADNI; Disease-modifying therapy; Aβ1–42; Tau
7.  Hippocampal volumes predict risk of dementia with Lewy bodies in mild cognitive impairment 
Neurology  2016;87(22):2317-2323.
To predict the risk of probable dementia with Lewy bodies (DLB) competing with Alzheimer disease (AD) dementia by hippocampal volume (HV) in patients with mild cognitive impairment (MCI) with impairments in amnestic or nonamnestic cognitive domains.
Patients with MCI (n = 160) from the Mayo Clinic Alzheimer's Disease Research Center, who participated in an MRI study at baseline from 2005 to 2014, were followed with approximately annual clinical evaluations. HVs were analyzed from 3T MRIs using FreeSurfer (5.3). Hippocampal atrophy was determined from the most normal 10th percentile of the measurement distributions in a separate cohort of clinically diagnosed patients with AD dementia. The subdistribution hazard ratios for progression to probable DLB and AD dementia were estimated by taking into account the competing risks.
During a median (range) follow-up of 2.0 (0.7–8.1) years, 20 (13%) patients with MCI progressed to probable DLB, and 61 (38%) progressed to AD dementia. The estimated subdistribution hazard ratio (95% confidence interval) for normal HV relative to hippocampal atrophy for progression to AD dementia was 0.56 (0.34–0.91; p = 0.02) after taking into account the competing risks. The estimated hazard ratio for normal HV relative to hippocampal atrophy for progression to probable DLB was 4.22 (1.42–12.6; p = 0.01) after adjusting for age and after including the MCI subtype in the model.
Preserved hippocampal volumes are associated with increased risk of probable DLB competing with AD dementia in patients with MCI. Preservation of HV may support prodromal DLB over AD, particularly in patients with MCI with nonamnestic features.
PMCID: PMC5135023  PMID: 27807186
8.  Role for the microtubule-associated protein tau variant p.A152T in risk of α-synucleinopathies 
Neurology  2015;85(19):1680-1686.
To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies.
In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls.
The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63–2.98, p = 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62–20.51, p = 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04–12.17, p = 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85–25.72, p = 0.08) but this was not statistically significant and therefore should be interpreted with caution.
Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies.
PMCID: PMC4653108  PMID: 26333800
9.  Spectrum of cognition short of dementia 
Neurology  2015;85(19):1712-1721.
To understand the neuropsychological basis of dementia risk among persons in the spectrum including cognitive normality and mild cognitive impairment.
We quantitated risk of progression to dementia in elderly persons without dementia from 2 population-based studies, the Framingham Heart Study (FHS) and Mayo Clinic Study of Aging (MCSA), aged 70 to 89 years at enrollment. Baseline cognitive status was defined by performance in 4 domains derived from batteries of neuropsychological tests (that were similar but not identical for FHS and MCSA) at cut scores corresponding to SDs of ≤−0.5, −1, −1.5, and −2 from normative means. Participants were characterized as having no cognitive impairment (reference group), or single or multiple amnestic or nonamnestic profiles at each cut score. Incident dementia over the following 6 years was determined by consensus committee at each study separately.
The pattern of hazard ratios for incident dementia, rates of incident dementia and positive predictive values across cognitive test cut scores, and number of affected domains was similar although not identical across the FHS and MCSA. Dementia risks were higher for amnestic profiles than for nonamnestic profiles, and for multidomain compared with single-domain profiles.
Cognitive domain subtypes, defined by neuropsychologically derived cut scores and number of low-performing domains, differ substantially in prognosis in a conceptually logical manner that was consistent between FHS and MCSA. Neuropsychological characterization of elderly persons without dementia provides valuable information about prognosis. The heterogeneity of risk of dementia cannot be captured concisely with one test or a single definition or cutpoint.
PMCID: PMC4653114  PMID: 26453643
10.  Performance of the CogState computerized battery in the Mayo Clinic Study on Aging 
The feasibility and validity of brief computerized cognitive batteries at the population-level are unknown.
Non-demented participants (n = 1660, age 50–97) in the Mayo Clinic Study on Aging completed the computerized CogState battery and standard neuropsychological battery. The correlation between tests was examined and comparisons between CogState performance on the personal computer (PC) and iPad (n = 331), and in the Clinic vs. at home (n = 194), were assessed.
We obtained valid data on >97% of participants on each test. Correlations between the CogState and neuropsychological tests ranged from −0.462 to 0.531. While absolute differences between the PC and iPad were small and participants preferred the iPad, performance on the PC was faster. Participants performed faster on Detection, One Card Learning, and One Back at home compared to the Clinic.
The computerized CogState battery, especially the iPad, was feasible, acceptable, and valid in the population.
PMCID: PMC4595161  PMID: 25858683
Computerized cognitive battery; Epidemiology; Neuropsychology; Cognitively normal; Mild cognitive impairment; Population-based cohort study
11.  TDP-43 and pathological subtype of Alzheimer’s disease impact clinical features 
Annals of neurology  2015;78(5):697-709.
To determine whether the frequency of TDP-43 deposition in Alzheimer’s disease (AD) differs across pathologically defined AD subtypes (Hippocampal sparing [HpSp]; Typical and Limbic), and to further examine the relationship between TDP-43, pathological subtype, and clinical features in AD.
We identified all cases with pathologically-confirmed AD (NIA-Reagan intermediate-high probability, Braak stage IV–VI) independent of cognitive status (n=188). Neurofibrillary tangle counts were performed using thioflavin-S microscopy in hippocampus and three neocortical regions, and all cases were subtyped: HpSp AD Pathology (n=19); Typical AD Pathology (n=136); Limbic AD Pathology (n=33). TDP-43 immunoreactivity was performed in multiple brain regions to assess for the presence of TDP-43 and TDP-43 stage. All cases were clinically sub-classified at presentation as Amnestic AD Dementia versus Atypical AD Dementia. Statistical analysis was performed using linear and penalized logistic regression to assess associations with pathological subtype, and the effects of TDP-43, accounting for possible interactions between pathological subtype and TDP-43.
TDP-43 deposition was frequent in Typical (59%) and Limbic AD pathologies (67%), but not HpSp AD Pathology (21%) (p=0.003). The observed associations of TDP-43 with greater memory loss, naming and functional decline, and smaller hippocampal volumes, closest to death, did not differ across AD pathological subtype. Clinical presentation was associated with pathological subtype (p=0.01), but not TDP-43 (p=0.69).
Although the frequency of TDP-43 deposition in AD varies by pathological subtype, the observed effects of TDP-43 on clinical/MRI features are consistent across pathological subtypes. Clinical presentation in AD is driven by pathological subtype, not by TDP-43.
PMCID: PMC4623932  PMID: 26224156
TDP-43; Alzheimer’s disease; hippocampal sparing; memory; amnestic; atypical
13.  An autoradiographic evaluation of AV-1451 Tau PET in dementia 
It is essential to determine the specificity of AV-1451 PET for tau in brain imaging by using pathological comparisons. We performed autoradiography in autopsy-confirmed Alzheimer disease and other neurodegenerative disorders to evaluate the specificity of AV-1451 binding for tau aggregates.
Tissue samples were selected that had a variety of dementia-related neuropathologies including Alzheimer disease, primary age-related tauopathy, tangle predominant dementia, non-Alzheimer disease tauopathies, frontotemporal dementia, parkinsonism, Lewy body disease and multiple system atrophy (n = 38). Brain tissue sections were stained for tau, TAR DNA-binding protein-43, and α-synuclein and compared to AV-1451 autoradiography on adjacent sections.
AV-1451 preferentially localized to neurofibrillary tangles, with less binding to areas enriched in neuritic pathology and less mature tau. The strength of AV-1451 binding with respect to tau isoforms in various neurodegenerative disorders was: 3R + 4R tau (e.g., AD) > 3R tau (e.g., Pick disease) or 4R tau. Only minimal binding of AV-1451 to TAR DNA-binding protein-43 positive regions was detected. No binding of AV-1451 to α-synuclein was detected. “Off-target” binding was seen in vessels, iron-associated regions, substantia nigra, calcifications in the choroid plexus, and leptomeningeal melanin.
Reduced AV-1451 binding in neuritic pathology compared to neurofibrillary tangles suggests that the maturity of tau pathology may affect AV-1451 binding and suggests complexity in AV-1451 binding. Poor association of AV-1451 with tauopathies that have preferential accumulation of either 4R tau or 3R tau suggests limited clinical utility in detecting these pathologies. In contrast, for disorders associated with 3R + 4R tau, such as Alzheimer disease, AV-1451 binds tau avidly but does not completely reflect the early stage tau progression suggested by Braak neurofibrillary tangle staging. AV-1451 binding to TAR DNA-binding protein-43 or TAR DNA-binding protein-43 positive regions can be weakly positive. Clinical use of AV-1451 will require a familiarity with distinct types of “off-target” binding.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-016-0315-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4906968  PMID: 27296779
AV-1451; Tau; Alzheimer’s disease; TDP-43; Pick Disease; Corticobasal degeneration; Progressive supranuclear palsy; Tauopathy; Pick’s disease; Atypical Alzheimer’s disease; Frontotemporal dementia
14.  Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases 
Scientific Data  2016;3:160089.
Previous genome-wide association studies (GWAS), conducted by our group and others, have identified loci that harbor risk variants for neurodegenerative diseases, including Alzheimer's disease (AD). Human disease variants are enriched for polymorphisms that affect gene expression, including some that are known to associate with expression changes in the brain. Postulating that many variants confer risk to neurodegenerative disease via transcriptional regulatory mechanisms, we have analyzed gene expression levels in the brain tissue of subjects with AD and related diseases. Herein, we describe our collective datasets comprised of GWAS data from 2,099 subjects; microarray gene expression data from 773 brain samples, 186 of which also have RNAseq; and an independent cohort of 556 brain samples with RNAseq. We expect that these datasets, which are available to all qualified researchers, will enable investigators to explore and identify transcriptional mechanisms contributing to neurodegenerative diseases.
PMCID: PMC5058336  PMID: 27727239
Neurodegeneration; Genetics of the nervous system; Genome-wide association studies; RNA sequencing
15.  Direct medical costs and source of cost differences across the spectrum of cognitive decline: A population-based study 
Objective cost estimates and source of cost differences are needed across the spectrum of cognition, including cognitively normal (CN), mild-cognitive-impairment (MCI), newly-discovered dementia, and prevalent dementia.
Subjects were a subset of the Mayo Clinic Study of Aging stratified-random sampling of Olmsted County, MN, residents aged 70-89 years. A neurologist reviewed provider-linked medical records to identify prevalent-dementia (review date=index). Remaining subjects were invited to participate in prospective clinical/neuropsychological assessments; participants were categorized as CN, MCI, or newly-discovered-dementia (assessment date=index). Costs for medical services/procedures 1-year pre-index (excluding indirect and long-term care costs) were estimated using line-item provider-linked administrative data. We estimated contributions of care-delivery site and comorbid conditions (including and excluding neuropsychiatric diagnoses) to between-category cost differences.
Annual mean medical costs for CN, MCI, newly-discovered-dementia, and prevalent-dementia were $6,042, $6,784, $9,431, $11,678 respectively. Hospital inpatient costs contributed 70% of total costs for prevalent dementia and accounted for differences between CN and both prevalent and newly-discovered dementia. Ambulatory costs accounted for differences between CN and MCI. Age-, sex-, education-adjusted differences reached significance for CN versus newly-discovered and prevalent-dementia and for MCI versus prevalent-dementia. After considering all comorbid diagnoses, between-category differences were reduced (e.g., prevalent-dementia minus MCI (from $4,842 to $3,575); newly-discovered-dementia minus CN (from $3,578 to$711). Following exclusion of neuropsychiatric diagnoses from comorbidity adjustment, between-category differences tended to revert to greater differences.
Cost estimates did not differ significantly between CN and MCI. Substantial differences between MCI and prevalent dementia reflected high inpatient costs for dementia and appear partly related to co-occurring Mental Disorders. Such comparisons can help inform models aimed at identifying where, when, and for which individuals proposed interventions might be cost-effective.
PMCID: PMC4543557  PMID: 25858682
Dementia; Cognitive status; Mild cognitive impairment; Economics; Utilization; Cost
16.  GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer’s disease implicates microglial activation gene IL1RAP 
Brain  2015;138(10):3076-3088.
In a genome-wide study, Ramanan et al. discover an association between the microglial activation gene IL1RAP and higher rates of amyloid plaque accumulation as measured by PET in prodromal Alzheimer’s disease. Activated microglia may be crucial in amyloid clearance, and targeting the interleukin-1/IL1RAP pathway may be a potential therapeutic approach.
In a genome-wide study, Ramanan et al. discover an association between the microglial activation gene IL1RAP and higher rates of amyloid plaque accumulation as measured by PET in prodromal Alzheimer’s disease. Activated microglia may be crucial in amyloid clearance, and targeting the interleukin-1/IL1RAP pathway may be a potential therapeutic approach.
Brain amyloid deposition is thought to be a seminal event in Alzheimer’s disease. To identify genes influencing Alzheimer’s disease pathogenesis, we performed a genome-wide association study of longitudinal change in brain amyloid burden measured by 18F-florbetapir PET. A novel association with higher rates of amyloid accumulation independent from APOE (apolipoprotein E) ε4 status was identified in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P = 1.38 × 10−9) and was validated by deep sequencing. IL1RAP rs12053868-G carriers were more likely to progress from mild cognitive impairment to Alzheimer’s disease and exhibited greater longitudinal temporal cortex atrophy on MRI. In independent cohorts rs12053868-G was associated with accelerated cognitive decline and lower cortical 11C-PBR28 PET signal, a marker of microglial activation. These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process.
PMCID: PMC4671479  PMID: 26268530
Alzheimer’s disease; amyloid; genetics; interleukin-1; microglia
17.  DNAJC13 p.Asn855Ser mutation screening in Parkinson’s disease and pathologically confirmed Lewy body disease patients 
Recently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinson’s disease (PD) in a multi-incident Mennonite family. In the present study we have sequenced the mutation containing exon of the DNAJC13 gene in a Caucasian series consisting of 1938 patients with clinical PD and 838 pathologically diagnosed Lewy Body Disease (LBD). Our sequence analysis did not identify any coding variants in exon 24 of DNAJC13. Two previously described variants in intron 23 (rs200204728 and rs2369796) were observed. Our results indicate that the region surrounding the DNAJC13 p.Asn855Ser substitution is highly conserved and mutations in this exon are not a common cause of PD or LBD among Caucasian populations.
PMCID: PMC4542017  PMID: 26278106
DNAJC13; Parkinson’s disease; Lewy body disease; genetics
18.  Sample size calculations for clinical trials targeting tauopathies: A new potential disease target 
Journal of neurology  2015;262(9):2064-2072.
Disease-modifying therapies are being developed to target tau pathology, and should, therefore, be tested in primary tauopathies. We propose that progressive apraxia of speech should be considered one such target group. In this study, we investigate potential neuroimaging and clinical outcome measures for progressive apraxia of speech and determine sample size estimates for clinical trials. We prospectively recruited 24 patients with progressive apraxia of speech who underwent two serial MRI with an interval of approximately two years. Detailed speech and language assessments included the Apraxia of Speech Rating Scale (ASRS) and Motor Speech Disorders (MSD) severity scale. Rates of ventricular expansion and rates of whole brain, striatal and midbrain atrophy were calculated. Atrophy rates across 38 cortical regions were also calculated and the regions that best differentiated patients from controls were selected. Sample size estimates required to power placebo-controlled treatment trials were calculated. The smallest sample size estimates were obtained with rates of atrophy of the precentral gyrus and supplementary motor area, with both measures requiring less than 50 subjects per arm to detect a 25% treatment effect with 80% power. These measures outperformed the other regional and global MRI measures and the clinical scales. Regional rates of cortical atrophy therefore provide the best outcome measures in progressive apraxia of speech. The small sample size estimates demonstrate feasibility for including progressive apraxia of speech in future clinical treatment trials targeting tau.
PMCID: PMC4573830  PMID: 26076744
Clinical treatment trials; tau; rates; MRI; apraxia of speech; PPAOS
19.  Longitudinal plasma amyloid beta in Alzheimer’s disease clinical trials 
Little is known about the utility of plasma Aβ in clinical trials of Alzheimer’s disease.
We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n=405, 24 months) and (2) simvastatin in mild to moderate Alzheimer’s (n=225, 18 months).
Baseline plasma Aβ was not related to cognitive or clinical progression. We observed a decrease in plasma Aβ40 and 42 among APOE-ε4 carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in Aβ compared to placebo. We found significant storage time effects and considerable plate-to-plate variation.
We found no support for the utility of plasma Aβ as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Aβ may prove useful in pharmacodynamic studies of anti-amyloid drugs.
PMCID: PMC4387108  PMID: 25301682
Alzheimer’s Disease; mild cognitive impairment; MCI; plasma amyloid; biomarkers; apolipoprotein E; bioassay; luminex; innogenetics; donepezil; simvastatin
20.  Frequency and Topography of Cerebral Microbleeds in Dementia with Lewy bodies Compared to Alzheimer’s Disease 
Parkinsonism & related disorders  2015;21(9):1101-1104.
To determine the frequency and topographic distribution of cerebral microbleeds (CMBs) in dementia with Lewy bodies (DLB) in comparison to CMBs in Alzheimer disease dementia (AD).
Consecutive probable DLB (n= 23) patients who underwent 3-tesla T2* weighted gradient-recalled-echo MRI, and age and gender matched probable Alzheimer’s disease patients (n=46) were compared for the frequency and location of CMBs.
The frequency of one or more CMBs was similar among patients with DLB (30%) and AD (24%). Highest densities of CMBs were found in the occipital lobes of patients with both DLB and AD. Patients with AD had greater densities of CMBs in the temporal lobes and deep or infratentorial regions compared to DLB (p<0.05)
CMBs are as common in patients with DLB as in patients with AD, with highest densities observed in the occipital lobes, suggesting common pathophysiologic mechanisms underlying CMBs in both diseases.
PMCID: PMC4554804  PMID: 26205074
Dementia with Lewy bodies; Cerebral Microbleeds; Alzheimer disease; Cerebral amyloid angiopathy; T2* weighted gradient-recalled-echo MRI
21.  Integration of bioinformatics and imaging informatics for identifying rare PSEN1 variants in Alzheimer’s disease 
BMC Medical Genomics  2016;9(Suppl 1):30.
Pathogenic mutations in PSEN1 are known to cause familial early-onset Alzheimer’s disease (EOAD) but common variants in PSEN1 have not been found to strongly influence late-onset AD (LOAD). The association of rare variants in PSEN1 with LOAD-related endophenotypes has received little attention. In this study, we performed a rare variant association analysis of PSEN1 with quantitative biomarkers of LOAD using whole genome sequencing (WGS) by integrating bioinformatics and imaging informatics.
A WGS data set (N = 815) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort was used in this analysis. 757 non-Hispanic Caucasian participants underwent WGS from a blood sample and high resolution T1-weighted structural MRI at baseline. An automated MRI analysis technique (FreeSurfer) was used to measure cortical thickness and volume of neuroanatomical structures. We assessed imaging and cerebrospinal fluid (CSF) biomarkers as LOAD-related quantitative endophenotypes. Single variant analyses were performed using PLINK and gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O).
A total of 839 rare variants (MAF < 1/√(2 N) = 0.0257) were found within a region of ±10 kb from PSEN1. Among them, six exonic (three non-synonymous) variants were observed. A single variant association analysis showed that the PSEN1 p. E318G variant increases the risk of LOAD only in participants carrying APOE ε4 allele where individuals carrying the minor allele of this PSEN1 risk variant have lower CSF Aβ1–42 and higher CSF tau. A gene-based analysis resulted in a significant association of rare but not common (MAF ≥ 0.0257) PSEN1 variants with bilateral entorhinal cortical thickness.
This is the first study to show that PSEN1 rare variants collectively show a significant association with the brain atrophy in regions preferentially affected by LOAD, providing further support for a role of PSEN1 in LOAD. The PSEN1 p. E318G variant increases the risk of LOAD only in APOE ε4 carriers. Integrating bioinformatics with imaging informatics for identification of rare variants could help explain the missing heritability in LOAD.
PMCID: PMC4989889  PMID: 27535542
Whole genome sequencing; Imaging genetics; Gene-based association of rare variants; PSEN1
22.  A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers 
Neurology  2016;87(5):539-547.
Biomarkers have become an essential component of Alzheimer disease (AD) research and because of the pervasiveness of AD pathology in the elderly, the same biomarkers are used in cognitive aging research. A number of current issues suggest that an unbiased descriptive classification scheme for these biomarkers would be useful. We propose the “A/T/N” system in which 7 major AD biomarkers are divided into 3 binary categories based on the nature of the pathophysiology that each measures. “A” refers to the value of a β-amyloid biomarker (amyloid PET or CSF Aβ42); “T,” the value of a tau biomarker (CSF phospho tau, or tau PET); and “N,” biomarkers of neurodegeneration or neuronal injury ([18F]-fluorodeoxyglucose–PET, structural MRI, or CSF total tau). Each biomarker category is rated as positive or negative. An individual score might appear as A+/T+/N−, or A+/T−/N−, etc. The A/T/N system includes the new modality tau PET. It is agnostic to the temporal ordering of mechanisms underlying AD pathogenesis. It includes all individuals in any population regardless of the mix of biomarker findings and therefore is suited to population studies of cognitive aging. It does not specify disease labels and thus is not a diagnostic classification system. It is a descriptive system for categorizing multidomain biomarker findings at the individual person level in a format that is easy to understand and use. Given the present lack of consensus among AD specialists on terminology across the clinically normal to dementia spectrum, a biomarker classification scheme will have broadest acceptance if it is independent from any one clinically defined diagnostic scheme.
PMCID: PMC4970664  PMID: 27371494
23.  Suspected non-Alzheimer disease pathophysiology—concept and controversy 
Nature reviews. Neurology  2016;12(2):117-124.
Suspected non-Alzheimer disease pathophysiology (SNAP) is a biomarker-based concept that applies to individuals with normal levels of amyloid-β biomarkers in the brain, but in whom biomarkers of neurodegeneration are abnormal. The term SNAP has been applied to individuals who are clinically normal for their age and to individuals with mild cognitive impairment, but is applicable to any amyloid-negative, neurodegeneration-positive individual regardless of clinical status, except when the pathology underlying neurodegeneration can be confidently inferred from the clinical presentation. SNAP is present in ~23% of clinically normal individuals aged >65 years and in ~25% of mildly cognitively impaired individuals. APOE4 is underrepresented in individuals with SNAP compared with amyloid-positive individuals. Clinically normal and mildly impaired individuals with SNAP have worse clinical and/or cognitive outcomes than individuals with normal levels of neurodegeneration and amyloid-β biomarkers. In this Perspectives article we describe the available data on SNAP and address topical controversies in the field.
PMCID: PMC4784257  PMID: 26782335
24.  Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease 
Alzheimer's & Dementia  2016;12(8):862-871.
The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.
We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study.
We confirm that variation in/near APOE/TOMM40 (P = 6 × 10−14) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10−4), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10−10 OR = 1.9 [1.5–2.3]); rs72907046 near FAM46A (P = 1 × 10−9 OR = 3.2 [2.1–4.9]); and rs2525776 near SEMA3C (P = 1 × 10−8, OR = 3.3 [2.1–5.1]).
We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.
PMCID: PMC4982482  PMID: 26993346
Posterior cortical atrophy; Alzheimer's disease; Genetics; GWAS; Selective vulnerability; APOE
25.  Serum Adiponectin Levels, Neuroimaging, and Cognition in the Mayo Clinic Study of Aging 
Adiponectin, a protein involved in inflammatory pathways, may impact the development and progression of Alzheimer’s disease (AD). Adiponectin levels have been associated with mild cognitive impairment (MCI) and AD; however, its association with Alzheimer-associated neuroimaging and cognitive outcomes is unknown.
Determine the cross-sectional association between plasma adiponectin and neuroimaging and cognitive outcomes in an older population-based sample.
Multivariable adjusted regression models were used to investigate the association between plasma adiponectin and hippocampal volume (HVa), PiB-PET, FDG PET, cortical thickness, MCI diagnosis, and neuropsychological test performance. Analyses included 535 non-demented participants aged 70 and older enrolled in the Mayo Clinic Study of Aging.
Women had higher adiponectin than men (12,631 ng/mL vs. 8,908 ng/mL, P < .001). Among women, higher adiponectin was associated with smaller HVa (B=−0.595; 95% CI −1.19, −0.005), poorer performance in language (B−0.676; 95% CI −1.23, −0.121) and global cognition (B=−0.459; 95% CI −0.915, −0.002), and greater odds of a MCI diagnosis (OR=6.23; 95% CI 1.20, 32.43). In analyses stratified by sex and elevated amyloid (PiB-PET SUVR>1.4), among women with elevated amyloid, higher adiponectin was associated with smaller HVa (B=−0.723; 95% CI −1.43, −0.014), poorer performance in memory (B=−1.02; 95% CI −1.73, −0.312), language (B=−0.896; 95% CI −1.58, −0.212), and global (B=−0.650; 95% CI −1.18, −0.116) cognition, and greater odds of MCI (OR=19.34; 95% CI 2.72, 137.34).
Higher plasma adiponectin was associated with neuroimaging and cognitive outcomes among women. Longitudinal analyses are necessary to determine whether higher adiponectin predicts neurodegeneration and cognitive decline.
PMCID: PMC4955718  PMID: 27163809

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