Search tips
Search criteria

Results 1-25 (267)

Clipboard (0)

Select a Filter Below

more »
more »
Year of Publication
more »
1.  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
2.  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
3.  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
4.  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
5.  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
6.  Obesity, insulin resistance and incident small vessel disease on MRI: the Atherosclerosis Risk in Communities Study 
Background and purpose
The term “metabolic syndrome” (MetS) describes the clustering of risk factors found in many individuals with obesity. Due to their pathophysiology, we hypothesized that two features of MetS, central obesity and insulin resistance (IR), would be associated with cerebrovascular changes on MRI, and specifically with incident lacunar disease and not white matter hyperintensity progression (WMH).
Risk factors were defined at study baseline in 934 participants in the Atherosclerosis Risk in Communities (ARIC) study who completed two brain MRIs approximately ten years apart. WMH progression and incident lacunes between the two MRIs were determined. An IR score for each participant was created using principal component analysis of 11 risk factors, including (among others): insulin, HOMA-IR, body mass index (BMI) and waist circumference. MetS (presence/absence), using standard clinical definitions, and IR score at the first MRI, were independent variables, evaluated in multivariate logistic regression to determine odds of WMH progression (Q5 vs. Q1–4) and incident lacunes.
MetS (adjusted OR 1.98; 95% confidence interval (CI) 1.28, 3.05) and IR score (adjusted OR per 1-standard deviation increase: 1.33, 95% CI 1.05, 1.68) were associated with incident lacunes but not with WMH progression. Insulin, HOMA-IR and BMI were not associated with incident lacunes or WMH progression in separate models.
The IR score and central obesity are associated with incident lacunar disease but not WMH progression in individuals. Central obesity and IR may be important risk factors to target to prevent lacunar disease.
PMCID: PMC4624467  PMID: 26451022
metabolic syndrome; white matter hyperintensities; lacunes; obesity; insulin resistance; leukoaraiosis
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  TREM2 p.R47H substitution is not associated with dementia with Lewy bodies 
Neurology: Genetics  2016;2(4):e85.
Dementia with Lewy bodies (DLB) is the second leading cause of neurodegenerative dementia in the elderly and is clinically characterized by the presence of cognitive decline, parkinsonism, REM sleep behavior disorder, and visual hallucinations.1,2 At autopsy, α-synuclein–positive Lewy-related pathology is observed throughout the brain. Concomitant Alzheimer disease–related pathology including amyloid plaques and, to a lesser degree, neurofibrillary tangles are often present.2 The clinical characteristics of DLB share overlapping features with Alzheimer disease dementia (AD) and Parkinson disease (PD). A recent genetic association study examining known hits from PD and AD identified variants at both the α-synuclein (SNCA) and APOE loci as influencing the individual risk to DLB.3 These findings would suggest that DLB may be a distinct disease with shared genetic risk factors with PD and AD.
PMCID: PMC4946771  PMID: 27458607
14.  Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease 
Acta neuropathologica  2015;130(1):77-92.
Frontotemporal lobar degeneration with TAR DNA binding protein 43 inclusions (FTLD-TDP) is the most common pathology associated with frontotemporal dementia (FTD). Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) and mutations in progranulin (GRN) are the major known genetic causes of FTLD-TDP; however, the genetic etiology in the majority of FTLD-TDP remains unexplained.
In this study, we performed whole-genome sequencing in 104 pathologically confirmed FTLD-TDP patients from the Mayo Clinic brain bank negative for C9ORF72 and GRN mutations and report on the contribution of rare single nucleotide and copy-number variants in 21 known neurodegenerative disease genes. Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and TANK-binding kinase 1 (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and p.A481V missense mutation in trans, while case B carried a deletion of OPTN exons 13–15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1. Cases C–E carried heterozygous missense mutations in TBK1, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain. Quantitative mRNA expression and protein analysis in cerebellar tissue showed a striking reduction of OPTN and/or TBK1 expression in 4 out of 5 patients supporting pathogenicity in these specific patients and suggesting a loss-of-function disease mechanism. Importantly, neuropathologic examination showed FTLD-TDP type A in the absence of motor neuron disease in 3 pathogenic mutation carriers.
In conclusion, we highlight TBK1 as an important cause of pure FTLD-TDP, identify the first OPTN mutations in FTLD-TDP, and suggest a potential oligogenic basis for at least a subset of FTLD-TDP patients. Our data further adds to the growing body of evidence linking ALS and FTD and suggests a key role for the OPTN/TBK1 pathway in these diseases.
PMCID: PMC4470809  PMID: 25943890
Whole-genome sequencing; FTLD-TDP; OPTN; TBK1; oligogenic mechanism
15.  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
16.  White matter integrity in dementia with Lewy bodies: A Voxel-Based Analysis of Diffusion Tensor Imaging 
Neurobiology of aging  2015;36(6):2010-2017.
Many patients with dementia with Lewy bodies have overlapping Alzheimer's disease (AD)–related pathology, which may contribute to white matter (WM) diffusivity alterations on diffusion tensor imaging (DTI). Consecutive patients with DLB (n=30), age and sex matched AD patients (n=30), and cognitively normal controls (CN; n=60) were recruited. All subjects underwent DTI, 18F 2-fluoro-deoxy-d-glucose (FDG) and 11C Pittsburgh compound B (PiB) PET scans. DLB patients had reduced fractional anisotropy (FA) in the parieto-occipital WM but not elsewhere compared to CN, and elevated FA in parahippocampal WM compared to AD patients, which persisted after controlling for Aβ load in DLB. The pattern of WM FA alterations on DTI was consistent with the more diffuse posterior parietal and occipital glucose hypometabolism of FDG PET in the cortex. DLB is characterized by a loss of parieto-occipital WM integrity, independent of concomitant AD-related Aβ load. Cortical glucose hypometabolism accompanies WM FA alterations with a concordant pattern of gray and white matter involvement in the parieto-occipital lobes in DLB.
PMCID: PMC4433563  PMID: 25863527
dementia with Lewy bodies; diffusion tensor imaging; white matter integrity; amyloid-beta load; voxel-based analysis; cortical hypometabolism
18.  Plasma phospholipids and prevalence of mild cognitive impairment and/or dementia in the ARIC Neurocognitive Study (ARIC-NCS) 
Phospholipids are altered in brains of patients with dementia and some studies suggest their plasma levels may be useful in the detection of mild cognitive impairment (MCI) and dementia.
We measured 188 plasma metabolites in participants who underwent a detailed neuropsychological assessment and classified as normal (n = 153), MCI (n = 145), or dementia (n = 143) by expert adjudication.
Among 10 phospholipids recently implicated as altered in dementia, higher concentration of PC aa C36:6 was significantly associated with decreased prevalence of dementia (odds ratio = 0.71, 95% confidence interval = 0.50–1.00 per 1−SD increase). Adding these phospholipids to a model including multiple predictors of dementia led to only minimal improvement in detection (C statistic changed from 0.702 to 0.71).
Some phospholipids and metabolites were altered in MCI and dementia but cross-sectional association was relatively weak and did not improve detection of MCI and dementia beyond information provided by clinical variables.
PMCID: PMC4925799  PMID: 27408938
Phospholipids; Plasma; Mild cognitive impairment; MCI; Dementia; Metabolomics; Metabolites; ARIC-NCS; ARIC; Alzheimer's disease; AD
19.  Risk and protective factors for cognitive impairment in persons aged 85 years and older 
Neurology  2015;84(18):1854-1861.
To determine risk and protective factors for mild cognitive impairment (MCI) among persons 85 years and older.
Participants in the population-based prospective Mayo Clinic Study of Aging were comprehensively evaluated at baseline and at 15 monthly intervals to determine incident MCI. At baseline, lifestyle factors in midlife and late life were assessed by self-reported questionnaire; vascular and comorbid conditions were abstracted from participants' medical records.
Of 256 participants who were cognitively normal at enrollment (median age 87.3 years, 62% women), 121 developed MCI at a median 4.1 years of follow-up. Predictors of MCI were APOE ε4 allele (hazard ratio [HR] 1.89; p = 0.008), current depressive symptoms (HR 1.78; p = 0.02), midlife onset of hypertension (HR 2.43; p = 0.005), increasing number of vascular diseases (HR 1.13; p = 0.02), and chronic conditions from the Charlson Comorbidity Index (HR 1.08; p = 0.006). Models were adjusted for sex and education, with age as the time variable. The risk of MCI was reduced for participants who reported engagement in artistic (HR 0.27; p = 0.03), craft (HR 0.55; p = 0.02), and social (HR 0.45; p = 0.005) activities in both midlife and late life, and in the use of a computer in late life (HR 0.47; p = 0.008).
Chronic disease burden increases risk of MCI, whereas certain lifestyle factors reduce risk in persons 85 years and older. This implies that preventive strategies for MCI may need to begin in midlife and should persist throughout late life.
PMCID: PMC4433468  PMID: 25854867
20.  Brain atrophy over time in genetic and sporadic frontotemporal dementia: a study on 198 serial MRI 
To determine the utility of longitudinal MRI measurements as potential biomarkers in the main genetic variants of frontotemporal dementia (FTD), including microtubule-associated protein tau (MAPT) and progranulin (GRN) mutations, and C9ORF72 repeat expansions, as well as sporadic FTD.
In this longitudinal study, 58 subjects were identified that had at least two MRI and MAPT mutations (n=21), GRN mutations (n=11), C9ORF72 repeat expansions (n=11) or sporadic FTD (n=15). A total of 198 serial MRI were analyzed. Rates of whole brain atrophy were calculated using the boundary-shift integral. Regional rates of atrophy were calculated using tensor-based morphometry. Sample size estimates were calculated.
Progressive brain atrophy was observed in all groups, with fastest rates of whole brain atrophy in GRN, followed by sporadic FTD, C9ORF72 and MAPT. All variants showed greatest rates in frontal and temporal lobes, with parietal lobes also strikingly affected in GRN. Regional rates of atrophy across all lobes were greater in GRN compared to the other groups. C9ORF72 showed greater rates of atrophy in left cerebellum and right occipital lobe than MAPT, and sporadic FTD showed greater rates in anterior cingulate than C9ORF72 and MAPT. Sample size estimates were lowest using temporal lobe rates in GRN, ventricular rates in MAPT and C9ORF72, and whole brain rates in sporadic FTD.
These data support the utility of using rates of atrophy as outcome measures in future drug trials in FTD and show that different imaging biomarkers may offer advantages in the different variants of FTD.
PMCID: PMC4390434  PMID: 25683866
MRI; longitudinal; frontotemporal dementia; genetics; tensor-based morphometry
21.  Hearing Impairment and Cognitive Decline: A Pilot Study Conducted Within the Atherosclerosis Risk in Communities Neurocognitive Study 
American Journal of Epidemiology  2015;181(9):680-690.
Hearing impairment (HI) is prevalent, is modifiable, and has been associated with cognitive decline. We tested the hypothesis that audiometric HI measured in 2013 is associated with poorer cognitive function in 253 men and women from Washington County, Maryland (mean age = 76.9 years) in a pilot study carried out within the Atherosclerosis Risk in Communities Neurocognitive Study. Three cognitive tests were administered in 1990–1992, 1996–1998, and 2013, and a full neuropsychological battery was administered in 2013. Multivariable-adjusted differences in standardized cognitive scores (cross-sectional analysis) and trajectories of 20-year change (longitudinal analysis) were modeled using linear regression and generalized estimating equations, respectively. Hearing thresholds for pure tone frequencies of 0.5–4 kHz were averaged to obtain a pure tone average in the better-hearing ear. Hearing was categorized as follows: ≤25 dB, no HI; 26–40 dB, mild HI; and >40 dB, moderate/severe HI. Comparing participants with moderate/severe HI to participants with no HI, 20-year rates of decline in memory and global function differed by −0.47 standard deviations (P = 0.02) and −0.29 standard deviations (P = 0.02), respectively. Estimated declines were greatest in participants who did not wear a hearing aid. These findings add to the limited literature on cognitive impairments associated with HI, and they support future research on whether HI treatment may reduce risk of cognitive decline.
PMCID: PMC4408947  PMID: 25841870
aging; cognition; cognitive decline; hearing impairment; memory; perbycussis
22.  Age, sex and APOE ε4 effects on memory, brain structure and β-amyloid across the adult lifespan 
JAMA neurology  2015;72(5):511-519.
Typical cognitive aging may be defined as age associated changes in cognitive performance in individuals who remain free of dementia. Ideally the full adult age spectrum should be included to assess brain imaging findings associated with typical aging.
To compare age, sex and Apolipoprotein E (APOE ε4) effects on memory, brain structure (adjusted hippocampal volume, HVa) and amyloid PET in cognitively normal individuals aged 30 to 95 years old.
Design, Setting, and Participants
Cross sectional observational study (Marc 2006 to October 2014) at an academic medical center. We studied 1246 cognitively normal subjects; 1209 participants aged 50–95 years old enrolled in a population-based study of cognitive aging and 37 self-selected volunteers aged 30–49.
Main Outcomes and Measures
Memory, HVa, and amyloid PET
Overall, memory worsened from age 30 years through the 90s. HVa worsened gradually from 30 years to the mid-60s and more steeply beyond that age. The median amyloid PET was low until age 70 years and increased thereafter. Memory was worse in men than women overall (p<0.001) and more specifically beyond age 40 years. HVa was lower in men than women overall (p<0.001) and more specifically beyond age 60 years. There was no sex difference in amyloid PET at any age. Within each sex, memory performance and HVa were not different by APOE ε4 at any age. From age 70 years onward APOE ε4 carriers had significantly greater median amyloid PET load than noncarriers. However the ages at which 10% of the population were amyloid PET positive were 57 years for APOE ε4 carriers and 64 years for non-carriers.
Conclusions and Relevance
Male sex is associated with worse memory and HVa among cognitively normal individuals while APOE ε4 is not. In contrast, APOE ε4 is associated with greater amyloid PET values (from age 70 years onward) while sex is not. Worsening memory and HVa occur at earlier ages than abnormal amyloid PET. Therefore, neuropathological processes other than β-amyloidosis must underlie declines in brain structure and memory function in middle age. Our findings are consistent with a model of late-onset Alzheimer’s disease in which β-amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits.
PMCID: PMC4428984  PMID: 25775353
Cognitive Aging; Amyloid Imaging; Alzheimer Disease; Memory Performance; Brain Atrophy
23.  Network-driven plasma proteomics expose molecular changes in the Alzheimer’s brain 
Biological pathways that significantly contribute to sporadic Alzheimer’s disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.
To access this information we probed relative levels of close to 600 secreted signaling proteins from patients’ blood samples using antibody microarrays and mapped disease-specific molecular networks. Using these networks as seeds we then employed independent genome and transcriptome data sets to corroborate potential pathogenic pathways.
We identified Growth-Differentiation Factor (GDF) signaling as a novel Alzheimer’s disease-relevant pathway supported by in vivo and in vitro follow-up experiments, demonstrating the existence of a highly informative link between cellular pathology and changes in circulatory signaling proteins.
Electronic supplementary material
The online version of this article (doi:10.1186/s13024-016-0095-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4845325  PMID: 27112350
24.  Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium 
Debette, Stéphanie | Ibrahim Verbaas, Carla A. | Bressler, Jan | Schuur, Maaike | Smith, Albert | Bis, Joshua C. | Davies, Gail | Wolf, Christiane | Gudnason, Vilmundur | Chibnik, Lori B. | Yang, Qiong | deStefano, Anita L. | de Quervain, Dominique J.F. | Srikanth, Velandai | Lahti, Jari | Grabe, Hans J. | Smith, Jennifer A. | Priebe, Lutz | Yu, Lei | Karbalai, Nazanin | Hayward, Caroline | Wilson, James F. | Campbell, Harry | Petrovic, Katja | Fornage, Myriam | Chauhan, Ganesh | Yeo, Robin | Boxall, Ruth | Becker, James | Stegle, Oliver | Mather, Karen A. | Chouraki, Vincent | Sun, Qi | Rose, Lynda M. | Resnick, Susan | Oldmeadow, Christopher | Kirin, Mirna | Wright, Alan F. | Jonsdottir, Maria K. | Au, Rhoda | Becker, Albert | Amin, Najaf | Nalls, Mike A. | Turner, Stephen T. | Kardia, Sharon L.R. | Oostra, Ben | Windham, Gwen | Coker, Laura H. | Zhao, Wei | Knopman, David S. | Heiss, Gerardo | Griswold, Michael E. | Gottesman, Rebecca F. | Vitart, Veronique | Hastie, Nicholas D. | Zgaga, Lina | Rudan, Igor | Polasek, Ozren | Holliday, Elizabeth G. | Schofield, Peter | Choi, Seung Hoan | Tanaka, Toshiko | An, Yang | Perry, Rodney T. | Kennedy, Richard E. | Sale, Michèle M. | Wang, Jing | Wadley, Virginia G. | Liewald, David C. | Ridker, Paul M. | Gow, Alan J. | Pattie, Alison | Starr, John M. | Porteous, David | Liu, Xuan | Thomson, Russell | Armstrong, Nicola J. | Eiriksdottir, Gudny | Assareh, Arezoo A. | Kochan, Nicole A. | Widen, Elisabeth | Palotie, Aarno | Hsieh, Yi-Chen | Eriksson, Johan G. | Vogler, Christian | van Swieten, John C. | Shulman, Joshua M. | Beiser, Alexa | Rotter, Jerome | Schmidt, Carsten O. | Hoffmann, Wolfgang | Nöthen, Markus M. | Ferrucci, Luigi | Attia, John | Uitterlinden, Andre G. | Amouyel, Philippe | Dartigues, Jean-François | Amieva, Hélène | Räikkönen, Katri | Garcia, Melissa | Wolf, Philip A. | Hofman, Albert | Longstreth, W.T. | Psaty, Bruce M. | Boerwinkle, Eric | DeJager, Philip L. | Sachdev, Perminder S. | Schmidt, Reinhold | Breteler, Monique M.B. | Teumer, Alexander | Lopez, Oscar L. | Cichon, Sven | Chasman, Daniel I. | Grodstein, Francine | Müller-Myhsok, Bertram | Tzourio, Christophe | Papassotiropoulos, Andreas | Bennett, David A. | Ikram, Arfan M. | Deary, Ian J. | van Duijn, Cornelia M. | Launer, Lenore | Fitzpatrick, Annette L. | Seshadri, Sudha | Mosley, Thomas H.
Biological psychiatry  2014;77(8):749-763.
Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.
We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia-and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10−6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.
rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10−10) and replication cohorts (p = 5.65 × 10−8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10−8, and rs6813517 [SPOCK3], p = 2.58 × 10−8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.
This largest study to date exploring the genetics of memory function in ~ 40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
PMCID: PMC4513651  PMID: 25648963
Alzheimer disease; Dementia; Epidemiology; Genetics; Population-based; Verbal declarative memory
25.  Association of hospitalization with long-term cognitive and brain MRI changes in the ARIC cohort 
Neurology  2015;84(14):1443-1453.
To determine whether hospitalization is associated with subsequent cognitive decline or changes on brain MRI in a community-based cohort.
Baseline and follow-up cognitive testing (n = 2,386) and MRI scans with standardized assessments (n = 885) were available from a subset of white and black participants in the Atherosclerosis Risk in Communities study. Cognitive tests included the Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test (WFT). Hospitalization characteristics were determined using ICD-9 codes. Regression models adjusted for demographics, education, comorbidities, and APOE ε4 were used to estimate the independent association of hospitalization with changes in cognition or neuroimaging.
Over a mean 14.1 years between visits, 1,266 participants (53.1%) were hospitalized. Hospitalization compared with no hospitalization was associated with greater decline in DSST scores (1.25 points greater decline, p < 0.001) but no difference in DWRT or WFT score change. Each additional hospitalization, as well as a critical illness vs noncritical illness hospitalization, was associated with greater decline in DSST scores. A subset of participants (n = 885) underwent MRI scans separated by 10.5 years. Hospitalization (n = 392) compared with no hospitalization was associated with a 57% higher odds of increasing ventricular size at follow-up. Each additional hospitalization, as well as having a critical illness vs noncritical illness hospitalization, and having a hospitalization with major surgery vs no surgery was associated with greater odds of increased ventricular size.
Cognitive decline and neuroimaging changes may occur after hospitalization, independent of baseline demographics and comorbidities.
PMCID: PMC4395884  PMID: 25762715

Results 1-25 (267)