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author:("dopman, David")
1.  When Being Thin Is Not a Virtue 
PMCID: PMC4501482  PMID: 19093935
2.  TDP-43 in Alzheimer’s disease is not associated with clinical FTLD or Parkinsonism 
Journal of neurology  2014;261(7):1344-1348.
Widespread deposition of TAR DNA-binding protein of 43 kDa (TDP-43), a major protein inclusion commonly found in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) can also be seen in a subset of cases with Alzheimer’s disease (AD). Some of these AD cases have TDP-43 immunoreactivity in basal ganglia (BG) and substantia nigra (SN), regions that when affected can be associated with parkinsonian signs or symptoms, or even features suggestive of frontotemporal dementia. Here, we examined the presence of clinical features of FTLD, parkinsonian signs and symptoms, and BG atrophy on MRI, in 51 pathologically confirmed AD cases (Braak neurofibrillary tangle stage IV–VI) with widespread TDP-43 deposition, with and without BG and SN involvement. All 51 cases had presented with progressive cognitive impairment with prominent memory deficits. None of the patients demonstrated early behavioral disinhibition, apathy, loss of empathy, stereotyped behavior, hyperorality, and/or executive deficits. Furthermore, TDP-43 deposition in BG or SN had no significant association with tremor (p = 0.80), rigidity (p = 0.19), bradykinesia (p = 0.19), and gait/postural instability (p = 0.39). Volumes of the BG structures were not associated with TDP-43 deposition in the BG. The present study demonstrates that TDP-43 deposition in pathologically confirmed AD cases is not associated with a clinical manifestation suggestive of FTLD, or parkinsonian features.
PMCID: PMC4101047  PMID: 24760339
TDP-43; Alzheimer’s disease; Frontotemporal dementia; Parkinsonism
3.  Frontotemporal dementia and its subtypes: a genome-wide association study 
Ferrari, Raffaele | Hernandez, Dena G | Nalls, Michael A | Rohrer, Jonathan D | Ramasamy, Adaikalavan | Kwok, John B J | Dobson-Stone, Carol | Brooks, William S | Schofield, Peter R | Halliday, Glenda M | Hodges, John R | Piguet, Olivier | Bartley, Lauren | Thompson, Elizabeth | Haan, Eric | Hernández, Isabel | Ruiz, Agustín | Boada, Mercè | Borroni, Barbara | Padovani, Alessandro | Cruchaga, Carlos | Cairns, Nigel J | Benussi, Luisa | Binetti, Giuliano | Ghidoni, Roberta | Forloni, Gianluigi | Galimberti, Daniela | Fenoglio, Chiara | Serpente, Maria | Scarpini, Elio | Clarimón, Jordi | Lleó, Alberto | Blesa, Rafael | Waldö, Maria Landqvist | Nilsson, Karin | Nilsson, Christer | Mackenzie, Ian R A | Hsiung, Ging-Yuek R | Mann, David M A | Grafman, Jordan | Morris, Christopher M | Attems, Johannes | Griffiths, Timothy D | McKeith, Ian G | Thomas, Alan J | Pietrini, P | Huey, Edward D | Wassermann, Eric M | Baborie, Atik | Jaros, Evelyn | Tierney, Michael C | Pastor, Pau | Razquin, Cristina | Ortega-Cubero, Sara | Alonso, Elena | Perneczky, Robert | Diehl-Schmid, Janine | Alexopoulos, Panagiotis | Kurz, Alexander | Rainero, Innocenzo | Rubino, Elisa | Pinessi, Lorenzo | Rogaeva, Ekaterina | George-Hyslop, Peter St | Rossi, Giacomina | Tagliavini, Fabrizio | Giaccone, Giorgio | Rowe, James B | Schlachetzki, J C M | Uphill, James | Collinge, John | Mead, S | Danek, Adrian | Van Deerlin, Vivianna M | Grossman, Murray | Trojanowsk, John Q | van der Zee, Julie | Deschamps, William | Van Langenhove, Tim | Cruts, Marc | Van Broeckhoven, Christine | Cappa, Stefano F | Le Ber, Isabelle | Hannequin, Didier | Golfier, Véronique | Vercelletto, Martine | Brice, Alexis | Nacmias, Benedetta | Sorbi, Sandro | Bagnoli, Silvia | Piaceri, Irene | Nielsen, Jørgen E | Hjermind, Lena E | Riemenschneider, Matthias | Mayhaus, Manuel | Ibach, Bernd | Gasparoni, Gilles | Pichler, Sabrina | Gu, Wei | Rossor, Martin N | Fox, Nick C | Warren, Jason D | Spillantini, Maria Grazia | Morris, Huw R | Rizzu, Patrizia | Heutink, Peter | Snowden, Julie S | Rollinson, Sara | Richardson, Anna | Gerhard, Alexander | Bruni, Amalia C | Maletta, Raffaele | Frangipane, Francesca | Cupidi, Chiara | Bernardi, Livia | Anfossi, Maria | Gallo, Maura | Conidi, Maria Elena | Smirne, Nicoletta | Rademakers, Rosa | Baker, Matt | Dickson, Dennis W | Graff-Radford, Neill R | Petersen, Ronald C | Knopman, David | Josephs, Keith A | Boeve, Bradley F | Parisi, Joseph E | Seeley, William W | Miller, Bruce L | Karydas, Anna M | Rosen, Howard | van Swieten, John C | Dopper, Elise G P | Seelaar, Harro | Pijnenburg, Yolande AL | Scheltens, Philip | Logroscino, Giancarlo | Capozzo, Rosa | Novelli, Valeria | Puca, Annibale A | Franceschi, M | Postiglione, Alfredo | Milan, Graziella | Sorrentino, Paolo | Kristiansen, Mark | Chiang, Huei-Hsin | Graff, Caroline | Pasquier, Florence | Rollin, Adeline | Deramecourt, Vincent | Lebert, Florence | Kapogiannis, Dimitrios | Ferrucci, Luigi | Pickering-Brown, Stuart | Singleton, Andrew B | Hardy, John | Momeni, Parastoo
Lancet neurology  2014;13(7):686-699.
Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. All participants had European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) and suggestive single-nucleotide polymorphisms.
We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8) that encompassed the HLA locus at 6p21.3 in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC, for the behavioural FTD subtype. Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation incis.
Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and possibly to shed light on the pathomechanisms contributing to FTD.
The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/ MRC Centre on Parkinson’s disease, Alzheimer’s Research UK, and Texas Tech University Health Sciences Center.
PMCID: PMC4112126  PMID: 24943344
4.  Davunetide for Progressive Supranuclear Palsy: a multicenter, randomized, double-blind, placebo controlled trial 
Lancet neurology  2014;13(7):676-685.
Davunetide (AL-108, NAP) is an eightamino acid peptide that promotes microtubule stability and decreases tau phosphorylation in pre-clinical studies. Since PSP is tightly linked to tau pathology, davunetide could be an effective treatment for PSP.The goals of this study were to evaluate the efficacy and safety of davunetide in PSP.
A phase 2/3 double-blind, parallel group, clinical trial of davunetide 30 mg or placebo (randomized 1:1) administered intranasally twice daily for 52 weeks was conducted at 48centers. Participants met modifiedNNIPPS criteria for possible or probable PSP. Co-primary endpointswere the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England ADL(SEADL) scale at up to 52 weeks. Data from all individuals who received at least one dose of medication and had a post-baseline efficacy assessment were compared using a rank-based method.Secondary outcomes included the Clinical Global Impression of Change (CGIC) and the change in regional brain volumeon MRI. identifier: NCT01110720.
360 participants were screened, 313 were randomized and 243 (77.6%) completed the study. There were no group differences in PSPRS (mean difference: 0.49 [95% CI: −1.5, 2.5], p = 0.72) or SEADL (1% [−2, 4%], p = 0.76) change from baseline (CFB) and mean 52 week CFB PSPRS scores were similar between the davunetide (11.3 [9.8,12.8]) and placebo groups (10.9 [9.1, 13.0]). There wereno differences in any of the secondary or exploratory endpoints. There were 11deaths in the davunetide group and tenin the placebo group. There were more nasal adverse events in the davunetide group.
Davunetide is well tolerated but is not an effective treatment for PSP. Clinical trials of disease modifying therapy are feasible in PSP and should be pursued with other promising tau-directed therapies.
Allon Therapeutics
PMCID: PMC4129545  PMID: 24873720
5.  Accelerated vs. unaccelerated serial MRI based TBM-SyN measurements for Clinical Trials in Alzheimer’s disease 
NeuroImage  2015;113:61-69.
Our primary objective was to compare the performance of unaccelerated vs. accelerated structural MRI for measuring disease progression using serial scans in Alzheimer’s disease (AD).
We identified cognitively normal (CN), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI) and AD subjects from all available Alzheimer’s Disease Neuroimaging Initiative (ADNI) subjects with usable pairs of accelerated and unaccelerated scans. There were a total of 696 subjects with baseline and 3 month scans, 628 subjects with baseline and 6 month scans and 464 subjects with baseline and 12 month scans available. We employed the Symmetric Diffeomorphic Image Normalization method (SyN) for normalization of the serial scans to obtain Tensor Based Morphometry (TBM) maps which indicate the structural changes between pairs of scans. We computed a TBM-SyN summary score of annualized structural changes over 31 regions of interest (ROIs) that are characteristically affected in AD. TBM-SyN scores were computed using accelerated and unaccelerated scan pairs and compared in terms of agreement, group-wise discrimination, and sample size estimates for a hypothetical therapeutic trial.
We observed a number of systematic differences between TBM-SyN scores computed from accelerated and unaccelerated pairs of scans. TBM-SyN scores computed from accelerated scans tended to have overall higher estimated values than those from unaccelerated scans. However, the performance of accelerated scans was comparable to unaccelerated scans in terms of discrimination between clinical groups and sample sizes required in each clinical group for a therapeutic trial. We also found that the quality of both accelerated vs. unaccelerated scans were similar.
Accelerated scanning protocols reduce scan time considerably. Their group-wise discrimination and sample size estimates were comparable to those obtained with unaccelerated scans. The two protocols did not produce interchangeable TBM-SyN estimates, so it is arguably important to use either accelerated pairs of scans or unaccelerated pairs of scans throughout the study duration.
PMCID: PMC4456670  PMID: 25797830
6.  Antemortem MRI findings associated with microinfarcts at autopsy 
Neurology  2014;82(22):1951-1958.
To determine antemortem MRI findings associated with microinfarcts at autopsy.
Patients with microinfarcts (n = 22) and patients without microinfarcts (n = 44) who underwent antemortem MRI were identified from a dementia clinic–based, population–based, and community clinic–based autopsy cohort. The microinfarct and no-microinfarct groups were matched on age at MRI, age at death, sex, APOE status, Mini-Mental State Examination score, and pathologic diagnosis of Alzheimer disease. Brain infarcts were assessed on fluid-attenuated inversion recovery (FLAIR) MRI. White matter hyperintensities on FLAIR MRI and hippocampal volumes on T1-weighted MRI were quantified using automated methods. A subset of subjects with microinfarcts (n = 15) and a matched group of subjects without microinfarcts (n = 15) had serial T1-weighted MRIs and were included in an analysis of global and regional brain atrophy rates using automated methods.
The presence of cortical (p = 0.03) and subcortical (p = 0.02) infarcts on antemortem MRI was associated with presence of microinfarcts at autopsy. Higher numbers of cortical (p = 0.05) and subcortical (p = 0.03) infarcts on antemortem MRI were also associated with presence of microinfarcts. Presence of microinfarcts was not associated with white matter hyperintensities and cross-sectional hippocampal volume on antemortem MRI. Whole-brain and regional precuneus, motor, and somatosensory atrophy rates were higher in subjects with microinfarcts compared to subjects without microinfarcts.
Microinfarcts increase brain atrophy rates independent of Alzheimer disease pathology. Association between microinfarct pathology and macroinfarcts on MRI suggests either common risk factors or a shared pathophysiology and potentially common preventive targets.
PMCID: PMC4105260  PMID: 24793188
7.  Association of hypometabolism and amyloid levels in aging, normal subjects 
Neurology  2014;82(22):1959-1967.
We evaluated the relationship of amyloid, seen on Pittsburgh compound B (PiB)-PET, and metabolism, seen on [18F]-fluorodeoxyglucose (FDG)-PET, in normal subjects to better understand pathogenesis and biomarker selection in presymptomatic subjects.
Normal participants (aged 70–95 years; 600 with PiB-PET, FDG-PET, and MRI) were included. We performed a cross-sectional evaluation and subcategorized participants into amyloid-negative (<1.4), high-normal (1.4–1.5), positive (1.5–2.0), and markedly positive (>2.0) PiB standardized uptake value ratio groups representing different levels of amyloid brain load. Associations with metabolism were assessed in each group. Relationships with APOE ε4 carriage were evaluated.
Hypometabolism in “Alzheimer disease (AD)-signature” regions was strongly associated with PiB load. Hypometabolism was greater with more positive PiB levels. Additional, more-diffuse cortical hypometabolism was also found to be associated with PiB, although less so. No hypermetabolism was seen in any subset. No significant incremental hypometabolism was seen in APOE-positive vs -negative subjects.
Hypometabolism in PiB-positive, cognitively normal subjects in a population-based cohort occurs in AD-signature cortical regions and to a lesser extent in other cortical regions. It is more pronounced with higher amyloid load and supports a dose-dependent association. The effect of APOE ε4 carriage in this group of subjects does not appear to modify their hypometabolic “AD-like” neurodegeneration. Consideration of hypometabolism associated with amyloid load may aid trials of AD drug therapy.
PMCID: PMC4105262  PMID: 24793183
8.  Early Alzheimer's Disease Neuropathology Detected by Proton MR Spectroscopy 
The Journal of Neuroscience  2014;34(49):16247-16255.
Proton magnetic resonance spectroscopy (1H-MRS) is sensitive to early neurodegenerative processes associated with Alzheimer's disease (AD). Although 1H-MRS metabolite ratios of N-acetyl aspartate (NAA)/creatine (Cr), NAA/myoinositol (mI), and mI/Cr measured in the posterior cingulate gyrus reveal evidence of disease progression in AD, pathologic underpinnings of the 1H-MRS metabolite changes in AD are unknown. Pathologically diagnosed human cases ranging from no likelihood to high likelihood AD (n = 41, 16 females and 25 males) who underwent antemortem 1H-MRS of the posterior cingulate gyrus at 3 tesla were included in this study. Immunohistochemical evaluation was performed on the posterior cingulate gyrus using antibodies to synaptic vesicles, hyperphosphorylated tau (pTau), neurofibrillary tangle conformational-epitope (cNFT), amyloid-β, astrocytes, and microglia. The slides were digitally analyzed using Aperio software, which allows neuropathologic quantification in the posterior cingulate gray matter. MRS and pathology associations were adjusted for time from scan to death. Significant associations across AD and control subjects were found between reduced synaptic immunoreactivity and both NAA/Cr and NAA/mI in the posterior cingulate gyrus. Higher pTau burden was associated with lower NAA/Cr and NAA/mI. Higher amyloid-β burden was associated with elevated mI/Cr and lower NAA/mI ratios, but not with NAA/Cr. 1H-MRS metabolite levels reveal early neurodegenerative changes associated with AD pathology. Our findings support the hypothesis that a decrease in NAA/Cr is associated with loss of synapses and early pTau pathology, but not with amyloid-β or later accumulation of cNFT pathology in the posterior cingulate gyrus. In addition, elevation of mI/Cr is associated with the occurrence of amyloid-β plaques in AD.
PMCID: PMC4252542  PMID: 25471565
Alzheimer's disease; digital microscopy; magnetic resonance spectroscopy; neuropathology; posterior cingulate; tau
9.  Dementia in MS complicated by coexistent Alzheimer disease 
Neurology: Clinical Practice  2014;4(3):226-230.
Distinguishing dementia due to multiple sclerosis (MS) from that of an accompanying neurodegenerative dementia coexisting with MS has been difficult. The recent introduction of Alzheimer disease (AD) biomarkers of amyloid-β and neuronal degeneration has improved diagnosis of AD premortem. We describe 3 patients with MS with coexisting AD, 1 diagnosed at autopsy before AD biomarkers were available and 2 diagnosed premortem by decreased CSF amyloid-β1-42/tau index, MRI, and 18F-flourodeoxyglucose-PET patterns. AD biomarkers may be of diagnostic value in selected patients with severe dementia and MS.
PMCID: PMC4121466  PMID: 25110620
10.  Regional Proton Magnetic Resonance Spectroscopy Patterns in Dementia with Lewy Bodies 
Neurobiology of aging  2014;35(6):1483-1490.
Magnetic resonance spectroscopy (MRS) characteristics of dementia with Lewy bodies (DLB) Alzheimer’s disease (AD) and cognitively normal controls (CN) were compared. DLB (n=34), AD (n=35) and CN (n=148) participated in a MRS study from frontal, posterior cingulate and occipital voxels. We investigated DLB patients with preserved hippocampal volumes to determine the MRS changes in DLB with low probability of overlapping AD pathology. DLB patients were characterized by decreased NAA/Cr in the occipital voxel. AD patients were characterized by lower NAA/Cr in the frontal and posterior cingulate voxels. Normal NAA/Cr levels in the frontal voxel differentiated DLB patients with preserved hippocampal volumes from AD patients. DLB and AD patients had elevated Cho/Cr and mI/Cr in the posterior cingulate. MRS abnormalities associated with loss of neuronal integrity localized to the occipital lobes in DLB, and the posterior cingulate gyri and frontal lobes in AD. This pattern of MRS abnormalities may have a role in differential diagnosis of DLB and in distinguishing DLB patients with overlapping AD pathology.
PMCID: PMC3961495  PMID: 24468473
Dementia with Lewy Bodies; Magnetic resonance spectroscopy; Alzheimer’s disease
11.  TDP-43 is a key player in the clinical features associated with Alzheimer’s disease 
Acta neuropathologica  2014;127(6):811-824.
The aim of this study was to determine whether the TAR DNA-binding protein of 43kDa (TDP-43) independently has any effect on the clinical and neuroimaging features typically ascribed to Alzheimer’s disease (AD) pathology, and whether TDP-43 pathology could help shed light on the phenomenon of resilient cognition in AD. Three-hundred forty-two subjects pathologically diagnosed with AD were screened for the presence, burden and distribution of TDP-43. All had been classified as cognitively impaired or normal, prior to death. Atlas-based parcellation and voxel-based morphometry were used to assess regional atrophy on MRI. Regression models controlling for age at death, apolipoprotein ε4 and other AD-related pathologies were utilized to explore associations between TDP-43 and cognition or brain atrophy, stratified by Braak stage. Additionally, we determined whether the effects of TDP-43 were mediated by hippocampal sclerosis. One-hundred ninety-five (57%) cases were TDP-positive. After accounting for age, apolipoprotein ε4, and other pathologies, TDP-43 had a strong effect on cognition, memory loss, and medial temporal atrophy in AD. These effects were not mediated by hippocampal sclerosis. TDP-positive subjects were 10× more likely to be cognitively impaired at death compared to TDP-negative subjects. Greater cognitive impairment and medial temporal atrophy were associated with greater TDP-43 burden and more extensive TDP-43 distribution. TDP-43 is an important factor in the manifestation of the clinico-imaging features of AD. TDP-43 also appears to be able to overpower what has been termed resilient brain aging. TDP-43 therefore should be considered a potential therapeutic target for the treatment of AD.
PMCID: PMC4172544  PMID: 24659241
TDP-43; Alzheimer disease; resilience; APOE ε4; Braak stage; MRI
12.  Progranulin protein levels are differently regulated in plasma and CSF 
Neurology  2014;82(21):1871-1878.
We aimed to investigate the relationship between plasma and CSF progranulin (PGRN) levels.
Plasma and CSF PGRN were measured in a cohort of 345 subjects from the Mayo Clinic Study of Aging by ELISA. Single nucleotide polymorphism genotyping was performed using TaqMan assays. Associations between PGRN and sex, age at sample collection, diagnosis, single nucleotide polymorphism genotypes (GRN, SORT1, and APOE), and Pittsburgh compound B score were explored separately in CSF and plasma using single variable linear regression models. Pearson partial correlation coefficient was used to estimate the correlation of PGRN in CSF and plasma.
Plasma (p = 0.0031) and CSF (p = 0.0044) PGRN significantly increased with age, whereas plasma PGRN levels were 7% lower (p = 0.0025) and CSF PGRN levels 5% higher (p = 0.0024) in male compared with female participants. Correcting for age and sex, higher plasma PGRN was associated with higher CSF PGRN (partial r = 0.17, p = 0.004). In plasma, both rs5848 (GRN; p = 0.002) and rs646776 (SORT1; p = 3.56E-7) were associated with PGRN, while only rs5848 showed highly significant association in CSF (p = 5.59E-14). Age, sex, rs5848 genotype, and plasma PGRN together accounted for only 18% of the variability observed in CSF PGRN.
While some correlation exists between plasma and CSF PGRN, age, sex, and genetic factors differently affect PGRN levels. Therefore, caution should be taken when using plasma PGRN to predict PGRN changes in the brain. These findings further highlight that plasma PGRN levels may not accurately predict clinical features or response to future frontotemporal lobar degeneration therapies.
PMCID: PMC4105255  PMID: 24771538
13.  Baseline Neuropsychiatric Symptoms and the Risk of Incident Mild Cognitive Impairment: A Population-Based Study 
The American journal of psychiatry  2014;171(5):572-581.
We conducted a prospective cohort study to estimate the incidence of mild cognitive impairment (MCI) by baseline neuropsychiatric status, in the setting of the Mayo Clinic Study of Aging.
A classification of normal cognitive aging, MCI, and dementia was adjudicated by an expert consensus panel based on published criteria. Hazard ratios (HR) and 95% confidence intervals (95% CI) were computed using Cox proportional hazards model, with age as a time scale. Baseline Neuropsychiatric Inventory Questionnaire data were available on 1,587 cognitively normal persons who underwent at least one follow-up visit.
We followed the cohort (N=1,587) to incident MCI (N=365) or censoring variables (N=179) for a median of 5 years. The following baseline neuropsychiatric symptoms significantly predicted incident MCI, after adjusting for age, sex, education and medical comorbidity: agitation (HR=3.06; 95% CI=1.89–4.93), apathy (HR=2.26; 95% CI=1.49–3.41), anxiety (HR=1.87; 95% CI=1.28–2.73), irritability (HR=1.84; 95% CI=1.31–2.58), and depression (HR=1.63; 95% CI=1.23–2.16). Delusion (HR=0.55; 95% CI=0.08–3.95) and hallucination (HR=1.48; 95% CI=0.37–5.99) did not predict incident MCI. A secondary analysis showed that euphoria (HR=11.3; 95% CI=3.44–37.2), disinhibition (HR=5.18; 95% CI=2.24–12.0) and nighttime behavior (HR=2.04; 95% CI=1.11–3.76) were significant predictors of non-amnestic MCI but not of amnestic MCI. By contrast, depression predicted amnestic MCI (HR=1.74; 95% CI=1.22–2.47) but not non-amnestic MCI (HR=1.18; 95% CI=0.64–2.16).
Non-psychotic symptoms predicted incident MCI. However, the associations between baseline euphoria, disinhibition, delusions, hallucinations, and the outcome of incident MCI should be considered preliminary since the observations were based on small number of events.
PMCID: PMC4057095  PMID: 24700290
14.  Impact of Differential Attrition on the Association of Education With Cognitive Change Over 20 Years of Follow-up 
American Journal of Epidemiology  2014;179(8):956-966.
Studies of long-term cognitive change should account for the potential effects of education on the outcome, since some studies have demonstrated an association of education with dementia risk. Evaluating cognitive change is more ideal than evaluating cognitive performance at a single time point, because it should be less susceptible to confounding. In this analysis of 14,020 persons from a US cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, we measured change in performance on 3 cognitive tests over a 20-year period, from ages 48–67 years (1990–1992) through ages 70–89 years (2011–2013). Generalized estimating equations were used to evaluate the association between education and cognitive change in unweighted adjusted models, in models incorporating inverse probability of attrition weighting, and in models using cognitive scores imputed from the Telephone Interview for Cognitive Status for participants not examined in person. Education did not have a strong relationship with change in cognitive test performance, although the rate of decline was somewhat slower among persons with lower levels of education. Methods used to account for selective dropout only marginally changed these observed associations. Future studies of risk factors for cognitive impairment should focus on cognitive change, when possible, to allow for reduction of confounding by social or cultural factors.
PMCID: PMC3966720  PMID: 24627572
aging; cognition; cognitive decline; cognitive reserve; education
15.  Mortality in mild cognitive impairment varies by subtype, sex and lifestyle factors. The Mayo Clinic Study of Aging 
Journal of Alzheimer's disease : JAD  2015;45(4):1237-1245.
Etiologic differences in mild cognitive impairment (MCI) subtypes may impact mortality.
To assess the rate of death in MCI overall, and by subtype, in the population-based Mayo Clinic Study of Aging.
Participants aged 70–89 years at enrollment were clinically evaluated at baseline and 15-month intervals to assess diagnoses of MCI and dementia. Mortality in MCI cases vs. cognitively normal (CN) individuals was estimated using Cox proportional hazards models.
Over a median follow-up of 5.8 years, 331 of 862 (38.4%) MCI cases and 224 of 1292 (17.3%) cognitively normal participants died. Compared to CN individuals, mortality was elevated in persons with MCI (hazard ratio [HR] = 2.03; 95% CI: 1.61 to 2.55), and was higher for non-amnestic MCI (naMCI; HR = 2.47; 95% CI: 1.80 to 3.39) than for amnestic MCI (aMCI; HR = 1.89; 95% CI: 1.48 to 2.41) after adjusting for confounders. Mortality varied significantly by sex, education, history of heart disease, and engaging in moderate physical exercise (p for interaction <0.05 for all). Mortality rate estimates were highest in MCI cases who were men, did not exercise, had heart disease, and had higher education vs. CN without these factors, and for naMCI cases vs. aMCI cases without these factors.
These findings suggest stronger impact of etiologic factors on naMCI mortality. Prevention of heart disease, exercise vigilance, may reduce MCI mortality. Delayed MCI diagnosis in persons with higher education impacts mortality, and higher mortality in men may explain similar dementia incidence by sex in our cohort.
PMCID: PMC4398642  PMID: 25697699
Mild cognitive impairment; mortality; cohort studies; incidence studies; prognosis; outcomes research
16.  Association of type 2 diabetes with brain atrophy and cognitive impairment 
Neurology  2014;82(13):1132-1141.
We investigated the associations of diabetes and hypertension with imaging biomarkers (markers of neuronal injury and ischemic damage) and with cognition in a population-based cohort without dementia.
Participants (n = 1,437, median age 80 years) were evaluated by a nurse and physician and underwent neuropsychological testing. A diagnosis of cognitively normal, mild cognitive impairment (MCI), or dementia was made by an expert panel. Participants underwent MRI to determine cortical and subcortical infarctions, white matter hyperintensity (WMH) volume, hippocampal volume (HV), and whole brain volume (WBV). The medical records were reviewed for diabetes and hypertension in midlife or later.
Midlife diabetes was associated with subcortical infarctions (odds ratio, 1.85 [95% confidence interval, 1.09–3.15]; p = 0.02), reduced HV (−4% [−7 to −1.0]; p = 0.01), reduced WBV (−2.9% [−4.1 to −1.6]), and prevalent MCI (odds ratio, 2.08; p = 0.01). The association between diabetes and MCI persisted with adjustment for infarctions and WMH volume but was attenuated after adjustment for WBV (1.60 [0.87–2.95]; p = 0.13) and HV (1.82 [1.00–3.32]; p = 0.05). Midlife hypertension was associated with infarctions and WMH volume and was marginally associated with reduced performance in executive function. Effects of late-life onset of diabetes and hypertension were few.
Midlife onset of diabetes may affect late-life cognition through loss of brain volume. Midlife hypertension may affect executive function through ischemic pathology. Late-life onset of these conditions had fewer effects on brain pathology and cognition.
PMCID: PMC3966799  PMID: 24647028
17.  Retinal Microvascular Abnormalities Predict Progression of Brain Microvascular Disease: An ARIC MRI Study 
Background and Purpose
Brain microvascular disease leads to leukoaraiosis and lacunar infarcts, and contributes to risk of stroke and cognitive decline. Given a shared pathophysiology, retinal microvascular signs are expected to predict brain microvascular disease progression. We investigated if either leukoaraiosis volume progression measured continuously or combined with incident lacunar infarcts would better demonstrate expected associations with retinal disease than has previously been shown.
830 participants in the Atherosclerosis Risk in Communities study ages 55 and older and without previous stroke received an initial brain MRI, retinal photography, and 10 years later, a follow up MRI. We evaluated retinal vascular sign phenotypes as predictors of 1) leukoaraiosis volume increase and 2) a new score combining leukoaraiosis volume change and incident lacunar infarcts. Hypertension and diabetes were evaluated as confounders and effect modifiers.
Individuals with any retinopathy (3.34 cm3; 95% CI 0.74–5.96) or with AV nicking (2.61cm3; 95% CI 0.80–4.42) each had greater progression of leukoaraiosis than those without these conditions. Any retinopathy (OR 3.18; 95% CI 1.71–5.89) or its components—microaneurysms (OR 3.06; 95% CI 1.33–7.07) and retinal hemorrhage (OR 3.02; 95% CI 1.27–7.20)—as well as AV nicking (OR 1.93; 95% CI 1.24–3.02) and focal arteriolar narrowing (OR 1.76; 95% CI 1.19–2.59), were associated with a higher quartile of a novel brain microvascular disease score combining leukoaraiosis progression with incident subclinical lacunes.
A novel scoring method revealed associations of retinal signs with leukoaraiosis progression and brain microvascular disease which have not been shown before.
PMCID: PMC4191897  PMID: 24549866
retina; leukoaraiosis; lacune
18.  Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum 
Brain  2015;138(5):1370-1381.
Murray et al. examine the correspondence between Thal amyloid phase, tau pathology and clinical characteristics in a large Alzheimer’s disease autopsy series. They extrapolate their findings to an autopsy cohort for which Pittsburgh compound-B imaging data are available, and evaluate the neuropathological significance of a quantitative amyloid-β imaging cut-off point.
Murray et al. examine the correspondence between Thal amyloid phase, tau pathology and clinical characteristics in a large Alzheimer’s disease autopsy series. They extrapolate their findings to an autopsy cohort for which Pittsburgh compound-B imaging data are available, and evaluate the neuropathological significance of a quantitative amyloid-β imaging cut-off point.
Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer’s disease, was incorporated into the latest National Institute of Ageing – Alzheimer’s Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer’s disease dementia published by the National Institute of Ageing – Alzheimer’s Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem 11C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of 11C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. 11C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical 11C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer’s disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer’s disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted 11C-Pittsburgh compound B standard uptake value ratio. In the 35 cases with ante-mortem amyloid imaging, a transition between Thal amyloid phases 1 to 2 seemed to correspond to 11C-Pittsburgh compound B standard uptake value ratio of 1.4, which when using our pipeline is the cut-off point for detection of clear amyloid-positivity regardless of clinical diagnosis. Alzheimer’s disease cases who were older and were APOE-ε4 negative tended to have lower amyloid phases. Although Thal amyloid phase predicted clinical characteristics of Alzheimer’s disease patients, the pre-mortem clinical status was driven by Braak tangle stage. Thal amyloid phase correlated best with 11C-Pittsburgh compound B values, but not Braak tangle stage or cerebral amyloid angiopathy. The 11C-Pittsburgh compound B cut-off point value of 1.4 was approximately equivalent to a Thal amyloid phase of 1–2.
PMCID: PMC4407190  PMID: 25805643
Alzheimer’s disease; neuropathology; Thal amyloid phase; Pittsburgh compound B; Braak tangle stage
19.  TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia 
Acta neuropathologica  2014;127(3):397-406.
Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions (with or without motor neuron disease [MND]; cohort 2), and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls (11.9% versus 19.1%, odds ratio (OR): 0.57, p=0.014; same direction as carriers of GRN mutations). The strongest evidence was provided by FTD patients (OR: 0.33, p=0.009) followed by FTD/MND patients (OR: 0.38, p=0.017), whereas no significant difference was observed in MND patients (OR: 0.85, p=0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR: 0.77, p=0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR: 0.26, p<0.001).
Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations, and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.
PMCID: PMC3944829  PMID: 24385136
C9ORF72; TMEM106B; frontotemporal dementia; motor neuron disease; amyotrophic lateral sclerosis; disease modifier
20.  Hypothyroidism and Risk of Mild Cognitive Impairment in Elderly Persons - A Population Based Study 
JAMA neurology  2014;71(2):201-207.
Association of clinical and subclinical hypothyroidism with mild cognitive impairment (MCI) is not established.
To evaluate the association of clinical and subclinical hypothyroidism with MCI in a large population based cohort.
A cross-sectional, population-based study.
Olmsted County, Minnesota.
Randomly selected participants were aged 70 to 89 years on October 1, 2004, and were without documented prevalent dementia. A total of 2,050 participants were evaluated and underwent in-person interview, neurological evaluation and neuropsychological testing to assess performance in memory, attention/executive function, visuospatial, and language domains. Subjects were diagnosed by consensus as cognitively normal, MCI or dementia according to published criteria. Clinical and subclinical hypothyroidism was ascertained from a medical records-linkage system.
Association of clinical and subclinical hypothyroidism with MCI.
Among 1904 eligible participants, the frequency of MCI was 16% in 1450 subjects with normal thyroid function, 17% in 313 subjects with clinical hypothyroidism, and 18% in 141 subjects with subclinical hypothyroidism. After adjusting for covariates (age, gender, education, education years, sex, ApoE ε 4, depression, diabetes, hypertension, stroke, BMI and coronary artery disease) we found no significant association between clinical or subclinial hypothyroidism and MCI [OR 0.99 (95% CI 0.66–1.48) and OR 0.88 (95% CI 0.38–2.03) respectively]. No effect of gender interaction was seen on these effects. In stratified analysis, the odds of MCI with clinical and subclinical hypothyroidisn among males was 1.02 (95%CI, 0.57–1.82) and 1.29 (95%CI 0.68–2.44), among females was 1.04 (95% 0.66–1.66) and 0.86 (95% CI 0.37–2.02) respectively.
In this population based cohort of eldery, neither clinical nor subclinical hypothyrpodism was associated with MCI. Our findings need to be validated in a separate settings using the published criteria for MCI and also confirmed in a longitudinal study.
PMCID: PMC4136444  PMID: 24378475
21.  Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal 
Neurology  2014;82(4):317-325.
To estimate rates of progression from mild cognitive impairment (MCI) to dementia and of reversion from MCI to being cognitively normal (CN) in a population-based cohort.
Participants (n = 534, aged 70 years and older) enrolled in the prospective Mayo Clinic Study of Aging were evaluated at baseline and every 15 months to identify incident MCI or dementia.
Over a median follow-up of 5.1 years, 153 of 534 participants (28.7%) with prevalent or incident MCI progressed to dementia (71.3 per 1,000 person-years). The cumulative incidence of dementia was 5.4% at 1 year, 16.1% at 2, 23.4% at 3, 31.1% at 4, and 42.5% at 5 years. The risk of dementia was elevated in MCI cases (hazard ratio [HR] 23.2, p < 0.001) compared with CN subjects. Thirty-eight percent (n = 201) of MCI participants reverted to CN (175.0/1,000 person-years), but 65% subsequently developed MCI or dementia; the HR was 6.6 (p < 0.001) compared with CN subjects. The risk of reversion was reduced in subjects with an APOE ε4 allele (HR 0.53, p < 0.001), higher Clinical Dementia Rating Scale–Sum of Boxes (HR 0.56, p < 0.001), and poorer cognitive function (HR 0.56, p < 0.001). The risk was also reduced in subjects with amnestic MCI (HR 0.70, p = 0.02) and multidomain MCI (HR 0.61, p = 0.003).
MCI cases, including those who revert to CN, have a high risk of progressing to dementia. This suggests that diagnosis of MCI at any time has prognostic value.
PMCID: PMC3929198  PMID: 24353333
22.  Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly 
Brain  2015;138(3):761-771.
Vemuri et al. show that amyloid and vascular pathologies are independent processes, and that both are major drivers of cognitive decline in the elderly. Cognitive reserve as measured by educational/occupational level and mid/late-life cognitive activity seems to offset the deleterious effects of both pathologies on cognitive trajectories.
Our primary objective was to investigate a biomarker driven model for the interrelationships between vascular disease pathology, amyloid pathology, and longitudinal cognitive decline in cognitively normal elderly subjects between 70 and 90 years of age. Our secondary objective was to investigate the beneficial effect of cognitive reserve on these interrelationships. We used brain amyloid-β load measured using Pittsburgh compound B positron emission tomography as a marker for amyloid pathology. White matter hyperintensities and brain infarcts were measured using fluid-attenuated inversion recovery magnetic resonance imaging as a marker for vascular pathology. We studied 393 cognitively normal elderly participants in the population-based Mayo Clinic Study of Aging who had a baseline 3 T fluid-attenuated inversion recovery magnetic resonance imaging assessment, Pittsburgh compound B positron emission tomography scan, baseline cognitive assessment, lifestyle measures, and at least one additional clinical follow-up. We classified subjects as being on the amyloid pathway if they had a global cortical amyloid-β load of ≥1.5 standard uptake value ratio and those on the vascular pathway if they had a brain infarct and/or white matter hyperintensities load ≥1.11% of total intracranial volume (which corresponds to the top 25% of white matter hyperintensities in an independent non-demented sample). We used a global cognitive z-score as a measure of cognition. We found no evidence that the presence or absence of vascular pathology influenced the presence or absence of amyloid pathology and vice versa, suggesting that the two processes seem to be independent. Baseline cognitive performance was lower in older individuals, in males, those with lower education/occupation, and those on the amyloid pathway. The rate of cognitive decline was higher in older individuals (P < 0.001) and those with amyloid (P = 0.0003) or vascular (P = 0.0037) pathologies. In those subjects with both vascular and amyloid pathologies, the effect of both pathologies on cognition was additive and not synergistic. For a 79-year-old subject, the predicted annual rate of global z-score decline was −0.02 if on neither pathway, −0.07 if on the vascular pathway, −0.08 if on the amyloid pathway and −0.13 if on both pathways. The main conclusions of this study were: (i) amyloid and vascular pathologies seem to be at least partly independent processes that both affect longitudinal cognitive trajectories adversely and are major drivers of cognitive decline in the elderly; and (ii) cognitive reserve seems to offset the deleterious effect of both pathologies on the cognitive trajectories.
PMCID: PMC4339775  PMID: 25595145
ageing; cognitive neurology; neuroimaging; neuro protective strategies
23.  Head trauma and in vivo measures of amyloid and neurodegeneration in a population-based study 
Neurology  2014;82(1):70-76.
We determined whether head trauma was associated with amyloid deposition and neurodegeneration among individuals who were cognitively normal (CN) or had mild cognitive impairment (MCI).
Participants included 448 CN individuals and 141 individuals with MCI from the Mayo Clinic Study of Aging who underwent Pittsburgh compound B (PiB)-PET, fluorodeoxyglucose-PET, and MRI. Head trauma was defined as a self-reported brain injury with at least momentary loss of consciousness or memory. Regression models examined whether head trauma was associated with each neuroimaging variable (assessed as continuous and dichotomous measures) in both CN and MCI participants, controlling for age and sex.
Among 448 CN individuals, 74 (17%) self-reported a head trauma. There was no difference in any neuroimaging measure between CN subjects with and without head trauma. Of 141 participants with MCI, 25 (18%) self-reported a head trauma. MCI participants with a head trauma had higher amyloid levels (by an average 0.36 standardized uptake value ratio units, p = 0.002).
Among individuals with MCI, but not CN individuals, self-reported head trauma with at least momentary loss of consciousness or memory was associated with greater amyloid deposition, suggesting that head trauma may be associated with Alzheimer disease–related neuropathology. Differences between CN individuals and individuals with MCI raise questions about the relevance of head injury–PET abnormality findings in those with MCI.
PMCID: PMC3873622  PMID: 24371306
24.  The neuropsychology of normal aging and preclinical Alzheimer’s disease 
An NIA-sponsored workgroup on preclinical Alzheimer’s disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD.
71 apolipoprotein E (APOE) e4 homozygotes (HMZ), 194 e3/4 heterozygotes (HTZ), and 356 e4 noncarriers (NC) aged 21–87 years who were cognitively healthy underwent neuropsychological testing every two years. Longitudinal trajectories of test scores were compared between APOE subgroups.
There was a significant effect of age on all cognitive domains in both APOE e4 carriers and NC. A significant effect of APOE e4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross sectional comparisons did not discriminate the groups.
While cognitive aging patterns are similar in APOE e4 carriers and NC, preclinical AD is characterized by a significant e4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory sensitive measures and longitudinal design.
PMCID: PMC3700591  PMID: 23541188
preclinical Alzheimer’s disease; cognitive aging; age-related memory loss; mild cognitive impairment; apolipoprotein E; longitudinal testing
25.  Association of diabetes with amnestic and nonamnestic mild cognitive impairment 
Type 2 diabetes may increase the risk of amnestic mild cognitive impairment (aMCI) through Alzheimer's disease (AD)-related and vascular pathology and may also increase the risk of nonamnestic MCI (naMCI) through vascular disease mechanisms. We examined the association of type 2 diabetes with mild cognitive impairment (MCI) and MCI subtype (aMCI and naMCI) overall and by sex.
Participants were Olmsted County, Minnesota residents (70 years and older) enrolled in a prospective, population-based study. At baseline and every 15 months thereafter, participants were evaluated using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing for a diagnosis of normal cognition, MCI, and dementia by a consensus panel. Type 2 diabetes was ascertained from the medical records of participants at baseline.
Over a median 4.0 years of follow-up, 348 of 1450 subjects developed MCI. Type 2 diabetes was associated (hazard ratio [95% confidence interval]) with MCI (1.39 [1.08–1.79]), aMCI (1.58 [1.17–2.15]; multiple domain: 1.58 [1.01–2.47]; single domain: 1.49 [1.09–2.05]), and the hazard ratio for naMCI was elevated (1.37 [0.84–2.24]). Diabetes was strongly associated with multiple-domain aMCI in men (2.42 [1.31–4.48]) and an elevated risk of multiple domain naMCI in men (2.11 [0.70–6.33]), and with single domain naMCI in women (2.32 [1.04–5.20]).
Diabetes was associated with an increased risk of MCI in elderly persons. The association of diabetes with MCI may vary with subtype, number of domains, and sex. Prevention and control of diabetes may reduce the risk of MCI and Alzheimer's disease.
PMCID: PMC3830601  PMID: 23562428
Mild cognitive impairment; Risk factors; Type 2 diabetes; Incidence; Cohort studies; Population-based studies; Sex differences; Diabetic retinopathy; Diabetic neuropathy

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