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1.  Role of β-amyloidosis and Neurodegeneration in Subsequent Imaging Changes in Mild Cognitive Impairment 
JAMA neurology  2015;72(12):1475-1483.
Importance
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).
Objective
To define the role of β-amyloidosis and neurodegeneration in the subsequent progression of topographic cortical structural and metabolic changes in MCI.
Design
Longitudinal, observational study with serial brain imaging.
Setting
Population-based cohort.
Participants
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.
Results
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.
doi:10.1001/jamaneurol.2015.2323
PMCID: PMC4735877  PMID: 26437123
2.  Spectrum of cognition short of dementia 
Neurology  2015;85(19):1712-1721.
Objective:
To understand the neuropsychological basis of dementia risk among persons in the spectrum including cognitive normality and mild cognitive impairment.
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1212/WNL.0000000000002100
PMCID: PMC4653114  PMID: 26453643
3.  Multimorbidity and Risk of Mild Cognitive Impairment. 
OBJECTIVES
To determine the association of multiple chronic conditions with risk of incident mild cognitive impairment (MCI)/dementia.
DESIGN
Prospective cohort study
SETTING
Olmsted County, Minnesota.
PARTICIPANTS
Cognitively normal individuals (N=2,176) enrolled in the Mayo Clinic Study of Aging (MCSA).
MEASUREMENTS
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.
RESULTS
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).
CONCLUSION
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.
doi:10.1111/jgs.13612
PMCID: PMC4607039  PMID: 26311270
mild cognitive impairment; dementia; multimorbidity
4.  Performance of the CogState computerized battery in the Mayo Clinic Study on Aging 
Background
The feasibility and validity of brief computerized cognitive batteries at the population-level are unknown.
Methods
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.
Results
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.
Conclusions
The computerized CogState battery, especially the iPad, was feasible, acceptable, and valid in the population.
doi:10.1016/j.jalz.2015.01.008
PMCID: PMC4595161  PMID: 25858683
Computerized cognitive battery; Epidemiology; Neuropsychology; Cognitively normal; Mild cognitive impairment; Population-based cohort study
6.  Sample size calculations for clinical trials targeting tauopathies: A new potential disease target 
Journal of neurology  2015;262(9):2064-2072.
Disease-modifying therapies are being developed to target tau pathology, and should, therefore, be tested in primary tauopathies. We propose that progressive apraxia of speech should be considered one such target group. In this study, we investigate potential neuroimaging and clinical outcome measures for progressive apraxia of speech and determine sample size estimates for clinical trials. We prospectively recruited 24 patients with progressive apraxia of speech who underwent two serial MRI with an interval of approximately two years. Detailed speech and language assessments included the Apraxia of Speech Rating Scale (ASRS) and Motor Speech Disorders (MSD) severity scale. Rates of ventricular expansion and rates of whole brain, striatal and midbrain atrophy were calculated. Atrophy rates across 38 cortical regions were also calculated and the regions that best differentiated patients from controls were selected. Sample size estimates required to power placebo-controlled treatment trials were calculated. The smallest sample size estimates were obtained with rates of atrophy of the precentral gyrus and supplementary motor area, with both measures requiring less than 50 subjects per arm to detect a 25% treatment effect with 80% power. These measures outperformed the other regional and global MRI measures and the clinical scales. Regional rates of cortical atrophy therefore provide the best outcome measures in progressive apraxia of speech. The small sample size estimates demonstrate feasibility for including progressive apraxia of speech in future clinical treatment trials targeting tau.
doi:10.1007/s00415-015-7821-5
PMCID: PMC4573830  PMID: 26076744
Clinical treatment trials; tau; rates; MRI; apraxia of speech; PPAOS
7.  Classification and clinicoradiologic features of primary progressive aphasia (PPA) and apraxia of speech 
The consensus criteria for the diagnosis and classification of primary progressive aphasia (PPA) have served as an important tool in studying this group of disorders. However, a large proportion of patients remain unclassifiable whilst others simultaneously meet criteria for multiple subtypes. We prospectively evaluated a large cohort of patients with degenerative aphasia and/or apraxia of speech using multidisciplinary clinical assessments and multimodal imaging. Blinded diagnoses were made using operational definitions with important differences compared to the consensus criteria. Of the 130 included patients, 40 were diagnosed with progressive apraxia of speech (PAOS), 12 with progressive agrammatic aphasia, 9 with semantic dementia, 52 with logopenic progressive aphasia, and 4 with progressive fluent aphasia, while 13 were unclassified. The PAOS and progressive fluent aphasia groups were least impaired. Performance on repetition and sentence comprehension was especially poor in the logopenic group. The semantic and progressive fluent aphasia groups had prominent anomia, but only semantic subjects had loss of word meaning and object knowledge. Distinct patterns of grey matter loss and white matter changes were found in all groups compared to controls. PAOS subjects had bilateral frontal grey matter loss, including the premotor and supplementary motor areas, and bilateral frontal white matter involvement. The agrammatic group had more widespread, predominantly left sided grey matter loss and white matter abnormalities. Semantic subjects had bitemporal grey matter loss and white matter changes, including the uncinate and inferior occipitofrontal fasciculi, whereas progressive fluent subjects only had left sided temporal involvement. Logopenic subjects had diffuse and bilateral grey matter loss and diffusion tensor abnormalities, maximal in the posterior temporal region. A diagnosis of logopenic aphasia was strongly associated with being amyloid positive, (46/52 positive). Our findings support consideration of an alternative way of identifying and categorizing subtypes of degenerative speech and language disorders.
doi:10.1016/j.cortex.2015.05.013
PMCID: PMC4522343  PMID: 26103600
Primary progressive aphasia; Progressive apraxia of speech; Volumetric based morphometry; Diffusion tensor imaging; Amyloid PET imaging
8.  Dominant Frontotemporal Dementia Mutations in 140 Cases of Primary Progressive Aphasia and Speech Apraxia 
Background
Mutations in three genes [chromosome 9 open-reading-frame 72 (C9ORF72); microtubule-associated protein tau (MAPT) and progranulin (GRN)] account for the vast majority of familial, and a proportion of sporadic, frontotemporal dementia (FTD) cases. Progressive apraxia of speech (PAOS) is a type of FTD characterized by speech production deficits without a known cause.
Methods
We therefore assessed for genetic mutations in C9ORF72, MAPT and GRN in 40 prospectively recruited PAOS patients. For comparison, we also assessed these mutations in 100 patients with primary progressive aphasia (PPA), including logopenic PPA (n = 54), nonfluent/agrammatic PPA (n = 17), semantic PPA (n = 16), and unclassifiable PPA (n = 13).
Results
The mean age at onset of PAOS patients was 66.7 years (± 9.3); 50% were women. Ten patients (25%) had ≥1 first-degree relative with a neurodegenerative disease. No mutations were found in any PAOS patient. In comparison, 36% of the PPA patients had a family history and 5 (5%) had a genetic mutation detected: MAPT (n = 0), GRN (n = 3) and C9ORF72 (n = 2).
Conclusions
Although limited by an overrepresentation of logopenic PPA, which frequently predicts Alzheimer’s disease pathology, this study suggests that mutations in the three genes most commonly associated with FTD are not associated with PAOS and are rarely associated with PPA.
doi:10.1159/000375299
PMCID: PMC4879710  PMID: 25765123
Genetics; C9ORF72; MAPT; Progranulin; Apraxia of speech; Semantic dementia; Logopenic progressive aphasia; Progressive nonfluent aphasia; PPA
9.  Risk and protective factors for cognitive impairment in persons aged 85 years and older 
Neurology  2015;84(18):1854-1861.
Objective:
To determine risk and protective factors for mild cognitive impairment (MCI) among persons 85 years and older.
Methods:
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.
Results:
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).
Conclusions:
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.
doi:10.1212/WNL.0000000000001537
PMCID: PMC4433468  PMID: 25854867
10.  Age, sex and APOE ε4 effects on memory, brain structure and β-amyloid across the adult lifespan 
JAMA neurology  2015;72(5):511-519.
Importance
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.
Objective
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
Results
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.
doi:10.1001/jamaneurol.2014.4821
PMCID: PMC4428984  PMID: 25775353
Cognitive Aging; Amyloid Imaging; Alzheimer Disease; Memory Performance; Brain Atrophy
11.  White Matter Integrity on DTI, Amyloid Load, and Neurodegeneration in Non-demented Elderly 
JAMA neurology  2014;71(12):1547-1554.
Importance
Pathophysiologic mechanisms leading to loss of white matter (WM) integrity and the temporal positioning of biomarkers of WM integrity relative to the biomarkers of gray matter (GM) neurodegeneration and amyloid load in the course of AD are poorly understood.
Objective
To investigate the effects of Alzheimer’s disease (AD)-related GM neurodegeneration and high β-amyloid on white matter (WM) microstructure in non-demented older adults.
Design
Longitudinal cohort study
Setting
Population-based Mayo Clinic Study of Aging.
Participants
Participants (n=701) with MRI/DTI and PET studies diagnosed as cognitively normal (CN; n=570) or mild cognitive impairment (MCI; n=131) were included. CN and MCI subjects were divided into biomarker-negative, amyloid- positive only, neurodegeneration- positive only, and amyloid plus neurodegeneration-positive groups based on their amyloid load on 11C-Pittsburgh compound-B PET, AD hypometabolic pattern on 18F-fluorodeoxyglucose PET and/or hippocampal atrophy on MRI.
Main Outcome Measure
Fractional anisotrophy (FA) from diffusion tensor imaging (DTI)
Results
No FA alterations were observed in biomarker-negative MCI, and amyloid-positive only CN and MCI groups. Conversely, neurodegeneration-positive only and amyloid plus neurodegeneration- positive CN and MCI groups consistently had decreased FA in the fornix, which correlated with cognitive performance (Rho=0.38; p<0.001). Patients with MCI had more extensive WM involvement than CN subjects, and greatest FA decreases were observed in the amyloid plus neurodegeneration-positive MCI group.
Conclusions and Relevance
High amyloid load does not influence DTI-based measures of WM integrity in the absence of co-existent GM neurodegeneration in non-demented older adults.
doi:10.1001/jamaneurol.2014.1482
PMCID: PMC4810441  PMID: 25347157
Diffusion tensor imaging; mild cognitive impairment; preclinical Alzheimer’s disease
12.  Neuropsychiatric symptoms, APOE ε4, and the risk of incident dementia 
Neurology  2015;84(9):935-943.
Objective:
To investigate the population-based interaction between a biological variable (APOE ε4), neuropsychiatric symptoms, and the risk of incident dementia among subjects with prevalent mild cognitive impairment (MCI).
Methods:
We prospectively followed 332 participants with prevalent MCI (aged 70 years and older) enrolled in the Mayo Clinic Study of Aging for a median of 3 years. The diagnoses of MCI and dementia were made by an expert consensus panel based on published criteria, after reviewing neurologic, cognitive, and other pertinent data. Neuropsychiatric symptoms were determined at baseline using the Neuropsychiatric Inventory Questionnaire. We used Cox proportional hazards models, with age as a time scale, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Models were adjusted for sex, education, and medical comorbidity.
Results:
Baseline agitation, nighttime behaviors, depression, and apathy significantly increased the risk of incident dementia. We observed additive interactions between APOE ε4 and depression (joint effect HR = 2.21; 95% CI = 1.24–3.91; test for additive interaction, p < 0.001); and between APOE ε4 and apathy (joint effect HR = 1.93; 95% CI = 0.93–3.98; test for additive interaction, p = 0.031). Anxiety, irritability, and appetite/eating were not associated with increased risk of incident dementia.
Conclusions:
Among prevalent MCI cases, baseline agitation, nighttime behaviors, depression, and apathy elevated the risk of incident dementia. There was a synergistic interaction between depression or apathy and APOE ε4 in further elevating the risk of incident dementia.
doi:10.1212/WNL.0000000000001307
PMCID: PMC4351664  PMID: 25653291
13.  Working memory and language network dysfunction in logopenic aphasia: a task-free fMRI comparison to Alzheimer’s dementia 
Neurobiology of aging  2014;36(3):1245-1252.
We aimed to determine whether network-level functional connectivity differs in two clinical variants of Alzheimer’s disease: logopenic primary progressive aphasia (lvPPA) and dementia of the Alzheimer’s type (DAT). Twenty-four lvPPA subjects with amyloid deposition on PET and task-free fMRI were matched to 24 amyloid-positive DAT subjects and 24 amyloid-negative controls. Independent-component analysis and spatial-temporal dual-regression were used to assess functional connectivity within the language network, left and right working memory networks and ventral default mode network. lvPPA showed reduced connectivity in left temporal language network and inferior parietal and prefrontal regions of the left working memory network compared to controls and DAT. Both groups showed reduced connectivity in parietal regions of the right working memory network compared to controls. Only DAT showed reduced ventral default mode network connectivity compared to controls. Aphasia severity correlated with connectivity in left working memory network within lvPPA. Patterns of network dysfunction differ across these two clinical variants of Alzheimer’s disease, with lvPPA particularly associated with disruptions in the language and left working memory networks.
doi:10.1016/j.neurobiolaging.2014.12.013
PMCID: PMC4346438  PMID: 25592958
Alzheimer’s disease; primary progressive aphasia; language; MRI; functional imaging
14.  Clinical and neuroimaging biomarkers of amyloid-negative logopenic primary progressive aphasia 
Brain and language  2015;142:45-53.
Logopenic primary progressive aphasia (lvPPA) is a progressive language disorder characterized by anomia, difficulty repeating complex sentences, and phonological errors. The majority, although not all, lvPPA patients have underlying Alzheimer’s disease. We aimed to determine whether clinical or neuroimaging features differ according to the deposition of Aβ on Pittsburgh-compound B PET in lvPPA. Clinical features, patterns of atrophy on MRI, hypometabolism on FDG-PET, and white matter tract degeneration were compared between six PiB-negative and 20 PiB-positive lvPPA patients. PiB-negative patients showed more asymmetric left-sided patterns of atrophy, hypometabolism and white matter tract degeneration, with greater left anteromedial temporal and medial prefrontal involvement, than PiB-positive patients. PiB-positive patients showed greater involvement of right temporoparietal and frontal lobes. There was very little evidence for clinical differences between the groups. Strikingly asymmetric neuroimaging findings with relatively preserved right hemisphere may provide clues that AD pathology is absent in lvPPA.
doi:10.1016/j.bandl.2015.01.009
PMCID: PMC4380294  PMID: 25658633
logopenic; primary progressive aphasia; Pittsburgh Compound B; magnetic resonance imaging; FDG-PET; progranulin; beta-amyloid
15.  Neuropsychiatric symptoms in primary progressive aphasia and apraxia of speech 
Aim
To conduct a prospective analysis of the neuropsychiatric symptoms(NPS) across the three categories of primary progressive aphasia(PPA) and apraxia of speech(PPAOS), to compare the prevalence and nature of the symptoms, and look at which symptoms could be helpful to better differentiate these PPA and PPAOS categories.
Methods
106 consecutive patients with a diagnosis of semantic variant{svPPA}(13), logopenic variant{lvPPA}(37), agrammatic variant{agPPA}(15) or PPAOS(41), were included in this prospective study. The NPS were measured by the Neuropsychiatric Inventory Questionnaire (NPI-Q).
Results
There were 65 patients with PPA and 41 with PPAOS diagnosis. The most distinguishing features between the two groups were anxiety, apathy, aberrant motor behavior and appetite, while among the subtypes of PPA were disinhibition and appetite changes. PPA and PPAOS patients initially exhibited depression but with increase in disease duration, the PPAOS patients showed apathy (55.5%) while the PPA patients showed disinhibition (28.6%) and aberrant motor behavior (14.3%).
Conclusion
Mood symptoms like anxiety and appetite changes are more likely to be present in initial stages of PPA whereas behavioral symptoms like aberrant motor behavior and apathy are likely to occur in PPAOS. The NPS seems to evolve with the progression of the disease in both PPA and PPAOS.
doi:10.1159/000369062
PMCID: PMC4464666  PMID: 25613190
neuropsychiatric symptoms; primary progressive aphasia; primary progressive apraxia of speech
16.  Clinical and MRI models predicting amyloid deposition in progressive aphasia and apraxia of speech 
NeuroImage : Clinical  2016;11:90-98.
Beta-amyloid (Aβ) deposition can be observed in primary progressive aphasia (PPA) and progressive apraxia of speech (PAOS). While it is typically associated with logopenic PPA, there are exceptions that make predicting Aβ status challenging based on clinical diagnosis alone. We aimed to determine whether MRI regional volumes or clinical data could help predict Aβ deposition. One hundred and thirty-nine PPA (n = 97; 15 agrammatic, 53 logopenic, 13 semantic and 16 unclassified) and PAOS (n = 42) subjects were prospectively recruited into a cross-sectional study and underwent speech/language assessments, 3.0 T MRI and C11-Pittsburgh Compound B PET. The presence of Aβ was determined using a 1.5 SUVR cut-point. Atlas-based parcellation was used to calculate gray matter volumes of 42 regions-of-interest across the brain. Penalized binary logistic regression was utilized to determine what combination of MRI regions, and what combination of speech and language tests, best predicts Aβ (+) status. The optimal MRI model and optimal clinical model both performed comparably in their ability to accurately classify subjects according to Aβ status. MRI accurately classified 81% of subjects using 14 regions. Small left superior temporal and inferior parietal volumes and large left Broca's area volumes were particularly predictive of Aβ (+) status. Clinical scores accurately classified 83% of subjects using 12 tests. Phonological errors and repetition deficits, and absence of agrammatism and motor speech deficits were particularly predictive of Aβ (+) status. In comparison, clinical diagnosis was able to accurately classify 89% of subjects. However, the MRI model performed well in predicting Aβ deposition in unclassified PPA. Clinical diagnosis provides optimum prediction of Aβ status at the group level, although regional MRI measurements and speech and language testing also performed well and could have advantages in predicting Aβ status in unclassified PPA subjects.
Highlights
•We examine whether MRI or clinical data can predict Aβ deposition in PPA and PAOS.•MRI and clinical data accurately classified 81% and 83% of subjects, respectively.•Small superior temporal gyri and phonological errors best predicted Aβ deposition.•In comparison, clinical diagnosis accurately classified 89% of subjects.•MRI and clinical data could predict discordant svPPA, lvPPA and unclassified cases.
doi:10.1016/j.nicl.2016.01.014
PMCID: PMC4752814  PMID: 26937376
Beta-amyloid; Primary progressive aphasia; Apraxia of speech; Volumetric MRI
17.  Late-Onset Alzheimer Risk Variants in Memory Decline, Incident Mild Cognitive Impairment and Alzheimer Disease 
Neurobiology of aging  2014;36(1):60-67.
Background
Genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) identified risk variants. We assessed the association of nine variants with memory and progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD).
Methods
Older Caucasians, cognitively normal at baseline and longitudinally evaluated at Mayo Clinic Rochester and Jacksonville, were assessed for associations of genetic variants with memory decline (n=2,262) using linear mixed models and for incident MCI/LOAD (n=2,674) with Cox proportional hazards models. Each variant was tested both individually and collectively using a single weighted risk score.
Results
APOE-ε4 was significantly associated with worse memory at baseline (β=-0.88, p=2.78E-03) and increased rate of 5-year decline (β=-1.43, p=3.71E-06) with highly significant overall effect on memory (p=3.88E-09). CLU-locus risk allele rs11136000-G was associated with worse memory at baseline (β=-0.51, p=0.012), but not with increased rate of decline. CLU allele was also associated with incident MCI/LOAD (hazard ratio=HR=1.14, p=0.049) in sensitivity analysis. MS4A6A-locus risk allele rs610932-C was associated with increased incident MCI/LOAD in primary analysis (HR=1.17, p=0.016) and had suggestive association with lower baseline memory (β=-0.35, p=0.08). PICALM-locus risk allele rs3851179-G had nominally significant HR in both primary and sensitivity analysis, but with a protective estimate. LOAD risk alleles ABCA7-rs3764650-C and EPHA1-rs11767557-A associated with increased rates of memory decline in the subset of subjects with a final diagnosis of MCI/LOAD. Risk scores excluding APOE were not significant, whereas APOE-inclusive risk scores associated with worse memory and incident MCI/LOAD.
Conclusions
The collective influence of the nine top LOAD GWAS variants on memory decline and progression to MCI/LOAD appears limited. Given the significant associations observed with APOE-ε4, discovery of the biologically functional variants at these loci may uncover stronger effects on memory and incident disease.
doi:10.1016/j.neurobiolaging.2014.07.042
PMCID: PMC4268433  PMID: 25189118
Alzheimer's disease; memory; mild cognitive impairment; genetic risk; association; cognitive decline
18.  Independent comparison of CogState computerized testing and a standard cognitive battery with neuroimaging 
Background
Inexpensive, non-invasive tools for assessing Alzheimer-type pathophysiologies are needed. Computerized cognitive assessments are prime candidates.
Methods
Cognitively normal participants, aged 51-71, with MRI, FDG-PET, amyloid PET, CogState computerized cognitive assessment, and standard neuropsychological tests were included. We first examined the association between the CogState battery and neuroimaging measures. We then compared that association to the one between standard neuropsychological z-scores and neuroimaging.
Results
Slower reaction times for CogState Identification and One Back, and lower memory and attention z-scores, were associated (P<.05) with FDG-PET hypometabolism. Slower time on the Groton Maze Learning Task and worse One Card Learning accuracy were associated (P<.05) with smaller hippocampal volumes. There were no associations with amyloid PET. Associations of CogState and neuropsychological z-scores with neuroimaging were small and of a similar magnitude.
Conclusions
CogState subtests were cross-sectionally comparable to standard neuropsychological tests in their relatively weak associations with neurodegeneration imaging markers.
doi:10.1016/j.jalz.2014.09.001
PMCID: PMC4273919  PMID: 25458308
Preclinical Alzheimer's disease; Neuropsychology; Computerized cognitive battery; Neuroimaging; Amyloid-beta; Hippocampal volume
19.  APOE4 influences β-amyloid burden in primary progressive aphasia and speech apraxia 
Background
Apolipoprotein E epsilon 4 (APOE4) is a risk factor for β-amyloid deposition in Alzheimer’s dementia. Its influence on β-amyloid deposition in speech and language disorders, including primary progressive aphasia (PPA), is unclear.
Methods
One hundred and thirty subjects with PPA or speech apraxia underwent APOE genotyping and Pittsburgh compound B (PiB) PET scanning. The relationship between APOE4 and PiB status, as well as severity and regional distribution of PiB, was assessed.
Results
Forty-five subjects had an APOE4 allele and 60 subjects were PiB-positive. The odds ratio for a subject with APOE4 being PiB-positive compared to a subject without APOE4 being PiB-positive was 10.2 (4.4–25.5, p<0.0001). APOE4 status did not influence regional PiB distribution or severity.
Conclusion
APOE4 increases the risk of β-amyloid deposition in PPA and speech apraxia, but does not influence regional β-amyloid distribution or severity.
doi:10.1016/j.jalz.2014.03.004
PMCID: PMC4254054  PMID: 24985533
Apolipoprotein; Pittsburgh Compound B; primary progressive aphasia; logopenic aphasia; speech apraxia
20.  Diabetes is Associated with Worse Executive Function in both Eastern and Western populations: Shanghai Aging Study and Mayo Clinic Study of Aging 
Background and Objectives
It remains unknown whether the association between diabetes mellitus (DM) and cognitive function differs in Eastern and Western populations. This study aimed to elucidate whether DM is associated with worse cognitive performance in both populations.
Methods
The Shanghai Aging Study (SAS) and the Mayo Clinic Study of Aging (MCSA) are two population-based studies with similar design and methodology in Shanghai, China and Rochester, MN USA. Non-demented participants underwent cognitive testing, and DM was assessed from the medical record. Separate analyses were performed in SAS and MCSA regarding the association between DM and cognitive performance.
Results
A total of 3348 Chinese participants in the SAS and 3734 American subjects in the MCSA were included. Compared with MCSA subjects, SAS participants were younger, less educated, and had lower frequency of vascular disease, APOE ε4 carriers and obesity. Participants with DM (compared to non-DM participants) performed significantly worse on all the cognitive domains in both the SAS and MCSA. After adjustment for age, sex and education, and vascular covariates, DM was associated with worse performance in executive function (β= −0.15, p = 0.001 for SAS, and β= −0.10, p = 0.008 for MCSA) in the total sample and in the cognitively normal sub-sample. Furthermore, DM was associated with poor performance in visuospatial skills, language, and memory in the SAS, but not in the MCSA.
Conclusions
Diabetes is associated with cognitive dysfunction, in particular exerts a negative impact on executive function regardless of race, age and prevalence of vascular risk factors.
doi:10.3233/JAD-150073
PMCID: PMC4617674  PMID: 26402765
cognition; diabetes mellitus; executive function; cross-sectional studies
21.  The evolution of primary progressive apraxia of speech 
Brain  2014;137(10):2783-2795.
Josephs et al. use a multi-modal approach to assess neuroanatomical and clinical changes over time in primary progressive apraxia of speech. They demonstrate that progressive atrophy of cortex, basal ganglia and midbrain accompanies the clinical progression, including the emergence of progressive supranuclear palsy five years post-onset in some subjects.
Primary progressive apraxia of speech is a recently described neurodegenerative disorder in which patients present with an isolated apraxia of speech and show focal degeneration of superior premotor cortex. Little is known about how these individuals progress over time, making it difficult to provide prognostic estimates. Thirteen subjects with primary progressive apraxia of speech underwent two serial comprehensive clinical and neuroimaging evaluations 2.4 years apart [median age of onset = 67 years (range: 49–76), seven females]. All underwent detailed speech and language, neurological and neuropsychological assessments, and magnetic resonance imaging, diffusion tensor imaging and 18F-fluorodeoxyglucose positron emission tomography at both baseline and follow-up. Rates of change of whole brain, ventricle, and midbrain volumes were calculated using the boundary-shift integral and atlas-based parcellation, and rates of regional grey matter atrophy were assessed using tensor-based morphometry. White matter tract degeneration was assessed on diffusion-tensor imaging at each time-point. Patterns of hypometabolism were assessed at the single subject-level. Neuroimaging findings were compared with a cohort of 20 age, gender, and scan-interval matched healthy controls. All subjects developed extrapyramidal signs. In eight subjects the apraxia of speech remained the predominant feature. In the other five there was a striking progression of symptoms that had evolved into a progressive supranuclear palsy-like syndrome; they showed a combination of severe parkinsonism, near mutism, dysphagia with choking, vertical supranuclear gaze palsy or slowing, balance difficulties with falls and urinary incontinence, and one was wheelchair bound. Rates of whole brain atrophy (1.5% per year; controls = 0.4% per year), ventricular expansion (8.0% per year; controls = 3.3% per year) and midbrain atrophy (1.5% per year; controls = 0.1% per year) were elevated (P ≤ 0.001) in all 13, compared to controls. Increased rates of brain atrophy over time were observed throughout the premotor cortex, as well as prefrontal cortex, motor cortex, basal ganglia and midbrain, while white matter tract degeneration spread into the splenium of the corpus callosum and motor cortex white matter. Hypometabolism progressed over time in almost all subjects. These findings demonstrate that some subjects with primary progressive apraxia of speech will rapidly evolve and develop a devastating progressive supranuclear palsy-like syndrome ∼ 5 years after onset, perhaps related to progressive involvement of neocortex, basal ganglia and midbrain. These findings help improve our understanding of primary progressive apraxia of speech and provide some important prognostic guidelines.
doi:10.1093/brain/awu223
PMCID: PMC4229741  PMID: 25113789
non-fluent speech; parkinsonism; progressive supranuclear palsy; disease progression; magnetic resonance imaging
22.  Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings 
Brain  2015;138(12):3747-3759.
In a cross-sectional imaging study of 1331 cognitively non-impaired subjects aged 50–89, Jack et al. assess the consequences of defining neurodegeneration in five different ways on demographic associations with neurodegeneration, and on amyloidosis and neurodegeneration biomarker status by age. Different neurodegeneration measures provide similar but not completely redundant information.
In a cross-sectional imaging study of 1331 cognitively non-impaired subjects aged 50–89, Jack et al. assess the consequences of defining neurodegeneration in five different ways on demographic associations with neurodegeneration, and on amyloidosis and neurodegeneration biomarker status by age. Different neurodegeneration measures provide similar but not completely redundant information.
We recently demonstrated that the frequencies of biomarker groups defined by the presence or absence of both amyloidosis (A+) and neurodegeneration (N+) changed dramatically by age in cognitively non-impaired subjects. Our present objectives were to assess the consequences of defining neurodegeneration in five different ways on the frequency of subjects classified as N+, on the demographic associations with N+, and on amyloidosis and neurodegeneration (A/N) biomarker group frequencies by age. This was a largely cross-sectional observational study of 1331 cognitively non-impaired subjects aged 50–89 drawn from a population-based study of cognitive ageing. We assessed demographic associations with N+, and A/N biomarker group frequencies by age where A+ was defined by amyloid PET and N+ was defined in five different ways: (i) abnormal adjusted hippocampal volume alone; (ii) abnormal Alzheimer’s disease signature cortical thickness alone; (iii) abnormal fluorodeoxyglucose positron emission tomography alone; (iv) abnormal adjusted hippocampal volume or abnormal fluorodeoxyglucose positron emission tomography; and (v) abnormal Alzheimer’s disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography. For each N+ definition, participants were assigned to one of four biomarker groups; A−N−, A+N−, A−N+, or A+N+. The three continuous individual neurodegeneration measures were moderately correlated (rs = 0.42 to 0.54) but when classified as normal or abnormal had only weak agreement (κ = 0.20 to 0.29). The adjusted hippocampal volume alone definition classified the fewest subjects as N+ while the Alzheimer’s disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography definition classified the most as N+. Across all N+ definitions, N+ subjects tended to be older, more often male and APOE4 carriers, and performed less well on functional status and learning and memory than N− subjects. For all definitions of neurodegeneration, (i) the frequency of A−N− was 100% at age 50 and declined monotonically thereafter; (ii) the frequency of A+N− increased from age 50 to a maximum in the mid-70s and declined thereafter; and3 (iii) the frequency of A−N+ (suspected non-Alzheimer’s pathophysiology) and of A+N+ increased monotonically beginning in the mid-50s and mid-60s, respectively. Overall, different neurodegeneration measures provide similar but not completely redundant information. Despite quantitative differences, the overall qualitative pattern of the A−N−, A+N−, A−N+, and A+N+ biomarker group frequency curves by age were similar across the five different definitions of neurodegeneration. We conclude that grouping subjects by amyloidosis and neurodegeneration status (normal/abnormal) is robust to different imaging definitions of neurodegeneration and thus is a useful way for investigators throughout the field to communicate in a common classification framework.
doi:10.1093/brain/awv283
PMCID: PMC4655341  PMID: 26428666
cognitive ageing; amyloid imaging; Alzheimer’s disease; preclinical Alzheimer’s disease; amyloid and neurodegeneration
23.  Identification of an atypical variant of logopenic progressive aphasia 
Brain and language  2013;127(2):10.1016/j.bandl.2013.02.007.
The purpose of this study was to examine the association between aphasia severity and neurocognitive function, disease duration and temporoparietal atrophy in 21 individuals with the logopenic variant of primary progressive aphasia (lvPPA). We found significant correlations between aphasia severity and neurocognitive severity as well as temporoparietal atrophy; but not disease duration. Cluster analysis identified three variants of lvPPA: (1) subjects with mild aphasia and short disease duration (mild typical lvPPA); (2) subjects with mild aphasia and long disease duration (mild atypical lvPPA); and, (3) subjects with severe aphasia and relatively long disease duration (severe typical lvPPA). All three variants showed temporoparietal atrophy, with the mild atypical group showing the least atrophy despite the longest disease duration. The mild atypical group also showed mild neuropsychological impairment. The subjects with mild aphasia and neuropsychological impairment despite long disease duration may represent a slowly progressive variant of lvPPA.
doi:10.1016/j.bandl.2013.02.007
PMCID: PMC3725183  PMID: 23566690
Primary progressive aphasia; Logopenic aphasia; Neurocognitive impairment; Temporoparietal atrophy; Voxel-based morphometry
24.  Practice effects and longitudinal cognitive change in normal aging vs. incident mild cognitive impairment and dementia in the Mayo Clinic Study of Aging 
The Clinical neuropsychologist  2013;27(8):10.1080/13854046.2013.836567.
The objective of this study was to examine practice effects and longitudinal cognitive change in a population based cohort classified as clinically normal at their initial evaluation. We examined 1390 individuals with a median age of 78.1 years and re-evaluated them up to four times at approximate 15 month intervals, with an average follow-up time of five years. Of the 1390 participants, 947 (69%) individuals remained cognitively normal, 397 (29%) progressed to mild cognitive impairment (MCI), and 46 (3%) to dementia. The stable normal group showed an initial practice effect in all domains which was sustained in memory and visuospatial reasoning. There was only a slight decline in attention and language after visit 3. We combined individuals with incident MCI and dementia to form one group representing those who declined. The incident MCI/dementia group showed an unexpected practice effect in memory from baseline to visit 2, with a significant decline thereafter. This group did not demonstrate practice effects in any other domain and showed a downward trajectory in all domains at each evaluation. Modeling cognitive change in an epidemiologic sample may serve as a useful benchmark for evaluating cognitive change in future intervention studies.
doi:10.1080/13854046.2013.836567
PMCID: PMC3869900  PMID: 24041121
Cognition; memory; practice effects; mild cognitive impairment; Alzheimer’s disease
25.  Amyloid Burden Correlates with Cognitive Decline in Alzheimer’s Disease Presenting with Aphasia 
Background
A subset of patients with Alzheimer’s disease (AD) present with early and prominent language deficits. It is unclear whether the burden of underlying β-amyloid pathology is associated with language or general cognitive impairment in these subjects.
Methods
Here, we assess the relationship between cortical β-amyloid burden on [11C]Pittsburgh compound B (PiB) PET and performance on the Montreal Cognitive Assessment (MoCA), the Wechsler Memory Scale-Third Edition (WMS-III), the Boston Naming Test (BNT), and the Western Aphasia Battery (WAB) using regression and correlation analyses in subjects presenting with aphasia that showed β-amyloid deposition on PiB PET.
Results
The global PiB ratio was inversely correlated with MoCA (p = 0.02) and the WMS-III Visual Reproduction (VR) subtest (VR I, p = 0.02; VR II, p = 0.04). However, the correlations between PiB ratio, BNT (p = 0.13), WAB aphasia quotient (p = 0.11), and WAB repetition scores (p = 0.34) were not significant.
Conclusion
This study demonstrates that an increased cortical β-amyloid burden is associated with cognitive impairment, but not language deficits, in AD subjects presenting with aphasia. The results suggest that β-amyloid deposition may partly contribute to impaired cognition in such patients while language dysfunction may be influenced by other pathologic mechanisms, perhaps downstream pathways of β-amyloid deposition.
doi:10.1111/ene.12331
PMCID: PMC4057296  PMID: 24330306
Dementia; Aphasia; PET; Beta-amyloid; PiB

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