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1.  Emerging Biomarkers in Cognition 
Clinics in geriatric medicine  2013;29(4):809-828.
Synopsis
The field of aging and dementia is rapidly evolving with the aim of identifying individuals in the earliest stages of disease processes. Biomarkers allow the clinician to demonstrate the presence of an underlying pathologic process and resultant synapse dysfunction and neurodegeneration, even in those earliest stages. For example, PET amyloid imaging and CSF Aβ42 provide direct evidence of amyloid deposition and structural MRI, FDG-PET or SPECT and CSF tau provide indirect evidence of synapse dysfunction and neurodegeneration when the pathologic process is due to Alzheimer's disease (AD). While this review will focus on biomarkers for mild cognitive impairment (MCI) due to AD, structural MRI, FDG-PET or SPECT, and PET with dopamine ligands are also valuable in suggesting non-AD pathologic processes. While these biomarkers are very useful and can even be applied to diagnostic criteria in MCI, several limitations exist. As the field continues to grow, several new biomarkers are emerging and ultimately, a more biological characterization of subjects’ underlying pathophysiologic spectra will be possible.
doi:10.1016/j.cger.2013.07.006
PMCID: PMC3968430  PMID: 24094298
Biomarkers; Dementia; Alzheimer's disease
2.  Hypothyroidism and Risk of Mild Cognitive Impairment in Elderly Persons - A Population Based Study 
JAMA neurology  2014;71(2):201-207.
IMPORTANCE
Association of clinical and subclinical hypothyroidism with mild cognitive impairment (MCI) is not established.
OBJECTIVE
To evaluate the association of clinical and subclinical hypothyroidism with MCI in a large population based cohort.
DESIGN
A cross-sectional, population-based study.
SETTING
Olmsted County, Minnesota.
PARTICIPANTS
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.
MAIN OUTCOME MEASURES
Association of clinical and subclinical hypothyroidism with MCI.
Results
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.
Conclusion
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.
doi:10.1001/jamaneurol.2013.5402
PMCID: PMC4136444  PMID: 24378475
3.  Criteria for Mild Cognitive Impairment Due to Alzheimer’s Disease in the Community 
Annals of neurology  2013;74(2):199-208.
Objective
The newly proposed National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria for mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) suggest a combination of clinical features and biomarker measures, but their performance in the community is not known.
Methods
The Mayo Clinic Study of Aging (MCSA) is a population-based longitudinal study of non-demented subjects in Olmsted County, Minnesota. A sample of 154 MCI subjects from the MCSA was compared to a sample of 58 amnestic MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI 1) to assess the applicability of the criteria in both settings and to assess their outcomes.
Results
In the MCSA, 14% and in ADNI 1 16% of subjects were biomarker negative. In addition, 14% of the MCSA and 12% of ADNI 1 subjects had evidence for amyloid deposition only, while 43% of MCSA and 55% of ADNI 1 subjects had evidence for amyloid deposition plus neurodegeneration (MRI atrophy, FDG PET hypometabolism or both). However, a considerable number of subjects had biomarkers inconsistent with the proposed AD model, e.g., 29% of MCSA subjects and 17% of the ADNI 1 subjects had evidence for neurodegeneration without amyloid deposition. These subjects may not be on an AD pathway. Neurodegeneration appears to be a key factor in predicting progression relative to amyloid deposition alone.
Interpretation
The NIA-AA criteria apply to most MCI subjects in both the community and clinical trials settings however, a sizeable proportion of subjects had conflicting biomarkers which may be very important and need to be explored.
doi:10.1002/ana.23931
PMCID: PMC3804562  PMID: 23686697
4.  Developing a national strategy to prevent dementia: Leon Thal Symposium 2009 
Among the major impediments to the design of clinical trials for the prevention of Alzheimer's disease (AD), the most critical is the lack of validated biomarkers, assessment tools, and algorithms that would facilitate identification of asymptomatic individuals with elevated risk who might be recruited as study volunteers. Thus, the Leon Thal Symposium 2009 (LTS'09), on October 27–28, 2009 in Las Vegas, Nevada, was convened to explore strategies to surmount the barriers in designing a multisite, comparative study to evaluate and validate various approaches for detecting and selecting asymptomatic people at risk for cognitive disorders/dementia. The deliberations of LTS'09 included presentations and reviews of different approaches (algorithms, biomarkers, or measures) for identifying asymptomatic individuals at elevated risk for AD who would be candidates for longitudinal or prevention studies. The key nested recommendations of LTS'09 included: (1) establishment of a National Database for Longitudinal Studies as a shared research core resource; (2) launch of a large collaborative study that will compare multiple screening approaches and biomarkers to determine the best method for identifying asymptomatic people at risk for AD; (3) initiation of a Global Database that extends the concept of the National Database for Longitudinal Studies for longitudinal studies beyond the United States; and (4) development of an educational campaign that will address public misconceptions about AD and promote healthy brain aging.
doi:10.1016/j.jalz.2010.01.008
PMCID: PMC4298995  PMID: 20298968
Alzheimer's disease; Dementia; Mild cognitive impairment; Prevention; Biomarkers; Diagnosis; Screening; Clinical trials; MCI; Asymptomatic; Risk factors; Registry; Longitudinal studies; Database; PAD2020; Leon Thal Symposium; Treatment; Drug development; Health policy
5.  Association of plasma and cortical beta-amyloid is modulated by APOE ε4 status 
Background
APOE ε4’s role as a modulator of the relationship between soluble plasma beta-amyloid (Aβ) and fibrillar brain Aβ measured by Pittsburgh Compound-B positron emission tomography ([11C]PiB PET) has not been assessed.
Methods
Ninety-six Alzheimer’s Disease Neuroimaging Initiative participants with [11C]PiB scans and plasma Aβ1-40 and Aβ1-42 measurements at time of scan were included. Regional and voxel-wise analyses of [11C]PiB data were used to determine the influence of APOE ε4 on association of plasma Aβ1-40, Aβ1-42, and Aβ1-40/Aβ1-42 with [11C]PiB uptake.
Results
In APOE ε4− but not ε4+ participants, positive relationships between plasma Aβ1-40/Aβ1-42 and [11C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ1-40/Aβ1-42 improved the explained variance in [11C]PiB binding compared to using APOE and plasma Aβ1-40/Aβ1-42 as separate terms.
Conclusions
The results suggest that plasma Aβ is a potential Alzheimer’s disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.
doi:10.1016/j.jalz.2013.01.007
PMCID: PMC3750076  PMID: 23541187
Alzheimer’s disease (AD); mild cognitive impairment (MCI); Alzheimer’s Disease Neuroimaging Initiative (ADNI); beta-amyloid (Aβ); plasma beta-amyloid; positron emission tomography (PET); Pittsburgh Compound-B ([11C]PiB); Apolipoprotein E (APOE)
6.  Association of diabetes with amnestic and nonamnestic mild cognitive impairment 
Background
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.
Methods
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.
Results
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]).
Conclusions
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.
doi:10.1016/j.jalz.2013.01.001
PMCID: PMC3830601  PMID: 23562428
Mild cognitive impairment; Risk factors; Type 2 diabetes; Incidence; Cohort studies; Population-based studies; Sex differences; Diabetic retinopathy; Diabetic neuropathy
7.  Association of Lifetime Intellectual Enrichment with Cognitive Decline in the Older Population 
JAMA neurology  2014;71(8):1017-1024.
IMPORTANCE
Intellectual lifestyle enrichment throughout life is increasingly viewed as a protective strategy against commonly observed cognitive decline in the elderly.
OBJECTIVE
To investigate the association of lifetime intellectual enrichment with baseline cognitive performance and rate of cognitive decline in a non-demented elderly population and to estimate difference (in years) associated with lifetime intellectual enrichment to the onset of cognitive impairment.
DESIGN, SETTING, PARTICIPANTS
Prospective analysis of subjects enrolled in the Mayo Clinic Study of Aging (MCSA), a longitudinal population-based study of cognitive aging in Olmsted County, Minnesota. We studied 1995 non-demented (1718 cognitively normal, 277 MCI) participants in MCSA who completed intellectual lifestyle measures at baseline and underwent at least one follow-up visit.
MAIN OUTCOMES AND MEASURES
We studied the effect of lifetime intellectual enrichment by separating the variables into two non-overlapping principal components: education/occupation-score and mid/late-life cognitive activity measure based on self-report questionnaires. A global cognitive Z-score served as our summary cognition measure. We used linear mixed-effects models to investigate the associations of demographic and intellectual enrichment measures with global cognitive Z-score trajectories.
RESULTS
Baseline cognitive performance was lower in older subjects and in those with lower education/occupation, lower mid/late-life cognitive activity, apolipoprotein E4 (APOE) genotype, and in men. The interaction between the two intellectual enrichment measures was significant such that the beneficial effect of mid/late-life cognitive activity on baseline cognitive performance was reduced with increasing education/occupation. Only baseline age, mid/late-life cognitive activity, and APOE4 genotype were significantly associated with longitudinal change in cognitive performance from baseline. For APOE4 carriers with high lifetime intellectual enrichment (75th percentile of both education/occupation and mid/late-life cognitive activity), the onset of cognitive impairment was about 8.7 years later compared with low lifetime intellectual enrichment (25th percentile of both education/occupation and mid/late-life cognitive activity) in an 80 year old subject.
CONCLUSIONS AND RELEVANCE
Higher levels of education/occupation were associated with higher levels of cognition. Higher levels of mid/late-life leisure activity were also associated with higher levels of cognition, but the slope of this relationship slightly increased over time. Lifetime intellectual enrichment might delay the onset of cognitive impairment and be used as a successful preventive intervention to reduce the impending dementia epidemic.
doi:10.1001/jamaneurol.2014.963
PMCID: PMC4266551  PMID: 25054282
8.  Abnormal daytime sleepiness in dementia with Lewy bodies compared to Alzheimer’s disease using the Multiple Sleep Latency Test 
Introduction
Excessive daytime sleepiness is a commonly reported problem in dementia with Lewy bodies (DLB). We examined the relationship between nighttime sleep continuity and the propensity to fall asleep during the day in clinically probable DLB compared to Alzheimer’s disease (AD) dementia.
Methods
A full-night polysomnography was carried out in 61 participants with DLB and 26 with AD dementia. Among this group, 32 participants with DLB and 18 with AD dementia underwent a daytime Multiple Sleep Latency Test (MSLT). Neuropathologic examinations of 20 participants with DLB were carried out.
Results
Although nighttime sleep efficiency did not differentiate diagnostic groups, the mean MSLT initial sleep latency was significantly shorter in participants with DLB than in those with AD dementia (mean 6.4 ± 5 minutes vs 11 ± 5 minutes, P <0.01). In the DLB group, 81% fell asleep within 10 minutes compared to 39% of the AD dementia group (P <0.01), and 56% in the DLB group fell asleep within 5 minutes compared to 17% in the AD dementia group (P <0.01). Daytime sleepiness in AD dementia was associated with greater dementia severity, but mean MSLT latency in DLB was not related to dementia severity, sleep efficiency the night before, or to visual hallucinations, fluctuations, parkinsonism or rapid eye movement sleep behavior disorder. These data suggest that abnormal daytime sleepiness is a unique feature of DLB that does not depend on nighttime sleep fragmentation or the presence of the four cardinal DLB features. Of the 20 DLB participants who underwent autopsy, those with transitional Lewy body disease (brainstem and limbic) did not differ from those with added cortical pathology (diffuse Lewy body disease) in dementia severity, DLB core features or sleep variables.
Conclusions
Daytime sleepiness is more likely to occur in persons with DLB than in those with AD dementia. Daytime sleepiness in DLB may be attributed to disrupted brainstem and limbic sleep–wake physiology, and further work is needed to better understand the underlying mechanisms.
doi:10.1186/s13195-014-0076-z
PMCID: PMC4266572  PMID: 25512763
9.  Neurocognitive speed associates with frontotemporal lobar degeneration TDP-43 subtypes 
Frontotemporal lobar degeneration (FTLD) is pathologically heterogeneous with TAR DNA binding protein 43 kDa (TDP-43) proteinopathy the most common substrate. Previous work has identified atrophy patterns across TDP-43 subtypes with Type A showing greater frontotemporal and parietal atrophy, Type C predominantly anterior temporal, and Type B predominantly posterior frontal. Despite neuroanatomical correlates of involvement, neuropsychological findings have been inconsistent. The current study utilized broader neurocognitive domains based on aggregated neuropsychological measures to distinguish between subtypes. We hypothesized that patterns of neurocognitive domain impairments would predict FTLD–TDP-43 subtype. Fifty-one patients, aged 38–87, were identified post mortem with pathologically confirmed FTLD with TDP-43. Participants were classified into subtypes A, B, or C. Patients had completed neuropsychological assessments as part of their clinical evaluation. Six cognitive domains were created: Language; Cognitive Speed; Memory; Learning; Visuoperception; and Fluency. Binary logistic regression was conducted. All but three patients could be classified as FTLD–TDP Types A, B, or C: 26 as Type A; nine as Type B; and 13 as Type C. Cognitive Speed scores were associated with Types A and C (p < 0.001 and p = 0.003, respectively). Impaired performances on the Trail Making Test differentiated Types A and C. Worse Boston Naming Test and Logical Memory (Immediate) (p < 0.05) scores also increased the likelihood of Type C phenotype. Findings suggest Cognitive Speed associates with TDP-43 subtypes. Type C also demonstrated language-specific involvement. Differences between TDP-43 subtypes further supports the notion of differences in pathophysiology or topography across these types.
doi:10.1016/j.jocn.2013.01.024
PMCID: PMC3825760  PMID: 24012243
Cognitive speed; Dementia; Frontotemporal lobar degeneration; Neuropathology; Neuropsychology; TDP-43
10.  CHRONIC OBSTRUCTIVE PULMONARY DISEASE IS ASSOCIATED WITH MILD COGNITIVE IMPAIRMENT: THE MAYO CLINIC STUDY OF AGING 
Mayo Clinic proceedings  2013;88(11):10.1016/j.mayocp.2013.08.012.
Objectives
To investigate the association of chronic obstructive pulmonary disease (COPD) with mild cognitive impairment (MCI) and MCI sub-types, amnestic MCI (a-MCI) and non-amnestic MCI (na-MCI), in a population-based study of elderly.
Patients and Methods
Participants included 1,927 individuals, aged 70 to 89 years, enrolled in the population-based, Mayo Clinic Study of Aging. Participants were evaluated with a nurse assessment, neurological evaluation, and neuropsychological testing and the diagnosis of MCI was made according to the standardized criteria by a consensus panel. COPD was identified by the review of medical records. The study was conducted from October 1, 2004, through July 31, 2007. The associations of COPD, and disease duration with MCI, and its subtypes were evaluated using logistic regression models adjusted for potential covariates.
Results
Of 1,927 subjects, 288 had COPD (men vs women 17.9% vs 11.8%, p<0.001). As compared to subjects without COPD, the subjects with COPD had higher prevalence of MCI (27.1% vs 14.6%, p<0.001). The odds ratio (OR) of MCI was almost two times higher in subjects with COPD (OR =1.90, 95 %CI =1.35 – 2.65), with a similar effect in men and women. The OR for MCI increased from 1.67 (97% CI, 1.00 – 2.69) in subjects with COPD duration of ≤ 5 years to 2.08 (95% CI, 1.36 – 3.14) in subjects > 5 years.
Conclusion
This population-based study suggests that COPD is associated with increased odds of having MCI and its sub-types. There was a dose-response association with duration of COPD, after controlling for the potential covariates.
doi:10.1016/j.mayocp.2013.08.012
PMCID: PMC3875365  PMID: 24182702
11.  Diabetes and Elevated HbA1c levels are Associated with Brain Hypometabolism but not Amyloid Accumulation 
Dysfunctional insulin signaling may affect brain metabolism or amyloid deposition. We investigated the associations of type 2 diabetes with amyloid accumulation measured using 11C-Pittsburgh Compound B (PiB) and brain hypometabolism measured using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET).
Methods
We studied a sample of non-demented participants from the population-based Mayo Clinic Study of Aging. All subjects underwent MRI, amyloid PET and FDG PET. Alzheimer’s disease (AD) signature and region of interest (ROI) measures for PiB retention ratio and FDG ratio were measured. Diabetes was assessed from the Rochester Epidemiology Project medical records-linkage system.
Results
Among 749 participants (median age 79.0 years; 56.5% male, 81.0% cognitively normal; 20.6% diabetics), FDG hypometabolism (FDG ratio < 1.31) in the AD signature meta-ROI was more common in diabetics (48.1%) than in non-diabetics (28.9%; p <0.001). The median FDG ratio was lower in diabetics vs. non-diabetics in the AD signature meta-ROI (1.32 vs. 1.40, p < 0.001), and in the angular (1.40 vs. 1.48, p < 0.001) and posterior cingulate gyri ROIs (1.63 vs. 1.72, p < 0.001). The odds ratio (OR [95% confidence interval]) for abnormal AD signature FDG hypometabolism was elevated (OR, 2.28 [1.56, 3.33]) in diabetics vs. non-diabetics after adjustment for age, sex, and education, and after additional adjustment for Apolipoprotein ε4 allele, glycemic level, and cognitive status (OR, 1.69 [1.10, 2.60]). However, AD signature PiB retention ratio was similar in diabetics vs. non-diabetics (OR, 1.03 [0.71, 1.51]; p = 0.87). In post-hoc analyses in non-diabetics, a 1% increase in HBA1c was associated with greater AD signature hypometabolism in cognitively normal subjects (OR, 1.93 [1.03, 3.62; p = 0.04]) and in the total cohort (OR 1.59 [0.92, 2.75; p = 0.10).
Conclusion
Diabetes and poor glycemic control in non-diabetics may enhance glucose hypometabolism in AD signature regions. These factors should be investigated in longitudinal studies for their role in detecting onset of symptoms in AD.
doi:10.2967/jnumed.113.132647
PMCID: PMC4011952  PMID: 24652830
Diabetes; cerebral glucose metabolism; FDG- and PiB-PET imaging; hemoglobin A1c; amyloid accumulation
12.  Quantitative neurofibrillary tangle density and brain volumetric MRI analyses in Alzheimer’s disease presenting as logopenic progressive aphasia 
Brain and language  2013;127(2):10.1016/j.bandl.2013.02.003.
Neurofibrillary tangles (NFTs) are one of the key histological lesions of Alzheimer’s disease (AD) and are associated with brain atrophy. We assessed regional NFT density in 30 patients with AD, 10 of which presented as the logopenic variant of primary progressive aphasia (lvPPA) and 20 that presented as dementia of the Alzheimer’s type (DAT). Regional grey matter volumes were measured using antemortem MRI. NFT density was significantly higher in left temporoparietal cortices in lvPPA compared to DAT, with no differences observed in hippocampus. There was a trend for the ratio of temporoparietal-to-hippocampal NFT density to be higher in lvPPA. The imaging findings mirrored the pathological findings, with smaller left temporoparietal volumes observed in lvPPA compared to DAT, and no differences observed in hippocampal volume. This study demonstrates that lvPPA is associated with a phenomenon of enhanced temporoparietal neurodegeneration, a finding that improves our understanding of the biological basis of lvPPA.
doi:10.1016/j.bandl.2013.02.003
PMCID: PMC3840097  PMID: 23541297
Primary progressive aphasia; Logopenic variant of primary progressive aphasia; Alzheimer’s disease; Neurofibrillary tangles; Hippocampus; MRI; Apolipoprotein E; TDP-43; Voxel-based morphometry; Alzheimer’s dementia
13.  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
14.  Subtle gait changes in patients with REM Behavior Disorder 
Background
Many people with REM sleep behavior disorder have an underlying synucleinopathy, the most common of which is Lewy body disease. Identifying additional abnormal clinical features may help in identifying those at greater risk of evolving to a more severe syndrome. As gait disorders are common in the synucleinopathies, early abnormalities in gait in those with REM sleep behavior disorder could help in identifying those at increased risk of developing overt parkinsonism and/or cognitive impairment.
Methods
We identified 42 probable REM sleep behavior disorder subjects and 492 controls using the Mayo Sleep Questionnaire and assessed gait velocity, cadence and stride dynamics with an automated gait analysis system.
Results
Cases and controls were similar in age (79.9 ± 4.7 & 80.1 ± 4.7, p= 0.74), UPDRS score (3.3 ± 5.5 & 1.9 ± 4.1, p=0.21) and Mini-Mental State Examination scores (27.2 ± 1.9 & 27.7 ± 1.6, p=0.10). A diagnosis of probable REM sleep behavior disorder was associated with decreased velocity (−7.9 cm/sec, 95%CI −13.8 to −2.0, p<0.01), cadence (−4.4 steps/min, 95%CI −7.6 to −1.3, p<0.01), and significantly increased double limb support variability (30%, 95%CI 6 – 60, p=0.01), greater stride time variability (29%, 95%CI 2 – 63, p=0.03) and swing time variability (46%, 95%CI 15 – 84, p<0.01).
Conclusions
Probable REM sleep behavior disorder is associated with subtle gait changes prior to overt clinical parkinsonism. Diagnosis of probable REM sleep behavior disorder supplemented by gait analysis may help as a screening tool for disorders of α-synuclein.
doi:10.1002/mds.25653
PMCID: PMC3952497  PMID: 24130124
REM Sleep Behavior Disorder; gait; gait variability
15.  Focal Hemosiderin Deposits and β-Amyloid Load in the ADNI Cohort 
Objective
Prevalence and risk factors for focal hemosiderin deposits are important considerations when planning amyloid–modifying trials for treatment and prevention of Alzheimer’s disease (AD).
Methods
Subjects were cognitively normal (n=171), early-mild cognitive impairment (MCI) (n=240), late-MCI (n=111) and AD (n=40) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Microhemorrhages and superficial siderosis were assessed at baseline and on all available MRIs at 3, 6 and 12 months. β-amyloid load was assessed with 18F-florbetapir PET.
Results
Prevalence of superficial siderosis was 1% and prevalence of microhemorrhages was 25% increasing with age (p<0.001) and β-amyloid load (p<0.001). Topographic densities of microhemorrhages were highest in the occipital lobes and lowest in the deep/infratentorial regions. A greater number of microhemorrhages at baseline was associated with a greater annualized rate of additional microhemorrhages by last follow-up (rank correlation=0.49;P<0.001).
Conclusion
Focal hemosiderin deposits are relatively common in the ADNI cohort and are associated with β-amyloid load.
doi:10.1016/j.jalz.2012.10.011
PMCID: PMC3770782  PMID: 23375568
ADNI; microhemorrhage; superficial siderosis; MRI; Amyloid; PET; Florbetapir; Alzheimer’s disease; mild cognitive impairment; early mild cognitive impairment
16.  Midbrain atrophy is not a biomarker of PSP pathology 
Background
Midbrain atrophy is a characteristic feature of progressive supranuclear palsy (PSP), although it is unclear whether it is associated with the PSP syndrome (PSPS) or PSP pathology. We aimed to determine whether midbrain atrophy is a useful biomarker of PSP pathology, or whether it is only associated with typical PSPS.
Methods
We identified all autopsy-confirmed subjects with the PSP clinical phenotype (i.e. PSPS) or PSP pathology and a volumetric MRI. Of 24 subjects with PSP pathology, 11 had a clinical diagnosis of PSPS (PSP-PSPS), and 13 had a non-PSPS clinical diagnosis (PSP-other). Three subjects had PSPS and corticobasal degeneration pathology (CBD-PSPS). Healthy control and disease control groups (i.e. a group without PSPS or PSP pathology) and a group with CBD pathology and corticobasal syndrome (CBD-CBS) were selected. Midbrain area was measured in all subjects.
Results
Midbrain area was reduced in each group with clinical PSPS (with and without PSP pathology). The group with PSP pathology and non-PSPS clinical syndromes did not show reduced midbrain area. Midbrain area was smaller in the subjects with PSPS compared to those without PSPS (p<0.0001), with an area under the receiver-operator-curve of 0.99 (0.88,0.99). A midbrain area cut-point of 92 mm2 provided optimum sensitivity (93%) and specificity (89%) for differentiation.
Conclusion
Midbrain atrophy is associated with the clinical presentation of PSPS, but not with the pathological diagnosis of PSP in the absence of the PSPS clinical syndrome. This finding has important implications for the utility of midbrain measurements as diagnostic biomarkers for PSP pathology.
doi:10.1111/ene.12212
PMCID: PMC3773014  PMID: 23746093
Progressive supranuclear palsy; tau; neuropathology; MRI; midbrain
17.  Associations of repeat sizes with clinical and pathological characteristics in C9ORF72 expansion carriers (Xpansize-72): a cross-sectional cohort study 
Lancet neurology  2013;12(10):10.1016/S1474-4422(13)70210-2.
Summary
Background
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are currently the major genetic cause of frontotemporal dementia (FTD) and motor neuron disease (MND). Presently, it is unknown whether expansion size affects disease severity or phenotypes.
Methods
We performed a cross-sectional Southern blot characterization study (Xpansize-72) in a cohort of subjects obtained at the Mayo Clinic and Banner Sun Health Research Institute. All subjects carried GGGGCC repeat expansions in C9ORF72, and high quality DNA was available from the frontal cortex, cerebellum and/or blood. Southern blotting techniques and densitometry were employed to estimate the repeat size of the most abundant expansion species. Comparisons of repeat sizes between tissues were made using Wilcoxon rank sum and Wilcoxon signed rank tests, and between disease subgroups using Kruskal-Wallis rank sum tests. The association of repeat size with age at onset and age at collection was evaluated using a Spearman’s test of correlation; whereas the association between repeat size and survival after disease onset was examined using Cox proportional hazards regression models.
Findings
Our cohort consisted of 84 C9ORF72 expansion carriers, including FTD patients (n=35), FTD/MND patients (n=16), MND patients (n=30), and unaffected subjects (n=3). We focused our analysis on three major tissue subgroups: frontal cortex (41 subjects [21 FTD, 11 FTD/MND, 9 MND]), cerebellum (40 subjects [20 FTD, 12 FTD/MND, 8 MND]), and blood (50 subjects [15 FTD, 9 FTD/MND, 23 MND, 3 unaffected expansion carriers]). Repeat lengths in the cerebellum were significantly smaller (median 12·3 kb [~1667 repeat units], IQR 11·1–14·3) than in the frontal cortex (median 33·8 kb [~5250 repeat units], IQR 23·5–44·9, p<0·0001), or in blood (median 18·6 kb [~2717 repeat units], IQR 13·9–28·1, p=0·0002). Within these tissues, there was no significant difference in repeat length between disease subgroups (cerebellum p=0·96, frontal cortex p=0·27, blood p=0·10). In the frontal cortex of FTD patients, repeat length correlated with age at onset (r=0·63, p=0·003) and age at collection (r=0·58, p=0·006); this correlation was not detected in the cerebellum or blood. Finally, only in the cerebellum, survival after disease onset was poorer in patients from our overall cohort with repeat lengths greater than 1467 repeat units (25th percentile, HR 3·27, 95% CI 1·34–7·95, p=0·009): the median survival was 4·8 years (IQR 3·0–7·4) in the group with longer expansions versus 7·4 years (IQR 6·3–10·9) in the group with smaller expansions.
Interpretation
Substantial variation in repeat size is observed between cerebellum, frontal cortex, and blood; relatively long repeat sizes in the cerebellum confer an important survival disadvantage. Our findings indicate that expansion size does affect disease severity, which could be relevant for genetic counseling.
doi:10.1016/S1474-4422(13)70210-2
PMCID: PMC3879782  PMID: 24011653
18.  Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene 
Background
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability.
Results
We examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 [UBAP1; p-value = 0.003], rs6052771 [PRNP; p-value = 0.003], and rs7403881 [MT-Ie; p-value = 0.003]), and six variants significantly associated with survival after onset (rs5848 [GRN; p-value = 0.001], rs7403881 [MT-Ie; p-value = 0.001], rs13268953 [ELP3; p-value = 0.003], the epsilon 4 allele [APOE; p-value = 0.004], rs12608932 [UNC13A; p-value = 0.003], and rs1800435 [ALAD; p-value = 0.003]).
Conclusions
Variants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion). Although validation of our findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense and RNA-processing pathways, and additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-1326-9-38) contains supplementary material, which is available to authorized users.
doi:10.1186/1750-1326-9-38
PMCID: PMC4190282  PMID: 25239657
C9ORF72; Frontotemporal dementia; Motor neuron disease; Genetic modifier; Repeat expansion
19.  APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study 
Molecular psychiatry  2013;19(3):351-357.
Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer’s disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir (18F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender, and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (rs429358, p = 5.5 × 10−14) and on chromosome 3 upstream of BCHE (rs509208, p = 2.7 × 10−8) in a region previously associated with serum butyrylcholinesterase activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB, and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. Butyrylcholinesterase has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of butyrylcholinesterase-modulating agents in the AD spectrum.
doi:10.1038/mp.2013.19
PMCID: PMC3661739  PMID: 23419831
Alzheimer’s disease (AD); amyloid; apolipoprotein E (APOE); butyrylcholinesterase (BCHE); florbetapir (AV-45); genome-wide association study (GWAS)
20.  The Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception 
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151–3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [18F]-fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants.
doi:10.1016/j.jalz.2013.05.1769
PMCID: PMC4108198  PMID: 23932184
Alzheimer's disease; Mild cognitive impairment; Amyloid; Tau; Biomarker
21.  Improved DTI registration allows voxel-based analysis that outperforms Tract-Based Spatial Statistics 
NeuroImage  2014;94:65-78.
Tract-Based Spatial Statistics (TBSS) is a popular software pipeline to coregister sets of diffusion tensor Fractional Anisotropy (FA) images for performing voxel-wise comparisons. It is primarily defined by its skeleton projection step intended to reduce effects of local misregistration. A white matter “skeleton” is computed by morphological thinning of the inter-subject mean FA, and then all voxels are projected to the nearest location on this skeleton. Here we investigate several enhancements to the TBSS pipeline based on recent advances in registration for other modalities, principally based on groupwise registration with the ANTS-SyN algorithm. We validate these enhancements using simulation experiments with synthetically-modified images. When used with these enhancements, we discover that TBSS's skeleton projection step actually reduces algorithm accuracy, as the improved registration leaves fewer errors to warrant correction, and the effects of this projection's compromises become stronger than those of its benefits. In our experiments, our proposed pipeline without skeleton projection is more sensitive for detecting true changes and has greater specificity in resisting false positives from misregistration. We also present comparative results of the proposed and traditional methods, both with and without the skeleton projection step, on three real-life datasets: two comparing differing populations of Alzheimer's disease patients to matched controls, and one comparing progressive supranuclear palsy patients to matched controls. The proposed pipeline produces more plausible results according to each disease's pathophysiology.
doi:10.1016/j.neuroimage.2014.03.026
PMCID: PMC4137565  PMID: 24650605
DTI; Fractional Anisotropy; Voxel-based analysis; VBM; TBSS; Registration
22.  Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology 
Brain  2013;136(8):2510-2526.
Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer’s pathology in their brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer’s pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer’s pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer’s changes (‘mismatches’), and demented Alzheimer’s cases. Quantification of amyloid-β plaque burden, stereologically-based counts of neurofibrillary tangles, neurons and reactive glia, and morphological analyses of axons were performed in the multimodal association cortex lining the superior temporal sulcus. Levels of synaptic integrity markers, and soluble monomeric and multimeric amyloid-β and tau species were measured. Our results indicate that some individuals can accumulate equivalent loads of amyloid-β plaques and tangles to those found in demented Alzheimer’s cases without experiencing dementia. Analyses revealed four main phenotypic differences among these two groups: (i) mismatches had striking preservation of neuron numbers, synaptic markers and axonal geometry compared to demented cases; (ii) demented cases had significantly higher burdens of fibrillar thioflavin-S-positive plaques and of oligomeric amyloid-β deposits reactive to conformer-specific antibody NAB61 than mismatches; (iii) strong and selective accumulation of hyperphosphorylated soluble tau multimers into the synaptic compartment was noted in demented cases compared with controls but not in mismatches; and (iv) the robust glial activation accompanying amyloid-β and tau pathologies in demented cases was remarkably reduced in mismatches. Further biochemical measurements of soluble amyloid-β species—monomers, dimers and higher molecular weight oligomers—in total brain homogenates and synaptoneurosomal preparations failed to demonstrate significant differences between mismatches and demented cases. Together, these data suggest that amyloid-β plaques and tangles do not inevitably result in neural system derangement and dementia in all individuals. We identified distinct phenotypic characteristics in the profile of brain fibrillar and soluble amyloid-β and tau accrual and in the glial response that discriminated demented and non-demented individuals with high loads of Alzheimer’s pathology. Amyloid-β deposition in the form of fibrillar plaques and intimately related oligomeric amyloid-β assemblies, hyperphosphorylated soluble tau species localized in synapses, and glial activation emerged in this series as likely mediators of neurotoxicity and altered cognition, providing further insight into factors and pathways potentially involved in human susceptibility or resilience to Alzheimer’s pathological changes.
doi:10.1093/brain/awt171
PMCID: PMC3722351  PMID: 23824488
Alzheimers disease; amyloid pathology; tau pathology; resilience; astrocytes; microglia
23.  Assessing the Temporal Relationship Between Cognition and Gait: Slow Gait Predicts Cognitive Decline in the Mayo Clinic Study of Aging 
Background.
The association between gait speed and cognition has been reported; however, there is limited knowledge about the temporal associations between gait slowing and cognitive decline among cognitively normal individuals.
Methods.
The Mayo Clinic Study of Aging is a population-based study of Olmsted County, Minnesota, United States, residents aged 70–89 years. This analysis included 1,478 cognitively normal participants who were evaluated every 15 months with a nurse visit, neurologic evaluation, and neuropsychological testing. The neuropsychological battery used nine tests to compute domain-specific (memory, language, executive function, and visuospatial skills) and global cognitive z-scores. Timed gait speed (m/s) was assessed over 25 feet (7.6 meters) at a usual pace. Using mixed models, we examined baseline gait speed (continuous and in quartiles) as a predictor of cognitive decline and baseline cognition as a predictor of gait speed changes controlling for demographics and medical conditions.
Results.
Cross-sectionally, faster gait speed was associated with better performance in memory, executive function, and global cognition. Both cognitive scores and gait speed declined over time. A faster gait speed at baseline was associated with less cognitive decline across all domain-specific and global scores. These results were slightly attenuated after excluding persons with incident mild cognitive impairment or dementia. By contrast, baseline cognition was not associated with changes in gait speed.
Conclusions.
Our study suggests that slow gait precedes cognitive decline. Gait speed may be useful as a reliable, easily attainable, and noninvasive risk factor for cognitive decline.
doi:10.1093/gerona/gls256
PMCID: PMC3712358  PMID: 23250002
Gait speed; Cognition; Longitudinal; Cohort study.
24.  MRS in Early and Presymptomatic Carriers of a Novel Octapeptide Repeat Insertion in the Prion Protein Gene 
To evaluate the proton MR spectroscopy (1H MRS) changes in carriers of a novel octapeptide repeat insertion in the Prion Protein Gene (PRNP) and family history of frontotemporal dementia with ataxia. Four at-risk mutation carriers and 13 controls were compared using single voxel, short TE, 1H MRS from the posterior cingulate gyrus. The mutation carriers had an increased choline/creatine, p=0.003 and increased myoinositol/creatine ratio, p=0.003. 1H MRS identified differences in markers of glial activity and choline metabolism in pre- and early symptomatic carriers of a novel PRNP gene octapeptide insertion. These findings expand the possible diagnostic utility of 1H MRS in familial prion disorders.
doi:10.1111/j.1552-6569.2012.00717.x
PMCID: PMC3480551  PMID: 22612156
MRS; MRI; familial prion disorders; frontotemporal dementia
25.  Age and APOE genotype influence rate of cognitive decline in non-demented elderly 
Neuropsychology  2013;27(4):10.1037/a0032707.
Objective
This study examined the impact of age and apolipoprotein E (APOE) genotype on the rate of cognitive decline in non-demented elderly participants in a simulated Alzheimer’s disease (AD) primary prevention treatment trial carried out by the Alzheimer’s Disease Cooperative Study.
Method
Cognitive tests were administered at baseline and at four subsequent annual evaluations to 417 non-demented participants (172 men, 245 women) between the ages of 74 and 93 (mean=79.13 ± 3.34). APOE genotyping was available for 286 of the participants.
Results
Four-year decline was evident on measures of orientation, memory, executive function and language. Faster decline was evident in APOE ε4+ (a genetic risk factor for AD; n=73) than ε4− participants (n=213), even after controlling for education, gender, ethnicity, and baseline functional and cognitive abilities. This discrepancy increased with increasing age indicating an age X genotype interaction.
Conclusions
These results are consistent with population-based studies, and extend the findings to a carefully-screened sample that meets inclusion and exclusion criteria for an AD primary prevention trial. The interaction between age and APOE genotype on rate of decline suggests that preclinical disease may be over represented in olderε4+ individuals. Thus, APOE genotype and age should be considered in the design of AD primary prevention treatment trials.
doi:10.1037/a0032707
PMCID: PMC3831285  PMID: 23876113
Cognitive decline; Apolipoprotein E; Aging

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