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1.  Arguing Against the Proposed Definition Changes of PD 
As members of the Lewy Body Dementia Association Scientific Advisory Council, we aim to address some of the issues raised in the article entitled, "Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease." In particular, we suggest that the one-year rule distinguishing Parkinson’s disease dementia from dementia with Lewy bodies is worth maintaining because it serves an important purpose in clinical practice, in clinical and basic science research, and in helping the lay community understand the complexity of these different clinical phenotypes. Furthermore, we believe that adding an additional diagnostic label, “PD (dementia with Lewy bodies subtype)”, will confuse rather than clarify the distinction between dementia with Lewy bodies and PD or PD dementia, and will not improve management or expedite therapeutic development. We present arguments supporting our contentions.
PMCID: PMC5168716  PMID: 27492190
2.  Role of β-amyloidosis and Neurodegeneration in Subsequent Imaging Changes in Mild Cognitive Impairment 
JAMA neurology  2015;72(12):1475-1483.
To understand how a model of Alzheimer disease pathophysiology based on β-amyloidosis and neurodegeneration predicts the regional anatomic expansion of hypometabolism and atrophy in persons with mild cognitive impairment (MCI).
To define the role of β-amyloidosis and neurodegeneration in the subsequent progression of topographic cortical structural and metabolic changes in MCI.
Longitudinal, observational study with serial brain imaging.
Population-based cohort.
Ninety six MCI participants (all >70 years) with serial imaging biomarkers from the Mayo Clinic Study of Aging or Mayo Alzheimer Disease Research Center. Participants were characterized initially as having elevated or not elevated brain β-amyloidosis (“A+” or “A−“) based on 11C-Pittsburgh compound B positron emission tomography (PET). They were further characterized initially by the presence or absence of neurodegeneration (“N+” or “N−“), where presence of neurodegeneration was defined by abnormally low hippocampal volume or hypometabolism in an Alzheimer Disease (AD)-like pattern on 18fluoro-deoxyglucose (FDG) PET.
Main Outcome Measures
Regional FDG Standardized Uptake Value ratio (SUVR) and grey matter volumes in medial temporal, lateral temporal, lateral parietal and medial parietal regions.
In the primary regions of interest, the A+N+ group had lower FDG SUVR and grey matter volumes at baseline, and showed large declines in FDG SUVR and grey matter volumes compared to the A−N+ and A−N−, but not the A+N− group. The A+N− group exhibited declines in FDG SUVR over time, which were not significantly different from the A−N+ or A−N− groups. The A−N+ group did not show declines in FDG SUVR or grey matter volume compared to A+N− or A−N− groups.
Conclusions and Relevance
Persons with MCI who were A+N+ demonstrated volumetric and metabolic worsening in temporal and parietal association areas, consistent with the expectation that the MCI stage in the Alzheimer pathway heralds incipient isocortical involvement. The A−N+ group, those with suspected non-Alzheimer pathophysiology, lacked a distinctive longitudinal volumetric or metabolic profile.
PMCID: PMC4735877  PMID: 26437123
3.  Hippocampal volumes predict risk of dementia with Lewy bodies in mild cognitive impairment 
Neurology  2016;87(22):2317-2323.
To predict the risk of probable dementia with Lewy bodies (DLB) competing with Alzheimer disease (AD) dementia by hippocampal volume (HV) in patients with mild cognitive impairment (MCI) with impairments in amnestic or nonamnestic cognitive domains.
Patients with MCI (n = 160) from the Mayo Clinic Alzheimer's Disease Research Center, who participated in an MRI study at baseline from 2005 to 2014, were followed with approximately annual clinical evaluations. HVs were analyzed from 3T MRIs using FreeSurfer (5.3). Hippocampal atrophy was determined from the most normal 10th percentile of the measurement distributions in a separate cohort of clinically diagnosed patients with AD dementia. The subdistribution hazard ratios for progression to probable DLB and AD dementia were estimated by taking into account the competing risks.
During a median (range) follow-up of 2.0 (0.7–8.1) years, 20 (13%) patients with MCI progressed to probable DLB, and 61 (38%) progressed to AD dementia. The estimated subdistribution hazard ratio (95% confidence interval) for normal HV relative to hippocampal atrophy for progression to AD dementia was 0.56 (0.34–0.91; p = 0.02) after taking into account the competing risks. The estimated hazard ratio for normal HV relative to hippocampal atrophy for progression to probable DLB was 4.22 (1.42–12.6; p = 0.01) after adjusting for age and after including the MCI subtype in the model.
Preserved hippocampal volumes are associated with increased risk of probable DLB competing with AD dementia in patients with MCI. Preservation of HV may support prodromal DLB over AD, particularly in patients with MCI with nonamnestic features.
PMCID: PMC5135023  PMID: 27807186
4.  An MRI‐Based Atlas for Correlation of Imaging and Pathologic Findings in Alzheimer's Disease 
Journal of Neuroimaging  2016;26(3):264-268.
Pathologic diagnosis is the gold standard in evaluating imaging measures developed as biomarkers for pathologically defined disorders. A brain MRI atlas representing autopsy‐sampled tissue can be used to directly compare imaging and pathology findings. Our objective was to develop a brain MRI atlas representing the cortical regions that are routinely sampled at autopsy for the diagnosis of Alzheimer's disease (AD).
Subjects (n = 22; ages at death = 70‐95) with a range of pathologies and antemortem 3T MRI were included. Histology slides from 8 cortical regions sampled from the left hemisphere at autopsy guided the localization of the atlas regions of interest (ROIs) on each subject's antemortem 3D T1‐weighted MRI. These ROIs were then registered to a common template and combined to form one ROI representing the volume of tissue that was sampled by the pathologists. A subset of the subjects (n = 4; ages at death = 79‐95) had amyloid PET imaging. Density of β‐amyloid immunostain was quantified from the autopsy‐sampled regions in the 4 subjects using a custom‐designed ImageScope algorithm. Median uptake values were calculated in each ROI on the amyloid‐PET images.
We found an association between β‐amyloid plaque density in 8 ROIs of the 4 subjects (total ROI n = 32) and median PiB SUVR (r 2 = .64; P < .0001).
In an atlas developed for imaging and pathologic correlation studies, we demonstrated that antemortem amyloid burden measured in the atlas ROIs on amyloid PET is strongly correlated with β‐amyloid density measured on histology. This atlas can be used in imaging and pathologic correlation studies.
PMCID: PMC4848115  PMID: 27017996
Alzheimer's disease; atlas; MRI; pathology
5.  Frequency and Topography of Cerebral Microbleeds in Dementia with Lewy bodies Compared to Alzheimer’s Disease 
Parkinsonism & related disorders  2015;21(9):1101-1104.
To determine the frequency and topographic distribution of cerebral microbleeds (CMBs) in dementia with Lewy bodies (DLB) in comparison to CMBs in Alzheimer disease dementia (AD).
Consecutive probable DLB (n= 23) patients who underwent 3-tesla T2* weighted gradient-recalled-echo MRI, and age and gender matched probable Alzheimer’s disease patients (n=46) were compared for the frequency and location of CMBs.
The frequency of one or more CMBs was similar among patients with DLB (30%) and AD (24%). Highest densities of CMBs were found in the occipital lobes of patients with both DLB and AD. Patients with AD had greater densities of CMBs in the temporal lobes and deep or infratentorial regions compared to DLB (p<0.05)
CMBs are as common in patients with DLB as in patients with AD, with highest densities observed in the occipital lobes, suggesting common pathophysiologic mechanisms underlying CMBs in both diseases.
PMCID: PMC4554804  PMID: 26205074
Dementia with Lewy bodies; Cerebral Microbleeds; Alzheimer disease; Cerebral amyloid angiopathy; T2* weighted gradient-recalled-echo MRI
6.  Cerebral microbleeds, CSF p-tau, and cognitive decline: significance of anatomical distribution 
Background and Purpose
Cerebral microbleeds are associated with aging, hypertension, and Alzheimer’s disease. Microbleeds in a lobar distribution are believed to reflect underlying amyloid angiopathy, whereas microbleeds in the deep gray matter and infratentorial brain are commonly seen with hypertension. However, it is unknown how microbleeds in either distribution are related to Alzheimer’s pathogenesis. The purpose of this analysis was to test whether lobar and deep gray/infratentorial microbleeds demonstrate differential associations with CSF beta-amyloid, CSF p-tau, and longitudinal cognitive decline.
Materials and Methods
626 subjects - 151 cognitively normal, 389 with mild cognitive impairment, and 86 with Alzheimer’s disease - from the Alzheimer’s Disease Neuroimaging Initiative who had 3 Tesla MRI scans and a lumbar puncture were included in the analysis. The number and location of microbleeds were visually assessed. Associations between lobar or deep gray/infratentorial microbleeds with levels of CSF beta-amyloid, abnormal CSF p-tau, and longitudinal cognitive decline were assessed using ordinary least squares, logistic, and mixed-effects regression models, adjusting for covariates.
Having three or more lobar microbleeds are associated with lower levels of CSF beta-amyloid (p=0.001). Adjusting for CSF beta-amyloid, lobar microbleeds are independently associated with a higher likelihood of having an abnormal CSF p-tau level (p=0.004). Lobar microbleeds are associated with accelerated longitudinal cognitive decline (p=0.007). Deep gray/infratentorial microbleeds demonstrated no significant associations.
Microbleed distribution demonstrated different associations with amyloid, tau, and cognition. Lobar and deep gray/infratentorial microbleeds should be considered separately with regards to Alzheimer’s disease pathogenesis.
PMCID: PMC4729288  PMID: 26228889
7.  Effects of hormone therapy on brain structure 
Neurology  2016;87(9):887-896.
To investigate the effects of hormone therapy on brain structure in a randomized, double-blinded, placebo-controlled trial in recently postmenopausal women.
Participants (aged 42–56 years, within 5–36 months past menopause) in the Kronos Early Estrogen Prevention Study were randomized to (1) 0.45 mg/d oral conjugated equine estrogens (CEE), (2) 50 μg/d transdermal 17β-estradiol, or (3) placebo pills and patch for 48 months. Oral progesterone (200 mg/d) was given to active treatment groups for 12 days each month. MRI and cognitive testing were performed in a subset of participants at baseline, and at 18, 36, and 48 months of randomization (n = 95). Changes in whole brain, ventricular, and white matter hyperintensity volumes, and in global cognitive function, were measured.
Higher rates of ventricular expansion were observed in both the CEE and the 17β-estradiol groups compared to placebo; however, the difference was significant only in the CEE group (p = 0.01). Rates of ventricular expansion correlated with rates of decrease in brain volume (r = −0.58; p ≤ 0.001) and with rates of increase in white matter hyperintensity volume (r = 0.27; p = 0.01) after adjusting for age. The changes were not different between the CEE and 17β-estradiol groups for any of the MRI measures. The change in global cognitive function was not different across the groups.
Ventricular volumes increased to a greater extent in recently menopausal women who received CEE compared to placebo but without changes in cognitive performance. Because the sample size was small and the follow-up limited to 4 years, the findings should be interpreted with caution and need confirmation.
Classification of evidence:
This study provides Class I evidence that brain ventricular volume increased to a greater extent in recently menopausal women who received oral CEE compared to placebo.
PMCID: PMC5035155  PMID: 27473135
8.  TREM2 p.R47H substitution is not associated with dementia with Lewy bodies 
Neurology: Genetics  2016;2(4):e85.
Dementia with Lewy bodies (DLB) is the second leading cause of neurodegenerative dementia in the elderly and is clinically characterized by the presence of cognitive decline, parkinsonism, REM sleep behavior disorder, and visual hallucinations.1,2 At autopsy, α-synuclein–positive Lewy-related pathology is observed throughout the brain. Concomitant Alzheimer disease–related pathology including amyloid plaques and, to a lesser degree, neurofibrillary tangles are often present.2 The clinical characteristics of DLB share overlapping features with Alzheimer disease dementia (AD) and Parkinson disease (PD). A recent genetic association study examining known hits from PD and AD identified variants at both the α-synuclein (SNCA) and APOE loci as influencing the individual risk to DLB.3 These findings would suggest that DLB may be a distinct disease with shared genetic risk factors with PD and AD.
PMCID: PMC4946771  PMID: 27458607
9.  Magnetic Resonance Imaging in ADNI 
ADNI is now in its 10th year. The primary objective of the MRI core of ADNI has been to improve methods for clinical trials in Alzheimer’s disease and related disorders.
We review the contributions of the MRI core from present and past cycles of ADNI (ADNI 1, GO and 2). We also review plans for the future – ADNI 3.
Contributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials.
Over the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in Alzheimer’s disease and will continue to do so in the future.
PMCID: PMC4523217  PMID: 26194310
10.  An autoradiographic evaluation of AV-1451 Tau PET in dementia 
It is essential to determine the specificity of AV-1451 PET for tau in brain imaging by using pathological comparisons. We performed autoradiography in autopsy-confirmed Alzheimer disease and other neurodegenerative disorders to evaluate the specificity of AV-1451 binding for tau aggregates.
Tissue samples were selected that had a variety of dementia-related neuropathologies including Alzheimer disease, primary age-related tauopathy, tangle predominant dementia, non-Alzheimer disease tauopathies, frontotemporal dementia, parkinsonism, Lewy body disease and multiple system atrophy (n = 38). Brain tissue sections were stained for tau, TAR DNA-binding protein-43, and α-synuclein and compared to AV-1451 autoradiography on adjacent sections.
AV-1451 preferentially localized to neurofibrillary tangles, with less binding to areas enriched in neuritic pathology and less mature tau. The strength of AV-1451 binding with respect to tau isoforms in various neurodegenerative disorders was: 3R + 4R tau (e.g., AD) > 3R tau (e.g., Pick disease) or 4R tau. Only minimal binding of AV-1451 to TAR DNA-binding protein-43 positive regions was detected. No binding of AV-1451 to α-synuclein was detected. “Off-target” binding was seen in vessels, iron-associated regions, substantia nigra, calcifications in the choroid plexus, and leptomeningeal melanin.
Reduced AV-1451 binding in neuritic pathology compared to neurofibrillary tangles suggests that the maturity of tau pathology may affect AV-1451 binding and suggests complexity in AV-1451 binding. Poor association of AV-1451 with tauopathies that have preferential accumulation of either 4R tau or 3R tau suggests limited clinical utility in detecting these pathologies. In contrast, for disorders associated with 3R + 4R tau, such as Alzheimer disease, AV-1451 binds tau avidly but does not completely reflect the early stage tau progression suggested by Braak neurofibrillary tangle staging. AV-1451 binding to TAR DNA-binding protein-43 or TAR DNA-binding protein-43 positive regions can be weakly positive. Clinical use of AV-1451 will require a familiarity with distinct types of “off-target” binding.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-016-0315-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4906968  PMID: 27296779
AV-1451; Tau; Alzheimer’s disease; TDP-43; Pick Disease; Corticobasal degeneration; Progressive supranuclear palsy; Tauopathy; Pick’s disease; Atypical Alzheimer’s disease; Frontotemporal dementia
11.  White matter integrity in dementia with Lewy bodies: A Voxel-Based Analysis of Diffusion Tensor Imaging 
Neurobiology of aging  2015;36(6):2010-2017.
Many patients with dementia with Lewy bodies have overlapping Alzheimer's disease (AD)–related pathology, which may contribute to white matter (WM) diffusivity alterations on diffusion tensor imaging (DTI). Consecutive patients with DLB (n=30), age and sex matched AD patients (n=30), and cognitively normal controls (CN; n=60) were recruited. All subjects underwent DTI, 18F 2-fluoro-deoxy-d-glucose (FDG) and 11C Pittsburgh compound B (PiB) PET scans. DLB patients had reduced fractional anisotropy (FA) in the parieto-occipital WM but not elsewhere compared to CN, and elevated FA in parahippocampal WM compared to AD patients, which persisted after controlling for Aβ load in DLB. The pattern of WM FA alterations on DTI was consistent with the more diffuse posterior parietal and occipital glucose hypometabolism of FDG PET in the cortex. DLB is characterized by a loss of parieto-occipital WM integrity, independent of concomitant AD-related Aβ load. Cortical glucose hypometabolism accompanies WM FA alterations with a concordant pattern of gray and white matter involvement in the parieto-occipital lobes in DLB.
PMCID: PMC4433563  PMID: 25863527
dementia with Lewy bodies; diffusion tensor imaging; white matter integrity; amyloid-beta load; voxel-based analysis; cortical hypometabolism
12.  White Matter Integrity on DTI, Amyloid Load, and Neurodegeneration in Non-demented Elderly 
JAMA neurology  2014;71(12):1547-1554.
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.
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.
Longitudinal cohort study
Population-based Mayo Clinic Study of Aging.
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)
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.
PMCID: PMC4810441  PMID: 25347157
Diffusion tensor imaging; mild cognitive impairment; preclinical Alzheimer’s disease
13.  Plasma sphingolipid changes with autopsy-confirmed Lewy body or Alzheimer's pathology 
The clinical and pathological phenotypes of Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) often overlap. We examined whether plasma lipids differed among individuals with autopsy-confirmed Lewy Body pathology or AD pathology.
We identified four groups with available plasma 2 years before death: high (n = 12) and intermediate-likelihood DLB (n = 14) based on the third report of the DLB consortium; dementia with Alzheimer's pathology (AD; n = 18); and cognitively normal with normal aging pathology (n = 21). Lipids were measured using ESI/MS/MS.
There were overall group differences in plasma ceramides C16:0, C18:1, C20:0, and C24:1 and monohexosylceramides C18:1 and C24:1. These lipids did not differ between the high-likelihood DLB and AD groups, but both groups had higher levels than normals. Plasma fatty acid levels did not differ by group.
Plasma ceramides and monohexosylceramides are elevated in people with dementia with either high-likelihood DLB or AD pathology.
PMCID: PMC4852484  PMID: 27152320
Alzheimer's disease; Lewy body; Autopsy; Lipids; Ceramide
14.  MRS in Mild Cognitive Impairment: Early Differentiation of Dementia with Lewy Bodies and Alzheimer's Disease 
Background and Purpose
Mild cognitive impairment (MCI) precedes both Alzheimer's disease (AD) dementia and with Lewy bodies (DLB). We investigated proton magnetic resonance spectroscopy (MRS) characteristics of MCI patients who progressed to DLB compared to those who progressed to AD dementia or remained stable.
Consecutive MCI patients who underwent single voxel MRS at baseline and progressed to DLB (n=10) were identified during a median follow-up period of 18 months. From the same cohort, we identified age- and sex-matched MCI patients who progressed to AD dementia (n=27) or remained stable (n=20) during a similar follow-up period. This study was approved by the Institutional Review Board and informed consent was from every subject.
MCI patients who progressed to AD dementia were characterized by lower N-acetylaspartate (NAA)/Cr ratio in the posterior cingulate voxel compared to those who progressed to DLB (p=0.001). Decreased NAA/Cr in the posterior cingulate voxel differentiated MCI patients who progressed to DLB from those who progressed to AD with an area under the receiver operating characteristic curve of 0.85 (p<0.001) on logistic regression analysis.
MRS may be useful in differentiating MCI patients with prodromal AD dementia from those with prodromal DLB for early disease-specific interventions.
PMCID: PMC4295004  PMID: 25039916
Magnetic resonance spectroscopy (MRS); mild cognitive impairment (MCI); dementia with Lewy Bodies (DLB); Alzheimer's disease; MRI
15.  Vascular imaging abnormalities and cognition: Mediation by Cortical Volume in non-demented persons: ARIC-NCS Study 
Background and Purpose
The relationships between cerebrovascular lesions visible on imaging and cognition are complex. We explored the possibility that cerebral cortical volume mediated the relationship.
1906 non-demented participants (59% women; 25% African-American; mean age 76.6 years) in the Atherosclerosis Risk in Communities (ARIC) study underwent cognitive assessments, risk factor assessments, and quantitative MR imaging for white matter hyperintensities (WMH) and infarcts. The Freesurfer imaging analysis pipeline was used to determine regional cerebral volumes. We examined associations of cognitive domain outcomes with cerebral volumes (hippocampus, and separate groups of posterior and frontal cortical regions of interest (ROI)) and cerebrovascular imaging features (presence of large or small cortical/subcortical infarcts and WMH volume). We performed mediation pathway analyses to assess the hypothesis that hippocampal and cortical volumes mediated associations between cerebrovascular imaging features and cognition.
In unmediated analyses, WMH and infarcts were both associated with worse psychomotor speed/executive function (PS/EF). In mediation analyses, WMH and infarcts associations on PS/EF were significantly attenuated, but not abolished, by the inclusion of the posterior cortical ROI volume in the models, and the infarcts on PS/EF association was attenuated, but not abolished, by inclusion of the frontal cortical ROI volume.
Both WMH and infarcts were associated with cortical volume, and both lesions were also associated with cognitive performance, implying shared pathophysiological mechanisms. Although cross-sectional, our findings suggest that WMH and infarcts could be proxies for clinically covert processes that directly damage cortical regions. Microinfarcts are one candidate for such a clinically covert process.
PMCID: PMC4308430  PMID: 25563642
Magnetic resonance imaging; cerebral small vessel disease; white matter hyperintensities; cerebral infarction; cognition
16.  Pattern of Brain Atrophy Rates in Autopsy-Confirmed Dementia with Lewy Bodies 
Neurobiology of aging  2014;36(1):452-461.
Dementia with Lewy bodies (DLB) is characterized by preserved whole brain and medial temporal lobe volumes compared to Alzheimer’s disease dementia (AD) on MRI. However, frequently coexistent AD-type pathology may influence the pattern of regional brain atrophy rates in DLB patients. We investigated the pattern and magnitude of the atrophy rates from two serial MRIs in autopsy-confirmed DLB (n=20) and mixed DLB/AD patients (n=22), compared to AD (n=30) and elderly non-demented controls (n=15), followed antemortem. DLB patients without significant AD-type pathology were characterized by lower global and regional rates of atrophy, similar to controls. The mixed DLB/AD patients displayed greater rates in the whole brain, temporo-parietal cortices, hippocampus and amygdala, and ventricle expansion, similar to AD patients. In the DLB and DLB/AD patients, the atrophy rates correlated with Braak neurofibrillary tangle stage, cognitive decline and progression of motor symptoms. Global and regional atrophy rates are associated with AD-type pathology in DLB, and can be used as biomarkers of AD progression in patients with LB pathology.
PMCID: PMC4268128  PMID: 25128280
autopsy-confirmed dementia with Lewy bodies; Alzheimer’s disease; serial MRI; atrophy rate; Braak neurofibrillary tangle stage; sample size estimate
17.  Independent comparison of CogState computerized testing and a standard cognitive battery with neuroimaging 
Inexpensive, non-invasive tools for assessing Alzheimer-type pathophysiologies are needed. Computerized cognitive assessments are prime candidates.
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.
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.
CogState subtests were cross-sectionally comparable to standard neuropsychological tests in their relatively weak associations with neurodegeneration imaging markers.
PMCID: PMC4273919  PMID: 25458308
Preclinical Alzheimer's disease; Neuropsychology; Computerized cognitive battery; Neuroimaging; Amyloid-beta; Hippocampal volume
20.  18F-fluorodeoxyglucose positron emission tomography, aging, and apolipoprotein E genotype in cognitively normal persons 
Neurobiology of aging  2014;35(9):2096-2106.
Our objective was to examine associations between glucose metabolism, as measured by 18F-fluorodeoxyglucose positron emission tomography (FDG PET), and age and to evaluate the impact of carriage of an apolipoprotein E (APOE) ε4 allele on glucose metabolism and on the associations between glucose metabolism and age. We studied 806 cognitively normal (CN) and 70 amyloid-imaging-positive cognitively impaired participants (35 with mild cognitive impairment and 35 with Alzheimer’s disease [AD] dementia) from the Mayo Clinic Study of Aging, Mayo Alzheimer’s Disease Research Center and an ancillary study who had undergone structural MRI, FDG PET, and 11C-Pittsburgh compound B (PiB) PET. Using partial volume corrected and uncorrected FDG PET glucose uptake ratios, we evaluated associations of regional FDG ratios with age and carriage of an APOE ε4 allele in CN participants between the ages of 30 and 95 years, and compared those findings with the cognitively impaired participants. In region-of-interest (ROI) analyses, we found modest but statistically significant declines in FDG ratio in most cortical and subcortical regions as a function of age. We also found a main effect of APOE ε4 genotype on FDG ratio, with greater uptake in ε4 noncarriers compared with carriers but only in the posterior cingulate and/or precuneus, lateral parietal, and AD-signature meta-ROI. The latter consisted of voxels from posterior cingulate and/or precuneus, lateral parietal, and inferior temporal. In age- and sex-matched CN participants the magnitude of the difference in partial volume corrected FDG ratio in the AD-signature meta-ROI for APOE ε4 carriers compared with noncarriers was about 4 times smaller than the magnitude of the difference between age- and sex-matched elderly APOE ε4 carrier CN compared with AD dementia participants. In an analysis in participants older than 70 years (31.3% of whom had elevated PiB), there was no interaction between PiB status and APOE ε4 genotype with respect to glucose metabolism. Glucose metabolism declines with age in many brain regions. Carriage of an APOE ε4 allele was associated with reductions in FDG ratio in the posterior cingulate and/or precuneus, lateral parietal, and AD-signature ROIs, and there was no interaction between age and APOE ε4 status. The posterior cingulate and/or precuneus and lateral parietal regions have a unique vulnerability to reductions in glucose metabolic rate as a function both of age and carriage of an APOE ε4 allele.
PMCID: PMC4053507  PMID: 24702820
Aging; Alzheimer’s disease; FDG positron emission tomography; Apolipoprotein E
21.  Dementia with Lewy bodies 
Neurology  2014;83(9):801-809.
To investigate clinical, imaging, and pathologic associations of the cingulate island sign (CIS) in dementia with Lewy bodies (DLB).
We retrospectively identified and compared patients with a clinical diagnosis of DLB (n = 39); patients with Alzheimer disease (AD) matched by age, sex, and education (n = 39); and cognitively normal controls (n = 78) who underwent 18F-fluorodeoxyglucose (FDG) and C11 Pittsburgh compound B (PiB)-PET scans. Among these patients, we studied those who came to autopsy and underwent Braak neurofibrillary tangle (NFT) staging (n = 10).
Patients with a clinical diagnosis of DLB had a higher ratio of posterior cingulate to precuneus plus cuneus metabolism, cingulate island sign (CIS), on FDG-PET than patients with AD (p < 0.001), a finding independent of β-amyloid load on PiB-PET (p = 0.56). Patients with CIS positivity on visual assessment of FDG-PET fit into the group of high- or intermediate-probability DLB pathology and received clinical diagnosis of DLB, not AD. Higher CIS ratio correlated with lower Braak NFT stage (r = −0.96; p < 0.001).
Our study found that CIS on FDG-PET is not associated with fibrillar β-amyloid deposition but indicates lower Braak NFT stage in patients with DLB. Identifying biomarkers that measure relative contributions of underlying pathologies to dementia is critical as neurotherapeutics move toward targeted treatments.
PMCID: PMC4155048  PMID: 25056580
22.  Antemortem MRI findings associated with microinfarcts at autopsy 
Neurology  2014;82(22):1951-1958.
To determine antemortem MRI findings associated with microinfarcts at autopsy.
Patients with microinfarcts (n = 22) and patients without microinfarcts (n = 44) who underwent antemortem MRI were identified from a dementia clinic–based, population–based, and community clinic–based autopsy cohort. The microinfarct and no-microinfarct groups were matched on age at MRI, age at death, sex, APOE status, Mini-Mental State Examination score, and pathologic diagnosis of Alzheimer disease. Brain infarcts were assessed on fluid-attenuated inversion recovery (FLAIR) MRI. White matter hyperintensities on FLAIR MRI and hippocampal volumes on T1-weighted MRI were quantified using automated methods. A subset of subjects with microinfarcts (n = 15) and a matched group of subjects without microinfarcts (n = 15) had serial T1-weighted MRIs and were included in an analysis of global and regional brain atrophy rates using automated methods.
The presence of cortical (p = 0.03) and subcortical (p = 0.02) infarcts on antemortem MRI was associated with presence of microinfarcts at autopsy. Higher numbers of cortical (p = 0.05) and subcortical (p = 0.03) infarcts on antemortem MRI were also associated with presence of microinfarcts. Presence of microinfarcts was not associated with white matter hyperintensities and cross-sectional hippocampal volume on antemortem MRI. Whole-brain and regional precuneus, motor, and somatosensory atrophy rates were higher in subjects with microinfarcts compared to subjects without microinfarcts.
Microinfarcts increase brain atrophy rates independent of Alzheimer disease pathology. Association between microinfarct pathology and macroinfarcts on MRI suggests either common risk factors or a shared pathophysiology and potentially common preventive targets.
PMCID: PMC4105260  PMID: 24793188
23.  Association of hypometabolism and amyloid levels in aging, normal subjects 
Neurology  2014;82(22):1959-1967.
We evaluated the relationship of amyloid, seen on Pittsburgh compound B (PiB)-PET, and metabolism, seen on [18F]-fluorodeoxyglucose (FDG)-PET, in normal subjects to better understand pathogenesis and biomarker selection in presymptomatic subjects.
Normal participants (aged 70–95 years; 600 with PiB-PET, FDG-PET, and MRI) were included. We performed a cross-sectional evaluation and subcategorized participants into amyloid-negative (<1.4), high-normal (1.4–1.5), positive (1.5–2.0), and markedly positive (>2.0) PiB standardized uptake value ratio groups representing different levels of amyloid brain load. Associations with metabolism were assessed in each group. Relationships with APOE ε4 carriage were evaluated.
Hypometabolism in “Alzheimer disease (AD)-signature” regions was strongly associated with PiB load. Hypometabolism was greater with more positive PiB levels. Additional, more-diffuse cortical hypometabolism was also found to be associated with PiB, although less so. No hypermetabolism was seen in any subset. No significant incremental hypometabolism was seen in APOE-positive vs -negative subjects.
Hypometabolism in PiB-positive, cognitively normal subjects in a population-based cohort occurs in AD-signature cortical regions and to a lesser extent in other cortical regions. It is more pronounced with higher amyloid load and supports a dose-dependent association. The effect of APOE ε4 carriage in this group of subjects does not appear to modify their hypometabolic “AD-like” neurodegeneration. Consideration of hypometabolism associated with amyloid load may aid trials of AD drug therapy.
PMCID: PMC4105262  PMID: 24793183
24.  Early Alzheimer's Disease Neuropathology Detected by Proton MR Spectroscopy 
The Journal of Neuroscience  2014;34(49):16247-16255.
Proton magnetic resonance spectroscopy (1H-MRS) is sensitive to early neurodegenerative processes associated with Alzheimer's disease (AD). Although 1H-MRS metabolite ratios of N-acetyl aspartate (NAA)/creatine (Cr), NAA/myoinositol (mI), and mI/Cr measured in the posterior cingulate gyrus reveal evidence of disease progression in AD, pathologic underpinnings of the 1H-MRS metabolite changes in AD are unknown. Pathologically diagnosed human cases ranging from no likelihood to high likelihood AD (n = 41, 16 females and 25 males) who underwent antemortem 1H-MRS of the posterior cingulate gyrus at 3 tesla were included in this study. Immunohistochemical evaluation was performed on the posterior cingulate gyrus using antibodies to synaptic vesicles, hyperphosphorylated tau (pTau), neurofibrillary tangle conformational-epitope (cNFT), amyloid-β, astrocytes, and microglia. The slides were digitally analyzed using Aperio software, which allows neuropathologic quantification in the posterior cingulate gray matter. MRS and pathology associations were adjusted for time from scan to death. Significant associations across AD and control subjects were found between reduced synaptic immunoreactivity and both NAA/Cr and NAA/mI in the posterior cingulate gyrus. Higher pTau burden was associated with lower NAA/Cr and NAA/mI. Higher amyloid-β burden was associated with elevated mI/Cr and lower NAA/mI ratios, but not with NAA/Cr. 1H-MRS metabolite levels reveal early neurodegenerative changes associated with AD pathology. Our findings support the hypothesis that a decrease in NAA/Cr is associated with loss of synapses and early pTau pathology, but not with amyloid-β or later accumulation of cNFT pathology in the posterior cingulate gyrus. In addition, elevation of mI/Cr is associated with the occurrence of amyloid-β plaques in AD.
PMCID: PMC4252542  PMID: 25471565
Alzheimer's disease; digital microscopy; magnetic resonance spectroscopy; neuropathology; posterior cingulate; tau
25.  Regional Proton Magnetic Resonance Spectroscopy Patterns in Dementia with Lewy Bodies 
Neurobiology of aging  2014;35(6):1483-1490.
Magnetic resonance spectroscopy (MRS) characteristics of dementia with Lewy bodies (DLB) Alzheimer’s disease (AD) and cognitively normal controls (CN) were compared. DLB (n=34), AD (n=35) and CN (n=148) participated in a MRS study from frontal, posterior cingulate and occipital voxels. We investigated DLB patients with preserved hippocampal volumes to determine the MRS changes in DLB with low probability of overlapping AD pathology. DLB patients were characterized by decreased NAA/Cr in the occipital voxel. AD patients were characterized by lower NAA/Cr in the frontal and posterior cingulate voxels. Normal NAA/Cr levels in the frontal voxel differentiated DLB patients with preserved hippocampal volumes from AD patients. DLB and AD patients had elevated Cho/Cr and mI/Cr in the posterior cingulate. MRS abnormalities associated with loss of neuronal integrity localized to the occipital lobes in DLB, and the posterior cingulate gyri and frontal lobes in AD. This pattern of MRS abnormalities may have a role in differential diagnosis of DLB and in distinguishing DLB patients with overlapping AD pathology.
PMCID: PMC3961495  PMID: 24468473
Dementia with Lewy Bodies; Magnetic resonance spectroscopy; Alzheimer’s disease

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