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1.  A Comparative Survey of the Topographical Distribution of Signature Molecular Lesions in Major Neurodegenerative Diseases 
The Journal of comparative neurology  2013;521(18):10.1002/cne.23430.
An understanding of the anatomic distributions of major neurodegenerative disease lesions is important to appreciate the differential clinical profiles of these disorders and to serve as neuropathological standards for emerging molecular neuroimaging methods. To address these issues, here we present a comparative survey of the topographical distribution of the defining molecular neuropathological lesions among ten neurodegenerative diseases from a large and uniformly assessed brain collection. Ratings of pathological severity in sixteen brain regions from 671 cases with diverse neurodegenerative diseases were summarized and analyzed. These included: a) amyloid-β and tau lesions in Alzheimer’s disease, b) tau lesions in three other tauopathies including Pick’s disease, progressive supranuclear palsy and corticobasal degeneration, c) α-synuclein inclusion ratings in four synucleinopathies including Parkinson’s disease, Parkinson’s disease with dementia, dementia with Lewy bodies and multiple system atrophy, and d) TDP-43 lesions in two TDP-43 proteinopathies, including frontotemporal lobar degeneration associated with TDP-43 and amyotrophic lateral sclerosis. The data presented graphically and topographically confirm and extend previous pathological anatomic descriptions and statistical comparisons highlight the lesion distributions that either overlap or distinguish the diseases in each molecular disease category.
PMCID: PMC3872132  PMID: 23881776
Alzheimer’s disease; Pick’s disease; corticobasal degeneration; progressive supranuclear palsy; Parkinson’s disease; Parkinson’s disease dementia; dementia with Lewy bodies; multiple system atrophy; frontotemporal lobar degeneration - TDP; amyotrophic lateral sclerosis; amyloid-β; Tau α-synuclein; TDP-43
2.  Amyloid Imaging in Atypical Presentations of Alzheimer’s Disease 
Current neurology and neuroscience reports  2013;13(12):10.1007/s11910-013-0412-x.
Alzheimer’s disease (AD) is thought to progress in a fairly stereotyped manner with episodic memory loss being the first and most salient domain of impairment reflecting the early pathology in structures supporting this function. However, there is considerable heterogeneity in the relative involvement of different cognitive domains and at the extreme are three syndromes associated with AD pathology: 1) Logopenic Progressive Aphasia, 2) Posterior Cortical Atrophy, and 3) Frontal Variant of AD. As each of these syndromes is variably associated with non-AD pathology and clinically overlaps with other presentations more commonly associated with different etiologies of neurodegeneration (e.g. progressive non-fluent aphasia), the use of amyloid imaging for detection of the molecular pathology of AD is of significant clinical value. The current manuscript will review several amyloid imaging studies of these populations which support autopsy case series and reveal a dissociation between the spatial distribution of amyloid pathology and clinical phenotype.
PMCID: PMC3863595  PMID: 24136459
atypical dementia; logopenic progressive aphasia; posterior cortical atrophy; frontal variant of Alzheimer’s disease; amyloid imaging
3.  Association of Plasma C-Reactive Protein Levels with Diagnosis of Alzheimer’s Disease 
Journal of the neurological sciences  2013;333(0):10.1016/j.jns.2013.05.028.
C-reactive protein (CRP) participates in the systemic response to inflammation. Previous studies report inconsistent findings regarding the relationship between plasma CRP and Alzheimer’s disease (AD). We measured plasma CRP in 203 subjects with AD, 58 subjects with mild cognitive impairment (MCI) and 117 normal aging subjects and administered annual mini-mental state examinations (MMSE) during a three year follow-up period to investigate CRP’s relationship with diagnosis and progression of cognitive decline. Adjusted for age, sex, and education, subjects with AD had significantly lower levels of plasma CRP than subjects with MCI and normal aging. However, there was no significant association between plasma CRP at baseline and subsequent cognitive decline as assessed by longitudinal changes in MMSE score. Our results support previous reports of reduced levels of plasma CRP in AD and indicate its potential utility as a biomarker for the diagnosis of AD.
PMCID: PMC3815534  PMID: 23978419
Alzheimer Disease; Mild Cognitive Impairment; C-Reactive Protein; Inflammation; Biological Markers
4.  Comparative accuracies of two common screening instruments for the classification of Alzheimer’s disease, mild cognitive impairment and healthy aging 
To compare the utility and diagnostic accuracy of the MoCA and MMSE in the diagnosis of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) in a clinical cohort.
321 AD, 126 MCI and 140 older adults with healthy cognition (HC) were evaluated using the the MMSE, MoCA, a standardized neuropsychological battery according to the Consortium to Establish a Registry of Alzheimer’s Disease (CERAD-NB) and an informant based measure of functional impairment, the Dementia Severity Rating Scale (DSRS). Diagnostic accuracy and optimal cut-off scores were calculated for each measure, and a method for converting MoCA to MMSE scores is presented also.
The MMSE and MoCA offer reasonably good diagnostic and classification accuracy as compared to the more detailed CERAD-NB; however, as a brief cognitive screening measure the MoCA was more sensitive and had higher classification accuracy for differentiating MCI from HC. Complementing the MMSE or the MoCA with the DSRS significantly improved diagnostic accuracy.
The current results support recent data indicating that the MoCA is superior to the MMSE as a global assessment tool, particularly in discerning earlier stages of cognitive decline. In addition, we found that overall diagnostic accuracy improves when the MMSE or MoCA is combined with an informant-based functional measure. Finally, we provide a reliable and easy conversion of MoCA to MMSE scores. However, the need for MCI-specific measures is still needed to increase the diagnostic specificity between AD and MCI.
PMCID: PMC4036230  PMID: 23260866
Alzheimer’s disease; Mild Cognitive Impairment; MMSE; MoCA; Diagnostic accuracy
5.  The effects of aging and Alzheimer's disease on cerebral cortical anatomy: Specificity and differential relationships with cognition 
NeuroImage  2013;76:332-344.
Although both normal aging and Alzheimer's disease (AD) are associated with regional cortical atrophy, few studies have directly compared the spatial patterns and magnitude of effects of these two processes. The extant literature has not addressed two important questions: 1) Is the pattern of age-related cortical atrophy different if cognitively intact elderly individuals with silent AD pathology are excluded? and 2) Does the age- or AD-related atrophy relate to cognitive function? Here we studied 142 young controls, 87 older controls, and 28 mild AD patients. In addition, we studied 35 older controls with neuroimaging data indicating the absence of brain amyloid. Whole-cortex analyses identified regions of interest (ROIs) of cortical atrophy in aging and in AD. Results showed that some regions are predominantly affected by age with relatively little additional atrophy in patients with AD, e.g., calcarine cortex; other regions are predominantly affected by AD with much less of an effect of age, e.g., medial temporal cortex. Finally, other regions are affected by both aging and AD, e.g., dorsolateral prefrontal cortex and inferior parietal lobule. Thus, the processes of aging and AD have both differential and partially overlapping effects on specific regions of the cerebral cortex. In particular, some frontoparietal regions are affected by both processes, most temporal lobe regions are affected much more prominently by AD than aging, while sensorimotor and some prefrontal regions are affected specifically by aging and minimally more by AD. Within normal older adults, atrophy in aging-specific cortical regions relates to cognitive performance, while in AD patients atrophy in AD-specific regions relates to cognitive performance. Further work is warranted to investigate the behavioral and clinical relevance of these findings in additional detail, as well as their histological basis; ROIs generated from the present study could be used strategically in such investigations.
PMCID: PMC4098706  PMID: 23507382
Magnetic resonance imaging; Cerebral cortex; Aging; Alzheimer' disease; Parietal lobe; Frontal lobe; Temporal lobe
6.  A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank 
Neurodegenerative diseases (NDs) are defined by the accumulation of abnormal protein deposits in the central nervous system (CNS), and only neuropathological examination enables a definitive diagnosis. Brain banks and their associated scientific programs have shaped the actual knowledge of NDs, identifying and characterizing the CNS deposits that define new diseases, formulating staging schemes, and establishing correlations between neuropathological changes and clinical features. However, brain banks have evolved to accommodate the banking of biofluids as well as DNA and RNA samples. Moreover, the value of biobanks is greatly enhanced if they link all the multidimensional clinical and laboratory information of each case, which is accomplished, optimally, using systematic and standardized operating procedures, and in the framework of multidisciplinary teams with the support of a flexible and user-friendly database system that facilitates the sharing of information of all the teams in the network. We describe a biobanking system that is a platform for discovery research at the Center for Neurodegenerative Disease Research at the University of Pennsylvania.
PMCID: PMC3933464  PMID: 23978324
Cerebrospinal fluid; Plasma; Serum; Autopsy; Neurodegeneration; Alzheimer’s Disease; Dementia; Genetics; Parkinson’s Disease; Frontotemporal lobar degeneration
7.  Resilient Brain Aging: Characterization of Discordance between Alzheimer’s Disease Pathology and Cognition 
Current Alzheimer research  2013;10(8):844-851.
Although it is now evident that normal cognition can occur despite significant AD pathology, few studies have attempted to characterize this discordance, or examine factors that may contribute to resilient brain aging in the setting of AD pathology.
More than 2,000 older persons underwent annual evaluation as part of participation in the Religious Orders Study or Rush Memory Aging Project. A total of 966 subjects who had brain autopsy and comprehensive cognitive testing proximate to death were analyzed. Resilience was quantified as a continuous measure using linear regression modeling, where global cognition was entered as a dependent variable and global pathology was an independent variable. Studentized residuals generated from the model represented the discordance between cognition and pathology, and served as measure of resilience. The relation of resilience index to known risk factors for AD and related variables was examined.
Multivariate regression models that adjusted for demographic variables revealed significant associations for early life socioeconomic status, reading ability, APOE-ε4 status, and past cognitive activity. A stepwise regression model retained reading level (estimate = 0.10, SE = 0.02; p < 0.0001) and past cognitive activity (estimate = 0.27, SE = 0.09; p = 0.002), suggesting the potential mediating role of these variables for resilience.
The construct of resilient brain aging can provide a framework for quantifying the discordance between cognition and pathology, and help identify factors that may mediate this relationship.
PMCID: PMC4060425  PMID: 23919768
Cognitive activity; Neuropathology; Reading level; Reserve; Resilience
8.  Familiarity-based memory as an early cognitive marker of preclinical and prodromal AD 
Neuropsychologia  2013;51(6):1094-1102.
There is great interest in the development of cognitive markers that differentiate “normal” age-associated cognitive change from that of Alzheimer's disease (AD) in its prodromal (i.e., mild cognitive impairment; MCI) or even preclinical stages. Dual process models posit that recognition memory is supported by the dissociable processes of recollection and familiarity. Familiarity-based memory has generally been considered to be spared during normal aging, but it remains controversial whether this type of memory is impaired in early AD. Here, we describe findings of estimates of recollection and familiarity in young adults (YA), cognitively normal older adults (CN), and patients with amnestic-MCI (a-MCI). These measures in the CN and a-MCI patients were then related to a structural imaging biomarker of AD that has previously been demonstrated to be sensitive to preclinical and prodromal AD, the Cortical Signature of AD (ADsig). Consistent with much work in the literature, recollection, but not familiarity, was impaired in CN versus YA. Replicating our prior findings, a-MCI patients displayed impairment in both familiarity and recollection. Finally, the familiarity measure was correlated with the ADsig biomarker across the CN and a-MCI group, as well as within the CN adults alone. No other standard psychometric measure was as highly associated with the ADsig, suggesting that familiarity may be a sensitive biomarker of AD-specific brain changes in preclinical and prodromal AD and that it may offer a qualitatively distinct measure of early AD memory impairment relative to normal age-associated change.
PMCID: PMC3742759  PMID: 23474075
Memory; Recollection; Familiarity; Alzheimer's disease; Medial temporal lobe; Preclinical Alzheimer's disease; Mild cognitive impairment
9.  Diagnostic effectiveness of quantitative [18F]flutemetamol PET imaging for detection of fibrillar amyloid β using cortical biopsy histopathology as the standard of truth in subjects with idiopathic normal pressure hydrocephalus 
PET imaging of amyloid-β (Aβ) in vivo holds promise for aiding in earlier diagnosis and intervention in Alzheimer’s disease (AD) and mild cognitive impairment. AD-like Aβ pathology is a common comorbidity in patients with idiopathic normal pressure hydrocephalus (iNPH). Fifty patients with iNPH needing ventriculo-peritoneal shunting or intracranial pressure monitoring underwent [18F]flutemetamol PET before (N = 28) or after (N = 22) surgery. Cortical uptake of [18F]flutemetamol was assessed visually by blinded reviewers, and also quantitatively via standard uptake value ratio (SUVR) in specific neocortical regions in relation to either cerebellum or pons reference region: the cerebral cortex of (prospective studies) or surrounding (retrospective studies) the biopsy site, the contralateral homolog, and a calculated composite brain measure. Aβ pathology in the biopsy specimen (standard of truth [SoT]) was measured using Bielschowsky silver and thioflavin S plaque scores, percentage area of grey matter positive for monoclonal antibody to Aβ (4G8), and overall pathology impression. We set out to find (1) which pair(s) of PET SUVR and pathology SoT endpoints matched best, (2) whether quantitative measures of [18F]flutemetamol PET were better for predicting the pathology outcome than blinded image examination (BIE), and (3) whether there was a better match between PET image findings in retrospective vs. prospective studies.
Of the 24 possible endpoint/SoT combinations, the one with composite-cerebellum SUVR and SoT based on overall pathology had the highest Youden index (1.000), receiver operating characteristic area under the curve (1.000), sensitivity (1.000), specificity (1.000), and sum of sensitivity and specificity for the pooled data as well as for the retrospective and prospective studies separately (2.00, for all 3). The BIE sum of sensitivity and specificity, comparable to that for quantitation, was highest using Bielschowsky silver as SoT for all SUVRs (ipsilateral, contralateral, and composite, for both reference regions). The composite SUVR had a 100% positive predictive value (both reference regions) for the overall pathology diagnosis. All SUVRs had a 100% negative predictive value for the Bielschowsky silver result.
Bielschowsky silver stain and overall pathology judgment showed the strongest associations with imaging results.
PMCID: PMC4003513  PMID: 24755237
Alzheimer’s disease; PET; Brain biopsy; [18F]flutemetamol; Fibrillar amyloid β; Normal pressure hydrocephalus
10.  Neuronal injury biomarkers and prognosis in ADNI subjects with normal cognition 
Based on previous studies, a preclinical classification for Alzheimer’s disease (AD) has been proposed. However, 1) specificity of the different neuronal injury (NI) biomarkers has not been studied, 2) subjects with subtle cognitive impairment but normal NI biomarkers (SCINIB) have not been included in the analyses and 3) progression to mild cognitive impairment (MCI) or dementia of the AD type (DAT), referred to here as MCI/DAT, varies between studies. Therefore, we analyzed data from 486 cognitively normal (CN) and 327 DAT subjects in the AD Neuroimaging Initiative (ADNI)-1/GO/2 cohorts.
In the ADNI-1 cohort (median follow-up of 6 years), 6.3% and 17.0% of the CN subjects developed MCI/DAT after 3 and 5 years follow-up, respectively. NI biomarker cutoffs [structural magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET) and cerebrospinal fluid (CSF) tau] were established in DAT patients and memory composite scores were calculated in CN subjects in a cross-sectional sample (n = 160). In the complete longitudinally followed CN ADNI cohort (n = 326, median follow-up of 2 years), CSF and MRI values predicted an increased conversion to MCI/DAT. Different NI biomarkers showed important disagreements for classifying subjects as abnormal NI [kappa = (−0.05)-(0.33)] and into AD preclinical groups. SCINIB subjects (5.0%) were more prevalent than AD preclinical stage 3 subjects (3.4%) and showed a trend for increased progression to MCI/DAT.
Different NI biomarkers lead to different classifications of ADNI subjects, while structural MRI and CSF tau measures showed the strongest predictive value for progression to MCI/DAT. The newly defined SCINIB category of ADNI subjects is more prevalent than AD preclinical stage individuals.
PMCID: PMC4008258  PMID: 24602322
Dementia; Alzheimer’s disease; Magnetic resonance imaging; Cerebrospinal fluid; Amyloid beta; Tau
11.  Cognitive decline and reduced survival in C9orf72 expansion Frontotemporal degeneration and Amyotrophic lateral sclerosis 
Significant heterogeneity in clinical features of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) cases with the pathogenic C9orf72 expansion (C9P) have been described. To clarify this issue, we compared a large C9P cohort with carefully matched non-expansion (C9N) cases with a known or highly-suspected underlying TDP-43 proteinopathy.
A retrospective-cohort study using available cross-sectional and longitudinal clinical and neuropsychological data, MRI voxel-based morphometry (VBM) and neuropathological assessment from 64 C9P cases (ALS=31, FTLD=33) and 79 C9N cases (ALS=36, FTLD=43).
C9P cases had an earlier age of onset (p=0.047), and in the subset of deceased patients, an earlier age of death (p=0.014) than C9N. C9P had more rapid progression than C9N: C9P ALS cases had a shortened survival (2.6±0.3 years) compared to C9N ALS (3.8±0.4 years; log-rankλ2=4.183,p=0.041), and C9P FTLD showed a significantly greater annualized rate of decline in letter fluency (4.5±1.3words/year) than C9N FTLD (1.4±0.8words/year, p=0.023). VBM revealed greater atrophy in the right fronto-insular, thalamus, cerebellum and bilateral parietal regions for C9P FTLD relative to C9N FTLD, and regression analysis related verbal fluency scores to atrophy in frontal and parietal regions. Neuropathologic analysis found greater neuronal loss in the mid-frontal cortex in C9P FTLD, and mid-frontal cortex TDP-43 inclusion severity correlated with poor letter fluency performance.
C9P cases may have a shorter survival in ALS and more rapid rate of cognitive decline related to frontal and parietal disease in FTLD. C9orf72 genotyping may provide useful prognostic and diagnostic clinical information for ALS and FTLD patients.
PMCID: PMC3543474  PMID: 23117491
Frontotemporal dementia; Amyotrophic lateral sclerosis; C9orf72; neuropsychological tests; neuroimaging
12.  Can MRI screen for CSF biomarkers in neurodegenerative disease? 
Neurology  2013;80(2):132-138.
Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) may have overlapping clinical presentations despite distinct underlying neuropathologies, thus making in vivo diagnosis challenging. In this study, we evaluate the utility of MRI as a noninvasive screening procedure for the differential diagnosis of AD and FTLD.
We recruited 185 patients with a clinically diagnosed neurodegenerative disease consistent with AD or FTLD who had a lumbar puncture and a volumetric MRI. A subset of 32 patients had genetic or autopsy-confirmed AD or FTLD. We used singular value decomposition to decompose MRI volumes and linear regression and cross-validation to predict CSF total tau (tt) and β-amyloid (Aβ1-42) ratio (tt/Aβ) in patients with AD and patients with FTLD. We then evaluated accuracy of MRI-based predicted tt/Aβ using 4 converging sources including neuroanatomic visualization and categorization of a subset of patients with genetic or autopsy-confirmed AD or FTLD.
Regression analyses showed that MRI-predicted tt/Aβ is highly related to actual CSF tt/Aβ. In each group, both predicted and actual CSF tt/Aβ have extensively overlapping neuroanatomic correlates: low tt/Aβ consistent with FTLD is related to ventromedial prefrontal regions while high tt/Aβ consistent with AD is related to posterior cortical regions. MRI-predicted tt/Aβ is 75% accurate at identifying underlying diagnosis in patients with known pathology and in clinically diagnosed patients with known CSF tt/Aβ levels.
MRI may serve as a noninvasive procedure that can screen for AD and FTLD pathology as a surrogate for CSF biomarkers.
PMCID: PMC3589187  PMID: 23269595
13.  Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease 
Neurobiology of aging  2012;34(1):157-168.
While neuritic plaques and neurofibrillary tangles in older adults are correlated with cognitive impairment and severity of dementia, it has long been recognized that the relationship is imperfect as some people exhibit normal cognition despite high levels of AD pathology. We compared the cellular, synaptic and biochemical composition of midfrontal cortices in female subjects from the Religious Orders Study who were stratified into three subgroups: 1) pathological AD with normal cognition (“AD-Resilient”), 2) pathological AD with AD-typical dementia (“AD-Dementia)” and 3) pathologically normal with normal cognition (“Normal Comparison”). The AD-Resilient group exhibited preserved densities of synaptophysin-labeled presynaptic terminals and synaptopodin-labeled dendritic spines compared to the AD-Dementia group, and increased densities of GFAP astrocytes compared to both the AD-Dementia and Normal Comparison group. Further, in a discovery antibody microarray protein analysis we identified a number of candidate protein abnormalities that were associated with diagnostic group. These data characterize cellular and synaptic features and identify novel biochemical targets that may be associated with resilient cognitive brain aging in the setting of pathological AD.
PMCID: PMC3478410  PMID: 22554416
cognitive reserve; synapse; synaptophysin; synaptopodin; glial fibrillary acidic protein; antibody microarray
14.  Vascular Disease and Dementias: Paradigm Shifts to Drive Research in New Directions 
Vascular disease was once considered the principal cause of aging-related dementia. More recently, however, research emphasis has shifted to studies of progressive neurodegenerative disease processes such as those giving rise to neuritic plaques, neurofibrillary tangles, and Lewy bodies. While these studies have led to critical insights and potential therapeutic strategies, interest in the role of systemic and cerebrovascular disease mechanisms waned and has received relatively less attention and research support. Recent studies suggest that vascular disease mechanisms play an important role in the risk for aging-related cognitive decline and disorders. Vascular disease frequently coexists with cognitive decline in aging individuals, shares many risk factors with dementias considered to be of the “Alzheimer-type,” and is observed more frequently than expected in postmortem material from individuals manifesting “specific” disease stigmata such as abundant plaques and tangles. Considerable difficulties have emerged in attempting to classify dementias as being related to vascular vs. neurodegenerative causes, and several systems of criteria have been used. Despite multiple attempts, a lack of consensus remains regarding the optimal means of incorporating vascular disease into clinical diagnostic, neurocognitive, or neuropathologic classification schemes for dementias.
We propose here an integrative, rather than a strictly taxonomic approach to the study and elucidation of how vascular disease mechanisms contribute to the development of dementias. We argue that, instead of discriminating between, e.g., “Alzheimer’s disease,” “vascular dementia,” and other diseases, there is a greater need to focus clinical and research efforts on elucidating specific pathophysiologic mechanisms that contribute to dementia phenotypes and neuropathologic outcomes. We outline a multi-tiered strategy, beginning with clinical and public health interventions that can be implemented immediately; enhancements to ongoing longitudinal studies to increase their informative value; and new initiatives to capitalize on recent advances in systems biology and network medicine. This strategy will require funding from multiple public and private sources to support collaborative and interdisciplinary research efforts in order to take full advantage of these opportunities and realize their societal benefits.
PMCID: PMC3640817  PMID: 23183137
15.  Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias 
Brain  2012;135(12):3749-3756.
A growing body of evidence demonstrates an association between vascular risk factors and Alzheimer’s disease. This study investigated the frequency and severity of atherosclerotic plaques in the circle of Willis in Alzheimer’s disease and multiple other neurodegenerative diseases. Semi-quantitative data from gross and microscopic neuropathological examinations in 1000 cases were analysed, including 410 with a primary diagnosis of Alzheimer’s disease, 230 with synucleinopathies, 157 with TDP-43 proteinopathies, 144 with tauopathies and 59 with normal ageing. More than 77% of subjects with Alzheimer’s disease had grossly apparent circle of Willis atherosclerosis, a percentage that was significantly higher than normal (47%), or other neurodegenerative diseases (43–67%). Age- and sex-adjusted atherosclerosis ratings were highly correlated with neuritic plaque, paired helical filaments tau neurofibrillary tangle and cerebral amyloid angiopathy ratings in the whole sample and within individual groups. We found no associations between atherosclerosis ratings and α-synuclein or TDP-43 lesion ratings. The association between age-adjusted circle of Willis atherosclerosis and Alzheimer’s disease–type pathology was more robust for female subjects than male subjects. These results provide further confirmation and specificity that vascular disease and Alzheimer’s disease are interrelated and suggest that common aetiologic or reciprocally synergistic pathophysiological mechanisms promote both vascular pathology and plaque and tangle pathology.
PMCID: PMC3577102  PMID: 23204143
atherosclerosis; neuritic plaques; neurofibrillary tangles; synuclein; TDP-43
16.  Integration and relative value of biomarkers for prediction of MCI to AD progression: Spatial patterns of brain atrophy, cognitive scores, APOE genotype and CSF biomarkers☆☆☆ 
NeuroImage : Clinical  2013;4:164-173.
This study evaluates the individual, as well as relative and joint value of indices obtained from magnetic resonance imaging (MRI) patterns of brain atrophy (quantified by the SPARE-AD index), cerebrospinal fluid (CSF) biomarkers, APOE genotype, and cognitive performance (ADAS-Cog) in progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) within a variable follow-up period up to 6 years, using data from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1). SPARE-AD was first established as a highly sensitive and specific MRI-marker of AD vs. cognitively normal (CN) subjects (AUC = 0.98). Baseline predictive values of all aforementioned indices were then compared using survival analysis on 381 MCI subjects. SPARE-AD and ADAS-Cog were found to have similar predictive value, and their combination was significantly better than their individual performance. APOE genotype did not significantly improve prediction, although the combination of SPARE-AD, ADAS-Cog and APOE ε4 provided the highest hazard ratio estimates of 17.8 (last vs. first quartile). In a subset of 192 MCI patients who also had CSF biomarkers, the addition of Aβ1–42, t-tau, and p-tau181p to the previous model did not improve predictive value significantly over SPARE-AD and ADAS-Cog combined. Importantly, in amyloid-negative patients with MCI, SPARE-AD had high predictive power of clinical progression. Our findings suggest that SPARE-AD and ADAS-Cog in combination offer the highest predictive power of conversion from MCI to AD, which is improved, albeit not significantly, by APOE genotype. The finding that SPARE-AD in amyloid-negative MCI patients was predictive of clinical progression is not expected under the amyloid hypothesis and merits further investigation.
•813 ADNI-1 subjects are analyzed using pattern recognition methods.•Combination of SPARE-AD and ADAS-Cog offer high predictive index on MCI progression.•Cox PH models showed predictors were highly associated with time to AD conversion.•SPARE-AD in amyloid-negative MCI patients predicts clinical progression.
PMCID: PMC3871290  PMID: 24371799
Early Alzheimer's disease; Biomarkers of AD; Magnetic resonance imaging; Dementia; Mild cognitive impairment; Cerebrospinal fluid; Amyloid
17.  Functional Connectivity Measured with Magnetoencephalography Identifies Persons with HIV Disease 
Brain imaging and behavior  2012;6(3):366-373.
There is need for a valid and reliable biomarker for HIV Associated Neurocognitive Disorder (HAND). The purpose of the present study was to provide preliminary evidence of the potential utility of neuronal functional connectivity measures obtained using magnetoencephalography (MEG) to identify HIV-associated changes in brain function. Resting state, eyes closed, MEG data from 10 HIV-infected individuals and 8 seronegative controls were analyzed using mutual information (MI) between all pairs of MEG sensors to determine whether there were functional brain networks that distinguished between subject groups based on cognition (global and learning) or on serostatus.
Three networks were identified across all subjects, but after permutation testing (at α < .005) only the one related to HIV serostatus was significant. The network included MEG sensors (planar gradiometers) above the right anterior region connecting to sensors above the left posterior region. A mean MI value was calculated across all connections from the anterior to the posterior groupings; that score distinguished between the serostatus groups with only one error (sensitivity = 1.00, specificity = .88 (X2 = 15.4, df = 1, p < .01, Relative Risk = .11). There were no significant associations between the MI value and the neuropsychological Global Impairment rating, substance abuse, mood disorder, age, education, CD4+ cell counts or HIV viral load.
We conclude that using a measure of functional connectivity, it may be possible to distinguish between HIV-infected and uninfected individuals, suggesting that MEG may have the potential to serve as a sensitive, non-invasive biomarker for HAND.
PMCID: PMC3351549  PMID: 22328062
HIV Disease; Cognition; Magnetoencephalography; Functional Connectivity
18.  Amyloid Imaging in Dementias With Atypical Presentation 
We explored the potential value of amyloid imaging in patients with atypical presentations of dementia. Twenty-eight patients with atypical dementia underwent PET imaging with the amyloid imaging tracer Pittsburgh Compound-B (PiB). Twenty-six had [18F]fluoro-2-deoxy-D-glucose (FDG) PET scans. After extensive clinical evaluation, this group of patients generated considerable diagnostic uncertainty and received working diagnoses that included possible AD (pAD), focal dementias [e.g. posterior cortical atrophy (PCA)], or cases in which no clear diagnostic category could be determined (dementia of uncertain etiology; DUE). Patients were classified as PiB-positive, -negative, or -intermediate based on objective criteria. Anterior-posterior (A-P) and left-right (L-R) indices of PiB and FDG uptake were calculated to examine differences in distribution of amyloid pathology and metabolic changes associated with clinical phenotype. Eleven patients (39%) were PiB-positive, 16 were PiB-negative (57%) and one (4%) was intermediate. By diagnostic category, 3/10 patients (30%) with DUE, 1/5 (20%) with primary progressive aphasia (PPA), 3/5 (60%) with posterior cortical atrophy (PCA), and 4/7 (57%) with pAD were PiB-positive. Brain metabolism of both PiB-positive and -negative patients were generally similar by phenotype, but differed from typical AD. PCA patients also appeared to differ in their relative distribution of PiB compared to typical AD, consistent with their atypical phenotype. AD pathology is frequently present in atypical presentations of dementia and can be identified by amyloid imaging. Clinical phenotype is more related to the pattern of cerebral hypometabolism than the presence/absence of amyloid pathology. These findings have diagnostic, prognostic, and therapeutic implications.
PMCID: PMC3517915  PMID: 22285638
Amyloid imaging; PiB; PET; Alzheimer’s Disease; Posterior Cortical Atrophy; dementia; focal dementia
20.  Potential Utility of Resting-State Magnetoencephalography as a Biomarker of CNS Abnormality in HIV Disease 
Journal of Neuroscience Methods  2012;206(2):176-182.
There is a lack of a neuroimaging biomarker for HIV-Associated Neurocognitive Disorder. We report magnetoencephalography (MEG) data from patients with HIV disease and risk-group appropriate controls that were collected to determine the MEG frequency profile during the resting state, and the stability of the profile over 24 weeks. 17 individuals (10 HIV+, 7 HIV−) completed detailed neurobehavioral evaluations and 10 minutes of resting-state MEG acquisition with a 306-channel whole-head system. The entire evaluation and MEG measurement were repeated 24 weeks later. Relative MEG power in the delta (0–4 Hz), theta (4–7 Hz), alpha (8–12 Hz), beta (12–30 Hz) and low gamma (30–50 Hz) bands was computed for 8 predefined sensor groups. The median stability of resting-state relative power over 24 weeks of follow-up was 0.80 with eyes closed, and 0.72 with eyes open. The relative gamma power in the right occipital (t(15) = 1.99, p < .06, r = −.46) and right frontal (t(15t) = 2.15, p < .05, r = −.48) regions was associated with serostatus. The effect of age on delta power was greater in the seropositive subjects (r2 = .51) than in the seronegative subjects (r2 = .11). Individuals with high theta-to-gamma ratios tended to have lower cognitive test performance, regardless of serostatus. The stability of the wide-band MEG frequency profiles over 24 weeks supports the utility of MEG as a biomarker. The links between the MEG profile, serostatus, and cognition suggest further research on its potential in HAND is needed.
PMCID: PMC3327782  PMID: 22414786
HIV; HIV-Associated Neurocognitive Disorder; Magnetoencephalography (MEG); Magnetic Source Imaging (MSI); Cognition; Reliability; Biomarker
21.  Arterial spin labeled MRI in prodromal Alzheimer's disease: A multi-site study☆ 
NeuroImage : Clinical  2013;2:630-636.
We examined differences in cerebral blood flow (CBF) measured by Arterial Spin Labeled perfusion MRI (ASL MRI) across the continuum from cognitively normal (CN) older adults to mild Alzheimer's Disease (AD) using data from the multi-site Alzheimer's Disease Neuroimaging Initiative (ADNI). Measures of CBF, in a predetermined set of regions (meta-ROI), and hippocampal volume were compared between CN (n = 47), patients with early and late Mild Cognitive Impairment [EMCI (n = 32), LMCI (n = 35)], and AD (n = 15). Associations between these measures and disease severity, assessed by Clinical Dementia Rating scale sum of boxes (CDR SB), were also assessed. Mean meta-ROI CBF was associated with group status and significant hypoperfusion was observed in LMCI and AD relative to CN. Hippocampal volume was associated with group status, but only AD patients had significantly smaller volumes than the CN. When examining the relationship between these measures and disease severity, both were significantly associated with CDR SB and appeared to provide independent prediction of status. In light of the tight link between CBF and metabolism, ASL MRI represents a promising functional biomarker for early diagnosis and disease tracking in AD and this study is the first to demonstrate the feasibility in a multi-site context in this population. Combining functional and structural measures, which can be acquired in the same scanning session, appears to provide additional information about disease severity relative to either measure alone.
•Arterial Spin Labeled (ASL) MRI is a promising AD biomarker. No prior multi-site study of this modality in AD.•We measured cerebral blood flow (CBF) in a FDG PET defined region.•Reduced CBF was associated with MCI and AD and correlated with disease severity.•Hippocampal volume and ASL provide complementary information.•ASL MRI can be applied to this population in a multi-site context.
PMCID: PMC3777751  PMID: 24179814
22.  Parietal Influence on Temporal Encoding indexed by simultaneous TMS and EEG 
Previous studies have suggested that contingent negative variation (CNV), as recorded by electroencaphalography (EEG), may serve as an index of temporal encoding. The interpretation of these studies is complicated by the fact that in a majority of studies the CNV signal was obtained at a time when subjects were not only registering stimulus duration but also making decisions and preparing to act. Previously, we demonstrated that repetitive transcranial magnetic stimulation (rTMS) of the right supramarginal gyrus (rSMG) in humans lengthened the perceived duration of a visual stimulus (Wiener, et al. 2010a), suggesting the rSMG is involved in basic encoding processes. Here, we report a replication of this effect with simultaneous EEG recordings during the encoding of stimulus duration. Stimulation of the rSMG led to an increase in perceived duration and the amplitude of N1 and CNV components recorded from frontocentral sites. Furthermore, the size of the CNV amplitude, but not N1, positively correlated with the size of the rTMS effect but negatively correlated with bias (the baseline tendency to report a comparison stimulus as shorter), suggesting that the CNV indexes stimulus duration. These results suggest that a feed-forward mechanism from parietal to prefrontal regions mediates temporal encoding, and demonstrate a dissociation between early and late phases of encoding processes.
PMCID: PMC3448365  PMID: 22933807
Temporal Attention; Time Perception; Contingent Negative Variation; Transcranial; Magnetic Stimulation; Electroencephalography; Bias
23.  Relationship between Plasma Analytes and SPARE-AD Defined Brain Atrophy Patterns in ADNI 
PLoS ONE  2013;8(2):e55531.
Different inflammatory and metabolic pathways have been associated with Alzheimeŕs disease (AD). However, only recently multi-analyte panels to study a large number of molecules in well characterized cohorts have been made available. These panels could help identify molecules that point to the affected pathways. We studied the relationship between a panel of plasma biomarkers (Human DiscoveryMAP®) and presence of AD-like brain atrophy patterns defined by a previously published index (SPARE-AD) at baseline in subjects of the ADNI cohort. 818 subjects had MRI-derived SPARE-AD scores, of these subjects 69% had plasma biomarkers and 51% had CSF tau and Aβ measurements. Significant analyte-SPARE-AD and analytes correlations were studied in adjusted models. Plasma cortisol and chromogranin A showed a significant association that did not remain significant in the CSF signature adjusted model. Plasma macrophage inhibitory protein-1α and insulin-like growth factor binding protein 2 showed a significant association with brain atrophy in the adjusted model. Cortisol levels showed an inverse association with tests measuring processing speed. Our results indicate that stress and insulin responses and cytokines associated with recruitment of inflammatory cells in MCI-AD are associated with its characteristic AD-like brain atrophy pattern and correlate with clinical changes or CSF biomarkers.
PMCID: PMC3568142  PMID: 23408997
24.  MRI cortical thickness biomarker predicts AD-like CSF and cognitive decline in normal adults 
Neurology  2012;78(2):84-90.
New preclinical Alzheimer disease (AD) diagnostic criteria have been developed using biomarkers in cognitively normal (CN) adults. We implemented these criteria using an MRI biomarker previously associated with AD dementia, testing the hypothesis that individuals at high risk for preclinical AD would be at elevated risk for cognitive decline.
The Alzheimer's Disease Neuroimaging Initiative database was interrogated for CN individuals. MRI data were processed using a published set of a priori regions of interest to derive a single measure known as the AD signature (ADsig). Each individual was classified as ADsig-low (≥1 SD below the mean: high risk for preclinical AD), ADsig-average (within 1 SD of mean), or ADsig-high (≥1 SD above mean). A 3-year cognitive decline outcome was defined a priori using change in Clinical Dementia Rating sum of boxes and selected neuropsychological measures.
Individuals at high risk for preclinical AD were more likely to experience cognitive decline, which developed in 21% compared with 7% of ADsig-average and 0% of ADsig-high groups (p = 0.03). Logistic regression demonstrated that every 1 SD of cortical thinning was associated with a nearly tripled risk of cognitive decline (p = 0.02). Of those for whom baseline CSF data were available, 60% of the high risk for preclinical AD group had CSF characteristics consistent with AD while 36% of the ADsig-average and 19% of the ADsig-high groups had such CSF characteristics (p = 0.1).
This approach to the detection of individuals at high risk for preclinical AD—identified in single CN individuals using this quantitative ADsig MRI biomarker—may provide investigators with a population enriched for AD pathobiology and with a relatively high likelihood of imminent cognitive decline consistent with prodromal AD.
PMCID: PMC3466670  PMID: 22189451
25.  Direct Comparison of FDG-PET and ASL-MRI in Alzheimer’s Disease 
The utility flourodeoxyglucose PET (FDG-PET) imaging in Alzheimer’s Disease (AD) diagnosis is well established. Recently, measurement of cerebral blood flow using arterial spin labeling MRI (ASL-MRI) has shown diagnostic potential in AD, though it has never been directly compared to FDG-PET.
We employed a novel imaging protocol to obtain FDG-PET and ASL-MRI images concurrently in 17 AD patients and 19 age-matched controls. Paired FDG-PET and ASL-MRI images from 19 controls and 15 AD patients were included for qualitative analysis, while paired images 18 controls and 13 AD patients were suitable for quantitative analyses.
The combined imaging protocol was well tolerated. Both modalities revealed very similar regional abnormalities in AD, as well as comparable sensitivity and specificity for the detection of AD following visual review by two expert readers. Interobserver agreement was better for FDG-PET (kappa 0.75, SE 0.12) than ASL-MRI (kappa 0.51, SE 0.15), intermodality agreement was moderate to strong (kappa 0.45-0.61), and readers were more confident of FDG-PET reads. Simple quantitative analysis of global cerebral FDG uptake (FDG-PET) or whole brain cerebral blood flow (ASL-MRI) showed excellent diagnostic accuracy for both modalities, with area under ROC curves of 0.90 for FDG-PET (95% CI 0.79-0.99) and 0.91 for ASL-MRI (95% CI 0.80-1.00).
Our results demonstrate that FDG-PET and ASL-MRI identify similar regional abnormalities and have comparable diagnostic accuracy in a small population of AD patients, and support the further study of ASL-MRI in dementia diagnosis.
PMCID: PMC3264701  PMID: 22018493
ASL; FDG; PET; MRI; Alzheimer’s disease; spin label; fluorodeoxyglucose; dementia

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