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1.  Plasma tau in Alzheimer disease 
Neurology  2016;87(17):1827-1835.
To test whether plasma tau is altered in Alzheimer disease (AD) and whether it is related to changes in cognition, CSF biomarkers of AD pathology (including β-amyloid [Aβ] and tau), brain atrophy, and brain metabolism.
This was a study of plasma tau in prospectively followed patients with AD (n = 179), patients with mild cognitive impairment (n = 195), and cognitive healthy controls (n = 189) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and cross-sectionally studied patients with AD (n = 61), mild cognitive impairment (n = 212), and subjective cognitive decline (n = 174) and controls (n = 274) from the Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study at Lund University, Sweden. A total of 1284 participants were studied. Associations were tested between plasma tau and diagnosis, CSF biomarkers, MRI measures, 18fluorodeoxyglucose-PET, and cognition.
Higher plasma tau was associated with AD dementia, higher CSF tau, and lower CSF Aβ42, but the correlations were weak and differed between ADNI and BioFINDER. Longitudinal analysis in ADNI showed significant associations between plasma tau and worse cognition, more atrophy, and more hypometabolism during follow-up.
Plasma tau partly reflects AD pathology, but the overlap between normal aging and AD is large, especially in patients without dementia. Despite group-level differences, these results do not support plasma tau as an AD biomarker in individual people. Future studies may test longitudinal plasma tau measurements in AD.
PMCID: PMC5089525  PMID: 27694257
2.  The transitional association between β-amyloid pathology and regional brain atrophy 
Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) associated with brain atrophy and cognitive decline. The functional form to model the association between Aβ and regional brain atrophy has not been well defined. In order to determine the relationship between Aβ and atrophy, we compared the performance of the usual dichotomization of cerebrospinal fluid (CSF) Aβ to identify subjects as Aβ+ and Aβ- with a trilinear spline model of CSF Aβ.
183 subjects with mild cognitive impairment and 108 cognitively normal controls with baseline CSF Aβ and up to 4 years of longitudinal MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed using mixed-effects regression. Piecewise-linear splines were used to evaluate the nonlinear nature of the association between CSF Aβ and regional atrophy and to identify points of acceleration of atrophy with respect to Aβ. Several parameterizations of CSF Aβ were compared using likelihood ratio tests and AIC. Periods of acceleration of atrophy in which subjects transition from CSF Aβ negativity to CSF Aβ positivity were estimated from the spline models and tested for significance.
Spline models resulted in better fits for many temporal and parietal regions compared with the dichotomous models. The trilinear model showed that periods of acceleration of atrophy varied greatly by region with early changes seen in the insula, amygdala, precuneus, hippocampus, and other temporal regions, occurring prior to the clinical threshold for CSF Aβ positivity.
The use of piecewise-linear splines provides an improved model of the nonlinear association between CSF Aβ and regional atrophy in regions implicated in the progression of Alzheimer's disease. The important biological finding of this work is that some brain regions show periods of accelerated volume loss well before the CSF Aβ42 threshold. This implies that signs of brain atrophy develop prior to the current conventional definition of “preclinical AD”.
PMCID: PMC4461550  PMID: 25499535
Alzheimer's disease; ADNI; trilinear; beta amyloid; atrophy
3.  Cerebrospinal fluid tau, neurogranin, and neurofilament light in Alzheimer's disease 
EMBO Molecular Medicine  2016;8(10):1184-1196.
Cerebrospinal fluid (CSF) tau (total tau, T‐tau), neurofilament light (NFL), and neurogranin (Ng) are potential biomarkers for neurodegeneration in Alzheimer's disease (AD). It is unknown whether these biomarkers provide similar or complementary information in AD. We examined 93 patients with AD, 187 patients with mild cognitive impairment, and 109 controls. T‐tau, Ng, and NFL were all predictors of AD diagnosis. Combinations improved the diagnostic accuracy (AUC 85.5% for T‐tau, Ng, and NFL) compared to individual biomarkers (T‐tau 80.8%; Ng 71.4%; NFL 77.7%). T‐tau and Ng were highly correlated (ρ = 0.79, P < 0.001) and strongly associated with β‐amyloid (Aβ) pathology, and with longitudinal deterioration in cognition and brain structure, primarily in people with Aβ pathology. NFL on the other hand was not associated with Aβ pathology and was associated with cognitive decline and brain atrophy independent of Aβ. T‐tau, Ng, and NFL provide partly independent information about neuronal injury and may be combined to improve the diagnostic accuracy for AD. T‐tau and Ng reflect Aβ‐dependent neurodegeneration, while NFL reflects neurodegeneration independently of Aβ pathology.
PMCID: PMC5048367  PMID: 27534871
Alzheimer's; biomarker; CSF; neurodegeneration; Biomarkers & Diagnostic Imaging; Neuroscience
4.  Assessing risk for preclinical β-amyloid pathology with APOE, cognitive, and demographic information 
Clinical trials in Alzheimer's disease are aimed at early stages of disease, including preclinical Alzheimer's disease. The high cost and time required to screen large numbers of participants for Aβ pathology impede the development of novel drugs. This study's objective was to evaluate the extent to which inexpensive and easily obtainable information can reduce the number of screen failures by increasing the proportion of Aβ+ participants identified for screening.
We used random forest models to evaluate the positive predictive value of demographics, APOE, and longitudinal cognitive rates in the prediction of amyloid pathology, measured by florbetapir PET or cerebrospinal fluid.
Predicting Aβ positivity with demographic, APOE, and cognitive information yielded a positive predictive value estimate of 0.65 (95% CI, 0.50–0.96), nearly a 60% increase over the reference Aβ+ prevalence in the cohort of 0.41.
By incorporating this procedure, clinical trial screening costs may be substantially reduced.
PMCID: PMC5045949  PMID: 27722193
Preclinical Alzheimer's; Amyloid; Clinical trials; Cognition; APOE
5.  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
6.  Brain structure and function as mediators of the effects of amyloid on memory 
Neurology  2015;84(11):1136-1144.
The objective of this study was to test whether effects of β-amyloid (Aβ) pathology on episodic memory were mediated by metabolism and gray matter volume in the early stages of Alzheimer disease.
This was a prospective cohort study. We measured baseline Aβ (using florbetapir-PET), brain function (using fluorodeoxyglucose-PET), and brain structure (using MRI). A mediation analysis was performed to test whether statistical effects of Aβ positivity on cross-sectional and longitudinal episodic memory were mediated by hypometabolism or regional gray matter volume in cognitively healthy controls (CN, n = 280) and mild cognitive impairment (MCI, n = 463).
Lower memory scores were associated with Aβ positivity (CN, mildly; MCI, strongly), smaller gray matter volumes (CN, few regions, including hippocampus; MCI, widespread), and hypometabolism. Smaller volumes and hypometabolism mediated effects of Aβ in MCI but not in CN. The strongest individual regions mediated up to approximately 25%. A combination of brain structure and function mediated up to approximately 40%. In several regions, gray matter atrophy and hypometabolism predicted episodic memory without being associated (at p < 0.05) with Aβ positivity.
Changes in brain structure and function appear to be, in part, downstream events from Aβ pathology, ultimately resulting in episodic memory deficits. However, Aβ pathology is also strongly related to memory deficits through mechanisms that are not quantified by these imaging measurements, and episodic memory decline is partly caused by Alzheimer disease–like brain changes independently of Aβ pathology.
PMCID: PMC4371407  PMID: 25681451
7.  Increased amyloidogenic APP processing in APOE ɛ4-negative individuals with cerebral β-amyloidosis 
Nature Communications  2016;7:10918.
Increased APP (amyloid precursor protein) processing causes β-amyloid (Aβ) accumulation in autosomal dominant Alzheimer's disease (AD), but it is unclear if it also affects sporadic Aβ accumulation. We tested healthy controls and patients with mild cognitive symptoms (N=331) in the BioFINDER study, using cerebrospinal fluid (CSF) Aβ40 as a surrogate for amyloidogenic APP processing. We find that levels of brain Aβ fibrils (measured by 18F-flutemetamol PET) are independently associated with high CSF Aβ40 (P<0.001) and APOE ɛ4 (P<0.001). The association between CSF Aβ40 and brain Aβ is stronger in APOE ɛ4-negative than in positive people (P=0.0080). The results are similar for CSF Aβ38 and for a combination of CSF Aβ38 and CSF Aβ40. In conclusion, sporadic Aβ accumulation may be partly associated with increased amyloidogenic APP production, especially in APOE ɛ4-negative subjects. The risk for sporadic AD may consequently depend on increased Aβ production, in addition to decreased Aβ clearance.
Autosomal dominant Alzheimer's disease is thought to be caused by increased amyloidogenic APP processing. Mattson et al. show that association between brain Aβ and cerobrospinal fluid Aβ40 levels is stronger in APOE ɛ4 negative people, suggesting that increased processing may also underlie sporadic disease.
PMCID: PMC4786682  PMID: 26948379
8.  Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease 
Brain  2014;138(3):772-783.
See Fagan (doi:10.1093/awu387) for a scientific commentary on this article.
CSF and PET biomarkers of β-amyloid are not always fully congruent. Mattsson et al. reveal that the markers provide partly independent information in Alzheimer's disease. CSF biomarkers may be more sensitive to early stages of disease pathogenesis, while PET imaging may reflect downstream pathology.
Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-β were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE ε4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-β was more strongly related to APOE ε4 whereas positron emission tomography amyloid-β was more strongly related to tau levels (P < 0.05). Discordance (mainly isolated cerebrospinal fluid amyloid-β positivity) differed by diagnostic group (P < 0.001) and was seen in 21% of cognitively healthy people but only 6% in dementia patients. The finding that cerebrospinal fluid and positron emission tomography amyloid-β provide partially independent information about a wide range of Alzheimer's measures supports the theory that these modalities represent partly different aspects of Alzheimer's pathology. The fact that mismatch, with positive cerebrospinal fluid amyloid-β but normal positron emission tomography amyloid-β, is relatively common in cognitively healthy people may be considered when using these biomarkers to identify early stage Alzheimer's disease. Reduced cerebrospinal fluid amyloid-β may be more strongly related to early stage Alzheimer's disease, whereas increased positron emission tomography amyloid-β may be more strongly related to disease progression.
PMCID: PMC4339769  PMID: 25541191
Alzheimer's disease; biomarker; cerebrospinal fluid; positron emission tomography; amyloid
9.  Brain Amyloid-β Burden Is Associated with Disruption of Intrinsic Functional Connectivity within the Medial Temporal Lobe in Cognitively Normal Elderly 
The Journal of Neuroscience  2015;35(7):3240-3247.
The medial temporal lobe is implicated as a key brain region involved in the pathogenesis of Alzheimer's disease (AD) and consequent memory loss. Tau tangle aggregation in this region may develop concurrently with cortical Aβ deposition in preclinical AD, but the pathological relationship between tau and Aβ remains unclear. We used task-free fMRI with a focus on the medical temporal lobe, together with Aβ PET imaging, in cognitively normal elderly human participants. We found that cortical Aβ load was related to disrupted intrinsic functional connectivity of the perirhinal cortex, which is typically the first brain region affected by tauopathies in AD. There was no concurrent association of cortical Aβ load with cognitive performance or brain atrophy. These findings suggest that dysfunction in the medial temporal lobe may represent a very early sign of preclinical AD and may predict future memory loss.
PMCID: PMC4331637  PMID: 25698758
Alzheimer's disease; amyloid; hippocampus; perirhinal cortex
10.  Evidence for age-associated cognitive decline from Internet game scores 
Lumosity's Memory Match (LMM) is an online game requiring visual working memory. Change in LMM scores may be associated with individual differences in age-related changes in working memory.
Effects of age and time on LMM learning and forgetting rates were estimated using data from 1890 game sessions for users aged 40 to 79 years.
There were significant effects of age on baseline LMM scores (β = −.31, standard error or SE = .02, P < .0001) and lower learning rates (β = −.0066, SE = .0008, P < .0001). A sample size of 202 subjects/arm was estimated for a 1-year study for subjects in the lower quartile of game performance.
Online memory games have the potential to identify age-related decline in cognition and to identify subjects at risk for cognitive decline with smaller sample sizes and lower cost than traditional recruitment methods.
PMCID: PMC4876906  PMID: 27239508
Online games; Cognitive decline; Alzheimer's disease; Internet game; Internet registry; Online cognitive assessments; Memory
11.  Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer’s disease and mild cognitive impairment 
Brain  2014;137(5):1550-1561.
Patients with Alzheimer’s disease show reduced cerebral blood flow, but it is unclear how this relates to β-amyloid pathology. By comparing patients with Alzheimer’s dementia, mild cognitive impairment, and controls, Mattsson et al. show that high β-amyloid load is associated with increased atrophy and reduced perfusion, independent of diagnosis.
Patients with Alzheimer’s disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-β pathology. Using 182 subjects from the Alzheimer’s Disease Neuroimaging Initiative we tested associations of amyloid-β with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer’s disease with dementia (n = 24). Based on the theory that Alzheimer’s disease starts with amyloid-β accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-β-negative controls and -positive subjects in different diagnostic groups, and if amyloid-β had different associations with cerebral blood flow and grey matter volume. Global amyloid-β load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-β load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-β-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-β with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-β being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-β pathology affects cerebral blood flow across the span from controls to dementia patients. Amyloid-β pathology has different associations with cerebral blood flow and volume, and may cause more loss of blood flow in early stages, whereas volume loss dominates in late disease stages.
PMCID: PMC3999717  PMID: 24625697
Alzheimer’s disease; beta-amyloid; PET imaging; perfusion imaging; magnetic resonance imaging
12.  Emerging β-Amyloid Pathology and Accelerated Cortical Atrophy 
JAMA neurology  2014;71(6):725-734.
The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in early stages of Alzheimer disease (AD) is not well understood.
To test the hypothesis that the development of Aβ pathology is related to increased regional atrophy in the brains of cognitively normal (CN) persons.
Design, Setting, and Participants
Longitudinal clinicobiomarker cohort study involving 47 CN control subjects and 15 patients with AD dementia. All participants underwent repeated cerebrospinal fluid Aβ42 and structural magnetic resonance imaging measurements for up to 4 years. Cognitively normal controls were classified using the longitudinal cerebrospinal fluid Aβ42 data and included 13 stable Aβ negative (normal baseline Aβ42 levels, with less than the median reduction over time), 13 declining Aβ negative (normal baseline Aβ42 levels, with greater than the median reduction over time), and 21 Aβ positive (pathologic baseline Aβ42 levels). All 15 patients with AD dementia were Aβ positive.
Main Outcomes and Measures
Group effects on regional gray matter volumes at baseline and over time, tested by linear mixed-effects models.
Baseline gray matter volumes were similar among the CN Aβ groups, but atrophy rates were increased in frontoparietal regions in the declining Aβ-negative and Aβ-positive groups and in amygdala and temporal regions in the Aβ-positive group. Aβ-positive patients with AD dementia had further increased atrophy rates in hippocampus and temporal and cingulate regions.
Conclusions and Relevance
Emerging Aβ pathology is coupled to increased frontoparietal (but not temporal) atrophy rates. Atrophy rates peak early in frontoparietal regions but accelerate in hippocampus, temporal, and cingulate regions as the disease progresses to dementia. Early-stage Aβ pathology may have mild effects on local frontoparietal cortical integrity while effects in temporal regions appear later and accelerate, leading to the atrophy pattern typically seen in AD.
PMCID: PMC4410966  PMID: 24781145
13.  Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease 
To find the combination of candidate biomarkers and cognitive endpoints to maximize statistical power and minimize cost of clinical trials of healthy elders at risk for cognitive decline due to Alzheimer's disease.
Four-hundred and twelve cognitively normal participants were followed over 7 years. Nonlinear methods were used to estimate the longitudinal trajectories of several cognitive outcomes including delayed memory recall, executive function, processing speed, and several cognitive composites by subgroups selected on the basis of biomarkers, including APOE-ε4 allele carriers, cerebrospinal fluid biomarkers (Aβ42, total tau, and phosphorylated tau), and those with small hippocampi.
Derived cognitive composites combining Alzheimer's Disease Assessment Scale (ADAS)-cog scores with additional delayed memory recall and executive function components captured decline more robustly across biomarker groups than any measure of a single cognitive domain or ADAS-cog alone. Substantial increases in power resulted when including only participants positive for three or more biomarkers in simulations of clinical trials.
Clinical trial power may be improved by selecting participants on the basis of amyloid and neurodegeneration biomarkers and carefully tailoring primary cognitive endpoints to reflect the expected decline specific to these individuals.
PMCID: PMC4435707  PMID: 26000325
14.  Neuroimaging abnormalities in adults with sickle cell anemia 
Neurology  2014;82(10):835-841.
This study was conducted to determine the relationship of frontal lobe cortical thickness and basal ganglia volumes to measures of cognition in adults with sickle cell anemia (SCA).
Participants included 120 adults with SCA with no history of neurologic dysfunction and 33 healthy controls (HCs). Participants were enrolled at 12 medical center sites, and raters were blinded to diagnostic group. We hypothesized that individuals with SCA would exhibit reductions in frontal lobe cortex thickness and reduced basal ganglia and thalamus volumes compared with HCs and that these structural brain abnormalities would be associated with measures of cognitive functioning (Wechsler Adult Intelligence Scale, 3rd edition).
After adjusting for age, sex, education level, and intracranial volume, participants with SCA exhibited thinner frontal lobe cortex (t = −2.99, p = 0.003) and reduced basal ganglia and thalamus volumes compared with HCs (t = −3.95, p < 0.001). Reduced volume of the basal ganglia and thalamus was significantly associated with lower Performance IQ (model estimate = 3.75, p = 0.004) as well as lower Perceptual Organization (model estimate = 1.44, p = 0.007) and Working Memory scores (model estimate = 1.37, p = 0.015). Frontal lobe cortex thickness was not significantly associated with any cognitive measures.
Our findings suggest that basal ganglia and thalamus abnormalities may represent a particularly salient contributor to cognitive dysfunction in adults with SCA.
PMCID: PMC3959758  PMID: 24523480
15.  Cerebrospinal Fluid α-Synuclein and Lewy Body-Like Symptoms in Normal Controls, Mild Cognitive Impairment, and Alzheimer’s Disease 
Journal of Alzheimer's disease : JAD  2015;43(3):1007-1016.
Reduced cerebrospinal fluid (CSF) α-synuclein has been described in synucleinopathies, including dementia with Lewy bodies (DLB). Common symptoms of DLB include visual hallucinations and visuospatial and executive deficits. Co-occurrence of Lewy body pathology is common in Alzheimer’s disease (AD) patients, but it is unknown if reduced CSF α-synuclein is associated with Lewy body-like symptomatology in AD.
Determine associations between CSF α-synuclein and Lewy body-like symptomatology.
We included 73 controls (NC), 121 mild cognitive impairment (MCI) patients, and 61 AD patients (median follow-up 3.5 years, range 0.6–7.8). We tested associations between baseline CSF α-synuclein and visual hallucinations and (longitudinal) cognition. Models were tested with and without co-varying for CSF total tau (T-tau), which is elevated in AD patients, and believed to reflect neurodegeneration.
Hallucinations were reported in 20% of AD patients, 13% of MCI patients, and 8% of NC. In AD, low CSF α-synuclein was associated with hallucinations. When adjusting for CSF T-tau, low CSF α-synuclein was associated with accelerated decline of executive function (NC, MCI, and AD), memory (MCI and AD), and language (MCI).
The associations of low CSF α-synuclein with hallucinations and poor executive function, which are hallmarks of DLB, indirectly suggest that this biomarker may reflect underlying synuclein pathology. The associations with memory and language in MCI and AD suggests either that reduced CSF α-synuclein also partly reflects global impaired neuronal/synaptic function, or that non-specific overall cognitive deterioration is accelerated in the presence of synuclein related pathology. The findings will require autopsy verification.
PMCID: PMC4350922  PMID: 25125463
Alpha-synuclein; Alzheimer’s disease; cerebrospinal fluid; cognition; hallucinations; tau
16.  Effects of CSF proteins on brain atrophy rates in cognitively healthy older adults 
Neurobiology of aging  2013;35(3):10.1016/j.neurobiolaging.2013.08.027.
Biomarkers associated with Alzheimer’s disease (AD)-like brain atrophy in healthy people may identify mechanisms involved in early stage AD. Aside from cerebrospinal fluid (CSF) β-amyloid42 (Aβ42) and tau, no studies have tested associations between CSF proteins and AD-like brain atrophy. We studied 90 healthy elders, who underwent lumbar puncture at baseline, and serial magnetic resonance imaging scans for up to 4 years. We tested statistical effects of baseline CSF proteins (N=70 proteins related to Aβ42-metabolism, microglial activity and synaptic/neuronal function) on atrophy rates in 7 AD-related regions. Besides effects of Aβ42 and phosphorylated tau (P-tau) that were seen in several regions, novel CSF proteins were found to have effects in inferior and middle temporal cortex (including Apolipoprotein CIII, Apolipoprotein D and Apolipoprotein H). Several proteins (including S100β and Matrix Metalloproteinase-3) had effects that depended on the presence of brain Aβ pathology, as measured by CSF Aβ42. Other proteins (including P-tau and Apolipoprotein D) had effects even after adjusting for CSF Aβ42. The statistical effects in this exploratory study were mild and not significant after correction for multiple comparisons, but some of the identified proteins may be associated with brain atrophy in healthy people. Proteins interacting with CSF Aβ42 may be related to Aβ brain pathology, while proteins associated with atrophy even after adjusting for CSF Aβ42 may be related to Aβ-independent mechanisms.
PMCID: PMC3864623  PMID: 24094581
cerebrospinal fluid; biomarkers; atrophy; longitudinal; Alzheimer’s disease
17.  Patterns of Reduced Cortical Thickness in Late Life Depression and Relationship to Psychotherapeutic Response 
Cortical atrophy has been associated with late life depression (LLD) and recent findings suggest that reduced right hemisphere cortical thickness is associated with familial risk for major depressive disorder but cortical thickness abnormalities in LLD have not been explored. Further, cortical atrophy has been posited as a contributor to poor antidepressant treatment response in LLD but the impact of cortical thickness on psychotherapy response is unknown. This study was conducted to evaluate patterns of cortical thickness in LLD and in relation to psychotherapy treatment outcomes.
Participants included 22 individuals with LLD and 12 age matched comparison subjects. LLD participants completed 12 weeks of psychotherapy and treatment response was defined as a 50% reduction in depressive symptoms. All participants participated in Magnetic Resonance Imaging (MRI) of the brain and cortical mapping of grey matter tissue thickness was calculated.
LLD individuals demonstrated thinner cortex than controls prominently in the right frontal, parietal, and temporal brain regions. Eleven participants (50%) exhibited positive psychotherapy response after 12 weeks of treatment. Psychotherapy non-responders demonstrated thinner cortex in bilateral posterior cingulate and parahippocampal cortices, left paracentral, precuneus, cuneus, and insular cortices, and the right medial orbito-frontal and lateral occipital cortices relative to treatment responders.
Our findings suggest more distributed right hemisphere cortical abnormalities in LLD than have been previously reported. Additionally, our findings suggest that reduced bilateral cortical thickness may be an important phenotypic marker of individuals at higher risk for poor response to psychotherapy.
PMCID: PMC3732520  PMID: 23567394
18.  Diagnostic accuracy of CSF Ab42 and florbetapir PET for Alzheimer's disease 
Reduced cerebrospinal fluid (CSF) β-amyloid42 (Aβ42) and increased florbetapir positron emission tomography (PET) uptake reflects brain Aβ accumulation. These biomarkers are correlated with each other and altered in Alzheimer's disease (AD), but no study has directly compared their diagnostic performance.
We examined healthy controls (CN, N = 169) versus AD dementia patients (N = 118), and stable (sMCI; no dementia, followed up for at least 2 years, N = 165) versus progressive MCI (pMCI; conversion to AD dementia, N = 59). All subjects had florbetapir PET (global and regional; temporal, frontal, parietal, and cingulate) and CSF Aβ42 measurements at baseline. We compared area under the curve (AUC), sensitivity, and specificity (testing a priori and optimized cutoffs). Clinical diagnosis was the reference standard.
CSF Aβ42 and (global or regional) PET florbetapir did not differ in AUC (CN vs. AD, CSF 84.4%; global PET 86.9%; difference [95% confidence interval] −6.7 to 1.5). CSF Aβ42 and global PET florbetapir did not differ in sensitivity, but PET had greater specificity than CSF in most comparisons. Sixteen CN progressed to MCI and AD (six Aβ negative, seven Aβ positive, and three PET positive but CSF negative).
The overall diagnostic accuracies of CSF Aβ42 and PET florbetapir were similar, but PET had greater specificity. This was because some CN and sMCI subjects appear pathological using CSF but not using PET, suggesting that low CSF Aβ42 not always translates to cognitive decline or brain Aβ accumulation. Other factors, including costs and side effects, may also be considered when determining the optimal modality for different applications.
PMCID: PMC4184556  PMID: 25356425
19.  Cognitive reserve associated with FDG-PET in preclinical Alzheimer disease 
Neurology  2013;80(13):1194-1201.
To examine the effect of education (a surrogate measure of cognitive reserve) on FDG-PET brain metabolism in elderly cognitively healthy (HC) subjects with preclinical Alzheimer disease (AD).
Fifty-two HC subjects (mean age 75 years) with FDG-PET and CSF measurement of Aβ1-42 were included from the prospective Alzheimer's Disease Neuroimaging Initiative biomarker study. HC subjects received a research classification of preclinical AD if CSF Aβ1-42 was <192 pg/mL (Aβ1-42 [+]) vs HC with normal Aβ (Aβ1-42 [−]). In regression analyses, we tested the interaction effect between education and CSF Aβ1-42 status (Aβ1-42 [+] vs Aβ1-42 [−]) on FDG-PET metabolism in regions of interest (ROIs) (posterior cingulate, angular gyrus, inferior/middle temporal gyrus) and the whole brain (voxel-based).
An interaction between education and CSF Aβ1-42 status was observed for FDG-PET in the posterior cingulate (p < 0.001) and angular gyrus ROIs (p = 0.03), but was not significant for the inferior/middle temporal gyrus ROI (p = 0.06), controlled for age, sex, and global cognitive ability (Alzheimer’s Disease Assessment Scale–cognitive subscale). The interaction effect was such that higher education was associated with lower FDG-PET in the Aβ1-42 (+) group, but with higher FDG-PET in the Aβ1-42 (−) group. Voxel-based analysis showed that this interaction effect was primarily restricted to temporo-parietal and ventral prefrontal brain areas.
Higher education was associated with lower FDG-PET in preclinical AD (Aβ1-42 [+]), suggesting that cognitive reserve had a compensatory function to sustain cognitive ability in presence of early AD pathology that alters FDG-PET metabolism.
PMCID: PMC3691784  PMID: 23486873
20.  Differences in Prefrontal, Limbic, and White Matter Lesion Volumes According to Cognitive Status in Elderly Patients with First-Onset Subsyndromal Depression 
PLoS ONE  2014;9(1):e87747.
The purpose of this preliminary study was to test the hypothesis that subsyndromal depression is associated with the volume of medial prefrontal regional gray matter and that of white matter lesions (WMLs) in the brains of cognitively normal older people. We also explored the relationships between subsyndromal depression and medial prefrontal regional gray matter volume, limbic regional gray matter volume, and lobar WMLs in the brains of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). We performed a cross-sectional study comparing patients with subsyndromal depression and nondepressed controls with normal cognition (n = 59), MCI (n = 27), and AD (n = 27), adjusting for sex, age, years of education, and results of the Mini-Mental State Examination. Frontal WML volume was greater, and right medial orbitofrontal cortical volume was smaller in cognitively normal participants with subsyndromal depression than in those without subsyndromal depression. No volume differences were observed in medial prefrontal, limbic, or WML volumes according to the presence of subsyndromal depression in cognitively impaired patients. The absence of these changes in patients with MCI and AD suggests that brain changes associated with AD pathology may override the changes associated with subsyndromal depression.
PMCID: PMC3909227  PMID: 24498184
21.  Effects of Baseline CSF α-Synuclein on Regional Brain Atrophy Rates in Healthy Elders, Mild Cognitive Impairment and Alzheimer’s Disease 
PLoS ONE  2013;8(12):e85443.
Cerebrospinal fluid (CSF) α-synuclein is reduced in synucleinopathies, including dementia with Lewy bodies, and some studies have found increased CSF α-synuclein in Alzheimer’s disease (AD). No study has explored effects of CSF α-synuclein on brain atrophy. Here we tested if baseline CSF α-synuclein affects brain atrophy rates and if these effects vary across brain regions, and across the cognitive spectrum from healthy elders (NL), to patients with mild cognitive impairment (MCI) and AD.
Baseline CSF α-synuclein measurements and longitudinal structural brain magnetic resonance imaging was performed in 74 NL, 118 MCI patients and 55 AD patients. Effects of baseline CSF α-synuclein on regional atrophy rates were tested in 1) four pre-hoc defined regions possibly associated with Lewy body and/or AD pathology (amygdala, caudate, hippocampus, brainstem), and 2) all available regions of interest. Differences across diagnoses were tested by assessing the interaction of CSF α-synuclein and diagnosis (testing NL versus MCI, and NL versus AD).
The effects of CSF α-synuclein on longitudinal atrophy rates were not significant after correction for multiple comparisons. There were tendencies for effects in AD in caudate (higher atrophy rates in subjects with higher CSF α-synuclein, P=0.046) and brainstem (higher atrophy rates in subjects with lower CSF α-synuclein, P=0.063). CSF α-synuclein had significantly different effects on atrophy rates in NL and AD in brainstem (P=0.037) and caudate (P=0.006).
Discussion: With the possible exception of caudate and brainstem, the overall weak effects of CSF α-synuclein on atrophy rates in NL, MCI and AD argues against CSF α-synuclein as a biomarker related to longitudinal brain atrophy in these diagnostic groups. Any effects of CSF α-synuclein may be attenuated by possible simultaneous occurrence of AD-related neuronal injury and concomitant Lewy body pathology, which may elevate and reduce CSF α-synuclein levels, respectively.
PMCID: PMC3877372  PMID: 24392009
22.  A composite score for executive functioning, validated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants with baseline mild cognitive impairment 
Brain imaging and behavior  2012;6(4):517-527.
The Alzheimer’s Disease Neuroimaging Initiative (ADNI) measures abilities broadly related to executive function (EF), including WAIS-R Digit Symbol Substitution, Digit Span Backwards, Trails A and B, Category Fluency, and Clock Drawing. This study investigates whether a composite executive function measure based on these multiple indicators has better psychometric characteristics than the widely used individual components. We applied item response theory methods to 800 ADNI participants to derive an EF composite score (ADNI-EF) from the above measures. We then compared ADNI-EF with component measures in 390 longitudinally-followed participants with mild cognitive impairment (MCI) with respect to: (1) Ability to detect change over time; (2) Ability to predict conversion to dementia; (3) Strength of cross-sectional association with MRI-derived measures of structures involved in frontal systems, and (4) Strength of baseline association with cerebrospinal fluid (CSF) levels of amyloid β1-42, total tau, and phosphorylated tau181P. ADNI-EF showed the greatest change over time, followed closely by Category Fluency. ADNI-EF needed a 40 % smaller sample size to detect change. ADNI-EF was the strongest predictor of AD conversion. ADNI-EF was the only measure significantly associated with all the MRI regions, though other measures were more strongly associated in a few of the regions. ADNI-EF was associated with all the CSF measures. ADNI-EF appears to be a useful composite measure of EF in MCI, as good as or better than any of its composite parts. This study demonstrates an approach to developing a psychometrically sophisticated composite score from commonly-used tests.
PMCID: PMC3684181  PMID: 22644789
Executive function; Mild cognitive impairment; Item response theory; Composite scores
23.  Development and assessment of a composite score for memory in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 
Brain imaging and behavior  2012;6(4):502-516.
We sought to develop and evaluate a composite memory score from the neuropsychological battery used in the Alzheimer’s Disease (AD) Neuroimaging Initiative (ADNI). We used modern psychometric approaches to analyze longitudinal Rey Auditory Verbal Learning Test (RAVLT, 2 versions), AD Assessment Schedule - Cognition (ADAS-Cog, 3 versions), Mini-Mental State Examination (MMSE), and Logical Memory data to develop ADNI-Mem, a composite memory score. We compared RAVLT and ADAS-Cog versions, and compared ADNI-Mem to AVLT recall sum scores, four ADAS-Cog-derived scores, the MMSE, and the Clinical Dementia Rating Sum of Boxes. We evaluated rates of decline in normal cognition, mild cognitive impairment (MCI), and AD, ability to predict conversion from MCI to AD, strength of association with selected imaging parameters, and ability to differentiate rates of decline between participants with and without AD cerebrospinal fluid (CSF) signatures. The second version of the RAVLT was harder than the first. The ADAS-Cog versions were of similar difficulty. ADNI-Mem was slightly better at detecting change than total RAVLT recall scores. It was as good as or better than all of the other scores at predicting conversion from MCI to AD. It was associated with all our selected imaging parameters for people with MCI and AD. Participants with MCI with an AD CSF signature had somewhat more rapid decline than did those without. This paper illustrates appropriate methods for addressing the different versions of word lists, and demonstrates the additional power to be gleaned with a psychometrically sound composite memory score.
PMCID: PMC3806057  PMID: 22782295
Memory; psychometrics; longitudinal analysis; cognition; hippocampus
24.  Greater regional brain atrophy rate in healthy elders with a history of cigarette smoking 
Little is known about the effects of cigarette smoking on brain morphological changes in the elderly. This study investigated the effects of a history of cigarette smoking on changes in regional brain volumes over 2-years in healthy, cognitively-intact elderly individuals. We predicted individuals with a history of cigarette smoking, compared to never smokers, demonstrate greater rate of atrophy over 2-years in regions that manifest morphological abnormalities in the early stages of Alzheimer Disease (AD), as well as the extended brain reward system (BRS), which is implicated in the development and maintenance of substance use disorders.
Participants were healthy, cognitively normal elderly controls (75.9±4.8 years of age) with any lifetime history of cigarette smoking (n = 68) and no history of smoking (n = 118). Data was obtained via the Alzheimer Disease Neuroimaging Initiative from 2005–2010. Participants completed four magnetic resonance scans over 2-years. A standardized protocol employing high resolution 3D T1-weighted sequences at 1.5 Tesla was used for structural imaging and regional brain volumetric analyses.
Smokers demonstrated significantly greater rate atrophy over 2-years than non-smokers in multiple brain regions associated with the early stages of AD as well as in the BRS. Groups were not different on rate of global cortical atrophy.
A history of cigarette smoking in this healthy elderly cohort was associated with decreased structural integrity of multiple brain regions, which was manifest as a greater rate of atrophy over 2-years in regions specifically affected by incipient AD as well as chronic substance abuse.
PMCID: PMC3484322  PMID: 23102121
Alzheimer Disease; MRI, neuroimaging; brain volumes; brain reward system; substance abuse; nicotine; brain atrophy; longitudinal
25.  Early Indications of Future Cognitive Decline: Stable versus Declining Controls 
PLoS ONE  2013;8(9):e74062.
This study aimed to identify baseline features of normal subjects that are associated with subsequent cognitive decline. Publicly available data from the Alzheimer’s Disease Neuroimaging Initiative was used to find differences in baseline clinical assessments (ADAScog, AVLT, FAQ) between cognitively healthy individuals who will suffer cognitive decline within 48 months and those who will remain stable for that period. Linear regression models indicated an individual’s conversion status was significantly associated with certain baseline neuroimaging measures, including posterior cingulate glucose metabolism. Linear Discriminant Analysis models built with baseline features derived from MRI and FDG-PET measures were capable of successfully predicting whether an individual will convert to MCI within 48 months or remain cognitively stable. The findings from this study support the idea that there exist informative differences between normal people who will later develop cognitive impairments and those who will remain cognitively stable for up to four years. Further, the feasibility of developing predictive models that can detect early states of cognitive decline in seemingly normal individuals was demonstrated.
PMCID: PMC3767625  PMID: 24040166

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