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1.  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.
doi:10.1093/brain/awu043
PMCID: PMC3999717  PMID: 24625697
Alzheimer’s disease; beta-amyloid; PET imaging; perfusion imaging; magnetic resonance imaging
2.  Emerging β-Amyloid Pathology and Accelerated Cortical Atrophy 
JAMA neurology  2014;71(6):725-734.
Importance
The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in early stages of Alzheimer disease (AD) is not well understood.
Objective
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.
Results
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.
doi:10.1001/jamaneurol.2014.446
PMCID: PMC4410966  PMID: 24781145
3.  Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease 
Objective
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.
Methods
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.
Results
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.
Interpretation
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.
doi:10.1002/acn3.192
PMCID: PMC4435707  PMID: 26000325
4.  Neuroimaging abnormalities in adults with sickle cell anemia 
Neurology  2014;82(10):835-841.
Objective:
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).
Methods:
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).
Results:
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.
Conclusions:
Our findings suggest that basal ganglia and thalamus abnormalities may represent a particularly salient contributor to cognitive dysfunction in adults with SCA.
doi:10.1212/WNL.0000000000000188
PMCID: PMC3959758  PMID: 24523480
5.  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.
Background
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.
Objective
Determine associations between CSF α-synuclein and Lewy body-like symptomatology.
Methods
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.
Results
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).
Conclusion
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.
doi:10.3233/JAD-141287
PMCID: PMC4350922  PMID: 25125463
Alpha-synuclein; Alzheimer’s disease; cerebrospinal fluid; cognition; hallucinations; tau
6.  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.
doi:10.1016/j.neurobiolaging.2013.08.027
PMCID: PMC3864623  PMID: 24094581
cerebrospinal fluid; biomarkers; atrophy; longitudinal; Alzheimer’s disease
7.  Patterns of Reduced Cortical Thickness in Late Life Depression and Relationship to Psychotherapeutic Response 
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jagp.2013.01.013
PMCID: PMC3732520  PMID: 23567394
8.  Diagnostic accuracy of CSF Ab42 and florbetapir PET for Alzheimer's disease 
Background
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.
Methods
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.
Results
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).
Interpretation
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.
doi:10.1002/acn3.81
PMCID: PMC4184556  PMID: 25356425
9.  Cognitive reserve associated with FDG-PET in preclinical Alzheimer disease 
Neurology  2013;80(13):1194-1201.
Objective:
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).
Methods:
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).
Results:
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.
Conclusions:
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.
doi:10.1212/WNL.0b013e31828970c2
PMCID: PMC3691784  PMID: 23486873
10.  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.
doi:10.1371/journal.pone.0087747
PMCID: PMC3909227  PMID: 24498184
11.  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.
Background
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.
Methods
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).
Results
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.
doi:10.1371/journal.pone.0085443
PMCID: PMC3877372  PMID: 24392009
12.  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.
doi:10.1007/s11682-012-9176-1
PMCID: PMC3684181  PMID: 22644789
Executive function; Mild cognitive impairment; Item response theory; Composite scores
13.  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.
doi:10.1007/s11682-012-9186-z
PMCID: PMC3806057  PMID: 22782295
Memory; psychometrics; longitudinal analysis; cognition; hippocampus
14.  Greater regional brain atrophy rate in healthy elders with a history of cigarette smoking 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jalz.2011.10.006
PMCID: PMC3484322  PMID: 23102121
Alzheimer Disease; MRI, neuroimaging; brain volumes; brain reward system; substance abuse; nicotine; brain atrophy; longitudinal
15.  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.
doi:10.1371/journal.pone.0074062
PMCID: PMC3767625  PMID: 24040166
16.  CSF Biomarker and PIB-PET–Derived Beta-Amyloid Signature Predicts Metabolic, Gray Matter, and Cognitive Changes in Nondemented Subjects 
Cerebral Cortex (New York, NY)  2011;22(9):1993-2004.
Beta-amyloid (Aβ) is a histopathological hallmark of Alzheimer’s disease dementia, but high levels of Aβ in the brain can also be found in a substantial proportion of nondemented subjects. Here we investigated which 2-year rate of brain and cognitive changes are present in nondemented subjects with high and low Aβ levels, as assessed with cerebrospinal fluid and molecular positron emission tomography (PET)–based biomarkers of Aβ. In subjects with mild cognitive impairment, increased brain Aβ levels were associated with significantly faster cognitive decline, progression of gray matter atrophy within temporal and parietal brain regions, and a trend for a faster decline in parietal Fludeoxyglucose (FDG)-PET metabolism. Changes in gray matter and FDG-PET mediated the association between Aβ and cognitive decline. In contrast, elderly cognitively healthy controls (HC) with high Aβ levels showed only a faster medial temporal lobe and precuneus volume decline compared with HC with low Aβ. In conclusion, the current results suggest not only that both functional and volumetric brain changes are associated with high Aβ years before the onset of dementia but also that HC with substantial Aβ levels show higher Aβ pathology resistance, lack other pathologies that condition neurotoxic effects of Aβ, or accumulated Aβ for a shorter time period.
doi:10.1093/cercor/bhr271
PMCID: PMC3500862  PMID: 22038908
Aβ; FDG-PET; MCI; PIB-PET
17.  Longitudinal Stability of Subsyndromal Symptoms of Depression in Individuals with Mild Cognitive Impairment: Relationship to Conversion to Dementia after Three Years 
Objective
To evaluate the degree to which longitudinal stability of subsyndromal symptoms of depression (SSD) is associated with conversion to dementia in patients with Mild Cognitive Impairment (MCI).
Methods
Data from 405 MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were analyzed. Participants were evaluated at baseline and 12 month intervals over three years. Participants were designated as MCI Converters if dementia was diagnosed within 3 years or as Cognitively Stable MCI if dementia was not diagnosed during this interval. SSD were evaluated utilizing the 15-item Geriatric Depression Scale (GDS). Endorsement of specific SSD at baseline and the stability of SSD over 36 months were compared between the two MCI groups.
Results
Baseline symptom endorsement and stability of total GDS scores did not differentiate MCI groups. Worsening of 4 individual items from the GDS over time (memory problems, feelings of helplessness, loss of interest, and preference for staying at home) differentiated MCI converters from cognitively stable MCI (p <0.05 for all). However, only increased endorsement of memory symptoms over time was associated with progression to dementia after controlling for other clinical variables (p=0.05).
Conclusions
SSD in MCI participants largely consist of cognitive symptoms and activity limitations and the stability of SSD over time differentiated the MCI groups better than baseline endorsement of symptoms. However, the only significant predictor of conversion to dementia was increased endorsement of memory problems, which likely represents insight into cognitive problems more than depressive symptomatology in MCI individuals.
doi:10.1002/gps.2713
PMCID: PMC3685477  PMID: 21744390
subsyndromal depression; longitudinal stability; mild cognitive impairment; insight; dementia
18.  Nonlinear time course of brain volume loss in cognitively normal and impaired elders 
Neurobiology of Aging  2010;33(5):845-855.
The goal was to elucidate the time course of regional brain atrophy rates relative to age in cognitively normal (CN) aging, mild cognitively impairment (MCI) and Alzheimer’s disease (AD), without a-priori models for atrophy progression. Regional brain volumes from 147 CN subjects, 164 stable MCI, 93 MCI-to-AD converters and 111 AD patients, between 51 to 91 years old and who had repeated 1.5T magnetic resonance imaging (MRI) scans over 30 months, were analyzed. Relations between regional brain volume change and age were determined using generalized additive models, an established non-parametric concept for approximating nonlinear relations. Brain atrophy rates varied nonlinearly with age, predominantly in regions of the temporal lobe. Moreover, the atrophy rates of some regions leveled off with increasing age in control and stable MCI subjects whereas those rates progressed further in MCI-to-AD converters and AD patients. The approach has potential uses for early detection of AD and differentiation between stable and progressing MCI.
doi:10.1016/j.neurobiolaging.2010.07.012
PMCID: PMC3032014  PMID: 20855131
Alzheimer’s disease; mild cognitive impairment; aging; brain atrophy; hippocampus; magnetic resonance imaging; generalized additive models
19.  Different associations of white matter lesions with depression and cognition 
BMC Neurology  2012;12:83.
Background
To test the hypothesis that white matter lesions (WML) are primarily associated with regional frontal cortical volumes, and to determine the mediating effects of these regional frontal cortices on the associations of WML with depressive symptoms and cognitive dysfunction.
Methods
Structural brains MRIs were performed on 161 participants: cognitively normal, cognitive impaired but not demented, and demented participants. Lobar WML volumes, regional frontal cortical volumes, depressive symptom severity, and cognitive abilities were measured. Multiple linear regression analyses were used to identify WML volume effects on frontal cortical volume. Structural equation modeling was used to determine the MRI-depression and the MRI-cognition path relationships.
Results
WML predicted frontal cortical volume, particularly in medial orbirtofrontal cortex, irrespective of age, gender, education, and group status. WML directly predicted depressive score, and this relationship was not mediated by regional frontal cortices. In contrast, the association between WML and cognitive function was indirect and mediated by regional frontal cortices.
Conclusions
These findings suggest that the neurobiological mechanisms underpinning depressive symptoms and cognitive dysfunction in older adults may differ.
doi:10.1186/1471-2377-12-83
PMCID: PMC3482604  PMID: 22920586
Leukoaraiosis; Depression; Cognition; Frontal lobe; Mediation
20.  Treatment With Cholinesterase Inhibitors and Memantine of Patients in the Alzheimer’s Disease Neuroimaging Initiative 
Archives of Neurology  2011;68(1):58-66.
Objectives
To assess the clinical characteristics and course of patients with mild cognitive impairment (MCI) and mild Alzheimer disease (AD) treated with cholinesterase inhibitors (ChEIs) and memantine hydrochloride.
Design
Cohort study.
Setting
The 59 recruiting sites for the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
Participants
Outpatients with MCI and AD in ADNI.
Main Outcome Measures
The AD Assessment Scale–cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR) scale, and Functional Activities Questionnaire (FAQ).
Results
A total of 177 (44.0%) of 402 MCI patients and 159 (84.6%) of 188 mild-AD patients were treated with ChEIs and 11.4% of MCI patients and 45.7% of AD patients with memantine at entry. Mild-cognitive-impairment patients who received ChEIs with or without memantine were more impaired, showed greater decline in scores, and progressed to dementia sooner than patients who did not receive ChEIs. Alzheimer-disease patients who received ChEIs and memantine took them longer, were more functionally impaired, and showed greater decline on the MMSE and CDR (but not on the ADAS-cog or FAQ) than those who received ChEIs only.
Conclusions
Academic physicians frequently prescribe ChEIs and memantine earlier than indicated in the US Food and Drug Administration–approved labeling to patients who are relatively more severely impaired or who are rapidly progressing toward cognitive impairment. The use of these medications in ADNI is associated with clinical decline and may affect the interpretation of clinical trial outcomes.
Study Registration
clinicalTrials.gov Identifier: NCT00106899
doi:10.1001/archneurol.2010.343
PMCID: PMC3259850  PMID: 21220675
21.  Characteristics and Performance of a Modified Version of the ADCS-CGIC CIBIC+ for Mild Cognitive Impairment Clinical Trials 
Introduction
The Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC) was modified for use in mild cognitive impairment (MCI) trials and tested in the ADCS MCI randomized clinical trial of donepezil, vitamin E and placebo. We assessed feasibility for its use by determining whether or not: (1) it distinguished a medication effect at 6- and 12- months, (2) baseline demographic or clinical characteristics predicted change, (3) there was an association between MCI-CGIC and change in other clinical measures in order to evaluate external or concurrent validity.
Methods
We used a generalized estimating equations approach for ordinal outcome data to test the effects of treatment, baseline characteristics and change in clinical measures on the MCI-CGIC over 12 months, and ordinal logistic regression to assess the association between MCI-CGIC and change in clinical measures at 6 months and 12 months.
Results
On the MCI-CGIC overall, 12.9% and 10.6% were rated as having improved, and 31.6% and 39.8% as having worsened over 6- and 12-months, respectively. The MCI-CGIC did not distinguish the donepezil or vitamin E groups from placebo at 6 and 12 months treatment. Variables at screening or baseline that were associated with worse CGIC scores over 6 and 12 months included white race, greater years of education, worse depression, dementia severity rating, cognitive, and daily activities scores, and lower memory domain scores on a neuropsychological battery. Rate of worsening on the MCI-CGIC over 12 months was associated with change on the AD Assessment Scale-cognitive (ADAS-cog) and on executive function. Worsening at 6 months and 12 months, separately, were associated with the corresponding change in ADAS-cog, ADL, BDI, MMSE, CDR-sb, memory, and executive function.
Conclusions
Change detected by the MCI-CGIC was associated with baseline clinical severity and with change in clinical ratings over 6 and 12 months, supporting the validity of a CGIC approach in MCI. The effect size of the donepezil-placebo difference was similar to that of other outcomes at 12 months. About 40% of MCI patients were judged worse and about 11% improved, consistent with clinical experience and other ratings.
doi:10.1097/WAD.0b013e31819cb760
PMCID: PMC2762354  PMID: 19812469
Mild cognitive impairment; Alzheimer's disease; dementia; global impression of change; rating scales; donepezil; vitamin E; clinical trials

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