Regional Atrophy Rates Research Articles

The relationship of small vessel disease burden on cerebral and regional brain atrophy rates and cognitive performance over one year of follow-up after transient ischemic attack

The relationship of small vessel disease burden on cerebral and regional brain atrophy rates and cognitive performance over one year of follow-up after transient ischemic attack

Network connectivity and local transcriptomic vulnerability underpin cortical atrophy progression in Parkinson’s disease

Parkinson’s disease pathology is hypothesized to spread through the brain via axonal connections between regions and is further modulated by local vulnerabilities within those regions. The resulting changes to brain morphology have previously been demonstrated in both prodromal and de novo Parkinson’s disease patients. However, it remains unclear whether the pattern of atrophy progression in Parkinson’s disease over time is similarly explained by network-based spreading and local vulnerability. We address this gap by mapping the trajectory of cortical atrophy rates in a large, multi-centre cohort of Parkinson’s disease patients and relate this atrophy progression pattern to network architecture and gene expression profiles. Across 4-year follow-up visits, increased atrophy rates were observed in posterior, temporal, and superior frontal cortices. We demonstrated that this progression pattern was shaped by network connectivity. Regional atrophy rates were strongly related to atrophy rates across structurally and functionally connected regions. We also found that atrophy progression was associated with specific gene expression profiles. The genes whose spatial distribution in the brain was most related to atrophy rate were those enriched for mitochondrial and metabolic function. Taken together, our findings demonstrate that both global and local brain features influence vulnerability to neurodegeneration in Parkinson’s disease.

Investigating Heterogeneity and Neuroanatomic Correlates of Longitudinal Clinical Decline in Atypical Alzheimer Disease.

The aims of this work were to compare rates of longitudinal change in neurologic and neuropsychological test performance between the logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA) variants of atypical Alzheimer disease (AD) and to use unbiased principal component analysis to assess heterogeneity in patterns of change and relationships to demographics and concurrent brain atrophy. Patients with PCA or LPA who were positive for amyloid and tau AD biomarkers and had undergone serial neurologic and neuropsychological assessments and structural MRI were identified. Rates of change in 13 clinical measures were compared between groups in a case-control design, and principal component analysis was used to assess patterns of clinical change unbiased by clinical phenotype. Components were correlated with rates of regional brain atrophy with tensor-based morphometry. Twenty-eight patients with PCA and 27 patients with LPA were identified. Those with LPA showed worse baseline performance and faster rates of decline in naming, repetition, and working memory, as well as faster rates of decline in verbal episodic memory, compared to those with PCA. Conversely, patients with PCA showed worse baseline performance in tests of visuospatial and perceptual function and on the Clinical Dementia Rating Scale and faster rates of decline in visuoperceptual function compared to those with LPA. Principal component analysis showed that patterns of clinical decline were highly heterogeneous across the cohort, with 10 principal components required to explain >90% of the variance. The first principal component reflected overall severity, with higher scores in LPA than PCA reflecting faster decline in LPA, and was related to left temporoparietal atrophy. The second and third principal components were not related to clinical phenotype but showed some relationship to regional atrophy. No relationships were identified between the principal components and age, sex, disease duration, amyloid PET findings, or apolipoprotein genotype. Longitudinal patterns of clinical decline differ between LPA and PCA but are heterogeneous and related to different patterns of topographic spread. PCA is associated with a more slowly progressive course than LPA.

A Targeted Association Study of Blood-Brain Barrier Gene SNPs and Brain Atrophy

Background: The blood-brain barrier (BBB) is formed by a high-density lining of endothelial cells, providing a border between circulating blood and the brain interstitial fluid. This structure plays a key role in protecting the brain microenvironment by restricting passage of certain molecules and circulating pathogens. Objective: To identify associations between brain volumetric changes and a set of 355 BBB-related single nucleotide polymorphisms (SNP). Method: In a population of 721 unrelated individuals, linear mixed effect models were used to assess if specific variants were linked to regional rates of atrophy over a 12-year time span. Four brain regions were investigated, including cortical grey matter, cortical white matter, ventricle, and hippocampus. Further, we also investigated the potential impact of history of hypertension, diabetes, and the incidence of stroke on regional brain volume change. Results: History of hypertension, diabetes, and stroke was not associated with longitudinal brain volume change. However, we identified a series of genetic variants associated with regional brain volume changes. The associations were independent of variation due to the APOEɛ4 allele and were significant post correction for multiple comparisons. Conclusion: This study suggests that key genes involved in the regulation of BBB integrity may be associated with longitudinal changes in specific brain regions. The derived polygenic risk scores indicate that these interactions are multigenic. Further research needs to be conducted to investigate how BBB functions maybe compromised by genetic variation.

Dynamic Regional Brain Atrophy Rates in the First Year After Ischemic Stroke.

Brain atrophy can be regarded as an end-organ effect of cumulative cardiovascular risk factors. Accelerated brain atrophy is described following ischemic stroke, but it is not known whether atrophy rates vary over the poststroke period. Examining rates of brain atrophy allows the identification of potential therapeutic windows for interventions to prevent poststroke brain atrophy. We charted total and regional brain volume and cortical thickness trajectories, comparing atrophy rates over 2 time periods in the first year after ischemic stroke: within 3 months (early period) and between 3 and 12 months (later period). Patients with first-ever or recurrent ischemic stroke were recruited from 3 Melbourne hospitals at 1 of 2 poststroke time points: within 6 weeks (baseline) or 3 months. Whole-brain 3T magnetic resonance imaging was performed at 3 time points: baseline, 3 months, and 12 months. Eighty-six stroke participants completed testing at baseline; 125 at 3 months (76 baseline follow-up plus 49 delayed recruitment); and 113 participants at 12 months. Their data were compared with 40 healthy control participants with identical testing. We examined 5 brain measures: hippocampal volume, thalamic volume, total brain and hemispheric brain volume, and cortical thickness. We tested whether brain atrophy rates differed between time points and groups. A linear mixed-effect model was used to compare brain structural changes, including age, sex, years of education, a composite cerebrovascular risk factor score, and total intracranial volume as covariates. Atrophy rates were greater in stroke than control participants. Ipsilesional hemispheric, hippocampal, and thalamic atrophy rates were 2 to 4 times greater in the early versus later period. Regional atrophy rates vary over the first year after stroke. Rapid brain volume loss in the first 3 months after stroke may represent a potential window for intervention. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02205424.

Associations among amyloid status, age, and longitudinal regional brain atrophy in cognitively unimpaired older adults

The goal of this study was to compare regional brain atrophy patterns in cognitively unimpaired (CU) older adults with and without brain accumulation of amyloid-β (Aβ) to elucidate contributions of Aβ, age, and other variables to atrophy rates. In 80 CU participants from the Alzheimer's Disease Neuroimaging Initiative, we determined effects of Aβ and age on longitudinal, regional atrophy rates, while accounting for confounding variables including sex, APOE ε4 genotype, white matter lesions, and cerebrospinal fluid total and phosphorylated tau levels. We not only found overlapping patterns of atrophy in Aβ+ versus Aβ− participants but also identified regions where atrophy pattern differed between the 2 groups. Higher Aβ load was associated with increased longitudinal atrophy in the entorhinal cortex, amygdala, and hippocampus, even when accounting for age and other variables. Age was associated with atrophy in insula, fusiform gyrus, and isthmus cingulate, even when accounting for Aβ. We found age by Aβ interactions in the postcentral gyrus and lateral orbitofrontal cortex. These results elucidate the separate and related effects of age, Aβ, and other important variables on longitudinal brain atrophy rates in CU older adults.

Staging of amyloid β, t-tau, regional atrophy rates, and cognitive change in a nondemented cohort: Results of serial mediation analyses

IntroductionCurrent models posit a sequence of amyloid β (Aβ), tau, atrophy, and cognitive change leading to Alzheimer's disease, but ambiguities remain. We examined these sequences via serial mediations. MethodsWe studied normal controls, early mild cognitive impairment, and late mild cognitive impairment individuals from the Alzheimer's Disease Neuroimaging Initiative 2 database for the mediation of baseline cerebrospinal fluid Aβ effects on 2-year cognitive change via regional longitudinal atrophy rate (AR) alone or AR and tau. ResultsIn normal controls, Aβ correlated directly with regional ARs and memory loss, with no mediations. In early mild cognitive impairment, tau and lateral temporal ARs serially mediated the influence of Aβ on memory while Aβ affected memory via hippocampal AR. Late mild cognitive impairment consistently showed serial mediations of tau followed by atrophy. However, Aβ effects on memory also continued to be specifically mediated by medial temporal ARs without intermediate tau. DiscussionBiomarker sequences vary by region and disease state, suggesting the need to refine current cascade models.

Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease.

Cerebral small vessel disease is a common condition associated with lacunar stroke, cognitive impairment and significant functional morbidity. White matter hyperintensities and brain atrophy, seen on magnetic resonance imaging, are correlated with increasing disease severity. However, how the two are related remains an open question. To better define the relationship between white matter hyperintensity growth and brain atrophy, we applied a semi-automated magnetic resonance imaging segmentation analysis pipeline to a 3-year longitudinal cohort of 99 subjects with symptomatic small vessel disease, who were followed-up for ≥1 years. Using a novel two-stage warping pipeline with tissue repair step, voxel-by-voxel rate of change maps were calculated for each tissue class (grey matter, white matter, white matter hyperintensities and lacunes) for each individual. These maps capture both the distribution of disease and spatial information showing local rates of growth and atrophy. These were analysed to answer three primary questions: first, is there a relationship between whole brain atrophy and magnetic resonance imaging markers of small vessel disease (white matter hyperintensities or lacune volume)? Second, is there regional variation within the cerebral white matter in the rate of white matter hyperintensity progression? Finally, are there regionally specific relationships between the rates of white matter hyperintensity progression and cortical grey matter atrophy? We demonstrate that the rates of white matter hyperintensity expansion and grey matter atrophy are strongly correlated (Pearson's R = -0.69, P < 1 × 10(-7)), and significant grey matter loss and whole brain atrophy occurs annually (P < 0.05). Additionally, the rate of white matter hyperintensity growth was heterogeneous, occurring more rapidly within long association fasciculi. Using voxel-based quantification (family-wise error corrected P < 0.05), we show the rate of white matter hyperintensity progression is associated with increases in cortical grey matter atrophy rates, in the medial-frontal, orbito-frontal, parietal and occipital regions. Conversely, increased rates of global grey matter atrophy are significantly associated with faster white matter hyperintensity growth in the frontal and parietal regions. Together, these results link the progression of white matter hyperintensities with increasing rates of regional grey matter atrophy, and demonstrate that grey matter atrophy is the major contributor to whole brain atrophy in symptomatic cerebral small vessel disease. These measures provide novel insights into the longitudinal pathogenesis of small vessel disease, and imply that therapies aimed at reducing progression of white matter hyperintensities via end-arteriole damage may protect against secondary brain atrophy and consequent functional morbidity.

Cerebrospinal Fluid Markers of Neurodegeneration and Rates of Brain Atrophy in Early Alzheimer Disease.

Measures of neuronal loss are likely good surrogates for clinical and radiological disease progression in Alzheimer disease (AD). Cerebrospinal fluid (CSF) markers of neuronal injury or neurodegeneration may offer usefulness in predicting disease progression and guiding outcome assessments and prognostic decisions in clinical trials of disease-modifying therapies. Visinin-like protein 1 (VILIP-1) has demonstrated potential usefulness as a marker of neuronal injury in AD. To investigate the usefulness of CSF VILIP-1, tau, p-tau181, and Aβ42 levels in predicting rates of whole-brain and regional atrophy in early AD and cognitively normal control subjects over time. Longitudinal observational study of brain atrophy in participants with early AD and cognitively normal controls. Study participants had baseline CSF biomarker measurements and longitudinal magnetic resonance imaging assessments for a mean follow-up period of 2 to 3 years. Mixed linear models assessed the ability of standardized baseline CSF biomarker measures to predict rates of whole-brain and regional atrophy over the follow-up period. The setting was The Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St Louis. Participants (mean age, 72.6 years) were individuals with a clinical diagnosis of very mild AD (n = 23) and cognitively normal controls (n = 64) who were enrolled in longitudinal studies of healthy aging and dementia. The study dates were 2000 to 2010. Correlations between baseline CSF biomarker measures and rates of whole-brain or regional atrophy in the AD and control cohorts over the follow-up period. Baseline CSF VILIP-1, tau, and p-tau181 levels (but not Aβ42 levels) predicted rates of whole-brain and regional atrophy in AD over the follow-up period. Baseline CSF VILIP-1 levels predicted whole-brain (P = .006), hippocampal (P = .01), and entorhinal (P = .001) atrophy rates at least as well as tau and p-tau181 in early AD. Cognitively normal controls whose CSF VILIP-1, tau, or p-tau181 levels were in the upper tercile had higher rates of whole-brain (P = .02, P = .003, and P = .02, respectively), hippocampal (P = .001, P = .01, and P = .02, respectively), and entorhinal (P = .007, P = .01, and P = .01, respectively) atrophy compared with those whose levels were in the lower 2 terciles. Cerebrospinal fluid VILIP-1 levels predict rates of whole-brain and regional atrophy similarly to tau and p-tau181 and may provide a useful CSF biomarker surrogate for neurodegeneration in early symptomatic and preclinical AD.

Brain atrophy over time in genetic and sporadic frontotemporal dementia: a study of 198 serial magnetic resonance images.

The aim of our study was to determine the utility of longitudinal magnetic resonance imaging (MRI) measurements as potential biomarkers in the main genetic variants of frontotemporal dementia (FTD), including microtubule-associated protein tau (MAPT) and progranulin (GRN) mutations and C9ORF72 repeat expansions, as well as sporadic FTD. In this longitudinal study, 58 subjects were identified who had at least two MRI and MAPT mutations (n=21), GRN mutations (n=11), C9ORF72 repeat expansions (n=11) or sporadic FTD (n=15). A total of 198 serial MRI measurements were analyzed. Rates of whole brain atrophy were calculated using the boundary shift integral. Regional rates of atrophy were calculated using tensor-based morphometry. Sample size estimates were calculated. Progressive brain atrophy was observed in all groups, with fastest rates of whole brain atrophy in GRN, followed by sporadic FTD, C9ORF72 and MAPT. All variants showed greatest rates in the frontal and temporal lobes, with parietal lobes also strikingly affected in GRN. Regional rates of atrophy across all lobes were greater in GRN compared to the other groups. C9ORF72 showed greater rates of atrophy in the left cerebellum and right occipital lobe than MAPT, and sporadic FTD showed greater rates in the anterior cingulate than C9ORF72 and MAPT. Sample size estimates were lowest using temporal lobe rates in GRN, ventricular rates in MAPT and C9ORF72, and whole brain rates in sporadic FTD. These data support the utility of using rates of atrophy as outcome measures in future drug trials in FTD and show that different imaging biomarkers may offer advantages in the different variants of FTD.

Abstract T P59: Brain Atrophy Rates Not Affected By Stroke Thrombolysis

Introduction: Despite clear outcome benefits, some physicians remain concerned about theoretical deleterious effects of intravenous thrombolysis. In the CANVAS study (Cognition and Neocortical Volume After Stroke) we have reported brain volume changes in patients following stroke. We sought here to compare brain atrophy rates of 3 groups of patients presenting with MCA stroke, versus a group of healthy control participants. Hypothesis: We hypothesized that IV thrombolysis would not affect brain atrophy rates following stroke. Methods: Three groups of patients with acute ischemic MCA stroke were included, 2 of whom received thrombolysis: 10 patients were imaged at 2 hours and at 3 months (Copenhagen cohort) and 9 patients imaged within 30 days of symptom onset and at 3 months (Melbourne CANVAS cohort). We compared regional and global brain volume and atrophy rates with 10 patients who did not receive thrombolysis and a group of 10 healthy control participants were also imaged at these timepoints. 3D MPRAGE images were acquired on a Siemens Trio 3T MRI scanner. Images were processed using Freesurfer V 5.1 with default settings. We compared baseline and 3 month average regional cortical thickness. Ipsilesional and contralesional results were analyzed separately. Paired sample t-tests were used to assess significant change. Results: There was no significant difference in brain volume between the 2 timepoints in our control participants. Ipsilesional white matter (WM) and gray matter (GM) volume declined over the 3 month period in all 3 stroke groups. There was no significant difference in brain atrophy rates between stroke patients who received IV thrombolysis and those who didn’t. Conclusions: In this pilot study, we found that thrombolysis did not affect brain atrophy rates in the stroke patients studied.

Longitudinal assessment of global and regional atrophy rates in Alzheimer's disease and dementia with Lewy bodies.

Background & objectivePercent whole brain volume change (PBVC) measured from serial MRI scans is widely accepted as a sensitive marker of disease progression in Alzheimer's disease (AD). However, the utility of PBVC in the differential diagnosis of dementia remains to be established. We compared PBVC in AD and dementia with Lewy bodies (DLB), and investigated associations with clinical measures.Methods72 participants (14 DLBs, 25 ADs, and 33 healthy controls (HCs)) underwent clinical assessment and 3 Tesla T1-weighted MRI at baseline and repeated at 12 months. We used FSL-SIENA to estimate PBVC for each subject. Voxelwise analyses and ANCOVA compared PBVC between DLB and AD, while correlational tests examined associations of PBVC with clinical measures.ResultsAD had significantly greater atrophy over 1 year (1.8%) compared to DLB (1.0%; p = 0.01) and HC (0.9%; p < 0.01) in widespread regions of the brain including periventricular areas. PBVC was not significantly different between DLB and HC (p = 0.95). There were no differences in cognitive decline between DLB and AD. In the combined dementia group (AD and DLB), younger age was associated with higher atrophy rates (r = 0.49, p < 0.01).ConclusionsAD showed a faster rate of global brain atrophy compared to DLB, which had similar rates of atrophy to HC. Among dementia subjects, younger age was associated with accelerated atrophy, reflecting more aggressive disease in younger people. PBVC could aid in differentiating between DLB and AD, however its utility as an outcome marker in DLB is limited.

The evolution of primary progressive apraxia of speech.

Primary progressive apraxia of speech is a recently described neurodegenerative disorder in which patients present with an isolated apraxia of speech and show focal degeneration of superior premotor cortex. Little is known about how these individuals progress over time, making it difficult to provide prognostic estimates. Thirteen subjects with primary progressive apraxia of speech underwent two serial comprehensive clinical and neuroimaging evaluations 2.4 years apart [median age of onset = 67 years (range: 49-76), seven females]. All underwent detailed speech and language, neurological and neuropsychological assessments, and magnetic resonance imaging, diffusion tensor imaging and (18)F-fluorodeoxyglucose positron emission tomography at both baseline and follow-up. Rates of change of whole brain, ventricle, and midbrain volumes were calculated using the boundary-shift integral and atlas-based parcellation, and rates of regional grey matter atrophy were assessed using tensor-based morphometry. White matter tract degeneration was assessed on diffusion-tensor imaging at each time-point. Patterns of hypometabolism were assessed at the single subject-level. Neuroimaging findings were compared with a cohort of 20 age, gender, and scan-interval matched healthy controls. All subjects developed extrapyramidal signs. In eight subjects the apraxia of speech remained the predominant feature. In the other five there was a striking progression of symptoms that had evolved into a progressive supranuclear palsy-like syndrome; they showed a combination of severe parkinsonism, near mutism, dysphagia with choking, vertical supranuclear gaze palsy or slowing, balance difficulties with falls and urinary incontinence, and one was wheelchair bound. Rates of whole brain atrophy (1.5% per year; controls = 0.4% per year), ventricular expansion (8.0% per year; controls = 3.3% per year) and midbrain atrophy (1.5% per year; controls = 0.1% per year) were elevated (P ≤ 0.001) in all 13, compared to controls. Increased rates of brain atrophy over time were observed throughout the premotor cortex, as well as prefrontal cortex, motor cortex, basal ganglia and midbrain, while white matter tract degeneration spread into the splenium of the corpus callosum and motor cortex white matter. Hypometabolism progressed over time in almost all subjects. These findings demonstrate that some subjects with primary progressive apraxia of speech will rapidly evolve and develop a devastating progressive supranuclear palsy-like syndrome ∼ 5 years after onset, perhaps related to progressive involvement of neocortex, basal ganglia and midbrain. These findings help improve our understanding of primary progressive apraxia of speech and provide some important prognostic guidelines.

Pattern of brain atrophy rates in autopsy-confirmed dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is characterized by preserved whole brain and medial temporal lobe volumes compared with Alzheimer's disease dementia (AD) on magnetic resonance imaging. However, frequently coexistent AD-type pathology may influence the pattern of regional brain atrophy rates in DLB patients. We investigated the pattern and magnitude of the atrophy rates from 2 serial MRIs in autopsy-confirmed DLB patients (n = 20) and mixed DLB/AD patients (n = 22), compared with AD (n = 30) and elderly nondemented control subjects (n = 15), followed antemortem. DLB patients without significant AD-type pathology were characterized by lower global and regional rates of atrophy, similar to control subjects. The mixed DLB/AD patients displayed greater atrophy rates in the whole brain, temporoparietal cortices, hippocampus and amygdala, and ventricle expansion, similar to AD patients. In the DLB and DLB/AD patients, the atrophy rates correlated with Braak neurofibrillary tangle stage, cognitive decline, and progression of motor symptoms. Global and regional atrophy rates are associated with AD-type pathology in DLB, and these rates can be used as biomarkers of AD progression in patients with LB pathology.

Brain atrophy rates in first degree relatives at risk for Alzheimer's

A positive family history (FH) raises the risk for late-onset Alzheimer's disease though, other than the known risk conferred by apolipoprotein ε4 (ApoE4), much of the genetic variance remains unexplained. We examined the effect of family history on longitudinal regional brain atrophy rates in 184 subjects (42% FH+, mean age 79.9) with mild cognitive impairment (MCI) enrolled in a national biomarker study. An automated image analysis method was applied to T1-weighted MR images to measure atrophy rates for 20 cortical and subcortical regions. Mixed-effects linear regression models incorporating repeated-measures to control for within-subject variation over multiple time points tested the effect of FH over a follow-up of up to 48 months. Most of the 20 regions showed significant atrophy over time. Adjusting for age and gender, subjects with a positive FH had greater atrophy of the amygdala (p < 0.01), entorhinal cortex (p < 0.01), hippocampus (p < 0.053) and cortical gray matter (p < 0.009). However, when E4 genotype was added as a covariate, none of the FH effects remained significant. Analyses by ApoE genotype showed that the effect of FH on amygdala atrophy rates was numerically greater in ε3 homozygotes than in E4 carriers, but this difference was not significant. FH+ subjects had numerically greater 4-year cognitive decline and conversion rates than FH− subjects but the difference was not statistically significant after adjusting for ApoE and other variables. We conclude that a positive family history of AD may influence cortical and temporal lobe atrophy in subjects with mild cognitive impairment, but it does not have a significant additional effect beyond the known effect of the E4 genotype.

Effects of Baseline CSF α-Synuclein on Regional Brain Atrophy Rates in Healthy Elders, Mild Cognitive Impairment and Alzheimer’s Disease

BackgroundCerebrospinal 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.MethodsBaseline 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).ResultsThe 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.

Mapping the Effect of the Apolipoprotein E Genotype on 4-Year Atrophy Rates in an Alzheimer Disease–related Brain Network

To determine the effect of the apolipoprotein E (APOE) genotype on atrophy rates of specific brain gray matter regions hypothesized to be key components of cognitive networks disrupted in Alzheimer disease. The Alzheimer's Disease Neuroimaging Initiative (ADNI) was approved by the institutional review boards of all participating sites. All subjects and their legal representatives gave written informed consent prior to data collection. The authors analyzed data from 237 subjects (mean age, 79.9 years; 40% female) with mild cognitive impairment (MCI) in the ADNI database and assessed the effect of the APOE ε4 and ε2 alleles on regional brain atrophy rates over a 12-48-month period. Brain regions were selected a priori: 15 experimental and five control regions were included. Regional atrophy rates were derived by using a fully automated algorithm applied to T1-weighted magnetic resonance (MR) imaging data. Analysis consisted of mixed-effects linear regression with repeated measures; results were adjusted for multiple testing with Bonferroni correction. Thirteen of 15 experimental regions showed a significant effect of ε4 for higher atrophy rates (P < .001 for all). Cohen d values ranged from 0.26 to 0.42, with the largest effects seen in the amygdalae and hippocampi. The transverse temporal cortex showed a trend (P = .02, but did not survive Bonferroni correction) for a protective effect (Cohen d value = 0.15) of ε2. No control region showed an APOE effect. The APOE ε4 allele is associated with accelerated rates of atrophy in 13 distinct brain regions in limbic and neocortical areas. This suggests the possibility of a genotype-specific network of related brain regions that undergo faster atrophy in MCI and potentially contribute to cognitive decline. Online supplemental material is available for this article.

Regional and whole-brain atrophy rates in autopsy-confirmed dementia with Lewy bodies and Alzheimer's disease

Regional and whole-brain atrophy rates in autopsy-confirmed dementia with Lewy bodies and Alzheimer's disease

Cerebral atrophy in mild cognitive impairment and Alzheimer disease

To quantify the regional and global cerebral atrophy rates and assess acceleration rates in healthy controls, subjects with mild cognitive impairment (MCI), and subjects with mild Alzheimer disease (AD). Using 0-, 6-, 12-, 18-, 24-, and 36-month MRI scans of controls and subjects with MCI and AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, we calculated volume change of whole brain, hippocampus, and ventricles between all pairs of scans using the boundary shift integral. We found no evidence of acceleration in whole-brain atrophy rates in any group. There was evidence that hippocampal atrophy rates in MCI subjects accelerate by 0.22%/year2 on average (p = 0.037). There was evidence of acceleration in rates of ventricular enlargement in subjects with MCI (p = 0.001) and AD (p < 0.001), with rates estimated to increase by 0.27 mL/year2 (95% confidence interval 0.12, 0.43) and 0.88 mL/year2 (95% confidence interval 0.47, 1.29), respectively. A post hoc analysis suggested that the acceleration of hippocampal loss in MCI subjects was mainly driven by the MCI subjects that were observed to progress to clinical AD within 3 years of baseline, with this group showing hippocampal atrophy rate acceleration of 0.50%/year2 (p = 0.003). The small acceleration rates suggest a long period of transition to the pathologic losses seen in clinical AD. The acceleration in hippocampal atrophy rates in MCI subjects in the ADNI seems to be driven by those MCI subjects who concurrently progressed to a clinical diagnosis of AD.

Genetic interactions associated with 12-month atrophy in hippocampus and entorhinal cortex in Alzheimer's Disease Neuroimaging Initiative

Missing heritability in late onset Alzheimer disease can be attributed, at least in part, to heterogeneity in disease status and to the lack of statistical analyses exploring genetic interactions. In the current study, we use quantitative intermediate phenotypes derived from magnetic resonance imaging data available from the Alzheimer's Disease Neuroimaging Initiative, and we test for association with gene-gene interactions within biological pathways. Regional brain volumes from the hippocampus (HIP) and entorhinal cortex (EC) were estimated from baseline and 12-month magnetic resonance imaging scans. Approximately 560,000 single nucleotide polymorphisms (SNPs) were available genome-wide. We tested all pairwise SNP-SNP interactions (approximately 151 million) within 212 Kyoto Encyclopedia of Genes and Genomes pathways for association with 12-month regional atrophy rates using linear regression, with sex, APOE ε4 carrier status, age, education, and clinical status as covariates. A total of 109 SNP-SNP interactions were associated with right HIP atrophy, and 125 were associated with right EC atrophy. Enrichment analysis indicated significant SNP-SNP interactions were overrepresented in the calcium signaling and axon guidance pathways for both HIP and EC atrophy and in the ErbB signaling pathway for HIP atrophy.