Whole-brain Atrophy Rates Research Articles

Brain Volume and Diffusion Markers as Predictors of Disability and Short-Term Disease Evolution in Multiple Sclerosis

MRI markers of neuroaxonal damage in MS have emerged as critical long-term predictors of MS-related disability. Here we investigated the potential of whole-brain diffusivity and brain volume for the prediction of cross-sectional disability and short- to medium-term clinical evolution. In this multimodal prospective longitudinal MRI study of 54 patients with MS (87% under immunomodulatory therapy, baseline and follow-up at a median of 12 months), ADC histogram analysis, WM lesion load, BPF, whole-brain atrophy rate, MSFC score, and EDSS score were obtained. A total of 44 patients with no relapse at both time points were included. At both time points, ADC histogram analysis provided robust predictors of the MSFC scores (maximal R(2) = 0.576, P < .001), incorporated cognition and fine-motor skill subscores, and EDSS scores. Significant changes beyond physiologic age-related changes at follow-up were noted for ADC histogram markers and BPF. Stronger diffusivity alterations and brain volume at baseline predicted MSFC decline, as demonstrated by multiple linear regression analysis (mean ADC, R(2) = 0.203; P = .003) and lower baseline BPF in patients with declined compared with stable MSFC scores (P = .001). Results were independent of intercurrent relapses. Diffusion histogram analysis provided stable surrogates of disability in MS and proved sensitive for monitoring disease progression during a median of 12 months. Advanced neuroaxonal pathology at baseline was indicative of an increased risk for sustained progression during a median of 12 months, independent of intercurrent relapses.

Longitudinal neuroimaging and neuropsychological profiles of frontotemporal dementia with C9ORF72 expansions.

IntroductionFrontotemporal dementia (FTD) is a common cause of early-onset dementia with a significant genetic component, as underlined by the recent identification of repeat expansions in the gene C9ORF72 as a major cause of FTD and motor neuron disease. Understanding the neurobiology and clinical phenomenology of this novel mutation is currently a major research focus. However, few data are available concerning the longitudinal evolution of this genetic disease. Here we present longitudinal neuropsychological and neuroimaging data on a cohort of patients with pathological repeat expansions in C9ORF72.MethodsFollowing a review of the University College London FTD DNA database, 20 cases were retrospectively identified with a C9ORF72 expansion. Twelve cases had longitudinal neuropsychology data available and six of these cases also had longitudinal volumetric brain magnetic resonance imaging. Cortical and subcortical volumes were extracted using FreeSurfer. Rates of whole brain, hemispheric, cerebellar and ventricular change were calculated for each subject. Nonlinear fluid registration of follow-up to baseline scan was performed to visualise longitudinal intra-subject patterns of brain atrophy and ventricular expansion.ResultsPatients had low average verbal and performance IQ at baseline that became impaired (< 5th percentile) at follow-up. In particular, visual memory, naming and dominant parietal skills all showed deterioration. Mean rates of whole brain atrophy (1.4%/year) and ventricular expansion (3.2 ml/year) were substantially greater in patients with the C9ORF72 mutation than in healthy controls; atrophy was symmetrical between the cerebral hemispheres within the C9ORF72 mutation group. The thalamus and cerebellum showed significant atrophy whereas no cortical areas were preferentially affected. Longitudinal fluid imaging in individual patients demonstrated heterogeneous patterns of progressive volume loss; however, ventricular expansion and cerebellar volume loss were consistent findings.ConclusionDisease evolution in C9ORF72-associated FTD is linked neuropsychologically with increasing involvement of parietal and amnestic functions, and neuroanatomically with rather diffuse and variable cortical and central atrophy but more consistent involvement of the cerebellum and thalamus. These longitudinal profiles are consistent with disease spread within a distributed subcortical network and demonstrate the feasibility of longitudinal biomarkers for tracking the evolution of the C9ORF72 mutation phenotype.

Rates of brain atrophy and clinical decline over 6 and 12-month intervals in PSP: Determining sample size for treatment trials

Imaging biomarkers are useful outcome measures in treatment trials. We compared sample size estimates for future treatment trials performed over 6 or 12-months in progressive supranuclear palsy using both imaging and clinical measures. We recruited 16 probable progressive supranuclear palsy patients that underwent baseline, 6 and 12-month brain scans, and 16 age-matched controls with serial scans. Disease severity was measured at each time-point using the progressive supranuclear palsy rating scale. Rates of ventricular expansion and rates of atrophy of the whole brain, superior frontal lobe, thalamus, caudate and midbrain were calculated. Rates of atrophy and clinical decline were used to calculate sample sizes required to power placebo-controlled treatment trials over 6 and 12-months. Rates of whole brain, thalamus and midbrain atrophy, and ventricular expansion, were increased over 6 and 12-months in progressive supranuclear palsy compared to controls. The progressive supranuclear palsy rating scale increased by 9 points over 6-months, and 18 points over 12-months. The smallest sample size estimates for treatment trials over 6-months were achieved using rate of midbrain atrophy, followed by rate of whole brain atrophy and ventricular expansion. Sample size estimates were further reduced over 12-month intervals. Sample size estimates for the progressive supranuclear palsy rating scale were worse than imaging measures over 6-months, but comparable over 12-months. Atrophy and clinical decline can be detected over 6-months in progressive supranuclear palsy. Sample size estimates suggest that treatment trials could be performed over this interval, with rate of midbrain atrophy providing the best outcome measure.

Trajectories of brain and hippocampal atrophy in FTD with mutations in MAPT or GRN

To use multiple serial MRI to assess rates and trajectories of brain and hippocampal atrophy in subjects with frontotemporal dementia (FTD) with progranulin (GRN) or microtubule-associated protein tau (MAPT) gene mutations. In this case-control study, we identified 8 subjects with mutations in GRN and 12 subjects with mutations in MAPT who had at least 2 serial MRIs. Serial MRIs were registered to baseline MRI for each subject using 9 df registration and rate of whole brain atrophy was calculated using the boundary-shift integral. Hippocampal volume was measured using Freesurfer. Mixed effects linear regression models were used to model volume change over time in both groups after adjusting for head size, age at baseline, and disease duration at baseline. The annual rate of whole brain atrophy in the MAPT subjects was 2.4% per year (95% confidence interval [CI] 1.9-2.8). The GRN subjects showed a higher rate of whole brain atrophy at 3.5% per year (95% CI 2.8-4.2; p = 0.01). Rates of hippocampal atrophy were not different across the groups (MAPT = 7.8% [95% CI 3.9-12], GRN = 6.5% [95% CI 1.7-11], p = 0.66). Rates of whole brain atrophy in GRN, and hippocampal atrophy in MAPT, were associated with age, with older subjects showing slower rates of atrophy (p = 0.01 and p < 0.001). Subjects with FTD with GRN mutations have a faster rate of whole brain atrophy than subjects with FTD with MAPT mutations, with similar rates of hippocampal atrophy. Rates of atrophy in both groups were associated with age. These findings are important for future treatment trials in FTD that use rates of atrophy as an outcome measure.

Androgen intervention therapy in a patient with familial Alzheimer's disease

associated withWBA, although this association was not observed in the ML direction. Conclusions: Our findings indicate that the rate of whole brain atrophy is related to trunk movement control during dual-task gait, but not normal gait. This supports the idea that dual-task gait is more cognitively demanding than normal gait. In addition, it suggests that trunk movement control recruits neuronal resources. Additional studies are necessary to further elucidate the effects of regional atrophy on the control of gait.

Elevated Plasma Homocysteine Is Associated with Increased Brain Atrophy Rates in Older Subjects with Mild Hypertension

We determined using serial MR imaging whether raised plasma homocysteine levels are associated with increased brain atrophy, white matter lesion (WML) progression or incidence of silent brain infarcts (SBIs) in older hypertensive subjects. Brain atrophy rates (0.58 ± 0.48% per year, mean ± SD) were significantly correlated with homocysteine (β = 0.46, p = 0.001 homocysteine; β = 0.44, p = 0.007 homocysteine/folate/B12 models) but not with folate or B12 levels. Progression of WML (0.08 ± 0.16%) was not associated with homocysteine level (B = 0.01, p = 0.29). New SBIs were uncommon. In older hypertensive individuals, plasma homocysteine levels are associated with increased rates of whole-brain atrophy but not WML progression.

Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis

TRACK-HD is a prospective observational study of Huntington's disease (HD) that examines disease progression in premanifest individuals carrying the mutant HTT gene and those with early stage disease. We report 12-month longitudinal changes, building on baseline findings. we did a 12-month follow-up of patients recruited from the four TRACK-HD study sites in Canada, France, the Netherlands, and the UK. Participants were premanifest individuals (preHD) carrying the mutant HTT gene, patients with early HD, and controls matched by age and sex with the combined preHD and early HD groups. Data were collected by use of 3T MRI and clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Statistical analysis assessed annualised change with the use of linear regression models to estimate differences between groups. 116 preHD individuals, 114 early HD patients, and 115 people in the control group completed follow-up. Four preHD individuals, nine early HD patients, and eight people in the control group did not complete the follow-up. A further nine participants, who completed follow-up assessments, were unable to undergo MRI. After adjustment for demographics, annualised rates of generalised and regional brain atrophy were higher in preHD and early HD groups than in controls. Whole-brain atrophy rates were 0·20% (95% CI 0·05-0·34; p=0·0071) per year higher in preHD participants and 0·60% (0·44-0·76; p<0·0001) in early HD patients, and caudate atrophy rates were 1·37% (0·99-1·75; p<0·0001) per year higher in preHD and 2·86% (2·34-3·39; p<0·0001) in early HD. Voxel-based morphometry revealed grey-matter and white-matter atrophy, even in subjects furthest from predicted disease onset. Quantitative imaging showed statistically significant associations with disease burden, an indicator of disease pathology, and total functional capacity, a widely-used clinical measure of disease severity. Relative to controls, decline in cognition and quantitative motor function was detectable in both pre- and early HD, as was deterioration in oculomotor function in early HD. quantitative imaging showed the greatest differentiation across the spectrum of disease and functional measures of decline were sensitive in early HD, with cognitive and quantitative motor impairment also detectable in preHD. We show longitudinal change over 12 months in generalised and regional brain volume, cognition, and quantitative motor tasks in individuals many years from predicted disease onset and show the feasibility of obtaining quantifiable endpoints for future trials.

Twelve-month whole-brain atrophy rates and estimated power to detect Alzheimer-slowing treatment effects in multicenter trials using Iterative Principal Component Analysis: Preliminary findings from the Alzheimer's Disease Neuroimaging Initiative

Twelve-month whole-brain atrophy rates and estimated power to detect Alzheimer-slowing treatment effects in multicenter trials using Iterative Principal Component Analysis: Preliminary findings from the Alzheimer's Disease Neuroimaging Initiative

Incidence of cerebral microbleeds

Cerebral microbleeds (MBs) are commonly observed in memory clinic patients. Little is known about occurrence of and risk factors for developing new MBs in this population. To investigate incidence of lobar and nonlobar MBs in a memory clinic population. Furthermore, to assess risk factors for the development of new MBs and their associations with other MRI changes. A total of 254 patients visiting our memory clinic, with repeat gradient-recalled echo T2*-weighted MRI, were included (scan interval 1.9 +/- 0.9 years). Baseline and incident MBs were regionally counted. White matter hyperintensities (WMH) and progression of WMH were assessed using visual rating scales. Baseline brain volume and whole-brain atrophy rate were estimated automatically. In a subset, APOE was determined. Thirty-one (12%) patients developed new MBs (range 1-19). Both multiple strictly lobar and nonlobar MBs at baseline predicted incident MBs (odds ratio [OR] 8.4; 95% confidence interval [CI] 2.2-33.2, and OR 33.8; 95% CI 8.1-140.8). Furthermore, baseline WMH grade (OR 1.2; 1.1-1.3), lacunar infarcts (OR 2.8; 1.3-6.0), and APOE epsilon2 carriership (OR 4.2; 1.4-12.5) predicted MB incidence. Incident MB patients had more progression of WMH (p < 0.01) and incident lacunar infarcts (p < 0.05). These relations were most prominent for incident nonlobar MBs. Incident strictly lobar MBs were associated with smoking. In addition to APOE genotype, presence and progression of small-vessel disease and vascular risk factors were predictors of new MBs. The latter are potentially modifiable, suggesting the possibility of preventing incident MBs, hopefully resulting in slower clinical decline.

Rate and acceleration of whole-brain atrophy in premanifest and early Huntington's disease

Huntington's disease (HD) produces progressive and ultimately widespread impairment of brain function. Neostriatal atrophy alone cannot account for whole-brain losses seen postmortem, and the mutant huntingtin protein and its neuropathologic sequelae are evident throughout the brain. Whole-brain atrophy quantification encompasses the totality of mutant huntingtin's effects on brain volume and may be useful in tracking progression in trials. We studied whole-brain atrophy in HD using a 2-year follow-up design, with three annual MRI scans. We recruited 20 control subjects, 21 premanifest mutation carriers, and 40 patients with early HD and used the brain boundary shift integral to study rate and acceleration of atrophy. Among subjects with an acceptable quality 2-year scan pair, age- and gender-standardized mean brain atrophy rate was greater (P < 0.001) in the patients with HD (n = 21; 0.88%/yr; 95% confidence interval: 0.62-1.13%/yr) than that in controls (n = 13; 0.16%/yr; 0.00-0.32%/yr). In the 12 patients with early HD in whom acceleration could be directly assessed there was evidence (P= 0.048) of acceleration year-on-year (mean acceleration = 0.69% yr(-2); 95% confidence interval: 0.01% yr(-2) to 1.37% yr(-2)), although this was not formally significantly different from that in controls (n = 7, P = 0.055). Statistically significantly increased atrophy rates and acceleration were not seen overall in the premanifest group, who were on average 18 years from predicted disease onset. We conclude that the study of whole-brain atrophy has the potential to inform our understanding of the neurobiology of HD and warrants further study as one means of assessing the outcomes of future clinical trials.

Measuring disease progression in frontotemporal lobar degeneration

There is currently much interest in biomarkers of disease activity in frontotemporal lobar degeneration (FTLD). We assessed MRI and behavioral measures of progression in a longitudinal FTLD cohort. Thirty-two patients with FTLD (11 behavioral variant frontotemporal dementia [bvFTD], 11 semantic dementia [SemD], 10 progressive nonfluent aphasia [PNFA]) and 24 age-matched healthy controls were assessed using volumetric brain MRI and standard behavioral measures (Mini-Mental State Examination, Frontal Assessment Battery, Clinical Dementia Rating Scale, Neuropsychiatric Inventory with Caregiver Distress scale) at baseline and 1 year later. A semi-automated image registration protocol was used to calculate annualized rates of brain atrophy (brain boundary shift integral [BBSI]) and ventricular expansion (ventricular boundary shift integral [VBSI]). Associations between these rates and changes in behavioral indices were investigated. Rates of whole brain atrophy were greater in the entire FTLD cohort and in each subgroup compared with controls (all p < or = 0.004). Rates of ventricular expansion were greater in the entire cohort (p < 0.001) and the SemD (p = 0.002) and PNFA (p = 0.05) subgroups compared with controls. Changes in Mini-Mental State Examination, Frontal Assessment Battery, and Clinical Dementia Rating Scale scores were associated with MRI measures of progression, though not uniformly across FTLD subgroups. Both BBSI and VBSI yielded feasible sample size estimates for detecting meaningful treatment effects in SemD and PNFA language subgroups. Sample sizes were substantially larger using MRI biomarkers for the bvFTD subgroup, and using behavioral biomarkers in general. Semi-automated MRI atrophy measures are potentially useful objective biomarkers of progression in frontotemporal lobar degeneration (FTLD); however, careful stratification of FTLD subtypes will be important in future clinical trials of disease-modifying therapies.

The clinical use of structural MRI in Alzheimer disease.

Structural imaging based on magnetic resonance is an integral part of the clinical assessment of patients with suspected Alzheimer dementia. Prospective data on the natural history of change in structural markers from preclinical to overt stages of Alzheimer disease are radically changing how the disease is conceptualized, and will influence its future diagnosis and treatment. Atrophy of medial temporal structures is now considered to be a valid diagnostic marker at the mild cognitive impairment stage. Structural imaging is also included in diagnostic criteria for the most prevalent non-Alzheimer dementias, reflecting its value in differential diagnosis. In addition, rates of whole-brain and hippocampal atrophy are sensitive markers of neurodegeneration, and are increasingly used as outcome measures in trials of potentially disease-modifying therapies. Large multicenter studies are currently investigating the value of other imaging and nonimaging markers as adjuncts to clinical assessment in diagnosis and monitoring of progression. The utility of structural imaging and other markers will be increased by standardization of acquisition and analysis methods, and by development of robust algorithms for automated assessment.

Memory complaints and increased rates of brain atrophy: risk factors for mild cognitive impairment and Alzheimer's disease

To determine rates of cerebral atrophy in individuals with symptoms of memory loss but no objective cognitive impairment (SNCI) and their association with future cognitive decline. Thirty-two SNCI subjects, 16 with mild cognitive impairment (MCI) and 27 control subjects had clinical assessment and magnetic resonance imaging at baseline and 1 year later. Rates of whole brain atrophy (WBA), hippocampal atrophy (HA) and ventricular enlargement (VE) were measured. Our outcome was clinical diagnosis at 2 years after entry into the study. The MCI group had greater rates of WBA, HA and VE than both controls and SNCI subjects. As a group SNCI subjects did not have significantly greater rates of atrophy than the controls. However, SNCI subjects who progressed to MCI or dementia had increased rates of atrophy compared with those who remained stable. Individuals with memory complaints but no objective memory deficits, who progress to MCI or dementia, have increased rates of cerebral atrophy.

Distinct profiles of brain atrophy in frontotemporal lobar degeneration caused by progranulin and tau mutations

Neural network breakdown is a key issue in neurodegenerative disease, but the mechanisms are poorly understood. Here we investigated patterns of brain atrophy produced by defined molecular lesions in the two common forms of genetically mediated frontotemporal lobar degeneration (FTLD). Nine patients with progranulin (GRN) mutations and eleven patients with microtubule-associated protein tau (MAPT) mutations had T1 MR brain imaging. Brain volumetry and grey and white matter voxel-based morphometry (VBM) were used to assess patterns of cross-sectional atrophy in the two groups. In a subset of patients with longitudinal MRI rates of whole-brain atrophy were derived using the brain-boundary-shift integral and a VBM-like analysis of voxel-wise longitudinal volume change was performed. The GRN mutation group showed asymmetrical atrophy whereas the MAPT group showed symmetrical atrophy. Brain volumes were smaller in the GRN group with a faster rate of whole-brain atrophy. VBM delineated a common anterior cingulate–prefrontal–insular pattern of atrophy in both disease groups. Additional disease-specific profiles of grey and white matter loss were identified on both cross-sectional and longitudinal imaging: GRN mutations were associated with asymmetrical inferior frontal, temporal and inferior parietal lobe grey matter atrophy and involvement of long intrahemispheric association white matter tracts, whereas MAPT mutations were associated with symmetrical anteromedial temporal lobe and orbitofrontal grey matter atrophy and fornix involvement. The findings suggest that the effects of GRN and MAPT mutations are expressed in partly overlapping but distinct anatomical networks that link specific molecular dysfunction with clinical phenotype.

Progression from mild cognitive impairment to Alzheimer's disease: effects of sex, butyrylcholinesterase genotype, and rivastigmine treatment.

Evaluate the effect of sex and butyrylcholinesterase (BuChE) genotype on the incidence of Alzheimer's disease (AD), cognitive and functional decline, brain volume changes, and response to rivastigmine treatment in individuals with mild cognitive impairment (MCI). This retrospective exploratory analysis from a 3-4 year, randomized, placebo-controlled study of rivastigmine in MCI patients included participants who consented to pharmacogenetic testing. Of a total of 1018 patients, 490 [253 (52%) female] were successfully genotyped for BuChE. In patients receiving placebo, the BuChE wt/wt genotype was associated with a statistically significant higher incidence of progression to AD and functional decline in women, compared with men with the BuChE wt/wt genotype. In patients with a BuChE-K allele receiving placebo, incidence of progression to AD and rate of functional decline were not significantly different by sex; however, cognitive decline was significantly faster in men. Statistically significant benefits of rivastigmine treatment on incident AD, functional decline, ventricular volume expansion, whole-brain atrophy, and white matter loss were evident in female BuChE wt/wt. Sex and BuChE genotype seem to differentially influence the type of decline in MCI patients, with more rapid progression of cognitive decline in male BuChE-K, and more incident AD and functional decline in female BuChE wt/wt. Cognitive decline in male BuChE-K and functional decline and incident AD in female BuChE wt/wt were significantly attenuated by rivastigmine. Rivastigmine treatment also significantly reduced ventricular expansion, whole-brain atrophy rate, and white matter loss in female BuChE wt/wt, suggesting a possible disease-modifying effect.

Whole‐brain atrophy as a measure of progression in premanifest and early Huntington's disease

Therapeutic trials in Huntington's disease (HD) are challenging as clinical progression is slow and variable and reliable biomarkers are lacking. We used magnetic resonance imaging and the brain boundary shift integral to quantify whole-brain atrophy rates over 1 year in early and premanifest HD subjects, and controls. Early HD subjects had statistically significantly (P = 0.007) increased (threefold higher) rates of whole-brain atrophy compared with controls. Higher atrophy rates were associated with longer CAG repeat length. MRI-based measures of whole-brain atrophy may have potential as a measure of progression in HD.

Tracking progression in frontotemporal lobar degeneration

Semantic dementia is a sporadic neurodegenerative disorder characterized by the progressive erosion of semantic processing and is one of the canonical subtypes of frontotemporal lobar degeneration. This study aimed to characterize the pattern of global and regional longitudinal brain atrophy in semantic dementia and to identify imaging biomarkers that could underpin therapeutic trials. Twenty-one patients with semantic dementia (including eight pathologically confirmed cases) underwent whole-brain and region-of-interest analyses on volumetric brain MRI scans at two time points. Sample size estimates for trials were subsequently calculated using these data. Mean (SD) whole-brain atrophy rate was 39.6 (31.9) mL/y [3.2 (12.0) mL/y in controls], with ventricular enlargement of 8.9 (4.4) mL/y [1.0 (1.0) mL/y in controls]. All patients had a smaller left temporal lobe at baseline [left mean 31.9 (6.9) mL, right mean 49.2 (9.5) mL; p < 0.0001]; however, the mean rate of atrophy was significantly greater in the right temporal lobe [right 3.9 (1.7) mL/y, left 2.8 (1.2) mL/y; p = 0.02]. Similarly, whereas the left hippocampus was smaller at baseline, the mean atrophy rate was significantly greater in the right hippocampus. Using the atrophy rates generated, sample size requirements for clinical trials were found to be smallest for temporal lobe measurement. These findings show that the rate of tissue loss in the right temporal lobe overtakes the left temporal lobe as semantic dementia evolves, consistent with the later development of symptoms attributable to right temporal lobe dysfunction. Furthermore, our findings demonstrate that MRI measures of temporal lobe volume loss could provide a feasible and sensitive index of disease progression in semantic dementia.

Whole-brain atrophy rate and CSF biomarker levels in MCI and AD: A longitudinal study

To assess associations between cerebrospinal fluid (CSF) biomarker levels and MRI-based whole-brain atrophy rate in mild cognitive impairment (MCI) and Alzheimer's disease (AD). We included 99 patients (47 AD, 29 MCI, 23 controls) who underwent lumbar puncture at baseline and repeat MRI. A subgroup of 48 patients underwent a second lumbar puncture. CSF levels of beta-amyloid(1-42) (A beta(1-42)), tau and tau phosphorylated at threonine-181 (P-tau(181)), and whole-brain atrophy rate were measured. Across groups, baseline A beta(1-42) and tau were modestly associated with whole-brain atrophy rate. Adjusted for age, sex and diagnosis, we found no association between A beta(1-42) or tau, and whole-brain atrophy rate. By contrast, high CSF levels of P-tau(181) showed a mild association with a lower whole-brain atrophy rate in AD but not in controls or MCI patients. Finally, whole-brain atrophy rate was associated with change in MMSE, but change in CSF biomarker levels was not. Whole-brain atrophy rate and CSF levels of A beta(1-42,) tau or P-tau(181) provide complementary information in patients with MCI and AD.

Gray matter atrophy in multiple sclerosis: A longitudinal study

To determine gray matter (GM) atrophy rates in multiple sclerosis (MS) patients at all stages of disease, and to identify predictors and clinical correlates of GM atrophy. MS patients and healthy control subjects were observed over 4 years with standardized magnetic resonance imaging (MRI) and neurological examinations. Whole-brain, GM, and white matter atrophy rates were calculated. Subjects were categorized by disease status and disability progression to determine the clinical significance of atrophy. MRI predictors of atrophy were determined through multiple regression. Subjects included 17 healthy control subjects, 7 patients with clinically isolated syndromes, 36 patients with relapsing-remitting MS (RRMS), and 27 patients with secondary progressive MS (SPMS). Expressed as fold increase from control subjects, GM atrophy rate increased with disease stage, from 3.4-fold normal in clinically isolated syndromes patients converting to RRMS to 14-fold normal in SPMS. In contrast, white matter atrophy rates were constant across all MS disease stages at approximately 3-fold normal. GM atrophy correlated with disability. MRI measures of focal and diffuse tissue damage accounted for 62% of the variance in GM atrophy in RRMS, but there were no significant predictors of GM atrophy in SPMS. Gray matter tissue damage dominates the pathological process as MS progresses, and underlies neurological disabillity. Imaging correlates of gray matter atrophy indicate that mechanisms differ in RRMS and SPMS. These findings demonstrate the clinical relevance of gray matter atrophy in MS, and underscore the need to understand its causes.

IC-P2-145: Whole-brain atrophy rate and CSF biomarker levels in MCI and AD: A longitudinal study

To assess associations between baseline and longitudinal cerebrospinal fluid (CSF) biomarker levels and whole-brain atrophy rate in mild cognitive impairment (MCI) and Alzheimer's disease (AD), and the ability of these markers to predict disease progression. We included 101 patients (47 AD, 30 MCI, 24 controls) who underwent lumbar puncture at baseline and repeat MRI (interval 1.7±0.7y). A subgroup of 49 patients (20 AD, 18 MCI, 11 controls) underwent a second lumbar puncture. CSF levels of beta-amyloid1–42 (Aβ1–42), tau and tau phosphorylated at threonine-181 (P-tau181) were measured. Whole-brain atrophy rate was measured from serial MRI and clinical progression was determined using the MMSE. Across diagnostic groups, baseline Aβ1–42 (r=0.30, p<0.01), and tau (r=-0.25, p=0.01) were associated with whole-brain atrophy rate, while P-tau181 was not (r=-0.13, p=0.18). After adjustment for age, sex and diagnosis, we found no association between Aβ1–42 or tau, and whole-brain atrophy rate. By contrast, high CSF levels of P-tau181 showed a mild association with a lower whole-brain atrophy rate in AD (β[SE] 0.77 [0.36], p=0.04) but not in controls or MCI patients. Finally, whole-brain atrophy rate was associated with change in MMSE (r=0.40, p<0.05), while change in CSF levels of Aβ1–42, (r=0.18, p=0.22), tau (r=-0.03, p=0.83), and P-tau181(r=-0.01, p=0.97) was not. Whole-brain atrophy rate and CSF levels of Aβ1–42, tau or P-tau181 provide independent information in patients with MCI and AD, with CSF markers reflecting a disease state, while whole-brain atrophy rate measured from serial MRI, reflects the rate of disease progression.