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Introduction: Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials., Methods: Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point., Results: Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point., Discussion: Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Structural MRI is widely used for investigating brain atrophy in many neurodegenerative disorders, with several research groups developing and publishing techniques to provide quantitative assessments of this longitudinal change. Often techniques are compared through computation of required sample size estimates for future clinical trials. However interpretation of such comparisons is rendered complex because, despite using the same publicly available cohorts, the various techniques have been assessed with different data exclusions and different statistical analysis models. We created the MIRIAD atrophy challenge in order to test various capabilities of atrophy measurement techniques. The data consisted of 69 subjects (46 Alzheimer's disease, 23 control) who were scanned multiple (up to twelve) times at nine visits over a follow-up period of one to two years, resulting in 708 total image sets. Nine participating groups from 6 countries completed the challenge by providing volumetric measurements of key structures (whole brain, lateral ventricle, left and right hippocampi) for each dataset and atrophy measurements of these structures for each time point pair (both forward and backward) of a given subject. From these results, we formally compared techniques using exactly the same dataset. First, we assessed the repeatability of each technique using rates obtained from short intervals where no measurable atrophy is expected. For those measures that provided direct measures of atrophy between pairs of images, we also assessed symmetry and transitivity. Then, we performed a statistical analysis in a consistent manner using linear mixed effect models. The models, one for repeated measures of volume made at multiple time-points and a second for repeated "direct" measures of change in brain volume, appropriately allowed for the correlation between measures made on the same subject and were shown to fit the data well. From these models, we obtained estimates of the distribution of atrophy rates in the Alzheimer's disease (AD) and control groups and of required sample sizes to detect a 25% treatment effect, in relation to healthy ageing, with 95% significance and 80% power over follow-up periods of 6, 12, and 24months. Uncertainty in these estimates, and head-to-head comparisons between techniques, were carried out using the bootstrap. The lateral ventricles provided the most stable measurements, followed by the brain. The hippocampi had much more variability across participants, likely because of differences in segmentation protocol and less distinct boundaries. Most methods showed no indication of bias based on the short-term interval results, and direct measures provided good consistency in terms of symmetry and transitivity. The resulting annualized rates of change derived from the model ranged from, for whole brain: -1.4% to -2.2% (AD) and -0.35% to -0.67% (control), for ventricles: 4.6% to 10.2% (AD) and 1.2% to 3.4% (control), and for hippocampi: -1.5% to -7.0% (AD) and -0.4% to -1.4% (control). There were large and statistically significant differences in the sample size requirements between many of the techniques. The lowest sample sizes for each of these structures, for a trial with a 12month follow-up period, were 242 (95% CI: 154 to 422) for whole brain, 168 (95% CI: 112 to 282) for ventricles, 190 (95% CI: 146 to 268) for left hippocampi, and 158 (95% CI: 116 to 228) for right hippocampi. This analysis represents one of the most extensive statistical comparisons of a large number of different atrophy measurement techniques from around the globe. The challenge data will remain online and publicly available so that other groups can assess their methods., (Copyright © 2015. Published by Elsevier Inc.)

Background: Huntington's disease is marked by progressive neuroanatomical changes, assumed to underlie the development of the disease's characteristic symptoms. Previous work has demonstrated longitudinal macrostructural white-matter atrophy, with some evidence of microstructural change focused in the corpus callosum., Objective: To more accurately characterise longitudinal patterns, we examined white matter microstructural change using Diffusion Tensor Imaging (DTI) data from three timepoints over a 15 month period., Methods: In 48 early-stage HD patients and 36 controls from the multi-site PADDINGTON project, diffusion tensor imaging (DTI) was employed to measure changes in fractional anisotropy (FA) and axial (AD) and radial diffusivity (RD) in 24 white matter regions-of-interest (ROIs)., Results: Cross-sectional analysis indicated widespread baseline between-group differences, with significantly decreased FA and increased AD and RD found in HD patients across multiple ROIs. Longitudinal rates of change differed significantly between HD patients and controls in the genu and body of corpus callosum, corona radiata and anterior limb of internal capsule. Change in RD in the body of the corpus callosum was significantly associated with baseline disease burden, but other clinical associations were not significant., Conclusions: We detected subtle longitudinal white matter changes in early HD patients. Progressive white matter abnormalities in HD may not be uniform throughout the brain, with some areas remaining static in the early symptomatic phase. Longer assessment periods across disease stages will help map this progressive trajectory.

Background: Secondary progressive multiple sclerosis, for which no satisfactory treatment presently exists, accounts for most of the disability in patients with multiple sclerosis. Simvastatin, which is widely used for treatment of vascular disease, with its excellent safety profile, has immunomodulatory and neuroprotective properties that could make it an appealing candidate drug for patients with secondary progressive multiple sclerosis., Methods: We undertook a double-blind, controlled trial between Jan 28, 2008, and Nov 4, 2011, at three neuroscience centres in the UK. Patients aged 18-65 years with secondary progressive multiple sclerosis were randomly assigned (1:1), by a centralised web-based service with a block size of eight, to receive either 80 mg of simvastatin or placebo. Patients, treating physicians, and outcome assessors were masked to treatment allocation. The primary outcome was the annualised rate of whole-brain atrophy measured from serial volumetric MRI. Analyses were by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00647348., Findings: 140 participants were randomly assigned to receive either simvastatin (n=70) or placebo (n=70). The mean annualised atrophy rate was significantly lower in patients in the simvastatin group (0·288% per year [SD 0·521]) than in those in the placebo group (0·584% per year [0·498]). The adjusted difference in atrophy rate between groups was -0·254% per year (95% CI -0·422 to -0·087; p=0·003); a 43% reduction in annualised rate. Simvastatin was well tolerated, with no differences between the placebo and simvastatin groups in proportions of participants who had serious adverse events (14 [20%] vs nine [13%])., Interpretation: High-dose simvastatin reduced the annualised rate of whole-brain atrophy compared with placebo, and was well tolerated and safe. These results support the advancement of this treatment to phase 3 testing., Funding: The Moulton Foundation [charity number 1109891], Berkeley Foundation [268369], the Multiple Sclerosis Trials Collaboration [1113598], the Rosetrees Trust [298582] and a personal contribution from A Pidgley, UK National Institute of Health Research (NIHR) University College London Hospitals/UCL Biomedical Research Centres funding scheme., (Copyright © 2014 Chataway et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.)

Background: TRACK-HD is a prospective observational biomarker study in premanifest and early Huntington's disease (HD). In this report we define a battery of potential outcome measures for therapeutic trials., Methods: We assessed longitudinal data collected at baseline, 12 months, and 24 months at sites in Leiden (Netherlands), London (UK), Paris (France), and Vancouver (Canada). Participants were individuals without HD but carrying the mutant HTT gene (ie, premanifest HD), patients with early HD, and healthy control individuals matched by age and sex to the combined HD groups. Data were collected with 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric assessments. We estimated adjusted, between-group differences in rates of change in these measures and concomitant longitudinal effect sizes., Findings: Longitudinal data were available for 116 control individuals, 117 premanifest gene carriers, and 116 participants with early HD. Significantly greater progressive grey-matter, white-matter, whole-brain, and regional atrophy was recorded in the premanifest and early HD groups than in the control group. Effect sizes for atrophy rates between participants with early HD and controls were largest in the caudate (2·04, 95% CI 1·68 to 2·48) and white matter (1·70, 1·40 to 2·08). Functional, quantitative motor, and cognitive measures deteriorated to a greater extent in the early HD group than in controls, with the largest effect size in the symbol digit modality test (1·00, 0·67 to 1·27). In the early HD group, changes in structural imaging and various cognitive and quantitative motor scores were associated with worsening total motor score (TMS) and total functional capacity (TFC). In the premanifest group, despite significant declines in regional and overall brain volumes, few functional variables showed significant 24 month change compared with controls; TMS, emotion recognition, and speeded tapping were exceptions. Premanifest individuals with progression, predefined as an increase in TMS score of 5 points or more, any TFC decline, or a new diagnostic confidence score of 4, exhibited higher rates of brain atrophy and deterioration on some quantitative motor tasks compared with other premanifest participants., Interpretation: On the basis of longitudinal effect size, we recommend several objective outcome measures for clinical trials in participants with early HD. Hypothetical treatment effects defined by slower longitudinal changes in these measures would be detectable over a realistic timescale with practical sample sizes. The restricted 24 month cognitive or motor decline in the premanifest sample illustrates the greater challenge in trial design for this group., Funding: CHDI/HighQ Foundation Inc., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Music perception generally involves processing the frequency relationships between successive pitches and extraction of the melodic contour. Previous evidence has suggested that the 'ups' and 'downs' of melodic contour are categorically and automatically processed, but knowledge of the brain regions that discriminate different types of contour is limited. Here, we examined melodic contour discrimination using multivariate pattern analysis (MVPA) of fMRI data. Twelve non-musicians were presented with various ascending and descending melodic sequences while being scanned. Whole-brain MVPA was used to identify regions in which the local pattern of activity accurately discriminated between contour categories. We identified three distinct cortical loci: the right superior temporal sulcus (rSTS), the left inferior parietal lobule (lIPL), and the anterior cingulate cortex (ACC). These results complement previous findings of melodic processing within the rSTS, and extend our understanding of the way in which abstract auditory sequences are categorized by the human brain., (Published by Elsevier Inc.)

Background: 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., Methods: 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., Findings: 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., Interpretation: 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.

Aim: 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., Methods: 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., Results: 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., Discussion: Individuals with memory complaints but no objective memory deficits, who progress to MCI or dementia, have increased rates of cerebral atrophy., (Copyright © 2010 John Wiley & Sons, Ltd.)

Introduction: We aimed to assess the value of a second MR scan in the radiological diagnosis of dementia., Methods: One hundred twenty subjects with clinical follow-up of at least 1 year with two scans were selected from a cognitive disorders clinic. Scans were reviewed as a single first scan (method A), two unregistered scans presented side-by-side (method B) and a registered pair (method C). Scans were presented to two neuroradiologists and a clinician together with approximate scan interval (if applicable) and age. Raters decided on a main and subtype diagnosis., Results: There was no evidence that differences between methods (expressed as relative odds of a correct response) differed between reviewers (p = 0.17 for degenerative condition or not, p = 0.5 for main diagnosis, p = 0.16 for subtype). Accordingly, results were pooled over reviewers. For distinguishing normal/non-progressors from degenerative conditions, the proportions correctly diagnosed were higher with methods B and C than with A (p = 0.001, both tests). The difference between method B and C was not statistically significant (p = 0.18). For main diagnosis, the proportion of correct diagnoses were highest with method C for all three reviewers; however, this was not statistically significant comparing with method A (p = 0.23) or with method B (p = 0.16). For subtype diagnosis, there was some evidence that method C was better than method A (p = 0.01) and B (p = 0.048)., Conclusions: Serial MRI and registration may improve visual diagnosis in dementia.

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., ((c) 2009 Movement Disorder Society.)

Objective: Caudate atrophy rate measured from serial MRI is proposed as a biomarker of HD progression that may be of use in assessing putative disease-modifying agents. Manual measurement techniques are the most widely applied but are time-consuming. We describe and evaluate an automated technique based on a local registration and boundary shift integral (BSI) approach at the caudate-CSF and caudate-white matter boundaries; caudate boundary shift integral (CBSI)., Methods: Two-year caudate volume change was measured in controls, premanifest HD and early HD using the CBSI and compared with a detailed manual measure in terms of 1) raw caudate volume change, 2) group differentiation, 3) associations with clinical variables and 4) rater requirements. CBSI additivity was assessed by comparing measurements over a single scan pair (baseline-->2 years), with the sum of measurements from two scan pairs (baseline-->1 year-->2 years)., Results: Techniques produced comparable caudate volume change measurements, although CBSI under-reported by 0.04 ml relative to manual. Both techniques distinguished controls, premanifest and early HD with a stepwise increase in rates across groups. Higher rates (CBSI and manual) were associated with increased proximity to estimated disease onset but not clinical change scores. CBSI reduced rater requirements by 2/3 (2 h per subject) relative to manual for this three time-point investigation. CBSI measurements over one scan pair showed good agreement with the sum of measurements from two scan pairs., Conclusions: CBSI results were comparable to a manual measure but with reduced rater requirements. CBSI may be of use in large-scale studies of HD.

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., ((c) 2009 Movement Disorder Society.)

We measured hippocampi on baseline-, 6- and 12-month scans in a group of AD (n=36) and control subjects (n=20). We found that mean annualised atrophy rates using 6-month intervals were comparable at a group level to those generated from a 12-month interval. Higher variance was seen using shorter intervals, although this was only significant in the control group. This has implications where shorter inter-scan intervals may be advantageous, such as rapid diagnosis, and tracking of disease progression including in a clinical trial.

Alzheimer's disease (AD) is associated with excess whole brain volume loss, and progressive cognitive impairment. We aimed to study the extent to which these two potential biomarkers of AD progression are correlated. Forty-six patients with sporadic AD were tested with a neuropsychometric battery including test of verbal and visual memory, vocabulary, arithmetic, naming, visuoperceptual skills and reasoning at two time-points, approximately 1 year apart; annualised rates of change for each test were calculated. Each subject also attended for up to twelve T1-weighted volumetric MRI scans at fixed intervals over a 2-year period. For each individual all possible scan-pairs were positionally registered, and whole brain atrophy rates were calculated using the brain boundary shift integral. Linear mixed models were used to investigate associations between atrophy rate and coincident change in each neuropsychometric score. Each model estimated the effect of a unit change in score, plus the additional effect of a fall to floor, after adjusting for baseline levels. 467 MRI scans were performed, permitting 2199 individual measures of change to be made. The model-derived mean atrophy rate was 2.23% per year with a between-subject SD of 0.99% per year. Increasing atrophy rate was significantly associated with rate of change in a number of non-memory based neuropsychological scores, with the strongest association seen with longitudinal change in matrix reasoning (p=0.004). These results provide further evidence that cerebral atrophy is a clinically relevant marker of AD progression. This methodology whereby data from patients falling to floor on a given test may be included and accounted for, rather than discarded, may find broader application in clinical studies incorporating neuropsychometric outcomes.

Background and Purpose: Alzheimer disease (AD) is accompanied by macroscopic atrophy on volumetric MR imaging. A few studies have also demonstrated reduction in magnetization transfer ratio (MTR), suggesting microstructural changes in remaining brain tissue. This study assessed the value of measuring MTR in addition to volumetric MR in differentiating patients with AD from control subjects., Materials and Methods: Volumetric T1-weighted images and 3D MTR maps were obtained from 18 patients with AD and 18 age-matched control subjects. Whole-brain (WB) and total hippocampal (Hc) volumes were measured using semiautomated techniques and adjusted for total intracranial volume. Mean MTR was obtained for WB and in the Hc region. Histogram analysis was performed for WB MTR. Among patients, associations between volumetric and MTR parameters and the Mini-Mental State Examination (MMSE) were explored., Results: Patients with AD had significantly reduced WB volume (P<.0001) and mean WB MTR (P=.002) and Hc volume (P<.0001) and Hc mean MTR (P<.0001) compared with control subjects. Histogram analysis of WB MTR revealed significant reduction in the 25th percentile point in patients with AD (P=.03). Both WB volume and mean MTR were independently associated with case-control status after adjusting for the other using linear regression models. However, measuring Hc mean MTR added no statistically significant discriminatory value over and above Hc volume measurement alone. Of all MR imaging parameters, only WB volume was significantly correlated with MMSE (r=0.47, P=.048)., Conclusions: This study demonstrates the independent reduction of WB volume and mean MTR in AD. This suggests that the 2 parameters reflect complementary aspects of the AD pathologic lesion at macrostructural and microstructural levels.

Background and Purpose: Brain atrophy is a proposed marker of disease progression in multiple sclerosis (MS). Many magnetic resonance imaging-based methods of atrophy quantification exist, but their relative sensitivity and precision is unclear. Our aim was to compare atrophy rates from the brain boundary shift integral (BBSI), structural image evaluation, using normalization of atrophy (SIENA) (both registration-based methods) and segmented brain volume difference, in patients with clinically isolated syndromes (CIS), relapsing remitting MS (RRMS), and controls., Methods: Thirty-seven CIS patients, 30 with early RRMS and 16 controls had T1-weighted volumetric imaging at baseline and 1 year. Brain atrophy rates were determined using segmented brain volume difference, BBSI, and SIENA., Results: BBSI and SIENA were more precise than subtraction of segmented brain volumes and were more sensitive distinguishing RRMS subjects from controls. A strong correlation was observed between BBSI and SIENA. Atrophy rates were greater in CIS and RRMS subjects than controls (RRMS P < .001). With all methods, significantly greater atrophy rates were observed in CIS patients who developed clinically definite MS relative to subjects who did not., Conclusion: Registration-based techniques are more precise and sensitive than segmentation-based methods in measuring brain atrophy, with BBSI and SIENA providing comparable results.

Cerebral atrophy calculated from serial MRI is a marker of Alzheimer's disease (AD) progression, and a potential outcome measure for therapeutic trials. Reducing within-subject variability in cerebral atrophy rates by acquiring more than two serial scans could allow for shorter clinical trials requiring smaller patient numbers. Forty-six patients with AD and 23 controls each had up to 10 serial MR brain scans over two years. Whole brain atrophy was calculated for each subject from every scan-pair. 708 volumetric MRI scans were acquired: 2199 measures of atrophy were made for patients, and 1182 for controls. A linear mixed model was used to characterise between and within-individual variability. These results were used to investigate the power of combining multiple serial scans in treatment trials of varying lengths. In AD, the mean whole brain atrophy rate was 2.23%/year (95% CI: 1.90-2.56%/year). The linear mixed model was shown to fit the data well and led to a formula (0.99(2) + (0.82/t)2) for the variance of atrophy rates calculated from two scans "t" years apart. Utilising five optimally timed scans with repeat scans at each visit reduced the component of atrophy rate variance attributable to within-subject variability by approximately 56%, equating to a approximately 40% sample size reduction (228 vs 387 patients per arm to detect 20% reduction in atrophy rate) in a six-month placebo-controlled trial. This benefit in terms of sample size is relatively reduced in longer trials, although adding extra scanning visits may have benefits when patient drop-outs are accounted for. We conclude that sample sizes required in short interval therapeutic trials using cerebral atrophy as an outcome measure may be reduced if multiple serial MRI is performed.

The authors measured the rate of whole-brain atrophy over 6 months in 13 patients with early Huntington disease (HD) and seven matched controls. Patients with early HD had significantly increased rates of whole-brain atrophy vs controls (mean [SD] HD, 1.10 [0.88]%/year; controls, 0.26 [0.54]%/year). The measurement of cerebral change over short time periods (e.g., 6 months) may be relevant for trials designed to assess effects on neurodegeneration or atrophy.

Background: Global brain atrophy rate calculated from serial MRI scans may be a surrogate marker of Alzheimer disease (AD) progression. Few studies have assessed atrophy in AD over short intervals., Methods: Thirty-eight patients with AD and 19 control subjects had MRI scans at baseline, 6 months, and 1 year. Ventricular change and whole-brain volume loss were calculated directly from the regions manually outlined on registered scans and using the automated (boundary shift integral [BSI]) technique. Sample sizes required to power placebo-controlled treatment trials over 6 months and 1 year were calculated using these techniques., Results: Increased rates of ventricular expansion and whole-brain atrophy were seen in AD compared with control subjects at both 6 and 12 months using manual and automated techniques (p < 0.001). Using the BSI consistently reduced measurement variability especially for whole-brain change. In clinical trials, at 6 months, significantly fewer patients would be required using the ventricular BSI (VBSI) compared with the brain BSI (BBSI) (e.g., 165 vs 410 per arm to provide 90% power to detect a 20% reduction in rate of change). At 1 year, sample size estimates were smaller than at 6 months, and the advantage of using VBSI instead of BBSI was less marked., Conclusions: In short-interval studies, using the ventricular boundary shift integral instead of the brain boundary shift integral may allow for disease-modifying effects to be demonstrated using significantly smaller sample sizes. This potential benefit must be balanced against the possibility that ventricular volumes may be more likely to be affected by factors other than neurodegeneration.

The extent to which cerebral atrophy in Alzheimer's disease changes with time is unknown. We used multiple MRI scans to measure progression of cerebral atrophy in 12 patients with Alzheimer's disease who were followed up from a presymptomatic stage through to moderately severe dementia. Analysis with hierarchical regression models with quadratic terms in time provided evidence of increasing yearly percentage losses in brain volume. At the time when patients were judged to have mild dementia (mini-mental state examination score MMSE=23), mean yearly loss of brain volume was 2.8% (95% CI 2.3-3.3), which rose by 0.32% per year (0.15-0.50). Our findings reinforce the need for early diagnosis and therapeutic intervention in Alzheimer's disease.

Objective: To investigate the effect of age on global and regional brain volumes and rates of atrophy, and to compare directly results based on cross-sectional and longitudinal data., Methods: Thirty-nine healthy control subjects (age range, 31-84 years) underwent serial magnetic resonance imaging assessments. Measurements included the whole-brain, temporal lobe, hippocampal, and ventricular volumes at baseline and for repeat scans., Results: We found significant decreases in cross-sectional whole-brain (P<.001), temporal lobe (P<.001), and hippocampal (P =.003) volumes and a significant increase in ventricular volume (P<.001) with increasing age. Cross-sectional and longitudinal estimates of atrophy rates were similar. We also found directional evidence of acceleration in atrophy rates with increasing age in all analyses, with the most marked changes occurring after 70 years of age. This increase in rates after 70 years of age was particularly marked in the ventricles (P<.001) and the hippocampi (P =.01)., Conclusions: We found a significant age-associated decrease in global and regional brain volumes. Some evidence indicates that this decline in brain volumes may be due to a nonlinear acceleration in rates of atrophy with increasing age. A better understanding of this process may help to discriminate normal age-related changes from neurodegenerative diseases.

Regional and global cerebral atrophy are inevitable features of Alzheimer's disease (AD). We assessed volumes and atrophy rates of brain structures in patients with familial AD during the period that they developed symptoms. Five patients with presymptomatic AD and 20 controls had two or more annual volumetric MRI brain scans. Volumes of brain, ventricles, temporal lobes, hippocampi, and entorhinal cortices (ECs) were measured. Rates of volume change were calculated from serial scans. There were no significant differences in baseline measures of whole brain, temporal lobe, or ventricular volume between patients and controls; averaged volumes of medial temporal lobe structures (both hippocampi and ECs) were 16.6% (95% confidence interval [CI], 3.3-28.0%) lower in patients. Atrophy rates for brain, temporal lobe, hippocampus, and EC were significantly increased in patients compared with controls (p < 0.05). Averaged atrophy rates from both hippocampi and ECs were 5.1% (95% CI, 3.0-7.1%) greater in patients than controls. Linear extrapolation backward suggested medial temporal lobe atrophy commenced 3.5 years (95% CI, 0.7-7.5 years) before onset, when all patients were asymptomatic. We conclude that increased medial temporal lobe atrophy rates are an early and distinguishing feature of AD and that pathological atrophy probably is occurring several years before the onset of symptoms.