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The primary objective of this study was to evaluate the rate of total brain atrophy (TBA) with serial magnetic resonance imaging (MRI), using the Brain Boundary Shift Integral (BBSI), in patients with probable Alzheimer's disease (AD) over the course of 52 weeks of treatment with memantine or placebo. This was a multi-national, randomized, double-blind, placebo-controlled, fixed-dose 1-year study. Patients were randomized (1 : 1) to treatment with placebo or memantine. Patients randomized to memantine were up-titrated to the target dose of 20 mg/day over 4 weeks. MRI scans were collected at screening and at Weeks 4, 42, and 52. Secondary efficacy assessments included several cognitive and behavioral scales. 518 patients were screened, 278 patients were randomized, and 217 patients completed the study. In the primary efficacy analysis, the differences in TBA rates between memantine (15.2 mL/year) and placebo (15.3 mL/year) were not statistically significant (-0.04 mL/year [(95% CI: -2.60, 2.52), p = 0.98]). There was a statistically significant correlation between change in TBA and change in most cognitive and behavioral scale scores. Patients who were not treated with acetyl cholinesterase inhibitors (AChEIs) showed a significantly lower TBA rate than patients treated with AChEIs. Memantine had a placebo-level incidence of adverse events. There were no statistically significant differences between memantine and placebo in total brain or hippocampal atrophy rates in patients with probable AD treated for 1 year. The biological relevance of cerebral atrophy was supported by a significant correlation between rate of atrophy and decline in cognitive and behavioral outcomes. [ABSTRACT FROM AUTHOR]

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder which presents with either behavioral or language impairment. The two language syndromes are known as progressive nonfluent aphasia (PNFA) and semantic dementia (SEMD). While cross-sectional imaging patterns of brain atrophy are well-described in FTLD, fewer studies have investigated longitudinal imaging changes. We measured longitudinal hemispheric and lobar atrophy rates using serial MRI in a cohort of 18 patients with PNFA and 17 patients with SEMD as well as 14 cognitively-normal control subjects. We subsequently calculated sample size estimates for clinical trials. Rates of left hemisphere atrophy were greater than rates of right hemisphere atrophy in both PNFA and SEMD with no significant differences between the groups. The disease groups showed asymmetrical atrophy (more severe on the left) at baseline with significantly increasing asymmetry over time. Within a hemisphere, the fastest rate of atrophy varied between lobes: in SEMD temporal > frontal > parietal > occipital, while in PNFA frontal > temporal/parietal > occipital. In SEMD, using temporal lobe measures of atrophy in clinical trials would provide the lowest sample sizes necessary, while in PNFA left hemisphere atrophy measures provided the lowest sample size. These patterns provide information about disease evolution in the FTLD language variants that is of both clinical and neurobiological relevance. [ABSTRACT FROM AUTHOR]

Objective: To identify cognitively normal individuals at risk of Alzheimer disease (AD) based on cerebrospinal fluid (CSF) Aβ1-42, and to determine rates of cerebral atrophy.Methods: Control subjects from the Alzheimer's Disease Neuroimaging Initiative with CSF and serial magnetic resonance imaging (MRI) were dichotomized on CSF Aβ1-42 (normal control [NC]-high > 192 pg/ml; NC-low ≤ 192 pg/ml). Baseline and 1-year MRIs were registered, and brain, hippocampal, and ventricular volumes and annualized volume changes were calculated. Baseline characteristics, CSF profiles, neuropsychology, brain volumes and atrophy rates, and APOE, PICALM, CLU, and TOMM40 genotypes were compared. Sample sizes to power presymptomatic clinical trials based on rate of atrophy were calculated.Results: Forty of 105 (38%) were classified as NC-low, and 65 (62%) as NC-high. There were no differences in age (76.3 ± 5.1 vs 74.9 ± 5.1 years), gender, brain volumes, and all but 1 cognitive score (Trails B; p = 0.015). The NC-low group had higher tau (p = 0.005) and p-tau (p < 0.001), and was more likely to be APOE4 positive (48% vs 11%, p < 0.001). The NC-low group had significantly higher whole brain loss (9.3 vs 4.4 ml/yr, p < 0.001), ventricular expansion (2.04 vs 0.95 ml/yr, p = 0.002), and hippocampal atrophy rate (0.07 vs 0.03 ml/yr, p = 0.029). Baseline Aβ1-42 level was strongly correlated with rate of brain atrophy only in the NC-low group (p < 0.001). Using 141 (95% confidence interval, 86-287) patients per arm provides 80% power in a 1-year treatment trial to show 25% slowing of brain atrophy in the NC-low group.Interpretation: A significant percentage of healthy older adults have CSF profiles consistent with AD and increased rates of brain atrophy, suggesting that they may be in the earliest stages of neurodegeneration. Brain atrophy may be a feasible outcome measure for AD prevention studies. [ABSTRACT FROM AUTHOR]

Background: Unbiased longitudinal studies are needed to understand the distributed neurodegenerative changes of Huntington's disease (HD). They may also provide tools for assessing disease-modifying interventions. The authors investigated the progression of regional atrophy in premanifest and early HD compared with controls.Methods: Nine controls, 17 premanifest and 21 early HD subjects underwent volumetric MRI at baseline and 2 years. Premanifest subjects were on average 18.1 years before predicted motor onset. Non-linear registration was used to model within-subject change over the scanning interval, and statistical parametric mapping was used to examine group differences and associations with clinical variables.Results: In early HD, increased grey-matter (GM) atrophy rates were evident throughout the subcortical GM and over selective cortical regions compared with controls. This group also demonstrated strikingly widespread increases in white-matter (WM) atrophy rates. The authors observed no significant differences between premanifest HD and controls. Longer CAG was associated with higher atrophy rates over large WM areas including brainstem and internal capsule and over small GM regions including thalamus and occipital cortex. Worse baseline motor score was associated with regionally increased rates in the thalamus, internal capsule and occipital lobe. Sample-size calculations indicate that 19 and 24 early HD subjects per treatment arm would need to complete a 2-year trial in order to detect a 50% reduction in WM and GM atrophy rates respectively.Conclusions: Degeneration of structural connectivity may play an important role in early HD symptoms. Assessment of WM and GM changes will be important in understanding the complexity of HD and its treatment. [ABSTRACT FROM AUTHOR]

Objective: To assess the relationship between MRI-derived changes in whole-brain and ventricular volume with change in cognitive scores in Alzheimer's disease (AD), mild cognitive impairment (MCI) and control subjects.Material and Methods: In total 131 control, 231 MCI and 99 AD subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort with T1-weighted volumetric MRIs from baseline and 12-month follow-up were used to derive volume changes. Mini mental state examination (MMSE), Alzheimer's disease assessment scale (ADAS)-cog and trails test changes were calculated over the same period.Results: Brain atrophy rates and ventricular enlargement differed between subject groups (p < 0.0005) and in MCI and AD were associated with MMSE changes. Both measures were additionally associated with ADAS-cog and trails-B in MCI patients, and ventricular expansion was associated with ADAS-cog in AD patients. Brain atrophy (p < 0.0005) and ventricular expansion rates (p = 0.001) were higher in MCI subjects who progressed to AD within 12 months of follow-up compared with MCI subjects who remained stable. MCI subjects who progressed to AD within 12 months had similar atrophy rates to AD subjects.Conclusion: Whole-brain atrophy rates and ventricular enlargement differed between patient groups and healthy controls, and tracked disease progression and psychological decline, demonstrating their relevance as biomarkers. [ABSTRACT FROM AUTHOR]

We investigated progression of atrophy in vivo, in Alzheimer's disease (AD), and mild cognitive impairment (MCI). We included 64 patients with AD, 44 with MCI and 34 controls with serial MRI examinations (interval 1.8 ± 0.7 years). A nonlinear registration algorithm (fluid) was used to calculate atrophy rates in six regions: frontal, medial temporal, temporal (extramedial), parietal, occipital lobes and insular cortex. In MCI, the highest atrophy rate was observed in the medial temporal lobe, comparable with AD. AD patients showed even higher atrophy rates in the extramedial temporal lobe. Additionally, atrophy rates in frontal, parietal and occipital lobes were increased. Cox proportional hazard models showed that all regional atrophy rates predicted conversion to AD. Hazard ratios varied between 2.6 (95% confidence interval (CI) = 1.1-6.2) for occipital atrophy and 15.8 (95% CI = 3.5-71.8) for medial temporal lobe atrophy. In conclusion, atrophy spreads through the brain with development of AD. MCI is marked by temporal lobe atrophy. In AD, atrophy rate in the extramedial temporal lobe was even higher. Moreover, atrophy rates also accelerated in parietal, frontal, insular and occipital lobes. Finally, in nondemented elderly, medial temporal lobe atrophy was most predictive of progression to AD, demonstrating the involvement of this region in the development of AD. [ABSTRACT FROM AUTHOR]

Background: Possession of one or more apolipoprotein E (APOE) e4 alleles may influence the distribution of atrophy and clinical phenotype. We aimed to assess the influence of APOE genotype on cortical thickness and regional brain volumes in AD (Alzheimer's disease). Methods: We included 38 patients (9 e4 non-carriers, 23 e4 heterozygotes, 6 e4 homozygotes) and 23 controls. Each subject had 2 magnetic resonance imaging (MRI) scans and a neuropsychological battery. Cortical thickness and isthmus cingulate volume were measured using FreeSurfer; the volumes of the hippocampus, whole brain, and lateral ventricles were calculated using manual and semi-automated volumetry. Results: Compared with controls, cortical thickness was significantly lower: in the bilateral temporal, posterior parietal and occipital regions in non-carriers, in the medial temporal and left parietal regions in heterozygotes, and in the medial temporal lobe in homozygotes. Comparisons between AD subgroups did not show significant differences. A trend for larger brain and isthmus cingulate volumes and smaller hippocampal [ABSTRACT FROM AUTHOR]

We report an isolated, slowly progressive, pure amnestic phenotype in a 59-year-old member of a family affected by autosomal dominant familial Alzheimer disease. Early-onset Alzheimer disease in this family was associated with a V717G mutation in the amyloid precursor protein gene (APP). Subjective impairment of episodic memory began in our subject at the age of 44 years and subsequent, longitudinal neuropsychologic assessment confirmed progressive, severe, global impairment of memory functions over a period of 14 years with preservation of other cognitive domains. The mean annual hippocampal atrophy rate, determined by volumetric magnetic resonance imaging was intermediate between values previously associated with cognitively normal individuals and those with sporadic Alzheimer disease. [ABSTRACT FROM AUTHOR]

There has been recent interest in the application of machine learning techniques to neuroimaging-based diagnosis. These methods promise fully automated, standard PC-based clinical decisions, unbiased by variable radiological expertise. We recently used support vector machines (SVMs) to separate sporadic Alzheimer's disease from normal ageing and from fronto-temporal lobar degeneration (FTLD). In this study, we compare the results to those obtained by radiologists. A binary diagnostic classification was made by six radiologists with different levels of experience on the same scans and information that had been previously analysed with SVM. SVMs correctly classified 95% (sensitivity/specificity: 95/95) of sporadic Alzheimer's disease and controls into their respective groups. Radiologists correctly classified 65-95% (median 89%; sensitivity/specificity: 88/90) of scans. SVM correctly classified another set of sporadic Alzheimer's disease in 93% (sensitivity/specificity: 100/86) of cases, whereas radiologists ranged between 80% and 90% (median 83%; sensitivity/specificity: 80/85). SVMs were better at separating patients with sporadic Alzheimer's disease from those with FTLD (SVM 89%; sensitivity/specificity: 83/95; compared to radiological range from 63% to 83%; median 71%; sensitivity/specificity: 64/76). Radiologists were always accurate when they reported a high degree of diagnostic confidence. The results show that well-trained neuroradiologists classify typical Alzheimer's disease-associated scans comparable to SVMs. However, SVMs require no expert knowledge and trained SVMs can readily be exchanged between centres for use in diagnostic classification. These results are encouraging and indicate a role for computerized diagnostic methods in clinical practice. [ABSTRACT FROM AUTHOR]

To be diagnostically useful, structural MRI must reliably distinguish Alzheimer's disease (AD) from normal aging in individual scans. Recent advances in statistical learning theory have led to the application of support vector machines to MRI for detection of a variety of disease states. The aims of this study were to assess how successfully support vector machines assigned individual diagnoses and to determine whether data-sets combined from multiple scanners and different centres could be used to obtain effective classification of scans. We used linear support vector machines to classify the grey matter segment of T1-weighted MR scans from pathologically proven AD patients and cognitively normal elderly individuals obtained from two centres with different scanning equipment. Because the clinical diagnosis of mild AD is difficult we also tested the ability of support vector machines to differentiate control scans from patients without post-mortem confirmation. Finally we sought to use these methods to differentiate scans between patients suffering from AD from those with frontotemporal lobar degeneration. Up to 96% of pathologically verified AD patients were correctly classified using whole brain images. Data from different centres were successfully combined achieving comparable results from the separate analyses. Importantly, data from one centre could be used to train a support vector machine to accurately differentiate AD and normal ageing scans obtained from another centre with different subjects and different scanner equipment. Patients with mild, clinically probable AD and age/sex matched controls were correctly separated in 89% of cases which is compatible with published diagnosis rates in the best clinical centres. This method correctly assigned 89% of patients with post-mortem confirmed diagnosis of either AD or frontotemporal lobar degeneration to their respective group. Our study leads to three conclusions: Firstly, support vector machines successfully separate patients with AD from healthy aging subjects. Secondly, they perform well in the differential diagnosis of two different forms of dementia. Thirdly, the method is robust and can be generalized across different centres. This suggests an important role for computer based diagnostic image analysis for clinical practice. [ABSTRACT FROM AUTHOR]

The patient with word-finding difficulty presents a common and challenging clinical problem. The complaint of 'word-finding difficulty' covers a wide range of clinical phenomena and may signify any of a number of distinct pathophysiological processes. Although it occurs in a variety of clinical contexts, word-finding difficulty generally presents a diagnostic conundrum when it occurs as a leading or apparently isolated symptom, most often as the harbinger of degenerative disease: the progressive aphasias. Recent advances in the neurobiology of the focal, language-based dementias have transformed our understanding of these processes and the ways in which they breakdown in different diseases, but translation of this knowledge to the bedside is far from straightforward. Speech and language disturbances in the dementias present unique diagnostic and conceptual problems that are not fully captured by classical models derived from the study of vascular and other acute focal brain lesions. This has led to a reformulation of our understanding of how language is organized in the brain. In this review we seek to provide the clinical neurologist with a practical and theoretical bridge between the patient presenting with word-finding difficulty in the clinic and the evidence of the brain sciences. We delineate key illustrative speech and language syndromes in the degenerative dementias, compare these syndromes with the syndromes of acute brain damage, and indicate how the clinical syndromes relate to emerging neurolinguistic, neuroanatomical and neurobiological insights. We propose a conceptual framework for the analysis of word-finding difficulty, in order both better to define the patient's complaint and its differential diagnosis for the clinician and to identify unresolved issues as a stimulus to future work. [ABSTRACT FROM AUTHOR]

The amygdala is severely atrophied at post-mortem in frontotemporal lobar degeneration (FTLD), and may contribute to the prominent behavioural changes that are early features of FTLD. The aim of this study was to assess amygdala atrophy using MRI in the main syndromic variants of FTLD and Alzheimer's disease (AD). Brain and amygdala volumes, adjusted for intracranial volume, were measured on 46 clinically diagnosed FTLD patients [22 frontal variant FTD (FTD), 14 semantic dementia (SD), 10 progressive non-fluent aphasia (PNFA)], 20 AD patients, and 17 controls. While severe amygdala atrophy was present in both FTLD (41% smaller than controls on the left; 33% on the right) and in AD (22% on the left; 19% on the right), the FTLD group had significantly greater amygdala atrophy (z = 3.21, p = 0.001 left, z = 2.50, p = 0.01 right) and left/right asymmetry (z = 2.03, p = 0.04) than AD. Amygdala atrophy was greater in SD than FTD, PNFA and AD (p < 0.02 for all). Highly asymmetrical atrophy was present in SD, greater on the left (z = 3.23, p = 0.001), and to a lesser extent in PNFA. Despite an overlap between clinical and radiological features of FTLD and AD, marked amygdala atrophy points towards a diagnosis of FTLD, with left greater than right atrophy suggestive of one of the language variants. [ABSTRACT FROM AUTHOR]

Objective: To determine whether Alzheimer's disease (AD) is associated with preferential atrophy of either the left or right hippocampus. Methods: We examined right-left asymmetry in hippocampal volume and atrophy rates in 32 subjects with probable AD and 50 age-matched controls. Hippocampi were measured on two serial volumetric MRI scans using a technique that minimizes laterality bias. Results: We found a non-significant trend for right > left (R > L) asymmetry in controls at both time points (R > L: 1.7%; CI: -0.3-3.7%; p = 0.1). AD subjects showed a similar non-significant trend for R > L asymmetry at baseline (R > L: 1.8%; CI: -1.9-5.5%; p = 0.32), but not at repeat (p = 0.739). Change in R/L ratio between visits in AD patients was significant (p = 0.02). The AD group had significantly higher variance in these ratios than the controls at baseline (p = 0.02), but not repeat (p = 0.06). AD patients had higher atrophy rates than controls (p < 0.001). Mean (CI) annualized atrophy rates for left and right hippocampi were 1.2% (0.5-1.8%) and 1.1% (0.5-1.8%) for the controls, and 4.6% (3.3-6.0%) and 6.3% (4.9-7.8%) for AD subjects. There was no significant asymmetry in atrophy rates in controls (p = 0.9), but borderline significantly higher atrophy rates in the right hippocampus of the AD group (p = 0.05) compared to the left. Presence of an APOEE4 allele had no significant effect on the size, asymmetry or atrophy rates in AD (p > 0.20). Conclusions: We report minor R > L asymmetry in hippocampal volumes in controls and present some evidence to suggest that there is a change in the natural R > L asymmetry during the progression of AD. [ABSTRACT FROM AUTHOR]

Detailed study of the very earliest phases of Alzheimer's disease (AD) is seldom possible, especially those changes preceding the development of mild cognitive impairment (MCI), which may occur years before diagnosis. Knowledge of imaging and neuropsychological features of these early stages would add insight into this poorly understood phase of the disease. We present data from a subject who entered a longitudinal study of individuals at risk of familial Alzheimer's disease (FAD), as a healthy volunteer with no memory complaints, undergoing 12 assessments between 1992 and 2003. Longitudinal MRI, neuropsychological and clinical data are presented over the decade preceding this man's diagnosis, through the asymptomatic and prodromal preludes to his presentation with MCI and on to eventual conversion to AD. [ABSTRACT FROM AUTHOR]

Background: In patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS), the extent of brain magnetic resonance imaging (MRI) lesion load influences the probability and time to development of clinically definite MS. Cerebral atrophy is recognised in established MS, but its time of onset and whether, in early disease, it is related to MRI lesion load or clinical outcome is less certain.Objectives: This study investigated ventricular enlargement over one year in CIS patients and explored its relation with lesion load and clinical outcome.Methods: A semi-automated thresholding technique for measuring ventricular volume (MIDAS) was applied to MRI scans in a cohort of 55 patients with CIS, recruited consecutively and imaged within three months of the onset of symptoms and again after one year.Results: Clinical MS had developed after one year in 16 of 40 patients with an abnormal baseline T2 scan and 2 of 15 with a normal scan. Significant ventricular enlargement was seen in 27 of 55 patients who fulfilled the new McDonald MRI criteria for MS using all available MRI at clinical follow up (median increase 0.3 cm(3), p=0.005) Significant increase in ventricular volume was also seen in the 18 of 55 patients who developed clinical MS over the follow up period (median increase 0.5 cm(3), p=0.006). There were significant but modest correlations between baseline lesion measures and subsequent ventricular enlargement.Conclusions: (1) Lesions and atrophy are both associated with early relapse leading to a diagnosis of clinical MS; (2) while lesions contribute to the development of atrophy, atrophy may also develop by other mechanisms. This suggests that MR measures have a complementary role in monitoring the course of MS, even from the earliest clinical stage. [ABSTRACT FROM AUTHOR]

Context: With ageing populations, the prevalence of dementia, especially Alzheimer's disease, is set to soar. Alzheimer's disease is associated with progressive cerebral atrophy, which can be seen on MRI with high resolution. Longitudinal MRI could track disease progression and detect neurodegenerative diseases earlier to allow prompt and specific treatment. Such use of MRI requires accurate understanding of how brain changes in normal ageing differ from those in dementia.Starting Point: Recently, Henry Rusinek and colleagues, in a 6-year longitudinal MRI study of initially healthy elderly subjects, showed that an increased rate of atrophy in the medial temporal lobe predicted future cognitive decline with a specificity of 91% and sensitivity of 89% (Radiology 2003; 229: 691-96). WHERE NEXT? As understanding of neurodegenerative diseases increases, specific disease-modifying treatments might become available. Serial MRI could help to determine the efficacy of such treatments, which would be expected to slow the rate of atrophy towards that of normal ageing, and might also detect the onset of neurodegeneration. The amount and pattern of excess atrophy might help to predict the underlying pathological process, allowing specific therapies to be started. As the precision of imaging improves, the ability to distinguish healthy ageing from degenerative dementia should improve. [ABSTRACT FROM AUTHOR]

Tracking progression in neurodegenerative diseases is hampered by the limitations of the clinical rating scales, which are seldom linear, suffer from floor and ceiling effects, lack the ability to distinguish symptomatic change from disease modification, and are limited by imperfect intra- and inter-rater reliability. The promise of an era of neuroprotective therapies renders urgent the search for reliable measures of progression. Biomarkers have the potential to enhance several aspects of both therapeutic trials and clinical practice. MRI-based measures of cerebral volume can provide a surrogate for neuronal loss and several techniques have been applied to elucidate disease processes, aid diagnosis, and enable monitoring of progression in a variety of Parkinsonian disorders, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy and Huntington's disease. We review the approaches to, and findings revealed by, serial volumetric MRI in these disorders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]