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Journal ArticleDOI

Baseline MRI predictors of conversion from MCI to probable AD in the ADNI cohort.

31 Jul 2009-Current Alzheimer Research (Bentham Science Publishers)-Vol. 6, Iss: 4, pp 347-361
TL;DR: It is indicated that degree of neurodegeneration of medial temporal structures was the best antecedent MRI marker of imminent conversion, with decreased hippocampal volume (left > right) being the most robust.
Abstract: The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a multi-center study assessing neuroimaging in diagnosis and longitudinal monitoring. Amnestic Mild Cognitive Impairment (MCI) often represents a prodromal form of dementia, conferring a 10-15% annual risk of converting to probable AD. We analyzed baseline 1.5T MRI scans in 693 participants from the ADNI cohort divided into four groups by baseline diagnosis and one year MCI to probable AD conversion status to identify neuroimaging phenotypes associated with MCI and AD and potential predictive markers of imminent conversion. MP-RAGE scans were analyzed using publicly available voxel-based morphometry (VBM) and automated parcellation methods. Measures included global and hippocampal grey matter (GM) density, hippocampal and amygdalar volumes, and cortical thickness values from entorhinal cortex and other temporal and parietal lobe regions. The overall pattern of structural MRI changes in MCI (n=339) and AD (n=148) compared to healthy controls (HC, n=206) was similar to prior findings in smaller samples. MCI-Converters (n=62) demonstrated a very similar pattern of atrophic changes to the AD group up to a year before meeting clinical criteria for AD. Finally, a comparison of effect sizes for contrasts between the MCI-Converters and MCI-Stable (n=277) groups on MRI metrics indicated that degree of neurodegeneration of medial temporal structures was the best antecedent MRI marker of imminent conversion, with decreased hippocampal volume (left > right) being the most robust. Validation of imaging biomarkers is important as they can help enrich clinical trials of disease modifying agents by identifying individuals at highest risk for progression to AD.

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Journal ArticleDOI
TL;DR: It is proposed that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease.
Abstract: In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.

2,581 citations

Journal ArticleDOI
TL;DR: The major accomplishments of ADNI have been the development of standardized methods for clinical tests, magnetic resonance imaging, positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting, and the improvement of clinical trial efficiency.
Abstract: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants.

906 citations


Cites background from "Baseline MRI predictors of conversi..."

  • ...Reproduced with permission from Ref [114]....

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  • ...Images are in on a specially constructed average brain template created from the subjects m Ref [133]....

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  • ...Table 6 Associations between imaging, clinical, and CSF biomarkers (correlation coefficients) CSF biomarker correlates Imaging or clinical biomarker N Clinical group Ab242 t-tau p-tau181p t-tau/Ab242 FDG-PET composite ROI Mean cortical PiB SUVR Reference Hippocampal volume (L/R) 388 Pooled sample 0.11*/0.17y 20.17y/0.21z 20.17y/20.23z 20.17y/20.21z 20.24*/20.23* [151] Mean cortical PiB SUVR 55 Pooled sample 20.73z 20.42x 0.49z 0.28* [34] FDG-PET composite ROI 0.33y 0.24 (P ¼ .08) 0.34y MMSE NS 0.26 (P ¼ .055) 0.28* 0.63z NS Ab242 0.38y APOE 34 77 CN 20.50z NS NS [146] 119 MCI 20.49z 0.39z 0.34y 54 AD 20.53z NS NS BMI 112 CN 0.19z 20.20z 20.43y [280] 193 MCI NS 20.17* 20.32z 100 AD NS NS NS Abbreviations: NS, not significant; SUVR, standard uptake value ratio....

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  • ...The studies of Morra et al [124], Wolz et al [64], Hua et al [112], and Risacher et al [115] all found that carriers of the APOE 34 allele had higher rates of hippocampal atrophy than noncarriers....

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  • ...They ygdala; Hp, hippocampus; V, ventricles; iLV, inferior lateral ventricles; Cd, ssion from Ref [122]....

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Journal ArticleDOI
TL;DR: It is hypothesized that fornix/hypothalamus deep brain stimulation (DBS) could modulate neurophysiological activity in these pathological circuits and possibly produce clinical benefits in Alzheimer's disease.
Abstract: Objective: Alzheimer disease (AD) is characterized by functional impairment in the neural elements and circuits underlying cognitive and memory functions. We hypothesized that fornix/hypothalamus deep brain stimulation (DBS) could modulate neurophysiological activity in these pathological circuits and possibly produce clinical benefits. Methods: We conducted a phase I trial in 6 patients with mild AD receiving ongoing medication treatment. Patients received continuous stimulation for 12 months. Three main lines of investigation were pursued including: (1) mapping the brain areas whose physiological function was modulated by stimulation using standardized low-resolution electromagnetic tomography, (2) assessing whether DBS could correct the regional alterations in cerebral glucose metabolism in AD using positron emission tomography (PET), and 3) measuring the effects of DBS on cognitive function over time using clinical scales and instruments. Results: DBS drove neural activity in the memory circuit, including the entorhinal, and hippocampal areas and activated the brain’s default mode network. PET scans showed an early and striking reversal of the impaired glucose utilization in the temporal and parietal lobes that was maintained after 12 months of continuous stimulation. Evaluation of the Alzheimer’s Disease Assessment Scale cognitive subscale and the Mini Mental State Examination suggested possible improvements and/or slowing in the rate of cognitive decline at 6 and 12 months in some patients. There were no serious adverse events. Interpretation: There is an urgent need for novel therapeutic approaches for AD. Modulating pathological brain activity in this illness with DBS merits further investigation. ANN NEUROL 2010;00:000–000

722 citations


Cites background from "Baseline MRI predictors of conversi..."

  • ...Neuroimaging has played a critical role in identifying the topography of dysfunctional brain areas, showing both morphological and volumetric structural changes, particularly in the entorhinal cortex and hippocampus, predating the cognitive symptoms and tracking with disease severity.(4,5) The structural abnormalities in AD are tightly coupled to functional disturbances....

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Journal ArticleDOI
08 Sep 2010-PLOS ONE
TL;DR: The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins, and is associated with a lower final cognitive test scores.
Abstract: Background: An increased rate of brain atrophy is often observed in older subjects, in particular those who suffer from cognitive decline. Homocysteine is a risk factor for brain atrophy, cognitive impairment and dementia. Plasma concentrations of homocysteine can be lowered by dietary administration of B vitamins. Objective: To determine whether supplementation with B vitamins that lower levels of plasma total homocysteine can slow the rate of brain atrophy in subjects with mild cognitive impairment in a randomised controlled trial (VITACOG, ISRCTN 94410159). Methods and Findings: Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B6 and B12 in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study. Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B12 (0.5 mg/d) and vitamin B6 (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans. Results: A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63–0.90] in the active treatment group and 1.08% [0.94– 1.22] in the placebo group (P=0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine .13 mmol/L was 53% lower in the active treatment group (P=0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category. Conclusions and Significance: The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer’s disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer’s disease, trials are needed to see if the same treatment will delay the development of Alzheimer’s disease.

639 citations


Cites background from "Baseline MRI predictors of conversi..."

  • ...An intermediate rate of atrophy is found in people with mild cognitive impairment (MCI) [6,7,8,9,10,11]....

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Journal ArticleDOI
TL;DR: In summary, both SPARE-AD and CSF biomarkers showed high baseline sensitivity, however, many MCI-NC had abnormal baseline Spatial Pattern of Abnormalities for Recognition of Early AD and CSFs, and longer follow-up will elucidate the specificity of baseline measurements.

502 citations

References
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Journal ArticleDOI
TL;DR: A simplified, scored form of the cognitive mental status examination, the “Mini-Mental State” (MMS) which includes eleven questions, requires only 5-10 min to administer, and is therefore practical to use serially and routinely.

76,181 citations


"Baseline MRI predictors of conversi..." refers background in this paper

  • ...As expected, neuropsychological test scores (MMSE [66, 67], Clinical Dementia Rating (CDR) [68], and the Functional Assessment Questionnaire (FAQ) [69]) varied significantly between groups (p<0....

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01 Jan 2002
TL;DR: The Mini-Mental State (MMS) as mentioned in this paper is a simplified version of the standard WAIS with eleven questions and requires only 5-10 min to administer, and is therefore practical to use serially and routinely.
Abstract: EXAMINATION of the mental state is essential in evaluating psychiatric patients.1 Many investigators have added quantitative assessment of cognitive performance to the standard examination, and have documented reliability and validity of the several “clinical tests of the sensorium”.2*3 The available batteries are lengthy. For example, WITHERS and HINTON’S test includes 33 questions and requires about 30 min to administer and score. The standard WAIS requires even more time. However, elderly patients, particularly those with delirium or dementia syndromes, cooperate well only for short periods.4 Therefore, we devised a simplified, scored form of the cognitive mental status examination, the “Mini-Mental State” (MMS) which includes eleven questions, requires only 5-10 min to administer, and is therefore practical to use serially and routinely. It is “mini” because it concentrates only on the cognitive aspects of mental functions, and excludes questions concerning mood, abnormal mental experiences and the form of thinking. But within the cognitive realm it is thorough. We have documented the validity and reliability of the MMS when given to 206 patients with dementia syndromes, affective disorder, affective disorder with cognitive impairment “pseudodementia”5T6), mania, schizophrenia, personality disorders, and in 63 normal subjects.

70,887 citations

Journal ArticleDOI
TL;DR: A set of automated procedures for obtaining accurate reconstructions of the cortical surface are described, which have been applied to data from more than 100 subjects, requiring little or no manual intervention.

9,599 citations


"Baseline MRI predictors of conversi..." refers methods in this paper

  • ...Automated Parcellation: VOIs, including bilateral hippocampi and amygdalar nuclei, were extracted using FreeSurfer V4 [56, 59-62]....

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Journal ArticleDOI
TL;DR: Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD, and appear to constitute a clinical entity that can be characterized for treatment interventions.
Abstract: Background Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials. Objective To characterize clinically subjects with MCI cross-sectionally and longitudinally. Design A prospective, longitudinal inception cohort. Setting General community clinic. Participants A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn. Main Outcome Measures The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale–Revised, Wechsler Memory Scale–Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, respectively. Results The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD. Conclusions Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.

8,255 citations


"Baseline MRI predictors of conversi..." refers background in this paper

  • ...Patients with MCI, specifically those with primary memory deficits or “amnestic MCI”, have a significantly higher likelihood to progress to probable AD, with a conversion rate of 10-15% per year [4]....

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