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.

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Objective-To test the hypothesis that magnetic resonance imaging (MRI)-based measurements of hippocampal volume were related to the risk of future conversion to Alzheimer's disease (AD) in elderly patients with a mild cognitive impairment (MCI) Background-Persons who develop AD pass through a transitional state which can be characterized as a MCI. However, in some patients MCI is a more benign condition which may not progress to AD or may do so slowly.

Magnetic resonance imaging(MRI) based volumetric measurements of medial temporal lobe (MTL) structures can discriminate between normal elderly controls and patients with Alzheimer's disease (AD) of moderate to advanced severity. In terms of clinical utility, however, a more important issue concerns the ability of the technique to differentiate between normal elderly controls and AD patients with the very mildest form of the disease. We performed MRI-based volume measurements of the hippocampus, parahippocampal gyrus, and amygdala in 126 cognitively normal elderly controls and 94 patients with probable AD. The diagnosis of AD was made according to NINDS/ADRDA criteria, and disease severity was categorized by Clinical Dementia Rating (CDR) scores. Patients with CDR = 0.5 were classified as very mild, CDR = 1 as mild, and CDR = 2 moderate disease severity.Volumes of each structure declined with increasing age in control subjects and did so in parallel for men and women. The volume of each measured MTL structure also declined with age in patients with AD. The volume of each MTL structure was significantly smaller in AD patients than control subjects (P<.001). Of the several MTL measures, the total hippocampal volume measurements were best at discriminating controls from AD cases. The mean hippocampal volumes for AD patients relative to controls by severity of disease were as follows: very mild AD (CDR 0.5) -1.75 SD below the control mean, mild AD (CDR 1) -1.99 SD, and moderate AD (CDR 2) -2.22 SD. Age and gender adjusted normalized MRI-based hippocampal volume measurements provide a sensitive marker of the MTL neuroanatomic degeneration in AD early in the disease process. KeywordsAlzheimer's Disease; Dementia; MRI; Quantitative MRI; Hippocampus Alzheimer's disease(AD) is the most common cause of dementia in individuals over 60 years of age(1-3). A well accepted biological concomitant of AD is cerebral atrophy(4). The rationale for quantitative magnetic resonance imaging (MRI) of medial temporal lobe (MTL) atrophy in the diagnosis of AD is: 1) A memory impairment is usually the earliest and most severe clinical manifestation of AD; 2) Medial temporal lobe (MTL) limbic structures are central to the integrity of declarative memory function (5); 3) MTL limbic structures are involved earliest and most extensively in the pathology of AD(6,7); and 4) several principal MTL limbic structures are amenable to accurate volumetric quantitation by MRI-the hippocampal 3) Relatively small numbers of subjects were included in individual studies. 4) Rigorous definitions of the severity of AD often were not employed. Most previous studies have included primarily subjects with AD of moderate severity. Consequently, the differences between the AD patients and control subjects with regard to MTL atrophy have been dramatic. The most important test of the utility of the technique would be in patients with very mild AD in whom the diagnostic decision making process is difficult.We report a large series of carefully evaluated and lon...

OBJECTIVES To investigate the efficacy of a novel brain plasticity–based computerized cognitive training program in older adults and to evaluate the effect on untrained measures of memory and attention and participant-reported outcomes. DESIGN Multisite randomized controlled double-blind trial with two treatment groups. SETTING Communities in northern and southern California and Minnesota. PARTICIPANTS Community-dwelling adults aged 65 and older (N = 487) without a diagnosis of clinically significant cognitive impairment. INTERVENTION Participants were randomized to receive a broadly-available brain plasticity–based computerized cognitive training program (intervention) or a novelty- and intensity-matched general cognitive stimulation program modeling treatment as usual (active control). Duration of training was 1 hour per day, 5 days per week, for 8 weeks, for a total of 40 hours. MEASUREMENTS The primary outcome was a composite score calculated from six subtests of the Repeatable Battery for the Assessment of Neuropsychological Status that use the auditory modality (RBANS Auditory Memory/Attention). Secondary measures were derived from performance on the experimental program, standardized neuropsychological assessments of memory and attention, and participant-reported outcomes. RESULTS RBANS Auditory Memory/Attention improvement was significantly greater (P = .02) in the experimental group (3.9 points, 95% confidence interval (CI) = 2.7–5.1) than in the control group (1.8 points, 95% CI = 0.6–3.0). Multiple secondary measures of memory and attention showed significantly greater improvements in the experimental group (word list total score, word list delayed recall, digits backwards, letter–number sequencing; P < .05), as did the participant-reported outcome measure (P = .001). No advantage for the experimental group was seen in narrative memory. CONCLUSION The experimental program improved generalized measures of memory and attention more than an active control program.

REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of normal skeletal muscle atonia during REM sleep with prominent motor activity accompanying dreaming. The terminology relating to RBD, and mechanisms underlying REM sleep without atonia and RBD based on data in cat and rat are presented. Neuroimaging data from the few published human cases with RBD associated with structural lesions in the brainstem are presented, in which the dorsal midbrain and pons are implicated. Pharmacological manipulations which alter RBD frequency and severity are reviewed, and the data from human neuropathological studies are presented. An anatomic framework and new schema for the pathophysiology of RBD are proposed based on recent data in rat regarding the putative flip-flop switch for REM sleep control. The structure in man analogous to the subcoeruleus region in cat and sublaterodorsal nucleus in rat is proposed as the nucleus (and its associated efferent and afferent pathways) crucial to RBD pathophysiology. The association of RBD with neurological disease ('secondary RBD') is presented, with emphasis on RBD associated with neurodegenerative disease, particularly the synucleinopathies. The hypothesized pathophysiology of RBD is presented in relation to the Braak staging system for Parkinson's disease, in which the topography and temporal sequence of synuclein pathology in the brain could explain the evolution of parkinsonism and/or dementia well after the onset of RBD. These data suggest that many patients with 'idiopathic' RBD are actually exhibiting an early clinical manifestation of an evolving neurodegenerative disorder. Such patients may be appropriate for future drug therapies that affect synuclein pathophysiology, in which the development of parkinsonism and/or dementia could be delayed or prevented. We suggest that additional clinicopathological studies be performed in patients with dementia or parkinsonism, with and without RBD, as well as in patients with idiopathic RBD, to further elucidate the pathophysiology and also characterize the clinical and pathophysiological relevance of RBD in neurodegenerative disease. Furthermore, longitudinal studies in patients with idiopathic RBD are warranted to characterize the natural history of such patients and prepare for future therapeutic trials.

Objectives-To correlate different methods of measuring rates of brain atrophy from serial MRI with corresponding clinical change in normal elderly subjects, patients with mild cognitive impairment (MCI), and probable Alzheimer's disease (AD).Methods-One-hundred sixty subjects were recruited from the Mayo Clinic AD Research Center and AD Patient Registry studies. At baseline 55 subjects were cognitively normal, 41 met criteria for MCI, and 64 met criteria for AD. Each subject went under an MRI examination of the brain at the time of the baseline clinical assessment and then again at the time of a follow-up clinical assessment, 1-5 years later. The annualized changes in volume of four structures were measured from the serial MRI studies -hippocampus, entorhinal cortex, whole brain, and ventricle. Rates of change on several cognitive tests/rating scales were also assessed. Subjects who were classified as normal or MCI at baseline could either remain stable or could convert to a lower functioning group. AD subjects were dichotomized into slow versus fast progressors.Results-All four atrophy rates were greater among normal subjects who converted to MCI or AD than those who remained stable; greater among MCI subjects who converted to AD than those who remained stable, and greater among fast than slow AD progressors. In general, atrophy on MRI was detected more consistently than decline on specific cognitive tests/rating scales._ With one exception, no differences were found among the four MRI rate measures in the strength of the correlation with clinical deterioration at different stages of the disease.Conclusions-These data support the use of rates of change from serial MR imaging studies in addition to standard clinical/psychometric measures as surrogate markers of disease progression in AD. Estimated sample sizes required to power a therapeutic trial in MCI were an order of magnitude less for MRI than for change measures based cognitive tests/rating scales.Psychometric tests and severity rating scales are the de facto gold standard for assessing disease progression in Alzheimer's disease (AD). Change measures from serial imaging studies have been proposed as an adjunctive surrogate marker of disease progression in AD with the expectation that imaging may provide better sensitivity and precision than standard clinical and psychometric measures(1-4). Various serial imaging approaches have been proposed including different structural magnetic resonance imaging (MRI) atrophy rate measures and also serial measures of glucose metabolism with positron emission tomography (PET). NIH Public Access Author ManuscriptNeurology. Author manuscript; available in PMC 2009 August 21. Published in final edited form as:Neurology. 2004 February 24; 62(4): 591-600. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 5-9) The fact that different serial imaging approaches have been proposed for largely the same objective raises obvious questions. Which imaging approach is best? Do some imaging measures of p...

Moderate to severe cognitive impairment is common and undiagnosed in hemodialysis patients. Further studies are needed to determine whether dialysis exacerbates the cognitive impairment attributable to underlying disease. Cognitive testing in hemodialysis patients before dialysis initiation and periodically may be warranted.