Clinical, laboratory, and imaging features generally distinguish neuromyelitis optica from MS. Patients with relapsing optic neuritis and myelitis may have neuromyelitis optica rather than MS. Patients with a relapsing course of neuromyelitis optica have a poor prognosis and frequently develop respiratory failure during attacks of cervical myelitis.

A multiple testing procedure is proposed for comparing two treatments when response to treatment is both dichotomous (i.e., success or failure) and immediate. The proposed test statistic for each test is the usual (Pearson) chi-square statistic based on all data collected to that point. The maximum number (N) of tests and the number (m1 + m2) of observations collected between successive tests is fixed in advance. The overall size of the procedure is shown to be controlled with virtually the same accuracy as the single sample chi-square test based on N(m1 + m2) observations. The power is also found to be virtually the same. However, by affording the opportunity to terminate early when one treatment performs markedly better than the other, the multiple testing procedure may eliminate the ethical dilemmas that often accompany clinical trials.

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.

Five procedures are considered for the comparison of two or more multivariate samples. These procedures include a newly proposed nonparametric rank-sum test and a generalized least squares test. Also considered are the following tests: ordinary least squares, Hotelling's T2, and a Bonferroni per-experiment error-rate approach. Applications are envisaged in which each variable represents a qualitatively different measure of response to treatment. The null hypothesis of no treatment difference is tested with power directed towards alternatives in which at least one treatment is uniformly better than the others. In all simulations the nonparametric procedure provided relatively good power and accurate control over the size of the test, and is recommended for general use. Alternatively, the generalized least squares procedure may also be useful with normally distributed data in moderate or large samples. A convenient expression for this procedure is obtained and its asymptotic relative efficiency with respect to the ordinary least squares test is evaluated.

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 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...

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Alzheimer disease and type 2 diabetes are characterized by increased prevalence with aging, a genetic predisposition, and comparable pathological features in the islet and brain (amyloid derived from amyloid ␤ protein in the brain in Alzheimer disease and islet amyloid derived from islet amyloid polypeptide in the pancreas in type 2 diabetes). Evidence is growing to link precursors of amyloid deposition in the brain and pancreas with the pathogenesis of Alzheimer disease and type 2 diabetes, respectively. Given these similarities, we questioned whether there may be a common underlying mechanism predisposing to islet and cerebral amyloid. To address this, we first examined the prevalence of type 2 diabetes in a community-based controlled study, the Mayo Clinic Alzheimer Disease Patient Registry (ADPR), which follows patients with Alzheimer disease versus control subjects without Alzheimer disease. In addition to this clinical study, we performed a pathological study of autopsy cases from this same community to determine whether there is an increased prevalence of islet amyloid in patients with Alzheimer disease and increased prevalence of cerebral amyloid in patients with type 2 diabetes. Patients who were enrolled in the ADPR (Alzheimer disease n ‫؍‬ 100, non-Alzheimer disease control subjects n ‫؍‬ 138) were classified according to fasting glucose concentration (FPG) as nondiabetic (FPG <110 mg/dl), impaired fasting glucose (IFG, FPG 110 -125 mg/dl), and type 2 diabetes (FPG >126 mg/dl). The mean slope of FPG over 10 years in each case was also compared between Alzheimer disease and non-Alzheimer disease control subjects. Pancreas and brain were examined from autopsy specimens obtained from 105 humans (first, 28 cases of Alzheimer disease disease vs. 21 non-Alzheimer disease control subjects and, second, 35 subjects with type 2 diabetes vs. 21 non-type 2 diabetes control subjects) for the presence of islet and brain amyloid. Both type 2 diabetes (35% vs. 18%; P < 0.05) and IFG (46% vs. 24%; P < 0.01) were more prevalent in Alzheimer disease versus non-Alzheimer disease control subjects, so 81% of cases of Alzheimer disease had either type 2 diabetes or IFG. The slope of increase of FPG with age over 10 years was also greater in Alzheimer disease than non-Alzheimer disease control subjects (P < 0.01). Islet amyloid was more frequent (P < 0.05) and extensive (P < 0.05) in patients with Alzheimer disease than in non-Alzheimer disease control subjects. However, diffuse and neuritic plaques were not more common in type 2 diabetes than in control subjects. In cases of type 2 diabetes when they were present, the duration of type 2 diabetes correlated with the density of diffuse (P < 0.001) and neuritic plaques (P < 0.01). In this community cohort from southeast Minnesota, type 2 diabetes and IFG are more common in patients with Alzheimer disease than in control subjects, as is the pathological hallmark of type 2 diabetes, islet amyloid. However, there was no increase in brain plaque formation in cases of type 2 diabet...