P. C. O'Brien

The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population‐based cohort: The Rochester Diabetic Neuropathy Study

The magnitude of the health problem from diabetic neuropathies remains inadequately estimated due to the lack of prospective population-based studies employing standardized and validated assessments of the type and stage of neuropathy as compared with background frequency. All Rochester, Minnesota, residents with diabetes mellitus on January 1, 1986, were invited to participate in a cross-sectional and longitudinal study of diabetic neuropathies (and also of other microvascular and macrovascular complications). Of 64,573 inhabitants on January 1, 1986 in Rochester, 870 (1.3%) had clinically recognized diabetes mellitus (National Diabetes Data Group criteria), of whom 380 were enrolled in the Rochester Diabetic Neuropathy Study. Of these, 102 (26.8%) had insulin-dependent diabetes mellitus (IDDM), and 278 (73.2%) had non-insulin-dependent diabetes mellitus (NIDDM). Approximately 10% of diabetic patients had neurologic deficits attributable to nondiabetic causes. Sixty-six percent of IDDM patients had some form of neuropathy; the frequencies of individual types were as follows: polyneuropathy, 54%; carpal tunnel syndrome, asymptomatic, 22%, and symptomatic, 11%; visceral autonomic neuropathy, 7%; and other varieties, 3%. Among NIDDM patients, 59% had various neuropathies; the individual percentages were 45%, 29%, 6%, 5%, and 3%. Symptomatic degrees of polyneuropathy occurred in only 15% of IDDM and 13% of NIDDM patients. The more severe stage of polyneuropathy, to the point that patients were unable to walk on their heels and also had distal sensory and autonomic deficits (stage 2b) occurred even less frequently–6% of IDDM and 1% of NIDDM patients. Overall, two thirds of diabetic patients have objective evidence for some variety of neuropathy, but only about 20% have symptoms, and only 6% of IDDM and only 1% of NIDDM patients have sufficiently severe polyneuropathy to be graded stage 2b, and none were graded stage 3. Approximately one quarter of patients had subclinical carpal tunnel syndrome, but only 7.7% had symptomatic carpal tunnel syndrome. Thus, diabetic peripheral neuropathy is frequent but less severe than generally thought. As generally believed, however, neuropathy, retinopathy, and nephropathy are significantly associated.

Rates of Hippocampal Atrophy Correlate with Change in Clinical Status in Aging and AD

Background: The cognitive continuum in the elderly population can be conceptually divided into those who are functioning normally (control subjects), those with a mild cognitive impairment (MCI), and those with probable AD. Objectives: To test the hypothesis that the annualized rates of hippocampal atrophy differ as a function of both baseline and change in clinical group membership (control, MCI, or AD). Methods: The authors identified 129 subjects from the Mayo Clinic AD Research Center/AD Patient Registry who met established criteria for normal control subjects, MCI, or probable AD, both at entry and at the time of a subsequent clinical follow-up evaluation 3 ± 1 years later. Each subject underwent an MRI examination of the head at the time of the initial assessment and at follow-up clinical assessment; the annualized percentage change in hippocampal volume was computed. Subjects who were classified as controls or patients with MCI at baseline could either remain cognitively stable or could decline to a lower functioning group over the period of observation. Results: The annualized rates of hippocampal volume loss for each of the three initial clinical groups decreased progressively in the following order: AD > MC > control. Within the control and MCI groups, those who declined had a significantly greater rate of volume loss than those who remained clinically stable. The mean annualized rates of hippocampal atrophy by follow-up clinical group were: control-stable 1.73%, control-decliner 2.81%, MCI-stable 2.55%, MCI-decliner 3.69%, AD 3.5%. Conclusion: Rates of hippocampal atrophy match both baseline cognitive status and the change in cognitive status over time in elderly persons who lie along the cognitive continuum from normal to MCI to AD.

Comparison of Different MRI Brain Atrophy Rate Measures with Clinical Disease Progression in AD

Objective: 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 patients with probable Alzheimer disease (AD). Methods: One hundred sixty subjects were recruited from the Mayo Clinic Alzheimer’s Disease Research Center and Alzheimer’s Disease Patient Registry Studies. At baseline, 55 subjects were cognitively normal, 41 met criteria for MCI, and 64 met criteria for AD. Each subject underwent 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 to 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 convert to a lower-functioning group. AD subjects were dichotomized into slow vs fast progressors. Results: All four atrophy rates were greater among normal subjects who converted to MCI or AD than among those who remained stable, greater among MCI subjects who converted to AD than among 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 MRI 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 on cognitive tests/rating scales.

Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia.

ObjectivesTo assess the diagnostic specificity of MRI-defined hippocampal atrophy for AD among individuals with a variety of pathologically confirmed conditions associated with dementia as well as changes attributable to typical aging, and to measure correlations among premortem MRI measurements of hippocampal atrophy, mental status examination performance, and the pathologic stage of AD. MethodsAn unselected series of 67 individuals participating in the Mayo Alzheimer’s Disease Research Center/Alzheimer’s Disease Patient Registry who had undergone a standardized antemortem MRI study and also postmortem examination were identified. Hippocampal volumes were measured from antemortem MRI. Each postmortem specimen was assigned a pathologic diagnosis and in addition, the severity of AD pathology was staged using the method of Braak and Braak. ResultsIndividuals with an isolated pathologic diagnosis of AD, hippocampal sclerosis, frontotemporal degeneration, and neurofibrillary tangle–only degeneration usually had substantial hippocampal atrophy, while those with changes of typical aging did not. Among all 67 subjects, correlations (all p < 0.001) were observed between hippocampal volume and Braak and Braak stage (r = −0.39), between hippocampal volume and Mini-Mental State Examination (MMSE) score (r = 0.60), and between MMSE score and Braak and Braak stage (r = −0.41). ConclusionsHippocampal atrophy, while not specific for AD, was a fairly sensitive marker of the pathologic AD stage (particularly among subjects with isolated AD pathology [r = −0.63, p = 0.001]) and consequent cognitive status.

Regional metabolic patterns in mild cognitive impairment and Alzheimer’s disease A 1H MRS study

Background: Mild cognitive impairment (MCI) is a recently described transitional clinical state between normal aging and AD. Assuming that amnestic MCI patients had pathologic changes corresponding to an early phase and probable AD patients to a later phase of the disease progression, the authors could approximate the temporal course of proton MR spectroscopic (1H MRS) alterations in AD with a cross-sectional sampling scheme. Methods: The authors compared 1H MRS findings in the superior temporal lobe, posterior cingulate gyri, and medial occipital lobe in 21 patients with MCI, 21 patients with probable AD, and 63 elderly controls. These areas are known to be involved at different neurofibrillary pathologic stages of AD. Results: The N-acetylaspartate (NAA)/creatine (Cr) ratios were significantly lower in AD patients compared to both MCI and normal control subjects in the left superior temporal and the posterior cingulate volumes of interest (VOI) and there were no between-group differences in the medial occipital VOI. Myoinositol (MI)/Cr ratios measured from the posterior cingulate VOI were significantly higher in both MCI and AD patients than controls. The choline (Cho)/Cr ratios measured from the posterior cingulate VOI were higher in AD patients compared to both MCI and control subjects. Conclusion: These findings suggest that the initial 1H MRS change in the pathologic progression of AD is an increase in MI/Cr. A decrease in NAA/Cr and an increase in Cho/Cr develop later in the disease course.

Brain Atrophy Rates Predict Subsequent Clinical Conversion in Normal Elderly and Amnestic MCI

Objective: To test the hypothesis that the atrophy rate measured from serial MRI studies is associated with time to subsequent clinical conversion to a more impaired state in both cognitively healthy elderly subjects and in subjects with amnestic mild cognitive impairment (MCI). Methods: Ninety-one healthy elderly patients and 72 patients with amnestic MCI who met inclusion criteria were identified from the Mayo Alzheimer’s Disease Research Center and Alzheimer’s Disease Patient Registry. Atrophy rates of four different brain structures—hippocampus, entorhinal cortex, whole brain, and ventricle—were measured from a pair of MRI studies separated by 1 to 2 years. The time of the second scan marked the beginning of the clinical observation period. Results: During follow-up, 13 healthy patients converted to MCI or Alzheimer disease (AD), whereas 39 MCI subjects converted to AD. Among those healthy at baseline, only larger ventricular annual percent volume change (APC) was associated with a higher risk of conversion (hazard ratio for a 1-SD increase 1.9, p = 0.03). Among MCI subjects, both greater ventricular volume APC (hazard ratio for a 1-SD increase 1.7, p < 0.001) and greater whole brain APC (hazard ratio for a 1-SD increase 1.4, p = 0.007) increased the risk of conversion to AD. Both ventricular APC (hazard ratio for a 1-SD increase 1.59, p = 0.001) and whole brain APC (hazard ratio for a 1-SD increase 1.32, p = 0.009) provided additional predictive information to covariate-adjusted cross-sectional hippocampal volume at baseline about the risk of converting from MCI to AD. Discussion: Higher whole brain and ventricle atrophy rates 1 to 2 years before baseline are associated with an increased hazard of conversion to a more impaired state. Combining a measure of hippocampal volume at baseline with a measure of either whole brain or ventricle atrophy rates from serial MRI scans provides complimentary predictive information about the hazard of subsequent conversion from mild cognitive impairment to Alzheimer disease. However, overlap among those who did vs those who did not convert indicate that these measures are unlikely to provide absolute prognostic information for individual patients.

Usefulness of MRI measures of entorhinal cortex versus hippocampus in AD

Objective: MRI-based measurements of hippocampal atrophy are a sensitive indicator of the early pathologic degeneration of the medial temporal lobe in AD. However, AD pathology appears first in the transentorhinal/entorhinal cortex, not the hippocampus. The authors tested the hypothesis that MRI-based measurements of the entorhinal cortex are more sensitive than measurements of hippocampal volume in discriminating among three clinical groups; controls, patients with a mild cognitive impairment (MCI), and patients with mild probable AD. Methods: The authors studied 30 controls, 30 patients with MCI, and 30 patients with AD who were matched among clinical groups on age, gender, and education. All underwent a standardized MRI protocol from which the authors made measurements of hippocampal volume, entorhinal cortex volume, and the cumulative length of the medial border of the entorhinal cortex. Results: Pairwise intergroup differences (p < 0.01) were found for all MRI measurements with the exception of the cumulative length of the entorhinal cortex, which did not differentiate controls from MCI patients. Whereas the hippocampal and entorhinal cortex volume measurements provided slightly better intergroup discrimination than the entorhinal distance measurement, overall differences in discriminating ability among the three MRI measurements were minor. Conclusions: Despite the theoretical rationale for the superiority of entorhinal measurements in early AD, the authors found MRI measurements of the hippocampus and entorhinal cortex were approximately equivalent at intergroup discrimination. Measurements of the hippocampus may be preferable because MRI depiction of the boundaries of the entorhinal cortex can be obscured by anatomic ambiguity, image artifact, or both.

Population-based study of the incidence of sudden unexplained death in epilepsy

Objective: To determine the population-based incidence of sudden unexplained death in epilepsy (SUDEP) and to determine the risk of SUDEP compared with the general population. Background: Prior studies of SUDEP have described a wide range of incidence and have suffered from selection bias and other methodologic limitations. A population-based study of the incidence of SUDEP has never been performed. Furthermore, the risk of sudden death in the epilepsy population has not been compared with that of the general population. Methods: All deaths in persons whose epilepsy was diagnosed between 1935 and 1994 in Rochester, MN, were reviewed. The rate of SUDEP was compared with the expected rate of sudden death in the general population for patients age 20 to 40 years to determine the standardized mortality ratio (SMR). Results: We identified nine cases of SUDEP. SUDEP accounted for 8.6% (7 of 81) of the deaths in persons 15 to 44 years of age. The incidence of SUDEP was 0.35 per 1,000 person-years. SMR for SUDEP was 23.7 (95% confidence interval, 7.7 to 55.0) compared with the general population. Conclusions: The incidence of SUDEP in our study was 0.35 per 1,000 person-years. SUDEP was responsible for 1.7% of deaths in our cohort. SUDEP is a rare cause of death in the epilepsy population but exceeds the expected rate of sudden death in the general population by nearly 24 times.

Memory and MRI-based hippocampal volumes in aging and AD

Objective: To demonstrate structural–functional relationships between MRI-based volumetric measurements of medial temporal lobe structures and cognitive function. Background: Previous work has documented the ability of MRI-based measurements of the hippocampus to discriminate between age-matched control subjects and patients with very mild AD. Relatively less is known about the correlation between medial temporal lobe structures and cognitive functions. Method: We evaluated structural–functional relationships among the hippocampal formation, parahippocampal gyrus, and amygdala, and measures of memory, language, and general cognitive performance in 220 probable AD patients and normal control subjects. Standardized instruments of memory and general cognitive function were used to assess subjects enrolled in a longitudinal study of aging and dementia. Results: The volume of the hippocampal formation predicted performance on most acquisition and recall measures across the spectrum of normal aging and AD. If the groups were segregated, most of the expected associations between medial temporal lobe structures and memory measures were observed in the AD patients. Conclusion: MRI-based hippocampal volumetry accurately depicts the structural–functional relationships between memory loss and hippocampal damage across the spectrum from normal aging to dementia.

Predictors of outcome of anterior temporal lobectomy for intractable epilepsy: A multivariate study

Objective: To identify presurgical and postsurgical factors that are independently predictive of the outcome of anterior temporal lobectomy (ATL) for intractable epilepsy. Background: There have been reports of prognostic studied 175 consecutive ATL patients who had at least 2 years of postsurgical follow-up. Significant factors on univariate analyses were subjected to stepwise logistic regression analysis. Results: On univariate analyses, two presurgical conditions were significantly associated with excellent seizure control at last follow-up: (1) unilateral hippocampal formation atrophy as detected on MRI and (2) all scalp interictal epileptiform discharges concordant with the location of ictal onset(p < 0.05). Three postsurgical factors that occurred during the first year were associated with excellent seizure outcome: the absence of interictal epileptiform discharges at 3 months, complete seizure control, and having only nondisabling seizures for those who did not become seizure free. Logistic regression analysis revealed the following to be independently predictive of excellent seizure control: MRI-detected unilateral hippocampal formation atrophy, concordant interictal epileptiform discharges, complete seizure control during the first postsurgical year, and having only nondisabling seizures during the first postsurgical year for those who did not become seizure free. Conclusions: Presurgical identification of unilateral hippocampal formation atrophy, or of interictal epileptiform discharges that are all concordant with the location of ictal onset, predict excellent outcome of ATL. However, the probability of excellent outcome is highest (94%) when both factors are present.