Alzheimer's Disease Patient Registry Research Articles

Antemortem volume loss mirrors TDP-43 staging in older adults with non-frontotemporal lobar degeneration.

Over the past decade, the transactive response DNA-binding protein of 43 kDa (TDP-43) has been recognized as a major protein in normal and pathological ageing, increasing the risk of cognitive impairment and dementia. In conditions distinct from the frontotemporal lobar degenerations, TDP-43 appears to progress in a stereotypical pattern. In the present study, we aimed at providing a better understanding of the effects of TDP-43 and other age-related neuropathologies on cross-sectional grey matter volume in a cohort of non-FTLD subjects. We included 407 individuals with an antemortem MRI and post-mortem brain tissue from the Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic Alzheimer's Disease Patient Registry, or the Mayo Clinic Study of Aging. All individuals were assigned pathological stages for TDP-43, tau, amyloid-β, Lewy bodies, argyrophilic grain disease and vascular pathologies. Robust regressions were performed in regions of interest and voxel-wise to explore the relationships between TDP-43 stages and grey matter volume while controlling for other pathologies. Grey matter volumes adjusted for pathological and demographic variables were also computed for each TDP-43-positive case to further characterize the sequential involvement of brain structures associated with TDP-43, irrespective of the TDP-43 staging scheme. Robust regressions showed that the extent of TDP-43 pathology was associated with the extent of grey matter atrophy. Specifically, we found that the volume in medial temporal regions (i.e. amygdala, entorhinal cortex, hippocampus) decreased progressively with advancing TDP-43 stages. Importantly, these effects were of similar magnitude to those related to tau stages. Additional analyses using adjusted grey matter volume demonstrated a sequential pattern of volume loss associated with TDP-43, starting within the medial temporal lobe, followed by early involvement of the temporal pole, and eventually encompassing additional temporal and frontal regions. Altogether, this study demonstrates the major and independent contribution of TDP-43 pathology on neurodegeneration and provides further insight into the regional distribution of TDP-43 in non-FTLD subjects. Along with previous studies, these findings emphasized the importance of targeting TDP-43 in future clinical trials to prevent its detrimental effect on grey matter volume and, eventually, cognition.

Association of Apolipoprotein E ε4 With Transactive Response DNA-Binding Protein 43

Transactive response DNA-binding protein 43 (TDP-43) is associated with Alzheimer disease (AD), progressive hippocampal atrophy, and cognitive decline. The apolipoprotein E (APOE) ε4 allele is strongly associated with β-amyloid (Aβ) aggregation and risk of AD, but its association with TDP-43 is unknown. To determine whether the APOE ε4 allele is a risk factor for TDP-43. This cross-sectional, genetic-histologic study analyzed APOE genotype, TDP-43 status (positive vs negative), Aβ status (positive vs negative), and tau neurofibrillary tangle stage (B0, Braak stage 0; B1, Braak stages I-II; B2, Braak stages III-IV; B3, Braak stage ≥ V). We fit structural equation models to map the association between APOE and TDP-43, Aβ, and tau, accounting for age and hippocampal sclerosis. We identified 751 participants with an AD pathological spectrum diagnosis and completed Aβ, tau, and TDP-43 data who were enrolled in the Mayo Clinic Alzheimer Disease Research Center, Mayo Clinic Alzheimer Disease Patient Registry, or the population based Mayo Clinic Study of Aging and died between May 12, 1999, and December 31, 2015. However, 13 were excluded from the analyses because of missing APOE data, leaving a total of 738 participants. Transactive response DNA-binding protein 43 was the main outcome of interest. We hypothesized that the APOE ε4 allele would be significantly directly and indirectly associated with TDP-43. The 751 study participants were older (median age [interquartile range], 87 years [51-105 years]), 395 (54%) were women, and 324 (44%) were APOE ε4 carriers. The patients died between May 12, 1999, and December 31, 2015. Accounting for age, Aβ, and tau, APOE ε4 had a direct association with TDP-43 (estimate [SE], 0.31 (0.11); P = .01). The association was present among individuals with an intermediate to high likelihood of having AD (neurofibrillary tangle stage B2/B3; n = 604 [81.8%]; estimate [SE], 0.51 [0.11]; P < .001), with a similar trend for those with a low likelihood of having AD (B1; n = 134 [18.2%]; estimate [SE], 0.54 [0.32]; P = .10). We also found an indirect association of APOE ε4 with TDP-43 via Aβ and tau (estimate [SE], 0.34 [0.06]; P < .001), which was similar in magnitude to the direct association and an indirect association of APOE ε4 with hippocampal sclerosis via TDP-43 (estimate [SE], 0.65 [0.26]; P = .01). The study's findings, which mapped a system of risk factors and outcomes, showed that the APOE ε4 allele appears to be a risk factor for TDP-43 independently of Aβ in patients with AD.

Decreased Expression of Sulfatase 2 in the Brains of Alzheimer's Disease Patients: Implications for Regulation of Neuronal Cell Signaling.

Background:The human sulfatase 1 (SULF1) and sulfatase 2 (SULF2) genes modulate cell signaling and homeostasis in many tissues. Gene expression analyses have implicated SULF2 in disease pathogenesis, including Alzheimer’s disease (AD), but changes in brain SULF2 expression have not been directly established.Objective:To investigate the expression of SULF1 and SULF2 in brain tissues from AD cases and cognitively normal controls.Methods:Autopsy tissue from AD cases (n = 20) and age-and gender-matched cognitively normal controls (n = 20) were identified from the Mayo Clinic Alzheimer’s Disease Patient Registry neuropathology database. Tissue slides were stained for SULF1 and SULF2 protein expression in the hippocampus and frontal lobe and an expression score computed from the proportion of cells stained and the intensity of staining (range 0 [no expression] to 9 [marked expression]).Results:SULF2 expression was reduced in AD cases. Compared to cognitively normal controls, SULF2 expression in AD cases was significantly decreased in the hippocampal Cornu Ammonis (CA) (mean score of 6.5 in cases versus 8.3 in controls; p = 0.003), in the gray matter of the parahippocampal gyrus (5.6 in cases versus 7.6 in controls; p = 0.003), and in the frontal lobe gray matter (5.4 in cases versus 7.4 in controls; p = 0.002). There was no difference in SULF1 expression in the hippocampus or frontal lobe of AD cases and controls. As expected there were no differences in SULF1 or SULF2 expression in white matter in AD cases compared to cognitively normal controls.Conclusion:Decreased SULF2 in specific regions of the brain occurs in AD.

Link between diabetes and cognitive impairment

Clinical experience and multiple research studies suggest that persons with diabetes are more likely to develop cognitive impairment or frank dementia, which may be Alzheimer’s type or vascular dementia. Initially, this may be subtle and manifest itself as mental slowing or apathy. On the other hand, patients with Alzheimer’s disease have an increased risk of developing type 2 diabetes. What both these groups have in common is advanced age, a genetic predisposition, and comparable pathological features in the pancreatic islets and the brain, namely amyloid derived from amyloid B protein in the brain of Alzheimer’s disease and islet amyloid derived from islet amyloid polypeptide in the pancreas in type 2 diabetes. A study of subjects from the Mayo Clinic Alzheimer Disease Patient Registry found that both Type 2 diabetes (35 percent vs. 18 percent; P<0.05) and impaired fasting glucose (46 percent vs. 24 percent; P<0.01) were more prevalent in Alzheimer’s disease vs. non-Alzheimer disease control subjects. Hence, 81 percent of cases of Alzheimer’s disease had either Type 2 diabetes or IFG. In selected subjects where autopsy data were available, isletcell amyloid was more frequent and extensive in patients with Alzheimer’s disease than the non-Alzheimer’s disease controls. However, diffuse neuritic plaques were not more common in patients with type 2 diabetes than in control subjects. The Honolulu-Asia Aging Study investigated the effects of brain aging in very old men of Japanese-American descent born between 1900 and 1919 utilizing MRI. The prevalence of diabetes in this cohort was 38 percent, and subjects with type 2 diabetes had a moderately increased risk of lacunes (small brain infarcts), (odds ratio (OR) 1.6), and atrophy of the hippocampus (OR 1.7). Those with a longer history of diabetes, those taking insulin, and those with complications had more common pathological changes commonly seen in dementia.

Anesthesia and Incident Dementia: A Population-Based, Nested, Case-Control Study

ObjectiveTo test the hypothesis that exposure to procedures requiring general anesthesia during adulthood is not significantly associated with incident dementia using a retrospective, population-based, nested, case-control study design. Participants and MethodsUsing the Rochester Epidemiology Project and the Mayo Clinic Alzheimer's Disease Patient Registry, residents of Olmsted County, Minnesota, diagnosed as having dementia between January 1, 1985, and December 31, 1994, were identified. For each incident case, a sex- and age-matched control was randomly selected from the general pool of Olmsted County residents who were dementia free in the index year of dementia diagnosis. Medical records were reviewed to determine exposures to procedures requiring anesthesia after age 45 years and before the index year. Data were analyzed using logistic regression. ResultsWe analyzed 877 cases of dementia, each with a corresponding control. Of the dementia cases, 615 (70%) underwent 1681 procedures requiring general anesthesia; of the controls, 636 (73%) underwent 1638 procedures. When assessed as a dichotomous variable, anesthetic exposure was not significantly associated with dementia (odds ratio, 0.89; 95% CI, 0.73-1.10; P=.27). In addition, no significant association was found when exposure was quantified as number of procedures (odds ratios, 0.87, 0.86, and 1.0 for 1, 2-3, and ≥4 exposures, respectively, compared with none; P=.51). ConclusionThis study found no significant association between exposure to procedures requiring general anesthesia after age 45 years and incident dementia.

Neuroimaging correlates of pathologically defined subtypes of Alzheimer's disease: a case-control study

Three subtypes of Alzheimer's disease (AD) have been pathologically defined on the basis of the distribution of neurofibrillary tangles: typical AD, hippocampal-sparing AD, and limbic-predominant AD. Compared with typical AD, hippocampal-sparing AD has more neurofibrillary tangles in the cortex and fewer in the hippocampus, whereas the opposite pattern is seen in limbic-predominant AD. We aimed to determine whether MRI patterns of atrophy differ between these subtypes and whether structural neuroimaging could be a useful predictor of pathological subtype at autopsy. We identified patients who had been followed up in the Mayo Clinic Alzheimer's Disease Research Center (Rochester, MN, USA) or in the Alzheimer's Disease Patient Registry (Rochester, MN, USA) between 1992 and 2005. To be eligible for inclusion, participants had to have had dementia, AD pathology at autopsy (Braak stage ≥IV and intermediate to high probability of AD), and an ante-mortem MRI. Cases were assigned to one of three pathological subtypes--hippocampal-sparing, limbic-predominant, and typical AD--on the basis of neurofibrillary tangle counts in hippocampus and cortex and ratio of hippocampal to cortical burden, without reference to neuronal loss. Voxel-based morphometry and atlas-based parcellation were used to compare patterns of grey matter loss between groups and with age-matched control individuals. Neuroimaging was obtained at the time of first presentation. To summarise pair-wise group differences, we report the area under the receiver operator characteristic curve (AUROC). Of 177 eligible patients, 125 (71%) were classified as having typical AD, 33 (19%) as having limbic-predominant AD, and 19 (11%) as having hippocampal-sparing AD. Most patients with typical (98 [78%]) and limbic-predominant AD (31 [94%]) initially presented with an amnestic syndrome, but fewer patients with hippocampal-sparing AD (eight [42%]) did. The most severe medial temporal atrophy was recorded in patients with limbic-predominant AD, followed by those with typical disease, and then those with hippocampal-sparing AD. Conversely, the most severe cortical atrophy was noted in patients with hippocampal-sparing AD, followed by those with typical disease, and then limbic-predominant AD. The ratio of hippocampal to cortical volumes allowed the best discrimination between subtypes (p<0·0001; three-way AUROC 0·52 [95% CI 0·47-0·52]; ratio of AUROC to chance classification 3·1 [2·8-3·1]). Patients with typical AD and non-amnesic initial presentation had a significantly higher ratio of hippocampal to cortical volumes (median 0·045 [IQR 0·035-0·056]) than did those with an amnesic presentation (0·041 [0·031-0·057]; p=0·001). Patterns of atrophy on MRI differ across the pathological subtypes of AD. MRI regional volumetric analysis can reliably track the distribution of neurofibrillary tangle pathology and can predict pathological subtype of AD at autopsy. US National Institutes of Health (National Institute on Aging).

Diagnostic Validity of Age and Education Corrections for the Mini‐Mental State Examination in Older African Americans

To investigate whether demographic (age and education) adjustments for the Mini-Mental State Examination (MMSE) attenuate mean score discrepancies between African-American and Caucasian adults and whether demographically adjusted MMSE scores improve the diagnostic classification accuracy of dementia in African-American adults over unadjusted MMSE scores. Cross-sectional study. Community-dwelling adults participating in the Mayo Clinic Alzheimer's Disease Patient Registry and Alzheimer's Disease Research Center. Three thousand two hundred fifty-four adults (2,819 Caucasian, 435 African American) aged 60 and older. MMSE score at study entry. African-American adults had significantly lower unadjusted MMSE scores (23.0±7.4) than Caucasian adults (25.3±5.4). This discrepancy persisted despite adjustment of MMSE scores for age and years of education using established regression weights or newly derived weights. Controlling for dementia severity at baseline and adjusting MMSE scores for age and quality of education attenuated this discrepancy. In African-American adults, an age- and education-adjusted MMSE cut score of 23/24 provided optimal dementia classification accuracy, but this represented only a modest improvement over an unadjusted MMSE cut score of 22/23. The posterior probability of dementia in African-American adults is presented for various unadjusted MMSE cut scores and prevalence rates of dementia. Age, dementia severity at study entry, and quality of educational experience are important explanatory factors in understanding the existing discrepancies in MMSE performance between Caucasian and African-American adults. These findings support the use of unadjusted MMSE scores when screening older African Americans for dementia, with an unadjusted MMSE cut score of 22/23 yielding optimal classification accuracy.

Predicting Alzheimer's Disease

A great deal of attention is being given to making the diagnosis of dementia and Alzheimer's disease at an earlier point in the clinical spectrum. However, the clinical features of this point on the spectrum are not well delineated. All non-demented subjects from the Mayo Clinic Alzheimer's Disease Patient Registry were eligible for evaluation. Two prediction models were considered: clinical criteria for mild cognitive impairment (MCI) and a cutoff score on the Free and Cued Selective Reminding Test (FCSRT) (<17). Proportional hazards regression models were used to assess the association between each of the two risk indicators and the onset of dementia. Models were fit to each risk indicator individually. An additional model included both indicators simultaneously. Hazard ratios and 95% confidence intervals were obtained from these models. Additionally, C-statistics were calculated to further compare the ability of the two criteria to discriminate between those who progressed to dementia versus those who did not . The significance of the difference between the two C-statistics was assessed using a bootstrap approach. 1,261 non-demented subjects were entered into the evaluation. Of these, 193 progressed to dementia. The mean age and education for the total group were 78.8 years and 13.4 years, respectively. The follow-up ranged from 0.9 to 18.1 years, with a median of 5.2. Clinical MCI status was significantly associated with the outcome of dementia. Those classified as MCI had a hazard ratio for risk of dementia onset of 10.15 (95% CI: 7.59-13.57, p < 0.001). Those with summed learning scores over three trials on the FCSRT of 17 or less were at an increased risk of progression to dementia (HR = 9.10, 95% CI: 6.72-12.33, p < 0.001). When both criteria were included in the same model, both provided independent information for the risk of dementia. The C-statistic calculated for the MCI model (0.78) was 11% higher than that for the FCSRT model (0.70, p < 0.001). Clinical MCI criteria outperformed a single memory test for predicting risk of developing subsequent dementia. Support: Mayo Clinic Alzheimer's Disease Patient Registry UO1 AG06786, P 50 AG16574, the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program.

Risk of dementia in MCI: combined effect of cerebrovascular disease, volumetric MRI, and 1H MRS.

To investigate the combined ability of hippocampal volumes, 1H magnetic resonance spectroscopy (MRS) metabolites, and cerebrovascular disease to predict the risk of progression to dementia in mild cognitive impairment (MCI). We identified 151 consecutively recruited subjects with MCI from the Mayo Clinic Alzheimer's Disease Research Center and Patient Registry who underwent MRI and 1H MRS studies at baseline and were followed up with approximately annual clinical examinations. A multivariable proportional hazards model that considered all imaging predictors simultaneously was used to determine whether hippocampal volumes, posterior cingulate gyrus 1H MRS metabolites, white matter hyperintensity load, and presence of cortical and subcortical infarctions are complementary in predicting the risk of progression from MCI to dementia. Seventy-five subjects with MCI progressed to dementia by last follow-up. The model that best predicted progression to dementia included age, sex, hippocampal volumes, N-acetylaspartate (NAA)/creatine (Cr) on 1H MRS, and cortical infarctions. Based on age- and sex-adjusted Kaplan-Meier plots, we estimated that by 3 years, 26% of the MCI patients with normal hippocampal volumes, NAA/Cr ratios >1 SD, and no cortical infarctions will progress to dementia, compared with 78% of the MCI patients with hippocampal atrophy, low NAA/Cr (< or =1 SD), and cortical infarction. Multiple magnetic resonance (MR) markers of underlying dementia pathologies improve the ability to identify patients with prodromal dementia over a single MR marker, supporting the concept that individuals with multiple brain pathologies have increased odds of dementia compared with individuals with a single pathology.

Recurrent seizures in patients with dementia: Frequency, seizure types, and treatment outcome

Patients with a primary neurodegenerative disorder associated with cognitive impairment are at increased risk for epilepsy. The goal of the present study was to characterize seizure type(s), etiological diagnosis of dementia, electroencephalogram (EEG) and imaging findings, and response to antiepileptic drug (AED) therapy in these individuals. A retrospective study was performed identifying patients in the Mayo Alzheimer Disease Patient Registry (ADPR) and Alzheimer Disease Research Center (ADRC) who were classified as having dementia and epilepsy from 1986 to 2006. Multiple clinical parameters were extracted from patient charts and evaluated to characterize the primary neurodegenerative disorder and seizure outcomes. Sixty-three of the 1738 ADPR and ADRC patients (3.6%) had epilepsy. Twenty-four of the 63 patients were excluded because of insufficient information regarding their epilepsy. The remaining 39 patients were analyzed. Twenty-eight of the 63 patients (72%) experienced complex partial seizures. Head MRI was performed in 35 patients (90%). Fourteen patients (36%) had MRI-identified structural lesions that included remote stroke and prior intracerebral hemorrhage. EEGs were obtained in 29 patients (74%). Fifteen patients (38%) had epileptiform discharges. Overall, it was found that 79% had an excellent response to AED therapy. Approximately one-third of the patients had dose-related side effects from an AED. The present study indicated that most individuals with the comorbidity of epilepsy and dementia have complex partial seizures that may be adequately controlled on AED therapy. The long-term effect of seizure activity on the neurodegenerative disorder is unknown.

Detecting Dementia With the Mini-Mental State Examination in Highly Educated Individuals

To evaluate the utility of Mini-Mental State Examination (MMSE) scores in detecting cognitive dysfunction in a sample of highly educated individuals. Archival data were reviewed on 4248 participants enrolled in the Mayo Clinic Alzheimer Disease Research Center and Alzheimer Disease Patient Registry. A total of 1141 primarily white (93%) individuals with 16 or more years of self-reported education were identified. These included 307 (164 men and 143 women) patients with dementia (any type), 176 (106 men and 70 women) patients with mild cognitive impairment, and 658 (242 men and 416 women) control participants without dementia. Mayo Clinic Alzheimer Disease Research Center and Alzheimer Disease Patient Registry cohort. Diagnostic accuracy estimates (sensitivity, specificity, and positive and negative predictive power) of MMSE cut scores in detecting cognitive dysfunction. In this sample of highly educated, largely white older adults, the standard MMSE cut score of 24 (23 or below) yielded a sensitivity of 0.66, a specificity of 0.99, and an overall correct classification rate of 89% in detecting dementia. A cut score of up to 27 (26 or below) resulted in an optimal balance of sensitivity and specificity (0.89 and 0.91, respectively) with an overall correct classification rate of 90%. In a cognitively impaired group (dementia and mild cognitive impairment), a cut score of 27 (sensitivity, 0.69; specificity, 0.91) or 28 (sensitivity and specificity, 0.78) might be more appropriate. Older patients with a college education who present with complaints of cognitive decline (reported by themselves or others) and score less than 27 on the MMSE are at a greater risk of being diagnosed with dementia and should be referred for a comprehensive dementia evaluation, including formal neuropsychological testing.

P-055: Longitudinal voxel based morphometry in AD: Optimizing the method to produce maps of gray matter change over time

Longitudinal Voxel-based morphometry (LVBM) provides a method to probe inter-group differences in rates of decline of gray matter (GM) density captured by serial MRI studies. To our knowledge, LVBM has not yet been used to study AD subjects, and possible variations of LVBM have not yet been explored. Our objective was to analyze a set of AD and control subjects using several variations of LVBM, and compare the results of each method. We selected 32 probable AD and 32 cognitively normal elderly control subjects from the Mayo Alzheimer's Disease Research Center and Alzheimer's Disease Patient Registry. Subjects had undergone two serial T1 weighted 3-D volumetric 1.5T MRI examinations, and were matched for age, gender, and inter-scan interval. We evaluated permutations of 2 different methodological implementations: the image used for normalization and segmentation (early image vs. soft-mean image); and modulation. This created 4 methods: early with or without modulation (methods 1–2); and soft-mean with or without modulation (methods 3–4). The basic steps of LVBM are: 1) Compute deformation from late to early image. 2) Create soft-mean of early and deformed-late images. 3) Create image of the deformation's Jacobian determinants. 4) Normalize and segment the early (methods 1–2), or soft-mean (methods 3–4) image, applying the normalization to the Jacobian image. 5) Multiply normalized Jacobian with segmented GM. 6) (methods 2,4) “Modulate” the normalized early and late GM images. 7) We generated and visually compared statistical maps from each method, showing areas where AD subjects had greater rates of GM loss than controls (p<0.005, uncorrected). Maps from methods 1–4 are displayed in 1-4, respectively. Results from each method are in agreement with general knowledge of neurofibrillary AD pathology. The hippocampus, medial and basal temporal lobe, posterior cingulate/precuneus, lateral temporal-parietal neocortex, and subfrontal regions were significantly affected. LVBM is a powerful tool. Using the soft-mean rather than the early image in step 4 slightly improves the results of group comparisons, and should therefore be used. Modulation slightly degrades the significance of the results, but gives a more accurate representation of GM volume, and should therefore be used.

Neuropsychological Differentiation of Dementia with Lewy Bodies from Normal Aging and Alzheimer's Disease

We examined the diagnostic utility of selected neuropsychological measures in the differentiation of dementia with Lewy bodies (DLB) from normal aging and Alzheimer's disease (AD). Patients with DLB (n = 87), AD (n = 138), and a group of normal controls (n = 103) were recruited from the Mayo Alzheimer's disease patient registry and Alzheimer's Disease Research Center. Neuropsychological measures shown to have utility in previous studies were included in the analysis. The final multivariate logistic regression model distinguishing DLB from normal controls included Auditory Verbal Learning Test (AVLT) percent retention, Block Design, Trail Making Test—Part A, and Benton Visual Form Discrimination. This model has a sensitivity of 88.6% and specificity of 96.1%. The final multivariate logistic model distinguishing DLB from AD included Trail Making Part A, Boston Naming Test (BNT), AVLT percent retention, and copy of the Rey-Osterrieth Complex Figure. This model had a sensitivity of 83.3% and a specificity of 91.4%. AVLT and BNT had negative coefficients, indicating that lower scores decreased the likelihood of DLB relative to AD. These finding extend prior research suggesting a cognitive profile that can aid in the clinical diagnosis of DLB. Early attention and visual perceptual disturbance suggests DLB, while early impairment in memory and naming suggests AD.

Mortality in amnestic mild cognitive impairment

To assess the hazard of death in persons with and without amnestic mild cognitive impairment (aMCI). From 1987 through 2003, persons with aMCI (n = 243) and an age- and gender-matched reference group of cognitively normal persons in Olmsted County, MN, were recruited through the Mayo Clinic Alzheimer's Disease Patient Registry and followed prospectively through 2004. Survival was estimated using Kaplan-Meier survival curves, and the hazard of death for the aMCI cohort vs the reference cohort was estimated using Cox proportional hazards models. Over a median follow-up of 5.7 years, persons with aMCI had increased mortality (hazard ratio [HR] = 1.7; 95% CI: 1.3 to 2.3) vs reference subjects. The hazard of death by aMCI subtype was 1.5 in persons with single-domain aMCI (95% CI: 1.1 to 2.1) and 2.9 in persons with multiple-domain aMCI (95% CI: 1.9 to 4.6) vs reference subjects. Analyses restricted to aMCI cases showed an interaction between aMCI subtype and APOE-epsilon4 allele status (p = 0.003). Among aMCI cases with an APOE-epsilon4 allele, there was no difference in mortality between single- and multiple-domain aMCI (HR = 1.2; 95% CI: 0.6 to 2.3). However, among aMCI cases with no APOE-epsilon4 allele, the hazard of death in multiple-domain aMCI was 4.6 (95% CI: 2.3 to 9.1) vs single-domain aMCI. Amnestic mild cognitive impairment is associated with increased mortality, which is greater in multiple-domain aMCI than in single-domain aMCI. Mortality in aMCI subtypes may vary by APOE-epsilon4 allele status.

Cognitive Measures Predict Pathologic Alzheimer Disease

Neuropsychologic testing is often used to infer neuropathologic processes, but clinicopathologic correlations for individual cognitive measures are based on a small number of published studies. To examine the usefulness of the age- and education-adjusted Mayo Cognitive Factor Scales (MCFS) obtained at participants' initial assessments for predicting the presence or absence of pathologic Alzheimer disease (AD). This was a longitudinal study of a cohort of elderly patients with and without cognitive complaints who were followed up until death. Mayo Cognitive Factor Scales age- and education-adjusted standard scores from the participants' initial evaluations were used to calculate classification accuracy statistics for neuropathologic AD diagnosis obtained approximately 6 years after testing. Subjects with non-AD diagnoses or substantial non-AD-related changes were excluded from the study. Academic medical center. One hundred two participants were evaluated clinically and underwent neuropathologic examination at autopsy. All were part of the Mayo Clinic Alzheimer's Disease Patient Registry or Alzheimer Disease Research Center. All Mayo Cognitive Factor Scale scores were significantly correlated with AD criteria. Logistic regression modeling including Mayo Cognitive Factor Scales Verbal Comprehension and Retention indices revealed high positive predictive value with moderate sensitivity and specificity for pathologic AD. Neuropsychologic test scores at initial evaluations were predictive of pathologic AD.

Brain atrophy rates predict subsequent clinical conversion in normal elderly and amnestic MCI

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). 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. 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. 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.

P1-105 Neuropsychologic profiles in clinical dementia testing: an investigation of the CERAD-NP test battery

Patients with a primary neurodegenerative disorder associated with cognitive impairment are at increased risk for epilepsy. The goal of the present study was to characterize seizure type(s), etiological diagnosis of dementia, electroencephalogram (EEG) and imaging findings, and response to antiepileptic drug (AED) therapy in these individuals.A retrospective study was performed identifying patients in the Mayo Alzheimer Disease Patient Registry (ADPR) and Alzheimer Disease Research Center (ADRC) who were classified as having dementia and epilepsy from 1986 to 2006. Multiple clinical parameters were extracted from patient charts and evaluated to characterize the primary neurodegenerative disorder and seizure outcomes.Sixty-three of the 1738 ADPR and ADRC patients (3.6%) had epilepsy. Twenty-four of the 63 patients were excluded because of insufficient information regarding their epilepsy. The remaining 39 patients were analyzed. Twenty-eight of the 63 patients (72%) experienced complex partial seizures. Head MRI was performed in 35 patients (90%). Fourteen patients (36%) had MRI-identified structural lesions that included remote stroke and prior intracerebral hemorrhage. EEGs were obtained in 29 patients (74%). Fifteen patients (38%) had epileptiform discharges. Overall, it was found that 79% had an excellent response to AED therapy. Approximately one-third of the patients had dose-related side effects from an AED.The present study indicated that most individuals with the comorbidity of epilepsy and dementia have complex partial seizures that may be adequately controlled on AED therapy. The long-term effect of seizure activity on the neurodegenerative disorder is unknown.

Survival after Initial Diagnosis of Alzheimer Disease

Alzheimer disease is an increasingly common condition in older people. Knowledge of life expectancy after the diagnosis of Alzheimer disease and of associations of patient characteristics with survival may help planning for future care. To investigate the course of Alzheimer disease after initial diagnosis and examine associations hypothesized to correlate with survival among community-dwelling patients with Alzheimer disease. Prospective observational study. An Alzheimer disease patient registry from a base population of 23 000 persons age 60 years and older in the Group Health Cooperative, Seattle, Washington. 521 newly recognized persons with Alzheimer disease enrolled from 1987 to 1996 in an Alzheimer disease patient registry. Baseline measurements included patient demographic features, Mini-Mental State Examination score, Blessed Dementia Rating Scale score, duration since reported onset of symptoms, associated symptoms, comorbid conditions, and selected signs. Survival was the outcome of interest. The median survival from initial diagnosis was 4.2 years for men and 5.7 years for women with Alzheimer disease. Men had poorer survival across all age groups compared with females. Survival was decreased in all age groups compared with the life expectancy of the U.S. population. Predictors of mortality based on proportional hazards models included a baseline Mini-Mental State Examination score of 17 or less, baseline Blessed Dementia Rating Scale score of 5.0 or greater, presence of frontal lobe release signs, presence of extrapyramidal signs, gait disturbance, history of falls, congestive heart failure, ischemic heart disease, and diabetes at baseline. The base population, although typical of the surrounding Seattle community, may not be representative of other, more diverse populations. In this sample of community-dwelling elderly persons who received a diagnosis of Alzheimer disease, survival duration was shorter than predicted on the basis of U.S. population data, especially for persons with onset at relatively younger ages. Features significantly associated with reduced survival at diagnosis were increased severity of cognitive impairment, decreased functional level, history of falls, physical examination findings of frontal release signs, and abnormal gait. The variables most strongly associated with survival were measures of disease severity at the time of diagnosis. These results should be useful to patients and families experiencing Alzheimer disease, other caregivers, clinicians, and policymakers when planning for future care needs.

Increased risk of type 2 diabetes in Alzheimer disease.

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 beta 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 diabetes, although when it was present, it correlated in extent with duration of diabetes. These data support the hypothesis that patients with Alzheimer disease are more vulnerable to type 2 diabetes and the possibility of linkage between the processes responsible for loss of brain cells and beta-cells in these diseases.

Cross‐cultural comparison of the Mini‐Mental State Examination in United Kingdom and United States participants with Alzheimer's disease

the relative difficulties of items on the Mini-Mental State Examination (MMSE) were compared in English-speaking Alzheimer's disease (AD) patients in the United States (US) and United Kingdom (UK). participants were aged 75 and over, with a clinical diagnosis of AD according to standardized methods. Initial MMSE scores from an AD patient registry in the US (n = 401), and a field survey in the UK (n = 139) were compared. Item Characteristic Curve analysis (ICC) was used to calculate the relative difficulty of individual MMSE items, adjusted for the remaining MMSE items. Age, gender, education, and severity of disease were evaluated as possible confounders. UK participants found it relatively more difficult to name their county than US participants did to name their state. The relative difficulties of registration and recall, repeating a phrase, and following verbal directions also were significantly higher for the UK participants, even after adjustment for other factors. differences between the cohorts could be explained by translation artifacts in the test items or by cultural differences in the manifestation of AD. In this study, most, if not all differences can be explained by the former. ICC analysis can be used to develop tests that are functionally equivalent, a prerequisite for comparing dementia in different populations.