Alzheimer Disease: Edland SD

Edland SD. · Department of Epidemiology, University of Washington, Seattle, WA 98195, USA. · Stat Med. · Pubmed #10844709 No free full text.

Abstract: Longitudinal studies are often interested in assessing the relationship between severity (level) and rate of change (slope). Blomqvist describes an estimator of this relationship that has been used in a variety of contexts. This paper reviews and generalizes the Blomqvist method. Most published applications of the Blomqvist method contain substantial bias because they fail to consider and accommodate confounding due to the pooling of multiple age cohorts in a single analysis. We describe this bias, and present an unbiased algorithm consistent with the intentions of Blomqvist. We also explore when it is appropriate to apply the Blomqvist analysis, and what inferences can be made using this statistic. Aetiological inference about premorbid level of function predicting future rate of decline is often desired, but may not be justified when modelling chronic progressive conditions, since differential progression prior to the start of longitudinal follow-up can induce a relationship between level and rate of decline, even in the absence of an aetiologically relevant association. We conclude that aetiological inference by the Blomqvist analysis is not appropriate in most investigations of chronic progressive disease. Using the model to develop descriptive and predictive equations in these circumstances, however, remains appropriate, as does testing simply for clinical heterogeneity in longitudinal rate of decline.

Lu PH, Edland SD, Teng E, Tingus K, Petersen RC, Cummings JL, Anonymous00975. · Departments of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Neurology. · Pubmed #19528519 No free full text.

Abstract: OBJECTIVE: To determine whether the presence of depression predicts higher rate of progression to Alzheimer disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and whether donepezil treatment beneficially affect this relationship. METHODS: The study sample was composed of 756 participants with aMCI from the 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study drug trial of donepezil and vitamin E. Beck Depression Inventory (BDI) was used to assess depressive symptoms at baseline and participants were followed either to the end of study or to the primary endpoint of progression to probable or possible AD. RESULTS: Cox proportional hazards regression, adjusted for age at baseline, gender, apolipoprotein genotype, and NYU paragraph delayed recall score, showed that higher BDI scores were associated with progression to AD (p = 0.03). The sample was stratified into depressed (BDI score > or =10; n = 208) and nondepressed (BDI <10; n = 548) groups. Kaplan-Meier analysis showed that among the depressed subjects, the proportion progressing to AD was lower for the donepezil group than the combined vitamin E and placebo groups at 1.7 years (p = 0.023), at 2.2 years (p = 0.025), and remained marginally lower at 2.7 years (p = 0.070). The survival curves among the three treatment groups did not differ within the nondepressed participants. CONCLUSIONS: Results suggest that depression is predictive of progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD) and treatment with donepezil delayed progression to AD among depressed subjects with aMCI. Donepezil appears to modulate the increased risk of AD conferred by the presence of depressive symptoms.

Ma QL, Galasko DR, Ringman JM, Vinters HV, Edland SD, Pomakian J, Ubeda OJ, Rosario ER, Teter B, Frautschy SA, Cole GM. · Department of Medicine, University of California, Los Angeles, California, USA. · Arch Neurol. · Pubmed #19364929 No free full text.

Abstract: BACKGROUND: The sortilin-related receptor SorLA/LR11 (LR11) is a transmembrane neuronal sorting protein that reduces beta-amyloid precursor protein trafficking to secretases, notably BACE1 that generates beta-amyloid, the principal component of senile plaques in Alzheimer disease (AD). LR11 protein is reduced in patients with late-onset AD, and LR11 polymorphisms have been associated with late-onset AD. OBJECTIVE: T o detect soluble LR11 and APP in cerebrospinal fluid (CSF) from patients with AD and control subjects, as (like beta-amyloid precursor protein) LR11 is cleaved near the membrane to release a large N-terminal fragment that is secreted to media from cultured cells. DESIGN: Case-control study. SETTING: Academic research. PARTICIPANTS: Patients with AD and control subjects. MAIN OUTCOME MEASURES: We evaluated CSF LR11, beta-amyloid precursor protein, and apolipoprotein E levels by Western blot in lumbar and postmortem CSF samples. RESULTS: LR11 levels were detectable and stable during 6 months in the CSF of patients with AD. LR11 levels were significantly reduced in lumbar samples from patients with mild to moderate probable AD, as well as in ventricular CSF from patients with autopsy-confirmed AD (predominantly Braak stage III-IV). Bivariate analysis with beta-amyloid 42 and LR11 levels improved diagnostic specificity for AD. Reduced LR11 levels are significantly correlated with soluble beta-amyloid precursor protein but not apolipoprotein E levels. CONCLUSION: Reduced LR11 levels in CSF of patients with AD may have potential as a diagnostic biomarker for patients with LR11 deficits that promote beta-amyloid production or as an index of therapeutic response in late-onset AD.

Whitehouse PJ, Rajcan JL, Sami SA, Patterson MB, Smyth KA, Edland SD, George DR. · University Memory and Aging Center, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH 44120-1013, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17135813 No free full text.

Abstract: Both psychosocial and biologic interventions may delay or prevent Alzheimer disease. Staying mentally active may help older people maintain their cognitive abilities. In the Alzheimer Disease Cooperative Study Prevention Instrument Project a book club was introduced as a recruitment and retention device. A 3-arm study was designed and included: a nonrandomized, self-selected group (n=211) who chose not to participate in the book club, and 2 groups randomly assigned to receive 2 books per year in individual self-improvement (n=210) or community involvement (n=207) categories. Participants reported their reactions to the selections and other reading behaviors. Results from the first 2 years revealed that most book club participants agreed with Likert-type statements indicating the readings were enjoyable (P<0.001), had an impact on their thinking (P=0.01), and were shared by them with others (P=0.002). Respondents in the community involvement group agreed more strongly with these statements than those in the self-improvement category. Comments from participants in response to open-ended questions in the reader survey revealed such themes as developing plans for successful aging and reflecting on attitudes and behaviors in their own lives. Further longitudinal analyses are planned to determine whether the book club influenced retention and whether participation was associated with slowing cognitive decline.

Patterson MB, Whitehouse PJ, Edland SD, Sami SA, Sano M, Smyth K, Weiner MF, Anonymous00341. · Case Western Reserve University, Cleveland, OH, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17135811 No free full text.

Abstract: Information about quality of life (QOL) is valuable in evaluating pharmaceutical agents but it is not adequately assessed in many dementia drug trials. In prevention trials, following participants to conversion to AD requires QOL scales appropriate for both normal and cognitively impaired individuals. Our objective was to evaluate the utility of several scales for subject or informant QOL assessment: Quality of Life-AD; Quality of Life Activity Inventory; SF-36; SF-12 (a shortened version of the SF-36); and Satisfaction with Life Scale. Measurements were collected from 644 subject-study partner pairs, half of whom completed the instruments at the clinic and half at home. Three-month test-retest data were collected. Scales administered at home or in clinic did not differ significantly. Subject self-ratings showed a wide range for all scales. Test-retest intraclass coefficients ranged from 0.67 to 0.77. Moderately high interscale associations suggest that the scales are measuring common aspects of QOL but are not equivalent. Furthermore, they differed with respect to associations with demographic variables and QOL determinants. We conclude that the QOL scores at baseline show sufficient range and reliability to suggest they will have utility in tracking QOL through conversion to dementia.

Galasko D, Bennett DA, Sano M, Marson D, Kaye J, Edland SD, Anonymous00339. · Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17135809 No free full text.

Abstract: BACKGROUND: In primary prevention trials for Alzheimer disease, the inception cohort typically has normal or minimally impaired complex activities of daily living (ADL). ADL change during a trial could trigger detailed evaluation or serve as an outcome measure. A brief, easily administered, and reliable ADL rating scale would assist prevention studies. OBJECTIVES: To develop an ADL scale for prevention trials that allows self-rating or completion by informants. METHODS: The Activities of Daily Living-Prevention Instrument (ADL-PI) was developed, comprising 15 ADL and 5 physical function questions. Six hundred forty-four elderly subjects participating in the Prevention Instrument Project completed a self-rated version of the ADL-PI, and informants for 632 subjects completed an informant version. Informants also completed a Mild Cognitive Impairment (MCI) ADL questionnaire to allow comparisons. RESULTS: Subjects performed well on all ADL scales at baseline. Completion of the ADL-PI questionnaires at home or in-clinic yielded comparable information. Scores from baseline to 3 months had good reliability. The ADL-PI, obtained from either self-report or informants, discriminated between subjects rated as CDR 0 and CDR 0.5. Subjects with worse baseline cognitive performance also had slightly worse ADL-PI scores. Preliminary analysis indicates that subjects who triggered cognitive evaluations had slightly lower baseline ADL-PI scores by both self and informant reports. CONCLUSIONS: The ADL-PI can be completed at home or in clinic, and has adequate reliability. The utility of self-administered and informant versions and predictive value of reported deficits requires further follow-up.

Salmon DP, Cummings JL, Jin S, Sano M, Sperling RA, Zamrini E, Petersen RC, Edland SD, Thal LJ, Ferris SH, Anonymous00337. · Department of Neurosciences, University of California, San Diego, La Jolla, California 92093-0948, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17135807 No free full text.

Abstract: The validity and reliability of clinic-based and telephone-based versions of a 4 word delayed recall test were evaluated in nondemented elderly individuals (n=644) participating in a simulated primary prevention clinical trial. There was no significant difference in the average scores achieved by participants tested in clinic (mean=3.40) or by telephone (mean=3.47) and the 2 groups had similar distributions of scores. Delayed recall scores were significantly, but weakly, correlated with scores on a rigorous verbal memory task, were lower in participants in Clinical Dementia Rating stage 0.5 than in those in Clinical Dementia Rating stage 0, and were lower in those with subjective memory complaints than in those without complaints. There was only fair correspondence between scores achieved at initial testing and 3 months later for both versions of the test. There were no differences in the average scores achieved by men or women, those older (age 80 to 93) or younger (age 75 to 79) than age 80, or those with white or nonwhite ethnicity. Participants with low education scored significantly lower than those with high education. Results suggest that clinic-based and telephone-based versions of the Four Word Delayed Recall Test are valid and reliable and can be used to screen for possible memory deficits in elderly individuals. However, the psychometric properties of the test are relatively weak and do not support the general use of the test for clinical and research purposes if the use of a more rigorous memory test with a wider range of possible scores is feasible.

Knopman DS, Petersen RC, Cha RH, Edland SD, Rocca WA. · The Mayo Alzheimer Disease Research Center, Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA. · Neurology. · Pubmed #16217048 No free full text.

Abstract: OBJECTIVE: To study coronary artery bypass grafting (CABG) as a risk factor for dementia and Alzheimer disease (AD) using a case-control design. METHODS: The authors used the records-linkage system of the Rochester Epidemiology Project to ascertain incident cases of dementia in Rochester, MN, for the 5-year period 1990 to 1994. The authors defined dementia and AD using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). Each case was individually matched by age (+/-1 year) and sex to a person drawn randomly from the same population, and free of dementia in the index year (year of onset of dementia in the matched case). RESULTS: Among 557 dementia cases, 24 (4.3%) had undergone a CABG prior to the onset of dementia with a median lag time of 5.5 years (range = 0.1 to 15.9). Among 557 controls, 28 subjects (5.0%) had undergone a CABG prior to the index year with a median lag time 3.9 years (range = 0.1 to 12.3); OR = 0.85 (95% CI = 0.49 to 1.49; p = 0.57) for dementia and OR = 0.78 (95% CI = 0.39 to 1.56; p = 0.48) for AD. The findings did not change after adjustment for education. The perioperative courses of cases and controls were comparable. Analyses including only the 481 cases of dementia with presumed neurodegenerative or cerebrovascular etiology were also negative. CONCLUSIONS: This population-based case-control study suggests that coronary artery bypass grafting is not a major risk factor for dementia overall, or for Alzheimer disease.

Myllykangas L, Wavrant-De Vrièze F, Polvikoski T, Notkola IL, Sulkava R, Niinistö L, Edland SD, Arepalli S, Adighibe O, Compton D, Hardy J, Haltia M, Tienari PJ. · Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland. · J Neurol Sci. · Pubmed #16023140 No free full text.

Abstract: Genetic linkage studies have provided evidence for a late-onset Alzheimer's disease (AD) susceptibility locus on chromosome 21q. We have tested, in a two-stage association study, whether allelic or haplotype variation of the beta-amyloid cleaving enzyme-2 (BACE2) locus on chromosome 21q affects the risk of late-onset AD. In stage-1, an unselected population-based sample of Finns aged 85 years or over (n=515) was analysed. Neuropathologic examination including beta-amyloid load quantification was possible in over 50% (n=264) of these subjects. AD patients (n=100) and controls (n=48) were defined by modified neuropathological NIA-RI criteria. Positive associations were taken as a hypothesis, and tested in stage-2 using 483 AD families from the USA. Four single nucleotide polymorphisms (SNPs) of BACE2 gene were tested in stage-1. A SNP close to exon-6 was associated with neuropathologically verified AD (p=0.02) and also with beta-amyloid load in non-selected autopsied subjects after conditioning with APOE genotype (p=0.001). In haplotype analysis a specific, relatively common haplotype (H5) was found to associate with AD (p=0.004) and a second haplotype (H7) showed a weaker association with protection against AD (p=0.04). In stage-2, the SNP association was not replicated, whereas the haplotype H5 association was replicated (p=0.004) and a trend to association was found with the putative protective haplotype H7 (two-sided p=0.08). BACE2 haplotype association with AD in two independent datasets provides further evidence for an AD susceptibility locus on chromosome 21q within or close to BACE2.

Tsuang D, Simpson KL, Li G, Barnhart RL, Edland SD, Bowen J, McCormick W, Teri L, Nochlin D, Larson EB, Thompson ML, Leverenz JB. · Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA. · Alzheimer Dis Assoc Disord. · Pubmed #15942323 links to  free full text

Abstract: Neuropathological (np) relative frequency estimates of dementia may be biased if the autopsied subjects are not representative of all dementia subjects within a target population. We identified characteristics that differed between autopsied and non-autopsied subjects from an incident-based dementia case series and compared autopsy-based estimates of the relative frequency of np diagnoses before and after adjusting for potential selection bias. Clinically demented subjects who were autopsied (n = 206), had died but were not autopsied (n = 271), were still alive (n = 71), or had dropped out of the study (n = 82) were included. Compared with non-autopsied subjects, autopsied subjects were more likely to be Caucasian, educated beyond high school, and married. They also tended to have a lower baseline Mini-Mental State Examination score and were more likely to have a clinical diagnosis of Alzheimer disease (AD) than non-autopsied subjects. Neuropathological AD with Lewy bodies (LB) had the largest crude relative frequency estimate at 38% of the autopsy sample, followed by 25% for AD with vascular lesions, 13% for pure AD, 13% for LB (with or without vascular lesions), and 8% for pure vascular pathologies. Adjustment for potential sources of selection bias had little effect on relative frequency estimates, suggesting that np diagnoses in the autopsied subjects provide reasonable dementia relative frequency estimates among all clinically demented cases in this series.

Kantarci K, Petersen RC, Boeve BF, Knopman DS, Tang-Wai DF, O'Brien PC, Weigand SD, Edland SD, Smith GE, Ivnik RJ, Ferman TJ, Tangalos EG, Jack CR. · Department of Diagnostic Radiology, Mayo Clinic 200 First St. SW, Rochester, MN 55905, USA. · Neurology. · Pubmed #15505154 No free full text.

Abstract: OBJECTIVE: To determine the 1H MR spectroscopic (MRS) findings and intergroup differences among common dementias: Alzheimer disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD). METHODS: The authors consecutively recruited 206 normal elderly subjects and 121 patients with AD, 41 with FTLD, 20 with DLB, and 8 with VaD. The 1H MRS metabolite ratio changes in common dementias were evaluated with respect to normal and also differences among the common dementias. RESULTS: N-acetylaspartate (NAA)/creatine (Cr) was lower than normal in patients with AD, FTLD, and VaD. Myo-inositol (mI)/Cr was higher than normal in patients with AD and FTLD. Choline (Cho)/Cr was higher than normal in patients with AD, FTLD, and DLB. There were no metabolite differences between patients with AD and FTLD or between patients with DLB and VaD. NAA/Cr was lower in patients with AD and FTLD than DLB. MI/Cr was higher in patients with AD and FTLD than VaD. MI/Cr was also higher in patients with FTLD than DLB. CONCLUSIONS: NAA/Cr levels are decreased in dementias that are characterized by neuron loss, such as AD, FTLD, and VaD. MI/Cr levels are elevated in dementias that are pathologically characterized by gliosis, such as AD and FTLD. Cho/Cr levels are elevated in dementias that are characterized by a profound cholinergic deficit, such as AD and DLB.

Edland SD. · Mayo Clinic and Foundation Division of Clinical Epidemiology, Rochester, MN 55905, USA. · J Mol Neurosci. · Pubmed #15181249 No free full text.

Abstract: Insulin-degrading enzyme (IDE) is a protease that degrades insulin and the beta-amyloid (Abeta) peptide implicated in Alzheimer's disease (AD). Hence, factors that influence IDE expression or IDE activity toward Abeta are potentially relevant to the etiology of AD. Hippocampal IDE mRNA levels are lower on average in subjects with an APOE epsilon4 allele, suggesting that the genetic risk conferred by APOE epsilon4 may be mediated in part by this allele's effect on IDE expression. Other factors that influence IDE may be relevant in non-epsilon4 carriers. For example, insulin, a competitive inhibitor of IDE activity toward Abeta, may be elevated in non-epsilon4 cases. We here report IDE gene promoter region variants that are associated with AD in subjects without an epsilon4 allele. If these promoter region variants prove to affect expression levels, they may be relevant to disease as well. Further investigation of the relationship between APOE genotype, IDE genetic variants, and the expression and activity of hippocampal IDE is warranted.

Knopman DS, Petersen RC, Edland SD, Cha RH, Rocca WA. · Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Neurology. · Pubmed #14872045 No free full text.

Abstract: The records-linkage system of the Rochester Epidemiology Project was used to ascertain incident cases of frontotemporal lobar degeneration (FTLD) in Rochester, MN, from 1990 through 1994. Four cases of FTLD were identified (all women); two were confirmed neuropathologically. All were of the behavioral-dysexecutive type and had onset before age 70. The incidence rates (new cases per 100,000 person-years) were 2.2 for ages 40 to 49, 3.3 for ages 50 to 59, and 8.9 for ages 60 to 69. For comparison, the corresponding rates for Alzheimer disease were 0.0, 3.3, and 88.9.

Edland SD, Slager S, Farrer M. · Division of Clinical Epidemiology, Department of Health Science Research, Mayo Clinic and Foundation, Rochester, MN 55905, USA. · Stat Med. · Pubmed #14716719 No free full text.

Abstract: Genetic association studies have identified important risk factors for Alzheimer's disease and other diseases. However, the ease with which these methods can be applied and the shear number of polymorphisms in the human genome has led to a well-characterized multiple comparison problem-given the number of genetic variants being tested, it is likely that many of the positive findings reported in the literature to date will prove to be false positive findings explained simply by random fluctuation in data and type I error. The disparity of findings in initial positive reports versus subsequent negative replication studies observed in the Alzheimer's disease literature underscores this problem. The problem of a high false positive rate can be addressed in part by using statistical correction for multiple comparisons in larger and statistically more powerful samples and in meta-analyses of smaller samples. National initiatives are now being considered to address this problem by encouraging sharing of genetic material. Of equal concern in planning future initiatives are methodological issues that are the domain of the epidemiologist. In fact, it is possible that disparate findings across case-control studies reported to date may be explained in part by problems in the design, analysis and interpretation of these studies. The involvement of epidemiologists may improve the situation in this regard. For example, population stratification bias, control selection bias and prevalent case bias can be minimized by careful study design and by appropriate statistical analysis. Regarding interpretation of case-control studies, a more careful consideration of the strength of evidence for a given genetic variant may help to temper enthusiasm for, or appropriately qualify, positive findings. Epidemiologists have well-developed causal criteria for this purpose. This paper reviews the current state of case-control studies of genetic variants in Alzheimer's disease from the epidemiological perspective. The problem of multiple comparisons and a high false positive rate is reviewed. The potential for bias in case-control studies of Alzheimer's disease is reviewed by way of example. Future initiatives to promote case-control studies of genetic variants in Alzheimer's disease can only benefit from increased awareness the tools of epidemiology.

Tang-Wai DF, Knopman DS, Geda YE, Edland SD, Smith GE, Ivnik RJ, Tangalos EG, Boeve BF, Petersen RC. · Department of Neurology, the Mayo Alzheimer's Disease Research Center, Mayo Clinic, Rochester, Minn. 55905, USA. · Arch Neurol. · Pubmed #14676056 links to  free full text

Abstract: BACKGROUND: The Mini-Mental State Examination (MMSE) is the most widely used brief screening measure of cognition, but it is not sensitive in detecting mild memory or other cognitive impairments. The Short Test of Mental Status (STMS) was specifically developed for use in dementia assessment and was intended to be more sensitive to problems of learning and mental agility that may be seen in mild cognitive impairment (MCI). OBJECTIVE: To compare the STMS and MMSE for detecting or predicting MCI. DESIGN: Comparison of STMS and MMSE scores at baseline among 4 groups of patients: 788 patients with stable normal cognition, 75 patients with normal cognition at baseline but who developed incident MCI or Alzheimer disease during follow-up, 129 patients with prevalent MCI at baseline, and 235 patients with prevalent mild Alzheimer disease. All patients and control subjects for this study were evaluated through the Mayo Alzheimer's Disease Patient Registry or the Mayo Clinic Alzheimer's Disease Research Center, Rochester, Minn, using a standardized diagnostic approach. RESULTS: The STMS was slightly more sensitive than the MMSE in discriminating between patients with stable normal cognition and patients with prevalent MCI. The STMS was superior to the MMSE in detecting deficits in cognition in individuals who had normal cognition at baseline but later developed incident MCI or Alzheimer disease. CONCLUSIONS: Compared with the MMSE, the STMS was better able to document MCI and was more sensitive in detecting deficits in cognition in individuals who had normal cognition at baseline but later developed incident MCI or Alzheimer disease.

Edland SD, Wavrant-De Vriesé F, Compton D, Smith GE, Ivnik R, Boeve BF, Tangalos EG, Petersen RC. · Division of Clinical Epidemiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA. · Neurosci Lett. · Pubmed #12809979 No free full text.

Abstract: Insulin degrading enzyme (IDE) is a protease that degrades insulin and the beta-amyloid peptide implicated in Alzheimer's disease (AD). We reexamined data on five previously reported IDE polymorphisms stratifying the analysis by the presence or absence of an apolipoprotein E (APOE) epsilon4 allele. Three IDE variants were associated with AD within epsilon4-negative subjects (genotype exact test P-values < or =0.02). A haplotype containing the minor variant at each of these sites represented an estimated 4.2% of case haplotypes versus 12.3% of control haplotypes among epsilon4-negative subjects. Lack of this minor haplotype may be predictive of AD, potentially explaining some fraction of disease within subjects without the APOE epsilon4 risk allele. Confirmation of this finding with a larger sample of cases and controls is warranted.

Kantarci K, Reynolds G, Petersen RC, Boeve BF, Knopman DS, Edland SD, Smith GE, Ivnik RJ, Tangalos EG, Jack CR. · Department of Diagnostic Radiology, Milwaukee, WI, USA. · AJNR Am J Neuroradiol. · Pubmed #12748083 links to  free full text

Abstract: BACKGROUND AND PURPOSE: Theoretically, proton ((1)H) MR spectroscopy at a higher field strength has the advantages of higher signal-to-noise ratio and improved spectral resolution. We therefore compared the ability of single-voxel (1)H MR spectroscopy at 1.5 and 3 T to diagnostically discriminate among cognitively normal elderly subjects, patients with mild cognitive impairment (MCI), and patients with Alzheimer disease (AD). METHODS: At both 1.5 and 3 T, we studied 41 cognitively normal elderly subjects, 20 patients with MCI, and 20 patients with AD. In each subject, (1)H MR spectroscopy was performed at TEs of 30 and 135 ms and from voxels placed over the posterior cingulate gyri. RESULTS: Average line widths and interexamination variability of metabolite ratios were higher at 3 T than at 1.5 T. Consistent quantification of glutamine (Gln) + glutamate/creatine (Cr) and Gln/Cr peak ratios occurred at 3 T but not at 1.5 T. Choline (Cho)/Cr (at TE = 135 ms) and myo-inositol (MI)/Cr were higher and N-acetylaspartate (NAA)/Cr (at TE = 135 ms) and NAA/MI were lower in patients with MCI than in cognitively normal subjects only at 1.5 T. MI/Cr and Cho/Cr were higher and NAA/Cr and NAA/MI were lower in patients with AD than in cognitively normal subjects at both 1.5 and 3 T. Differentiation of patients with AD from cognitively normal subjects by using the NAA/MI data was similar at both field strengths (P >.05). CONCLUSION: With currently available technology, the diagnostic performance of (1)H MR spectroscopy in patients with MCI and those with AD was not better at 3 T than at 1.5 T.

Knopman DS, Parisi JE, Boeve BF, Cha RH, Apaydin H, Salviati A, Edland SD, Rocca WA. · Department of Neurology, Mayo Clinic and Foundation, Rochester, MN 55905, USA. · Arch Neurol. · Pubmed #12707071 links to  free full text

Abstract: BACKGROUND: The validity of the clinical diagnosis of vascular dementia (VaD) remains suboptimal. OBJECTIVE: To investigate clinicopathologic correlations in VaD. METHODS: We used the medical records-linkage system of the Rochester Epidemiology Project to identify incident cases of dementia in Rochester, Minn, from January 1, 1985, through December 31, 1989. Dementia and Alzheimer disease (AD) were defined by the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Vascular dementia was defined by criteria including imaging results. Pathological characteristics of AD were quantified by means of standard scoring methods for neurofibrillary tangles and neuritic plaques. Vascular pathological findings were assessed by expert neuropathological opinion. RESULTS: Of 419 patients with dementia who died before the study, neuropathological examination results were available in 89 (21%) with median age at onset of 80 years (range, 50-96 years; 52 [58%] women). Pathological diagnoses were AD in 45 patients (51%), pure VaD in 12 (13%), combined AD and VaD in 11 (12%), and other diagnoses in the remaining 21 patients. Criteria for VaD that required either a temporal relationship between a stroke and dementia onset or worsening, or bilateral infarctions in specified locations demonstrated on imaging results (Mayo Clinic criteria) had 75% sensitivity and 81% specificity for pure VaD (positive likelihood ratio, 3.9; 95% confidence interval, 2.2-6.7). Five cases of pure VaD lacked the temporal relationship and accounted for the imperfect sensitivity of the criteria. CONCLUSIONS: In this population-based autopsy study, the presence of vascular pathological characteristics in the absence of major AD pathological findings was common. Pure VaD without overt clinical strokes remains a challenge for antemortem diagnosis.

Knopman DS, Rocca WA, Cha RH, Edland SD, Kokmen E. · Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. · Arch Neurol. · Pubmed #12533093 links to  free full text

Abstract: OBJECTIVE: To investigate the relationship between features and definitions of vascular dementia (VaD) and survival. DESIGN: We used the medical records linkage system of the Rochester Epidemiology Project to identify incident cases of dementia in Rochester from January 1, 1985, through December 31, 1989. Dementia and Alzheimer disease were defined using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Vascular dementia was defined by ad hoc criteria, including imaging. Each patient with dementia was matched by age and sex to a referent subject free of dementia. Patients with dementia and referent subjects were followed from the onset of dementia (or index year) through death, censoring, or the end of the study. RESULTS: We included 479 patients with incident dementia and 479 referent subjects. Overall, patients with VaD had worse mortality than referent subjects (relative risk [RR], 2.7; 95% confidence interval [CI], 1.9-3.9). Among patients with VaD, those with dementia temporally related to a stroke had a worse relative mortality (RR, 4.5; 95% CI, 2.7-7.4) than those with only imaging evidence of bilateral infarctions in gray matter structures (RR, 2.4; 95% CI, 1.5-3.8). Relative mortality estimates varied by using 3 sets of published diagnostic criteria for VaD. Patients with VaD had a higher RR of death (RR, 2.7; 95% CI, 1.9-3.9) than patients with dementia overall (RR, 1.8; 95% CI, 1.6-2.1) or patients with Alzheimer disease (RR, 1.4; 95% CI, 1.2-1.7). CONCLUSIONS: The relative mortality of patients with VaD varied depending on the set of diagnostic criteria used. A temporal relationship to a stroke was the strongest predictive feature for poor survival in patients with dementia.

Kantarci K, Xu Y, Shiung MM, O'Brien PC, Cha RH, Smith GE, Ivnik RJ, Boeve BF, Edland SD, Kokmen E, Tangalos EG, Petersen RC, Jack CR. · Department of Diagnostic Radiology, Mayo Clinic, Rochester, Minn., USA. · Dement Geriatr Cogn Disord. · Pubmed #12411762 No free full text.

Abstract: This study compares the diagnostic accuracy of magnetic resonance (MR)-based hippocampal volumetry, single voxel (1)H MR spectroscopy ((1)H MRS) and MR diffusion-weighted imaging (DWI) measurements in discriminating patients with amnestic mild cognitive impairment (MCI), Alzheimer's disease (AD) and normally aging elderly. Sixty-one normally aging elderly, 24 MCI and 22 AD patients underwent MR-based hippocampal volumetry, (1)H MRS and DWI. (1)H MRS voxels were placed over both of the posterior cingulate gyri, and N-acetyl aspartate (NAA)/creatine (Cr), myoinositol (MI)/Cr and NAA/MI ratios were obtained. Apparent diffusion coefficient (ADC) maps were derived from DWI, and hippocampal borders were traced to measure hippocampal ADC. At 80% specificity, the most sensitive single measurement to discriminate MCI (79%) and AD (86%) from controls was hippocampal volumes. The most sensitive single measurement to discriminate AD from MCI was posterior cingulate gyrus NAA/Cr (67%). At high specificity (>85-90%), combinations of MR measures had superior diagnostic sensitivity compared with any single MR measurement for the AD vs. control and control vs. MCI comparisons. The MR measures that best discriminate more from less affected individuals along the cognitive continuum from normal to AD vary with disease severity. Selection of imaging measures used for clinical assessment or monitoring efficiency of therapeutic intervention should be tailored to the clinical stage of the disease.

Edland SD, Rocca WA, Petersen RC, Cha RH, Kokmen E. · Department of Health Sciences Research, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. · Arch Neurol. · Pubmed #12374497 links to  free full text

Abstract: BACKGROUND: Incidence rates of Alzheimer disease (AD) were higher in women than in men in several recent European and Asian studies. Cohort studies in the United States, on the other hand, have consistently reported no difference in incidence across sex. OBJECTIVE: To measure age- and sex-specific incidence rates of dementia and AD for persons aged 50 years and older residing in Rochester, Minn, during 1985 to 1989. SUBJECTS AND METHODS: Cases were ascertained through the medical records linkage system of the Rochester Epidemiology Project, which encompasses the records of all medical care providers (including outpatient clinics, hospitals, general practitioners, and nursing homes) in Rochester. Computer indices of clinical diagnoses, histologic diagnoses, and medical procedures were screened for indications of dementia. All medical records of potential cases were reviewed and abstracted by a trained nurse abstractor. A neurologist (E.K.) confirmed the presence of dementia and established a differential diagnosis of AD using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and estimated the year of onset. RESULTS: A total of 482 incident cases of dementia were identified; 356 of them (73.9%) had AD. For both dementia and AD, incidence rates increased steeply with age, and there were no consistent differences between men and women. The sex pattern for AD did not change after removing cases with silent bilateral infarcts on imaging. CONCLUSIONS: Contrary to observations from European and Asian populations, women were not at increased risk of incident AD in Rochester. Our findings, based on a medical records linkage system, corroborate findings from several other US studies that involved the direct contact of cohort members. The consistency of findings across study designs suggests that sex or sex-related exposures do not consistently play a major role in AD causation in American populations.

Edland SD, Xu Y, Plevak M, O'Brien P, Tangalos EG, Petersen RC, Jack CR. · Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. · Neurology. · Pubmed #12136069 No free full text.

Abstract: A larger premorbid brain is hypothesized to provide neuronal reserve against AD. Using MRI data from ongoing studies of normal aging and AD, the authors tested this hypothesis. Mean total intracranial volume was 15.8 cm(3) smaller for cases among women (n = 121 normal and 104 AD; p = 0.24) and 10.1 cm(3) larger for cases among men (n = 63 normal and 62 AD; p = 0.59). These differences are small and nonsignificant, suggesting that head size per se is not a critical determinant of AD.

Leverenz JB, Agustin CM, Tsuang D, Peskind ER, Edland SD, Nochlin D, DiGiacomo L, Bowen JD, McCormick WC, Teri L, Raskind MA, Kukull WA, Larson EB. · Veterans Affairs Northwest Network Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, 1660 S Columbian Way, 116 MIRECC, Seattle, WA 98108, USA. · Arch Neurol. · Pubmed #12117357 links to  free full text

Abstract: BACKGROUND: Hippocampal sclerosis (HS) is a neuropathologic finding characterized by neuronal loss and gliosis in the CA-1 and subiculum of the hippocampus. Previous studies of HS have shown that this is a common postmortem finding in elderly subjects with dementia. However, these studies were from selected samples and therefore are not necessarily representative of patients seen in the general medical community. OBJECTIVES: To examine the clinical and pathologic characteristics of HS in a community-based case series of dementia and to compare these characteristics with those observed in subjects with Alzheimer disease (AD) from the same study sample. METHODS: One hundred thirty-four autopsy cases were available from a community-based registry of dementia. Sixteen cases (12%) had a postmortem diagnosis of HS. Thirty-two comparison control cases with a neuropathologic diagnosis of AD were selected from the same files. Each case of HS was reviewed for HS neuropathologic features, including severity, distribution, and additional pathologic processes. Blinded review of clinical characteristics for the HS and control groups was performed to assess risk factors. RESULTS: There was a wide range of severity and distribution of HS lesions between cases and substantial variability in lesion severity and age within individual cases. Serial neuropsychologic and behavioral assessments revealed similar clinical features and rates of dementia progression between HS and AD groups. Of all neuropsychologic tests performed at enrollment, only enhanced performance on Trails A differentiated the HS from the AD group (64 seconds, 0 errors vs 114 seconds, 0.6 errors; P< or = .05). The number of AD cases with at least 1 apolipoprotein epsilon 4 allele was significantly greater than the HS cases (61% vs 31%; chi(2) = 3.81, P< or = .05). Although medical record review indicated higher frequencies of clinical stroke and neuroradiologic white matter abnormalities in the HS group, risk factors for vascular disease and neuropathologic evidence of cerebrovascular disease did not differ between the groups. CONCLUSIONS: Our results suggest that HS is a frequent pathologic finding in community-based dementia. Individuals with HS have similar initial symptoms and rates of dementia progression to those with AD and therefore are frequently misclassified as having AD. Our clinical and pathologic findings suggest that HS has characteristics of a progressive disorder although the underlying cause remains elusive.

Jack CR, Dickson DW, Parisi JE, Xu YC, Cha RH, O'Brien PC, Edland SD, Smith GE, Boeve BF, Tangalos EG, Kokmen E, Petersen RC. · Department of Diagnostic Radiology, Mayo Clinic and Foundation, Rochester, MN 55905, USA. · Neurology. · Pubmed #11889239 No free full text.

Abstract: OBJECTIVES: To 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. METHODS: An 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. RESULTS: Individuals 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). CONCLUSIONS: Hippocampal 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.

Edland SD, Tobe VO, Rieder MJ, Bowen JD, McCormick W, Teri L, Schellenberg GD, Larson EB, Nickerson DA, Kukull WA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Alzheimer Dis Assoc Disord. · Pubmed #11882743 No free full text.

Abstract: The T4336C mitochondrial genetic variant was associated with Alzheimer disease in several previous studies. Recent investigations, however, failed to confirm this association. We tested this association in newly diagnosed Alzheimer disease cases and controls of similar age and gender recruited from an established HMO serving Seattle, Washington and surrounding areas. In this, the largest case-control study reported to date, the T4336C variant was not associated with Alzheimer disease overall (present in 6 of 236 cases and 7 of 328 controls; odds ratio = 1.20, 95% CI 0.33 to 4.22). There was evidence of effect modification by Apolipoprotein E (APOE) status--among subjects with an APOE epsilon 4 allele, the T4336C variant was associated with disease (present in 5 of 139 cases and none of 82 controls; odds ratio = infinity, 95% CI 0.73 to infinity). APOE may be an important modifier of the T4336C effect, potentially explaining variable findings across previous studies. Alternatively, the positive findings reported to date may simply reflect the problem of "type I" error inherent in genetic association studies. Substantially larger samples than are currently available would be required to resolve this question. G5460(A/T) variants were also investigated and found not to be associated with Alzheimer disease.