Distinguishing Alzheimer's Disease Research Articles

CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios: better diagnostic markers of Alzheimer disease.

The diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) must be improved before widespread clinical use. This study aimed to determine whether CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios are better diagnostic biomarkers of AD during both predementia and dementia stages in comparison to CSF Aβ42 alone. The study comprised three different cohorts (n = 1182) in whom CSF levels of Aβ42, Aβ40, and Aβ38 were assessed. CSF Aβs were quantified using three different immunoassays (Euroimmun, Meso Scale Discovery, Quanterix). As reference standard, we used either amyloid ((18)F-flutemetamol) positron emission tomography (PET) imaging (n = 215) or clinical diagnosis (n = 967) of well-characterized patients. When using three different immunoassays in cases with subjective cognitive decline and mild cognitive impairment, the CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios were significantly better predictors of abnormal amyloid PET than CSF Aβ42. Lower Aβ42, Aβ42/Aβ40, and Aβ42/Aβ38 ratios, but not Aβ40 and Aβ38, correlated with smaller hippocampal volumes measured by magnetic resonance imaging. However, lower Aβ38, Aβ40, and Aβ42, but not the ratios, correlated with non-AD-specific subcortical changes, that is, larger lateral ventricles and white matter lesions. Further, the Aβ42/Aβ40 and Aβ42/Aβ38 ratios showed increased accuracy compared to Aβ42 when distinguishing AD from dementia with Lewy bodies or Parkinson's disease dementia and subcortical vascular dementia, where all Aβs (including Aβ42) were decreased. The CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios are significantly better than CSF Aβ42 to detect brain amyloid deposition in prodromal AD and to differentiate AD dementia from non-AD dementias. The ratios reflect AD-type pathology better, whereas decline in CSF Aβ42 is also associated with non-AD subcortical pathologies. These findings strongly suggest that the ratios rather than CSF Aβ42 should be used in the clinical work-up of AD.

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Aβ and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Aβ and p-tau in large populations of individual synaptic terminals. Soluble Aβ oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Aβ was elevated in patients with early- and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Aβ oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Aβ-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Aβ drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed.

Exploring multifractal-based features for mild Alzheimer's disease classification.

Multifractal applications to resting state functional MRI (rs-fMRI) time series for diagnosing Alzheimer's disease (AD) are still limited. We aim to address two issues: (I) if and what multifractal features are sufficiently discriminative to detect AD from the healthy; (II) if AD classification could be further improved by combining multifractal features with traditional features in this field. Rs-fMRI data of 25 AD patients and 38 normal controls were analyzed. A set of multifractal features were systematically investigated. Traditional features in monofractal, linear, and network-based categories were also extracted for comparison and combination. Both support vector machines and multiple kernel learning (MKL) were used to perform classification with individual and combined features. We identified a multifractal feature, Δf, which has the strongest discriminative power among all the features in our study. Moreover, we found that the classification accuracy could be significantly improved from 69% (by Δf only) to up to 76%, when nonsparse MKL is used to combine Δf with the monofractal feature, Hurst. Finally, we showed that incorporating other multifractal features, α(0), Δα and Pc, could also improve traditional-feature-based AD classification. Our work demonstrated the potential usefulness of multifractal analysis for AD research, especially when combining with the traditional rs-fMRI features. It contributes to distinguishing AD from NC subjects. Magn Reson Med 76:259-269, 2016. © 2015 Wiley Periodicals, Inc.

Executive functioning and risk for Alzheimer's disease in the cognitively intact: Family history predicts Wisconsin Card Sorting Test performance.

Alzheimer's disease (AD) research typically focuses on memory. However, executive functioning (EF) deficits are also common among AD patients; these deficits are associated with decreased functioning in activities of daily living, an important criterion in diagnosing AD. A classic test of EF ability, the Wisconsin Card Sort Test (WCST), has demonstrated sensitivity to differentiating individuals with AD from healthy controls, discriminating AD groups based on disease severity, and distinguishing AD from other types of dementia. Such sensitivity to AD raises the possibility that the WCST is also sensitive to very early, preclinical differences between those who have heightened risk for AD and those with lower risks. The current study, therefore, examined WCST performance in healthy, cognitively intact older adults with a first-degree (i.e., sibling or parent) family history (FH) of AD (n = 18) and those with no such FH of AD (n = 24). Results revealed significant group differences for Categories Achieved, Percent Conceptual Level Responses, Total Errors, Perseverative Errors, and Non-Perseverative Errors, with the FH+ group consistently exhibiting poorer performance. Moreover, hierarchical regression analyses indicated that after accounting for age, sex, and education, FH significantly predicted all 5 of these variables. These results speak to the potential role of EF in bolstering the current understanding of early cognitive markers of future decline. Furthering what is known about the relationship between AD and nonmemory specific domains of cognition such as executive functioning may allow for better prediction of cognitive decline and potential progression to AD.

Florbetapir positron emission tomography and cerebrospinal fluid biomarkers

BackgroundWe evaluated the relationship between florbetapir-F18 positron emission tomography (FBP PET) and cerebrospinal fluid (CSF) biomarkers. MethodsAlzheimer's Disease Neuroimaging Initiative-Grand Opportunity and Alzheimer's Disease Neuroimaging Initiative 2 (GO/2) healthy control (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia subjects with clinical measures and CSF collected ±90 days of FBP PET data were analyzed using correlation and logistic regression. ResultsIn HC and MCI subjects, FBP PET anterior and posterior cingulate and composite standard uptake value ratios correlated with CSF amyloid beta (Aβ1–42) and tau/Aβ1–42 ratios. Using logistic regression, Aβ1–42, total tau (t-tau), phosphorylated tau181P (p-tau), and FBP PET composite each differentiated HC versus AD. Aβ1–42 and t-tau distinguished MCI versus AD, without additional contribution by FBP PET. Total tau and p-tau added discriminative power to FBP PET when classifying HC versus AD. ConclusionBased on cross-sectional diagnostic groups, both amyloid and tau measures distinguish healthy from demented subjects. Longitudinal analyses are needed.

Visuoperception test predicts pathologic diagnosis of Alzheimer disease in corticobasal syndrome.

To use the Visual Object and Space Perception Battery (VOSP) to distinguish Alzheimer disease (AD) from non-AD pathology in corticobasal syndrome (CBS). This clinicopathologic study assessed 36 patients with CBS on the VOSP. All were autopsied. The primary dependent variable was a binary pathologic outcome: patients with CBS who had primary pathologic diagnosis of AD (CBS-AD, n = 10) vs patients with CBS without primary pathologic diagnosis of AD (CBS-nonAD, n = 26). We also determined sensitivity and specificity of individual VOSP subtests. Patients with CBS-AD had younger onset (54.5 vs 63.6 years, p = 0.001) and lower memory scores on the Mattis Dementia Rating Scale-2 (16 vs 22 points, p = 0.003). Failure on the VOSP subtests Incomplete Letters (odds ratio [OR] 11.5, p = 0.006), Position Discrimination (OR 10.86, p = 0.008), Number Location (OR 12.27, p = 0.026), and Cube Analysis (OR 45.71 p = 0.0001) had significantly greater odds of CBS-AD than CBS-nonAD. These associations remained when adjusting for total Mattis Dementia Rating score, disease laterality, education, age, and sex. Receiver operating characteristic curves demonstrated significant accuracy for Incomplete Letters and all VOSP spatial subtests, with Cube Analysis performing best (area under the curve 0.91, p = 0.0004). In patients with CBS, failure on specific VOSP subtests is associated with greater odds of having underlying AD. There may be preferential involvement of the dorsal stream in CBS-AD. This study provides Class II evidence that some subtests of the VOSP accurately distinguish patients with CBS-AD from those without AD pathology (e.g., Cube Analysis sensitivity 100%, specificity 77%).

Regional Magnetic Resonance Imaging Measures for Multivariate Analysis in Alzheimer’s Disease and Mild Cognitive Impairment

Automated structural magnetic resonance imaging (MRI) processing pipelines are gaining popularity for Alzheimer’s disease (AD) research. They generate regional volumes, cortical thickness measures and other measures, which can be used as input for multivariate analysis. It is not clear which combination of measures and normalization approach are most useful for AD classification and to predict mild cognitive impairment (MCI) conversion. The current study includes MRI scans from 699 subjects [AD, MCI and controls (CTL)] from the Alzheimer’s disease Neuroimaging Initiative (ADNI). The Freesurfer pipeline was used to generate regional volume, cortical thickness, gray matter volume, surface area, mean curvature, gaussian curvature, folding index and curvature index measures. 259 variables were used for orthogonal partial least square to latent structures (OPLS) multivariate analysis. Normalisation approaches were explored and the optimal combination of measures determined. Results indicate that cortical thickness measures should not be normalized, while volumes should probably be normalized by intracranial volume (ICV). Combining regional cortical thickness measures (not normalized) with cortical and subcortical volumes (normalized with ICV) using OPLS gave a prediction accuracy of 91.5 % when distinguishing AD versus CTL. This model prospectively predicted future decline from MCI to AD with 75.9 % of converters correctly classified. Normalization strategy did not have a significant effect on the accuracies of multivariate models containing multiple MRI measures for this large dataset. The appropriate choice of input for multivariate analysis in AD and MCI is of great importance. The results support the use of un-normalised cortical thickness measures and volumes normalised by ICV.

Volumetric and visual rating of magnetic resonance imaging scans in the diagnosis of amnestic mild cognitive impairment and Alzheimer's disease

BackgroundIn the diagnosis of Alzheimer's disease (AD), structural magnetic resonance imaging (MRI) scans have been used primarily to exclude non‐Alzheimer's causes of dementia. However, the pattern and the extent of medial temporal atrophy on structural MRI scans, which correlate strongly with the pathological severity of AD, can be used to support the diagnosis of a degenerative dementia, especially AD, even in its early predementia stage.MethodsElderly subjects (n = 224) were diagnosed with either no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI), or AD. Hippocampal and hemispheric gray matter volumes were measured on structural MRI scans, and a new visual rating system was used to score the severity of medial temporal atrophy (VRS‐MTA) of the hippocampus (HPC), entorhinal cortex, and perirhinal cortex on a coronal image intersecting the mammillary bodies.ResultsAlthough both VRS‐MTA scores and HPC volumes distinguished between subjects with NCI, aMCI, and AD, subjects with aMCI and NCI could be better distinguished using right VRS‐MTA scores, in comparison with right HPC volumes. VRS‐MTA scores were more highly correlated with episodic memory and Clinical Dementia Rating scores. A combination of left sided VRS‐MTA scores and left sided hippocampal volume was the most predictive measure of diagnostic classification.ConclusionVRS‐MTA is a clinically convenient method or distinguishing aMCI or AD from NCI. As compared with volumetric measures, it provides better discriminatory power and correlates more strongly with memory and functional scores.

Regional coherence evaluation in mild cognitive impairment and Alzheimer's disease based on adaptively extracted magnetoencephalogram rhythms

This study assesses the connectivity alterations caused by Alzheimer's disease (AD) and mild cognitive impairment (MCI) in magnetoencephalogram (MEG) background activity. Moreover, a novel methodology to adaptively extract brain rhythms from the MEG is introduced. This methodology relies on the ability of empirical mode decomposition to isolate local signal oscillations and constrained blind source separation to extract the activity that jointly represents a subset of channels. Inter-regional MEG connectivity was analysed for 36 AD, 18 MCI and 26 control subjects in δ, θ, α and β bands over left and right central, anterior, lateral and posterior regions with magnitude squared coherence—c(f). For the sake of comparison, c(f) was calculated from the original MEG channels and from the adaptively extracted rhythms. The results indicated that AD and MCI cause slight alterations in the MEG connectivity. Computed from the extracted rhythms, c(f) distinguished AD and MCI subjects from controls with 69.4% and 77.3% accuracies, respectively, in a full leave-one-out cross-validation evaluation. These values were higher than those obtained without the proposed extraction methodology.

Free and Cued Selective Reminding Identifies Very Mild Dementia in Primary Care

The Free and Cued Selective Reminding Test (FCSRT) is used widely to identify very mild dementia; 3 alternative scoring procedures have been proposed based on free recall, total recall, and cue efficiency. We compared the predictive validity of these scoring procedures for the identification of very mild prevalent dementia (CDR=0.5), of incident dementia, and for distinguishing Alzheimer Disease (AD) and nonAD dementias. We tested 244 elderly African American and White primary care patients at 18 month intervals using a screening neuropsychologic battery that included the FCSRT and a comprehensive diagnostic neuropsychologic battery. Median follow-up was 2.6 years. Dementia diagnoses were assigned using standard criteria without access to the results of the screening battery. There were 50 prevalent and 28 incident dementia cases. At scores selected to provide specificities of 90%, free recall was more sensitive to incident and prevalent dementia than the other 2 measures. Patients with impaired free recall were 15 times more likely to have a prevalent dementia and their risk of future dementia was 4 times higher than patients with intact free recall. Neither race nor education affected prediction although older patients were at increased risk of future dementia. Total recall was more impaired in AD dementia than in nonAD dementias. The results indicate that using the FCSRT, free recall is the best measure for detecting prevalent dementia and predicting future dementia. Total recall impairment supports the diagnosis of AD rather than nonAD dementia.

New Imaging Technique May Distinguish Alzheimer Disease from Other Dementias

New Imaging Technique May Distinguish Alzheimer Disease from Other Dementias

CSF Studies Facilitate DNA Diagnosis in Familial Alzheimer's Disease Due to a Presenilin-1 Mutation

In sporadic Alzheimer's disease (AD), cerebrospinal fluid (CSF) analysis is becoming increasingly relevant to establish an early diagnosis. We present a case of familial AD due to a presenilin-1 mutation in which CSF studies suggested appropriate DNA diagnostics. A 38 year old Dutch man presented with dementia, spastic paraparesis, and frontal executive function impairments, mimicking familial Creutzfeldt Jakob disease and frontotemporal dementia. CSF studies, revealing increased total tau and phosphorylated-tau levels with decreased amyloid-beta42, distinguished familial AD from Creutzfeldt Jakob disease and frontotemporal dementia. A causative p.L424R PSEN1 mutation was subsequently identified.

Lateralization of 17Beta-Hydroxysteroid Dehydrogenase Type 10 in Hippocampi of Demented and Psychotic People

Objective: The multifunctional mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 could play a role in the development of Alzheimer disease via its high-affinity binding to amyloid-β peptides and its overexpression. Methods: We evaluated the specificity of alterations in mRNA/enzyme expression levels in human right and left hippocampi. Results: We observed a trend towards right/left laterality in nondemented nonpsychotic controls; however, the degree of asymmetry was higher for mRNA when compared to enzyme expression levels. In Alzheimer disease and schizophrenia, significant shifts to left/right asymmetry were found and the changes were associated with more marked increases in mRNA/enzyme expression in the left hemisphere. On the other hand, no alterations were observed in people with multi-infarct dementia. Conclusion: Our results support studies reporting an impairment of mitochondria in Alzheimer disease or schizophrenia and a higher vulnerability of the dominant hemisphere to pathological processes. Overexpression of the enzyme could be used to distinguish Alzheimer disease from multi-infarct dementia.

A comparison of 99mTc-exametazime and 123I-FP-CIT SPECT imaging in the differential diagnosis of Alzheimer's disease and dementia with Lewy bodies

The aim of this study is to investigate the diagnostic value of perfusion 99mTc-exametazime single photon emission computed tomography (SPECT) in the diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) in comparison with dopaminergic 123I-2beta-carbomethoxy-3beta-(4-iodophenyl)-n-(3-fluoropropyl) nortropane (FP-CIT) SPECT imaging. Subjects underwent 99mTc-exametazime scanning (39 controls, 36 AD, 30 DLB) and 123I-FP-CIT scanning (33 controls, 33 AD, 28 DLB). For each scan, five raters performed visual assessments blind to clinical diagnosis on selected transverse 99mTc-exametazime images in standard stereotactic space. Diagnostic accuracy of 99mTc-exametazime was compared to 123I-FP-CIT results for the clinically relevant subgroups AD and DLB using receiver operating characteristic (ROC) curve analysis. Inter-rater agreement for categorizing uptake was "moderate" (mean kappa = 0.53) for 99mTc-exametazime and "excellent" (mean kappa = 0.88) for 123I-FP-CIT. For AD and DLB, consensus rating matched clinical diagnosis in 56% of cases using 99mTc-exametazime and 84% using 123I-FP-CIT. In distinguishing AD from DLB, ROC analysis revealed superior diagnostic accuracy with 123I-FP-CIT (ROC curve area 0.83, sensitivity 78.6%, specificity 87.9%) compared to occipital 99mTc-exametazime (ROC curve area 0.64, sensitivity 64.3%, specificity 63.6%) p = 0.03. Diagnostic accuracy was superior with 123I-FP-CIT compared to 99mTc-exametazime in the differentiation of DLB from AD.

Lack of association between interleukin-1alpha polymorphism and Alzheimer disease or vascular dementia.

Recently, a C/T polymorphism in the promoter region of the interleukin 1-alpha (IL-1alpha) gene (position -889) was reported to be associated with Alzheimer disease. In this study, the polymorphism of IL-1alpha was examined in patients with Alzheimer disease, vascular dementia, and nondemented controls in a Chinese population in Taiwan. No difference was found in the IL-1alpha T allele frequency among the three groups. The predominant polymorphic allele ( approximately 90%) of IL-1alpha was the C allele. The APOE4 allele was overrepresented in the AD cohort. The presence of the APOE4 allele did not influence the IL-1alpha genotype or allele distribution. The prevalence of the IL-1alpha T allele, in particular the homozygous form, was lower than in whites and may account for the lack of association between IL-1alpha C/T polymorphism and Alzheimer disease among Chinese in Taiwan. The presence of the heterozygous IL-1alpha T allele cannot be used for distinguishing Alzheimer disease or vascular dementia from controls.

INCREASED OXIDATIVE DAMAGE IN LYMPHOCYTES OF ALZHEIMER'S DISEASE PATIENTS

Journal of the American Geriatrics SocietyVolume 45, Issue 12 p. 1536-1537 Free Access INCREASED OXIDATIVE DAMAGE IN LYMPHOCYTES OF ALZHEIMER'S DISEASE PATIENTS First published: 27 April 2015 https://doi.org/10.1111/j.1532-5415.1997.tb03212.xCitations: 2AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat To the Editor: Oxidative stress has been involved in the pathogenesis of several neurodegenerative diseases. Free radicals can damage cellular structures reacting with lipids, proteins, and nucleic acids. 8-hydroxy-2′-deoxyguanosine (8-OHdG) is a reliable marker of oxidative DNA modification. High levels of 8-OHdG were found in lymphocytes or mononuclear cells of subjects suffering from different autoimmune diseases1 or diabetes.2 In a previous study,3 we found a marked increase of nuclear and mitochondrial 8-OHdG in brains of Alzheimer disease (AD) patients compared with normal aged subjects. In order to further evaluate the presence of oxidative damage in AD, we measured 8-OHdG in lymphocytes obtained from 12 AD patients (mean age ± SD 73.3 ± 6.0) and 12 normal controls (mean age ± SD 75.8 ± 6.4). Ten milliliters of heparinized blood was layered on Lymphoprep (Nycomed) and centrifuged at 800 g. Nuclear DNA was extracted from pelleted lymphocytes after osmotic lysis of red blood cells and washing with saline. 8-OHdG was measured by means of HPLC with electrochemical detection as previously reported.3 A significantly higher content of 8-OHdG, expressed as fmol/μg DNA, was found in lymphocytes of AD patients (40.4 ± 12.2; range 24.9-59.8) compared with controls (23.7 ± 7.2; range 14.0 −35.2) (P < .001) (Figure 1). This finding might reflect an imbalance between oxidants and antioxidants4 or a defective DNA repair.5 The high levels of 8-OHdG both in brain tissue and in lymphocytes support the view of AD as a systemic disease whose alterations, although prominent in the central nervous system, also involve other tissues. Therefore, a greater effort in studying peripheral alterations in AD is advisable. Figure 1Open in figure viewerPowerPoint Scattergram of 8-OHdG content, expressed as fmol/μg DNA, in control and AD lymphocytes. REFERENCES 1 Bashir S, Harris G, Denman MA et al. Oxidative damage and cellular sensitivity to oxidative stress in human autoimmune diseases. Ann Rheum Dis 1993; 52: 659– 666. CrossrefCASPubMedWeb of Science®Google Scholar 2 Dandona P, Thusu K, Cook S, et al. Oxidative damage to DNA in diabetes mellitus. Lancet 1996; 347: 444– 445. CrossrefCASPubMedWeb of Science®Google Scholar 3 Mecocci P, MacGarvey U, Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann Neurol 1994; 36: 747– 751. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 4 Beal MF. Aging, energy and oxidative stress in neurodegenerative diseases. Ann Neurol 1995; 38: 357– 366. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 5 Parshad R, Sanford KK, Price FM et al. Fluorescent light-induced chromatid breaks distinguish Alzheimer disease cells from normal cells in tissue culture. Proc Natl Acad Sci USA 1996; 93: 5146– 5150. CrossrefCASPubMedWeb of Science®Google Scholar Citing Literature Volume45, Issue12December 1997Pages 1536-1537 FiguresReferencesRelatedInformation

Meta-analysis of the Hachinski Ischemic Score in pathologically verified dementias.

Our objectives were to investigate the utility of the Hachinski Ischemic Score (HIS) in differentiating patients with pathologically verified Alzheimer's disease (AD), multi-infarct dementia (MID), and "mixed" (AD plus cerebrovascular disease) dementia, and to identify the specific items of the HIS that best discriminate those dementia subtypes. Investigators from six sites participated in a meta-analysis by contributing original clinical data, HIS, and pathologic diagnoses on 312 patients with dementia (AD, 191; MID, 80; and mixed, 41). Sensitivity and specificity of the HIS were calculated based on varied cutoffs using receiver-operator characteristic curves. Logistic regression analyses were performed to compare each pair of diagnostic groups to obtain the odds ratio (OR) for each HIS item. The mean HIS (+/- SD) was 5.4 +/- 4.5 and differed significantly among the groups (AD, 3.1 +/- 2.5; MID, 10.5 +/- 4.1; mixed, 7.7 +/- 4.3). Receiver-operator characteristic curves showed that the best cutoff was < or = 4 for AD and > or = 7 for MID, as originally proposed, with a sensitivity of 89.0% and a specificity of 89.3%. For the comparison of MID versus mixed the sensitivity was 93.1% and the specificity was 17.2%, whereas for AD versus mixed the sensitivity was 83.8% and the specificity was 29.4%. HIS items distinguishing MID from AD were stepwise deterioration (OR, 6.06), fluctuating course (OR, 7.60), hypertension (OR, 4.30), history of stroke (OR, 4.30), and focal neurologic symptoms (OR, 4.40). Only stepwise deterioration (OR, 3.97) and emotional incontinence (OR, 3.39) distinguished MID from mixed, and only fluctuating course (OR, 0.20) and history of stroke (OR, 0.08) distinguished AD from mixed. Our findings suggest that the HIS performed well in the differentiation between AD and MID, the purpose for which it was originally designed, but that the clinical diagnosis of mixed dementia remains difficult. Further prospective studies of the HIS should include additional clinical and neuroimaging variables to permit objective refinement of the scale and improve its ability to identify patients with mixed dementia.

Fluorescent light-induced chromatid breaks distinguish Alzheimer disease cells from normal cells in tissue culture.

The neurodegeneration and amyloid deposition of sporadic Alzheimer disease (AD) also occur in familial AD and in all trisomy-21 Down syndrome (DS) patients, suggesting a common pathogenetic mechanism. We investigated whether defective processing of damaged DNA might be that mechanism, as postulated for the neurodegeneration in xeroderma pigmentosum, a disease with defective repair not only of UV radiation-induced, but also of some oxygen free radical-induced, DNA lesions. We irradiated AD and DS skin fibroblasts or blood lymphocytes with fluorescent light, which is known to cause free radical-induced DNA damage. The cells were then treated with either beta-cytosine arabinoside (araC) or caffeine, and chromatid breaks were quantified. At least 28 of 31 normal donors and 10 of 11 donors with nonamyloid neurodegenerations gave normal test results. All 12 DS, 11 sporadic AD, and 16 familial AD patients tested had abnormal araC and caffeine tests, as did XP-A cells. In one of our four AD families, an abnormal caffeine test was found in all 10 afflicted individuals (including 3 asymptomatic when their skin biopsies were obtained) and in 8 of 11 offspring at a 50% risk for AD. Our tests could prove useful in predicting inheritance of familial AD and in supporting, or rendering unlikely, the diagnosis of sporadic AD in patients suspected of having the disease.