Improving CSF biomarker accuracy in predicting prevalent and incident Alzheimer disease.

OBJECTIVE: To investigate factors, including cognitive and brain reserve, which may independently predict prevalent and incident dementia of the Alzheimer type (DAT) and to determine whether inclusion of identified factors increases the predictive accuracy of the CSF biomarkers Aß(42), tau, ptau(181), tau/Aß(42), and ptau(181)/Aß(42). METHODS: Logistic regression identified variables that predicted prevalent DAT when considered together with each CSF biomarker in a cross-sectional sample of 201 participants with normal cognition and 46 with DAT. The area under the receiver operating characteristic curve (AUC) from the resulting model was compared with the AUC generated using the biomarker alone. In a second sample with normal cognition at baseline and longitudinal data available (n = 213), Cox proportional hazards models identified variables that predicted incident DAT together with each biomarker, and the models' concordance probability estimate (CPE), which was compared to the CPE generated using the biomarker alone. RESULTS: APOE genotype including an ε4 allele, male gender, and smaller normalized whole brain volumes (nWBV) were cross-sectionally associated with DAT when considered together with every biomarker. In the longitudinal sample (mean follow-up = 3.2 years), 14 participants (6.6%) developed DAT. Older age predicted a faster time to DAT in every model, and greater education predicted a slower time in 4 of 5 models. Inclusion of ancillary variables resulted in better cross-sectional prediction of DAT for all biomarkers (p < 0.0021), and better longitudinal prediction for 4 of 5 biomarkers (p < 0.0022). CONCLUSIONS: The predictive accuracy of CSF biomarkers is improved by including age, education, and nWBV in analyses.

Alzheimer disease identification using amyloid imaging and reserve variables: proof of concept.

OBJECTIVE: Several factors may influence the relationship between Alzheimer disease (AD) lesions and the expression of dementia, including those related to brain and cognitive reserve. Other factors may confound the association between AD pathology and dementia. We tested whether factors thought to influence the association of AD pathology and dementia help to accurately identify dementia of the Alzheimer type (DAT) when considered together with amyloid imaging. METHODS: Participants with normal cognition (n = 180) and with DAT (n = 25), aged 50 years or older, took part in clinical, neurologic, and psychometric assessments. PET with the Pittsburgh compound B (PiB) tracer was used to measure brain amyloid, yielding a mean cortical binding potential (MCBP) reflecting PiB uptake. Logistic regression was used to generate receiver operating characteristic curves, and the areas under those curves (AUC), to compare the predictive accuracy of using MCBP alone vs MCBP together with other variables selected using a stepwise selection procedure to identify participants with DAT vs normal cognition. RESULTS: The AUC resulting from MCBP alone was 0.84 (95% confidence interval [CI] = 0.73-0.94; cross-validated AUC = 0.80, 95% CI = 0.68-0.92). The AUC for the predictive equation generated by a stepwise model including education, normalized whole brain volume, physical health rating, gender, and use of medications that may interfere with cognition was 0.94 (95% CI = 0.90-0.98; cross-validated AUC = 0.91, 95% CI = 0.85-0.96), an improvement (p = 0.025) over that yielded using MCBP alone. CONCLUSION: Results suggest that factors reported to influence associations between AD pathology and dementia can improve the predictive accuracy of amyloid imaging for the identification of symptomatic AD.

Absence of cognitive impairment or decline in preclinical Alzheimer's disease.

OBJECTIVE: To determine whether clinically nondemented elderly individuals with pathologically confirmed preclinical AD are characterized by cognitive decline as measured by psychometric tests before death. METHODS: Psychometric performance was examined retrospectively in 14 individuals who were nondemented at time of death and grouped in accordance with their neuropathologic findings: 1) Healthy brain (n = 9) was characterized by the absence of senile plaques or by only patchy neocortical deposits of plaques; 2) preclinical AD (n = 5) was characterized by neuritic and diffuse plaques distributed throughout the neocortex. All individuals showed neurofibrillary pathologic change in medial temporal lobe structures. For comparison, we also evaluated 10 individuals who died in the earliest symptomatic stage of dementia of the Alzheimer type (DAT). All individuals had been assessed by clinical and psychometric measures during life. The psychometric measures yielded a standardized factor score that represented global cognitive performance. RESULTS: At the last assessment before death, individuals with very mild DAT were impaired on the factor score and on individual psychometric measures with respect to the nondemented individuals. Those nondemented individuals with preclinical AD did not differ in performance from those with healthy brains. For individuals with at least three psychometric assessments during life, there was no decline in performance for either those with healthy brains (n = 5) or preclinical AD (n = 3), although decline was evident for very mild DAT individuals (n = 5). CONCLUSIONS: Pathologically confirmed preclinical AD is not associated with cognitive impairment or decline, even on measures shown to be sensitive to very mild DAT.

Failure to replicate a protective effect of allele 2 of NACP/alpha-synuclein polymorphism in Alzheimer's disease: an association study.

Recently, a dinucleotide repeat polymorphism was identified in the promoter of the nonamyloid component of plaques (NACP) gene, and it was shown that the NACP allele 2 was significantly associated with healthy elderly control individuals with at least one apolipoprotein E epsilon4 allele, suggesting a protective role for this allele in Alzheimer's disease. We genotyped the same NACP polymorphism in a comparable number of individuals diagnosed with dementia of the Alzheimer's type and in healthy, elderly controls. In our analysis, however, no protective effect for NACP allele 2, or any of the other NACP alleles, was observed.

A prospective study of cognitive function and onset of dementia in cognitively healthy elders.

OBJECTIVE: To examine the earliest cognitive changes associated with the onset of dementia as well as changes associated with normal aging. DESIGN: Longitudinal evaluation of participants with annual clinical and psychometric examinations for up to 15 1/2 years. SETTING AND PARTICIPANTS: Elderly volunteers (n = 82) enrolled with a Clinical Dementia Rating of 0 (cognitively intact) in longitudinal studies. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Clinical Dementia Rating and results of a 1 1/2-hour psychometric battery. RESULTS: As estimated with survival analysis, 40% of participants had a Clinical Dementia Rating greater than 0 (cognitive decline) within 12 years of enrollment; 59% of these were judged to have dementia of the Alzheimer type or incipient dementia. Participants with poorer performance on psychometric testing at enrollment were at higher risk for cognitive decline subsequently. The rate of change in psychometric performance before clinically detectable cognitive change occurred was not significantly different between those who eventually developed dementia and those who remained stable, except for performance on the Logical Memory subtest of the Wechsler Memory Scale. When subtle cognitive decline was clinically detected, however, an abrupt deterioration in performance on independently administered psychometric tests was observed. CONCLUSIONS: Cognitively healthy elderly people maintain stable cognitive performance when measured longitudinally by both careful clinical evaluation and repeated psychometric testing. This stability is maintained unless and until they develop a dementing illness, at which time a sharp decline in performance is observed.

Cerebral amyloid deposition and diffuse plaques in "normal" aging: Evidence for presymptomatic and very mild Alzheimer's disease.

The presence of senile plaques in the neocortex of apparently nondemented elderly persons often is accepted as part of "normal" aging. Alternatively, because cerebral deposition of beta-amyloid may be a key mechanism in the development of Alzheimer's disease (AD), the presence of beta-amyloid-containing plaques may represent very early AD. To examine the relationships of cognitively normal aging, very mild dementia of the Alzheimer type, and the presence of neocortical senile plaques, we performed clinicopathologic correlation in 21 longitudinally studied healthy elderly subjects (84.5 +/- 6.6 years old at death). Nine subjects had strikingly high plaque densities in the neocortex; two of these subjects died of head injury before which there was no evidence of cognitive impairment. The other seven subjects with high plaque densities had clinical evidence for very mild cognitive impairment (Clinical Dementia Rating score of 0.5) at some time during their course and mildly impaired psychometric performance at last assessment before death. The remaining 12 subjects had no clinical or psychometric impairment and had few or no neocortical AD lesions. These results suggest that senile plaques may not be part of normal aging but instead represent presymptomatic or unrecognized early symptomatic AD. The high density of senile plaques (predominately of the diffuse subtype) in the cortex of subjects just at the threshold of detectable dementia is consistent with the hypothesis that beta-amyloid deposition is an initial pathogenetic event in the development of AD.

Randomized trial to determine the optimum level of pouch-anal anastomosis in stapled restorative proctocolectomy.

PURPOSE: This study was undertaken to identify the optimum level of stapled ileal pouch-anal anastomosis. METHOD: A prospective, randomized trial was completed to compare double-stapled ileoanal anastomosis placed at the top of anal columns (high, n = 26) with anastomosis at the dentate line (low, n = 21). RESULTS: There was no significant difference in the overall complication rate between operations (high, n = 7, vs. low, n = 8; P < 0.21). Pouch-anal functional score (scale 0-12; 0 = excellent, 12 = poor) was significantly better in the high anastomosis group (median (range): 2 (1-9) vs. 5.5 (1-12); P < 0.05). Incontinence occurred in only two patients randomized to high anastomosis compared with six in the low anastomosis group. Nocturnal soiling was reported in three patients after high anastomosis and in six patients after dentate line anastomosis. Both operations caused a significant but comparable reduction of maximum and resting pressure (31 percent after high anastomosis (P < 0.05); 23 percent after low anastomosis (P < 0.05)). However, a significant fall in functional length of the anal canal was only seen after a low pouch-anal anastomosis (P < 0.05). CONCLUSION: Stapled pouch-anal anastomosis at the top of anal columns gives better functional results compared with a stapled anastomosis at the dentate line.

Randomized trial of internal anal sphincter plication with pelvic floor repair for neuropathic fecal incontinence.

PURPOSE: This study was designed to examine the role of adjuvant internal anal sphincter plication in women with neuropathic fecal incontinence undergoing pelvic floor repair. METHODS: We completed a randomized trial with symptomatic and physiologic assessment before and after surgery. RESULTS: There was no symptomatic advantage of adding internal sphincter plication; the mean improvement of functional score was 3.61 +/- 1.82 (standard deviation; P < 0.01) following pelvic floor repair alone compared with 2.80 +/- 1.66 (standard deviation; P < 0.01) when adjuvant internal and sphincter plication was added. The addition of internal sphincter plication was associated with a significant fall in maximum anal resting and squeezing pressures (P < 0.01). CONCLUSIONS: Addition of internal sphincter plication is not advised in women with neuropathic fecal incontinence treated by pelvic floor repair.

Scintigraphic defecography: quantitative and dynamic assessment of anorectal function.

PURPOSE: Conventional assessment of anorectal function with defecating videoproctography is semiquantitative and the high radiation exposure precludes prolonged or repeated testing. The aim of this study was to develop a dynamic scintigraphic method of assessing anorectal function. METHODS: Fourteen patients with fecal incontinence, 18 patients with chronic constipation, and 8 control subjects were assessed by scintigraphic defecography. This involves introduction of a technetium-99m-radiolabeled artificial stool into the rectum of the subject and acquisition of gamma camera images during evacuation. RESULTS: Mean evacuation rate was 2.8 percent/second in incontinent patients and 0.9 percent/second in constipated patients (P < 0.001). The mean anorectal angles were 136 degrees and 133 degrees, respectively. There were 18 cases of pelvic floor descent and 6 rectoceles. Scintigraphic defecography provides quantitative information on rectal evacuation. Anorectal angle and pelvic floor movement can be examined. The radiation dose to pelvic organs is significantly less than with videoproctography. CONCLUSION: We believe that scintigraphic defecography is the investigation of choice for objective and dynamic assessment of anorectal function.

Gadolinium enhancement in acute and chronic-progressive experimental allergic encephalomyelitis in the guinea pig.

Magnetic resonance imaging detects blood-brain barrier disruption after gadolinium-DTPA enhancement of central nervous system lesions of multiple sclerosis. Experimental allergic encephalomyelitis has many clinical and pathological features in common with multiple sclerosis including alterations in the integrity of the blood-brain barrier. We have compared T2-weighted cranial MR images with Gd-DTPA dimeglumine-enhanced T1-weighted images of myelin basic protein-induced acute (Days 8-42 postimmunization) and central nervous system-induced chronic-progressive (Days 70-95 postimmunization) forms of experimental allergic encephalomyelitis in the guinea pig. Although animals from both groups had abnormal T2-weighted images, only the myelin basic protein-acute-EAE animals (Days 14-24 postimmunization) showed enhancement on postcontrast MR studies. The different responses of the acute and chronic diseases may result from different immunogens, severity of disease, or different permeability of the blood-brain barrier. Therefore, gadolinium-DTPA-enhanced, T1-weighted MR images distinguish acutely active and chronic inflammatory lesions in experimental allergic encephalomyelitis.

Influence of age on clinical and psychometric assessment of subjects with very mild or mild dementia of the Alzheimer type.

OBJECTIVE: The influence of age on performance on clinical and psychometric assessments is examined in groups of nondemented persons and individuals with either very mild or mild dementia of the Alzheimer type (DAT). DESIGN: Initial clinical and psychometric assessments of persons enrolled in longitudinal studies of DAT and nondemented control subjects. SETTING: Alzheimer's Disease Research Center at Washington University, St Louis, Mo. PARTICIPANTS: Volunteer samples of 108 people (44 men, 64 women) with mild DAT, 61 people (30 men, 31 women) with very mild DAT, and 122 healthy nondemented people (45 men, 77 women) were recruited between 1979 and 1991. Age ranged from 54 to 87 years. Persons with confounding medical, neurologic, or psychiatric disorders were excluded. Dementia severity was staged using the Clinical Dementia Rating scale. MAIN OUTCOME MEASURES: Five brief quantitative clinical tests included in the 90-minute clinician administered protocol, as well as 14 tests included in a 2-hour psychometric test battery. RESULTS: Dementia severity affected performance on all measurements. Age did not influence performance on clinical assessments. There was a significant interaction between age and dementia severity on 10 of 14 psychometric measures. In general, older nondemented individuals performed less well than younger nondemented individuals while older mildly demented persons performed about the same as, or slightly better than, their younger counterparts. CONCLUSIONS: Age does not affect performance on brief clinical assessment instruments. However, age affects psychometric performance differently in cognitively intact persons when compared with persons with DAT. As a result, psychometric differentiation between cognitively normal and demented individuals is more difficult in older populations.

The influence of major depression on clinical and psychometric assessment of senile dementia of the Alzheimer type.

OBJECTIVE: The performance on standard clinical and psychometric assessments of eight elderly individuals with major unipolar depression alone and seven with depression plus mild senile dementia of the Alzheimer type was compared with that of 41 nondepressed subjects suffering from very mild senile dementia of the Alzheimer type, 66 with mild senile dementia of the Alzheimer type, and 83 age-matched subjects without senile dementia. METHOD: Subjects with depression alone, depression plus mild senile dementia of the Alzheimer type, and very mild and mild senile dementia of the Alzheimer type met strict inclusionary and exclusionary criteria. A 90-minute semistructured interview, including several brief standardized clinical scales, was used to assign a Clinical Dementia Rating to each subject according to published guidelines, and each subject was given a 2-hour psychometric test battery. Data were analyzed by one-way multivariate analysis of variance to ascertain if there was an effect of group on clinical and psychometric test scores. RESULTS: The eight depressed subjects without concurrent dementia performed as well as the 83 nondepressed subjects without dementia on most clinical measures; however, their performance on most psychometric measures closely resembled that of the 41 nondepressed subjects with very mild dementia. The performance of the seven subjects with depression plus mild dementia was comparable to that of the 66 nondepressed subjects with mild dementia on most clinical and psychometric measures. CONCLUSIONS: Although depressed subjects performed as well as subjects without dementia on many clinical assessments, psychometric testing was not able to distinguish depressed subjects from those with very mild senile dementia of the Alzheimer type. This demonstrates the need for careful psychiatric evaluation before interpreting deficits on psychometric tests as indicating the presence of very mild senile dementia of the Alzheimer type.

Very mild Alzheimer's disease: informant-based clinical, psychometric, and pathologic distinction from normal aging.

We compare clinicopathologic data from 10 subjects identified in the very mild stage of senile dementia of the Alzheimer type with findings from similar studies in four cognitively normal subjects. We based the diagnosis of very mild dementia in the 10 subjects on informant reports and the judgment of experienced clinicians. Deficits of some psychometric measures of memory, language, and speeded psychomotor performance were observed for these subjects. The histologic markers of Alzheimer's disease, including neurofibrillary tangles and both the "diffuse" and classic subtypes of senile plaques, were present in the neocortex in all 10 subjects but essentially were absent in the four controls. These findings indicate that even "questionable" dementia can be diagnostic for Alzheimer's disease. Furthermore, because truly normal aging may be unaccompanied by neocortical senile plaques and neurofibrillary tangles, the presence of these lesions should suggest the possibility of clinically undetected Alzheimer's disease.

Senile dementia and healthy aging: a longitudinal CT study.

Volumetric indexes of cerebral atrophy obtained by using computed tomography (CT) were measured longitudinally in patients with senile dementia of the Alzheimer type (SDAT) and in healthy elderly control subjects. Measurements were made three times over a 51-month period. Of the original 44 patients with SDAT, five were available for CT examination at the last time of assessment (51 months); in contrast, 41 of the original 58 control subjects were still available for study at 51 months. As a group, scans of SDAT subjects showed greater atrophy than those of control subjects in all volumetric indexes at each time of testing and demonstrated greater progression of atrophy during the study period. However, the overlap of indexes between the patients with SDAT and the control subjects indicates that CT data cannot be used alone to predict the presence or progression of dementia in individual cases.

Clinical and pathological aspects of parkinsonism in Alzheimer's disease. A role for extranigral factors?

To examine the natural history and pathogenesis of parkinsonism in Alzheimer's disease, 44 subjects with clearly established senile dementia of the Alzheimer type were studied during a 66-month period. Sixteen subjects (36%) developed idiopathic parkinsonism, and 12 subjects (27%) developed drug-induced parkinsonism; the chief clinical features of both types were bradykinesia and rigidity, but not resting tremor. The presence of parkinsonism was associated with global (rather than selective) cognitive impairment, as determined by psychometric testing, and with more rapid progression to advanced stages of dementia. The pathological correlates of clinical parkinsonism were heterogeneous in 10 subjects with Alzheimer's disease who were examined post mortem. Coexistent Parkinson's disease was observed in five cases and nonspecific nigral degenerative lesions were present in another three; however, two cases had neither histological changes nor reduced neuronal densities in the substantia nigra. These two cases suggested that extranigral lesions, possibly involving mesocortical dopaminergic pathways, may contribute to the development of parkinsonism in subjects with Alzheimer's disease.

Very mild senile dementia of the Alzheimer type. I. Clinical assessment.

We report a longitudinal study of 16 subjects originally enrolled in the Washington University (St Louis, Mo) Memory and Aging Project with Clinical Dementia Rating (CDR) of "questionable" dementia (CDR 0.5). A 0.5 rating was intended to characterize subjects in whom mild cognitive impairment due to senile dementia of the Alzheimer type was suspected but was insufficient in degree to warrant a diagnosis of definite dementia. Over an 84-month follow-up period, 11 of the 16 subjects either had Alzheimer's disease verified post mortem or had clinically progressed to a more advanced CDR stage in which the dementia was clearly evident. These results suggest that the CDR 0.5 stage likely represents the incipient clinical manifestation of Alzheimer's disease and that the majority of subjects with CDR 0.5 have "very mild senile dementia of the Alzheimer type." Performance on several standard clinical scales was significantly different when comparing a larger sample of controls (n = 83), subjects with CDR 0.5 (n = 41), and subjects with mild senile dementia of the Alzheimer type (score of 1; n = 68).

Evaluating mergers and acquisitions with a purchase investigation.

Mergers and acquisitions are risk transactions. Therefore, a well-planned and executed purchase investigation that considers financial, personnel, legal and risk management, third-party payer, and medical staff issues is imperative. Organizations that can successfully complete a purchase investigation will be able to make better informed, lower risk, financial decisions, and will have a competitive advantage in achieving strategic goals. This article is the third in a series on mergers and acquisitions. Other articles will include legal issues and capital planning.

Mergers and acquisitions: new arrangements in health care. Part 1.

Mergers and acquisitions are assuming a more important role in the healthcare industry today. These transactions require various issues be considered, such as valuation, capital planning, and so forth. In this article, the first in a five-part series on mergers and acquisitions, the fundamental methods and techniques of valuation are discussed. Some of these valuation methods, including comparative market transactions and free cash flow, are explained and examples are used to help potential purchasers and sellers to determine an organization's true value. Other articles in this series will include legal issues, tax implications, purchase investigations, and capital planning for mergers and acquisitions.