Background and Purpose-One possible mechanism of cognitive decline in individuals with subcortical vascular disease is disruption of cholinergic fibers by ischemic lesions, such as strategically located white matter hyperintensities (WMH). The authors applied a new MRI visual rating scale to assess WMH within cholinergic pathways in patients with Alzheimer Disease (AD) and subcortical ischemic microvascular disease. Methods-Subjects included 60 AD patients with and without WMH, matched for age, as well as 15 control subjects. A visual rating scale was developed based on published immunohistochemical tracings of the cholinergic pathways in humans. On 4 selected axial images, the severity of WMH in the cholinergic pathways was rated on a 3-point scale for ten regions, identified with major anatomical landmarks. A published, consensus-derived, general WMH scale was also applied. All subjects underwent standardized neuropsychological testing. Results-The Cholinergic Pathways HyperIntensities Scale showed reliability and was validated with volumetry of strategic WMH. After accounting for age and education in a multiple linear regression model, The Cholinergic Pathways HyperIntensities Scale ratings were associated with impaired performance on the Mattis Dementia Rating Scale (rϭ0.40; Pϭ0.02) and accounted for 12% of the variance (corrected r 2 ). A similar model was not significant for general WMH scores. Conclusions-The

In addition to the well-documented physical and mental health risks associated with caregiving, this study adds to a small body of literature demonstrating impaired cognitive functioning among family members providing end-of-life care. Secondary findings of both improvement and deterioration of cognition post caregiving provide tentative support for the possibility of reversing certain cognitive deficits by reducing caregiver stress.

Objective: To investigate changes in cognition, function, and behavior after 1 year in patients with Alzheimer disease being treated with cholinesterase inhibitors, in relation to the presence or absence of subcortical hyperintensities involving the cholinergic pathways. Design:One-year prospective cohort study.Setting: Memory Clinic, Sunnybrook Health Sciences Centre, University of Toronto.Patients: Ninety patients with possible/probable Alzheimer disease who were being treated with cholinesterase inhibitors at baseline.Interventions: Yearly standardized neuropsychological testing and brain magnetic resonance imaging (MRI). The Cholinergic Pathways Hyperintensities Scale (CHIPS) was applied to baseline MRIs to rate the severity of subcortical hyperintensities in cholinergic pathways. The consensus-derived Age-Related White Matter Changes (ARWMC) Rating Scale was used as a general measure of white matter disease burden.Main Outcome Measures: Tests of global cognition, function, and behavior and specific cognitive and functional domains.Results: Patients in the low CHIPS group were equivalent to those in the high CHIPS group with regard to baseline demographic characteristics, cognitive severity, and vascular risk factors. After covarying age and education, no differences were found after 1 year in overall cognition, function, and behavior or on memory, language, and visuospatial tasks. Patients in the high CHIPS group showed improvement on executive function and working memory tasks compared with those in the low CHIPS group. For the ARWMC scale, groups with and without white matter abnormalities were equivalent on baseline demographics and in cognitive, functional, and behavioral outcomes.Conclusion: Cerebrovascular compromise of the cholinergic pathways may be a factor that contributes more selectively than does total white matter lesion burden to response to cholinergic therapy in Alzheimer disease, particularly on frontal/executive tasks.

RÉSUMÉ: Marqueurs cognitifs de la progression de la maladie d'Alzheimer. Cette revue constitue un sommaire de la littérature sur l'utilisation de batteries de tests cognitifs pour suivre la progression de la maladie d'Alzheimer (MA). Les études publiées en anglais ont été identifiées par une recherche PubMed (1983PubMed ( -2004. Elles étaient incluses s'il s'agissait d'études longitudinales sur des patients atteints de MA probable, diagnostiquée selon les critères du National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association ou du Manuel diagnostique et statistique des maladies mentales III/IV; et si la validité et la fiabilité des techniques utilisées pour les évaluations successives étaient bien établies. Les études longitudinales sur la progression de la MA rapportent des taux annuels de progression très variables. Il n'est pas clair si cette observation est attribuable à l'évolution de la maladie chez des sous-groupes de patients ou à des taux de déclin en relation avec les stades de la maladie. Conclusions: Nous suggérons qu'une combinaison de tests cognitifs appropriés à différents stades de la maladie tels le Mattis Dementia Rating Scale et le Severe Impairment Battery, ainsi que des méthodes statistiques appropriées tenant compte de la variabilité individuelle du taux de déclin puissent évaluer la progression de la MA et pourraient être utiles dans les études futures.

Increased carotid intima-media thickness and plaque measurements are indicative of the presence of epicardial coronary stenosis. Plaque burden is a more sensitive imaging biomarker for ruling out significant coronary artery disease, including in younger individuals.

To determine if there are differential treatment effects of second-generation cholinesterase inhibitors over one year, 130 patients (untreated=65, treated=65) meeting NINCDS-ADRDA criteria for mild or moderate probable AD underwent standardized cognitive testing at baseline and 12 months later at a university memory clinic. Patients were followed either prior to or after the availability of treatment and were matched on education and baseline Mini Mental State Examination (MMSE). A detailed medical history evaluation was conducted. In this well matched longitudinal observational cohort study, there were no differences in the prevalence of comorbid illnesses, concomitant medication use or vascular risk factors except for a greater number of treated patients with a previous history of smoking. Separate repeated measures MANCOVAs on the MMSE, Mattis Dementia Rating Scale (DRS), and its 5 subscores (attention, initiation/perseveration, conceptualization, construction and memory) (Bonferroni corrected), after covarying for the effects of smoking, and SSRI use, showed less decline over one year in the treated group in overall cognition and in all subscores of the DRS except for memory (effect sizes 0.5-0.7). Less decline was also seen in the treated group in function and in instrumental and basic activities of daily living as measured with the Disability Assessment for Dementia Scale (DAD) (effect sizes 0.4-0.8). Executive, language and visuospatial functions, rather than memory, appeared to be more amenable to stabilization over one year by cholinesterase inhibitors in AD.

These findings have clinical relevance since functional ability has been increasingly recognized as a key outcome variable in AD treatment. It is also of note that the subscores reflecting executive functioning appear to drive these beneficial differences.

Introduction: Despite widespread use of second-generation cholinesterase inhibitors for the symptomatic treatment of Alzheimer's disease (AD), little is known about the long term effects of cholinergic treatment on global cognitive function and potential specific effects in different cognitive domains. The objectives of this study were to determine the association between cholinergic treatment and global cognitive function over one and two years in a cohort of patients with mild or moderate AD and identify potential differences in domain-specific cognitive outcomes within this cohort. Methods: A cohort of patients meeting the revised National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for mild or moderate AD, including patients both on treatment with a cholinesterase inhibitor and untreated controls (treated = 65, untreated = 65), were recruited from the Cognitive Neurology Clinic at Sunnybrook Health Sciences Centre, as part of the Sunnybrook Dementia Study. Patients were followed for one to two years and underwent standardized neuropsychological assessments to evaluate global and domain-specific cognitive function. Associations between cholinesterase inhibitor use and global and domain-specific cognitive outcome measures at one and two years of follow-up were estimated using mixed model linear regression, adjusting for age, education, and baseline mini mental state examination (MMSE). Results: At one year, treated patients showed significantly less decline in global cognitive function, and treatment and time effects across tests of executive and visuospatial function. At two years, there was a significant trend towards less decline in global cognition for treated patients. Moreover, treated patients showed significant treatment and time effects across tests of executive functioning, memory, and visuospatial function.