Vascular retinal biomarkers improves the detection of the likely cerebral amyloid status from hyperspectral retinal images.

INTRODUCTION: This study investigates the relationship between retinal image features and ß-amyloid (Aß) burden in the brain with the aim of developing a noninvasive method to predict the deposition of Aß in the brain of patients with Alzheimer's disease. METHODS: Retinal images from 20 cognitively impaired and 26 cognitively unimpaired cases were acquired (3 images per subject) using a hyperspectral retinal camera. The cerebral amyloid status was determined from binary reads by a panel of 3 expert raters on 18F-florbetaben positron-emission tomography (PET) studies. Image features from the hyperspectral retinal images were calculated, including vessels tortuosity and diameter and spatial-spectral texture measures in different retinal anatomical regions. RESULTS: Retinal venules of amyloid-positive subjects (Aß+) showed a higher mean tortuosity compared with the amyloid-negative (Aß-) subjects. Arteriolar diameter of Aß+ subjects was found to be higher than the Aß- subjects in a zone adjacent to the optical nerve head. Furthermore, a significant difference between texture measures built over retinal arterioles and their adjacent regions were observed in Aß+ subjects when compared with the Aß-. A classifier was trained to automatically discriminate subjects combining the extracted features. The classifier could discern Aß+ subjects from Aß- subjects with an accuracy of 85%. DISCUSSION: Significant differences in texture measures were observed in the spectral range 450 to 550 nm which is known as the spectral region known to be affected by scattering from amyloid aggregates in the retina. This study suggests that the inclusion of metrics related to the retinal vasculature and tissue-related textures extracted from vessels and surrounding regions could improve the discrimination performance of the cerebral amyloid status.

Real-life effectiveness and tolerability of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease: the EMBRACE study.

OBJECTIVE: To assess the real-life effectiveness and tolerability of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease (AD) in Canada. RESEARCH DESIGN AND METHODS: Eighteen-month observational, prospective, multi-center, open-label study conducted on AD patients with Standardized Mini-Mental State Examination (SMMSE) score of 10-26 and Global Deterioration Scale (GDS) score of 4-6. Patients were treated with the rivastigmine transdermal patch (Exelon patch*) 5 cm² (4.6 mg/24 hours) or 10 cm² (9.5 mg/24 hours), once daily. MAIN OUTCOME MEASURES: Primary outcome was change in SMMSE from baseline to 18 months. Secondary outcomes included change in SMMSE at 6 and 12 months and change in GDS, Assessment of Patient Ability (APA-C), Overall Patient Assessment Rating (OPAR), caregiver-reported compliance and treatment satisfaction at 6, 12, and 18 months. RESULTS: Among the 1204 patients enrolled, 969 were included in the ITT analysis. Mean (SD) age was 80.2 (8.00) years, disease duration was 0.6 (1.26) years, 62.0% of patients were women, 80.4% were living in the community, and 69.3% were treatment naïve. Mean (SD) baseline SMMSE and GDS scores were 21.8 (3.98) and 4.2 (0.61), respectively. Over 18 months of treatment there were no clinically significant changes in SMMSE and GDS. The majority of patients showed improvement or no change in GDS, APA-C and OPAR over 18 months. The proportion with reported improvement in GDS, APA-C and OPAR was higher than the proportion that deteriorated. Compliance improved from baseline to 18 months and for 88.2% of patients caregivers preferred the transdermal patch to oral medications. CONCLUSIONS: The rivastigmine transdermal patch is effective in maintaining cognitive function over 18 months of treatment in patients with mild-to-moderate AD. The safety profile was comparable to the data in the Canadian product monograph. Lack of a comparator group is a potential limitation of the study.

Patterns of cortical thinning in Alzheimer's disease and frontotemporal dementia.

In vivo measurement of cortical thickness is a sensitive representation of pathology in neurodegenerative disorders which primarily target the gray mantle. In this study we used magnetic resonance images to describe the patterns of cortical thinning in 11 frontotemporal dementia (FTD), 38 Alzheimer's disease (AD) and 34 healthy elderly (H(E)) subjects. AD and FTD displayed significant thinning of the cortical mantle compared to the H(E) group, but with distinctive distributions. AD subjects had significantly thinner cortex in all lobes whereas FTD compared to H(E) showed significant differences only in specific regions of frontal and temporal lobes. When compared to AD, the FTD subjects had a trend of thinner cortex in the anterior cingulate region and in selective regions of anterior frontal and temporal regions. In conclusion, the cortical thinning in dementia when compared to H(E), is disease specific whereby FTD subjects display a pattern distinct than that seen in Alzheimer's disease.

100 years after Alzheimer: contemporary neurology practice assessment of referrals for dementia.

BACKGROUND: The prevalence of dementia is placing an increased burden on specialists. METHODS: Canadian neurologists responded to a structured questionnaire to assess reasons for referral and services provided as well as to compare the neurologists' perceptions of their practice characteristics against cases seen over a 3-month period. RESULTS: The audit confirmed the participants' perception that family practitioners are the main referral source (358/453, 79%). Sixty-two percent of patients had undergone clinical investigation for dementia prior to being seen by the neurologist; 39% (177/453) were on pharmacotherapy at the time of referral, 68% were initiated on pharmacotherapy by the neurologist. A fifth of the referrals did not meet clinical criteria for dementia, which may be directly related to the prevalence of prior workup that did not include mental status testing. CONCLUSIONS: Neurologists currently treat patients referred for dementia who may already have been adequately evaluated and treated by primary care providers.

Diagnosis and treatment of dementia: 2. Diagnosis.

BACKGROUND: Dementia can now be accurately diagnosed through clinical evaluation, cognitive screening, basic laboratory evaluation and structural imaging. A large number of ancillary techniques are also available to aid in diagnosis, but their role in the armamentarium of family physicians remains controversial. In this article, we provide physicians with practical guidance on the diagnosis of dementia based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006. METHODS: We developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that pertained to key diagnostic issues in dementia. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care. RESULTS: Of the 1591 articles we identified on all aspects of dementia diagnosis, 1095 met our inclusion criteria; 620 were deemed to be of good or fair quality. From a synthesis of the evidence in these studies, we made 32 recommendations related to the diagnosis of dementia. There are clinical criteria for diagnosing most forms of dementia. A standard diagnostic evaluation can be performed by family physicians over multiple visits. It involves a clinical history (from patient and caregiver), a physical examination and brief cognitive testing. A list of core laboratory tests is recommended. Structural imaging with computed tomography or magnetic resonance imaging is recommended in selected cases to rule out treatable causes of dementia or to rule in cerebrovascular disease. There is insufficient evidence to recommend routine functional imaging, measurement of biomarkers or neuropsychologic testing. INTERPRETATION: The diagnosis of dementia remains clinically integrative based on history, physical examination and brief cognitive testing. A number of core laboratory tests are also recommended. Structural neuroimaging is advised in selected cases. Other diagnostic approaches, including functional neuroimaging, neuropsychological testing and measurement of biomarkers, have shown promise but are not yet recommended for routine use by family physicians.

Clinical diagnosis of dementia.

This paper presents recommendations deriving from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, concerning the clinical diagnosis of dementia. There are currently no universally accepted biological or radiological markers of dementia. In the absence of these, the diagnosis of dementia remains a clinical exercise aiming to integrate all available clinical and laboratory information. It is proposed that the currently used National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRA) criteria for diagnosis of Alzheimer's disease (AD) be retained. The currently available vascular dementia (VaD) diagnostic criteria have variable accuracy. An integrative approach to VaD diagnosis based on all the available evidence (history, vascular risk factors, physical exam, clinical course, neuroimaging, cognitive impairment pattern) is recommended. The separation of Lewy body dementia (DLB) from Parkinson's disease dementia (PDD) is based on the dominant clinical presenting feature of each syndrome, and relies on the duration of this feature: long duration of parkinsonian "motor" syndrome preceding dementia for PDD versus early/initial dementia accompanied by extrapyramidal symptoms for DLB. It is recognized that it is impossible clinically to characterize DLB with (pathologically) coexisting AD changes. The Frontotemporal group of dementia syndromes are discussed in regards to their typical clinical pictures, recognizing that their neuropathological substrate are not predictable from their mode of presentation. Finally, the particular rapid time sequence of evolution of the dementias due to prior disease is recognized as the clinically most useful distinguishing feature of these syndromes.

REM sleep behavior disorder and REM sleep without atonia in probable Alzheimer disease.

STUDY OBJECTIVE: To determine the frequency of rapid eye movement (REM) sleep behavior disorder (RBD) and REM sleep without atonia among patients with Alzheimer disease and control subjects. DESIGN: Overnight polysomnography. SETTINGS: Sleep laboratory. PATIENTS: Fifteen patients with probable Alzheimer disease (mean age +/-SD, 70.2+/-5.6) and 15 age-matched healthy control subjects (mean age +/- SD, 67.9 +/-5.4). INTERVENTION: N/A. RESULTS: Four patients with Alzheimer disease presented REM sleep with-out atonia. One of these patients had all the polysomnographic features of RBD, including behavioral manifestations during REM sleep. CONCLUSION: RBD is rare, but REM sleep without atonia is relatively fre-quent in patients with probable Alzheimer disease, a tauopathy.

The contribution of neuropsychiatric symptoms to the cost of dementia care.

OBJECTIVE: To estimate the contribution of behavioral and psychological symptoms of dementia (BPSD) to the costs of care. METHOD: A one-year prospective study of resource utilization recorded monthly by 500 caregivers of community dwelling patients with dementia. The effect of behavior on total, direct and indirect costs of care was examined. RESULTS: The total cost of care was $1,298 per month and there was a significant independent relationship between costs and BPSD. The incremental cost of a one point increase in Neuropsychiatric Inventory score was $30 per month (95% CI: $19-$41). CONCLUSION: BPSD contribute significantly to the overall costs of dementia care. Interventions targeted at BPSD may help to reduce the staggering societal costs of this illness.

Predictors of driving cessation in mild-to-moderate dementia.

BACKGROUND: Although physicians in most provinces are mandated to report patients whose driving ability is impaired by illness, little is known about dementia-related factors associated with driving cessation. The purpose of our study was to explore factors that may affect the likelihood of driving cessation in a sample of elderly, community-dwelling patients with dementia. METHODS: A 3-year prospective study, the Canadian Outcomes Study in Dementia (COSID) has enrolled 883 patients with mild-to-moderate dementia at 32 centres across Canada. Assessment tools included the Mini-Mental State Examination (MMSE) for cognition, the Global Deterioration Scale (GDS) for staging (severity), the Functional Autonomy Measurement System (SMAF) for function, and the Neuropsychiatric Inventory (NPI) for behaviour. Factors associated with the decision to quit driving after the baseline assessment were tested with Cox survival analysis. RESULTS: Of 719 subjects who were or had been drivers, 203 (28.2%) were still driving at baseline. Over an observation period that averaged 23 months, 97 (48.5%) of 200 patients quit driving. Factors predictive of driving cessation included GDS (hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.15-2.45), MMSE score (HR 0.90, 95% CI 0.83-0.97) and NPI findings (HR 1.63 for presence of > or = 3 behaviours, 95% CI 1.01-2.62). Among the NPI behaviours, when they were analyzed separately, agitation led to a decreased likelihood of driving cessation (p = 0.019), whereas apathy (p = 0.031) and hallucinations (p = 0.050) led to an increased likelihood. INTERPRETATION: Cognitive impairment and behaviours such as agitation, apathy and hallucinations were significant predictors of driving cessation in patients with a mild to moderate degree of dementia. These findings should be considered when one counsels patients and their families.

Rivastigmine for dementia associated with Parkinson's disease.

BACKGROUND: Cholinergic deficits are prominent in patients who have dementia associated with Parkinson's disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients. METHODS: Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson's disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer's Disease Cooperative Study-Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini-Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test. RESULTS: A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer's disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01). CONCLUSIONS: In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson's disease but also with higher rates of nausea, vomiting, and tremor.

Canadian Outcomes Study in Dementia: study methods and patient characteristics.

OBJECTIVE: To describe the methods and patient characteristics of the Canadian Outcomes Study in Dementia (COSID). METHODS: COSID is a 3-year prospective study of dementia patients living in the community at the time of study registration. We assessed patients' cognition, behaviour, and functioning every 6 months, using the Modified Mini-Mental State Examination (3MS), the Neuropsychiatric Inventory (NPI), and the Functional Autonomy Measurement System (SMAF), respectively. We assessed caregivers, using the Zarit Burden Interview (ZBI). Additional information included the Global Deterioration Scale (GDS), patients' driving status, and clinical information including family history, dementia type, concomitant medications, and comorbid conditions. From the patient or caregiver, we collected details of inpatient and outpatient resources used by the patient and (or) caregiver. RESULTS: We enrolled 766 patients from 31 Canadian sites. Overall mean age was 76.8 years, and mean age of onset was 73.1 years. Of the total patients, 98% were white, 54% were women, and 84% were diagnosed with Alzheimer's disease. Mean baseline 3MS was 66.5, NPI was 9.5, and SMAF was 18.30. Of these patients, 48% reported a GDS score of 3 (that is, moderate), 16% reported a GDS score of 4 (that is, moderately severe), and the remaining 36% reported a GDS score of 1 or 2 (that is, mild or very mild). At baseline, 83% of patients received cholinesterase inhibitors, 46% received nonsteroidal antiinflammatory drugs, 39% received vitamin E, and 25% received antidepressants. Adult day care and home help were the largest cost factors in this population, with mean monthly costs of $65 and $64, respectively. We found interesting differences in the resources used among geographic regions and care settings. CONCLUSIONS: COSID is already generating valuable information about treatment patterns, outcomes, and resource use in Canadian patients with dementia. As the data mature, it will be possible to build robust models on treatment effectiveness and costs of care.

Potential treatment effects of donepezil not detected in Alzheimer's disease clinical trials: a physician survey.

OBJECTIVES: Clinical trials of the cholinesterase inhibitor donepezil have used standard psychometric tools to evaluate treatment efficacy. These trials, however, appear not to capture clinically demonstrable, but otherwise unmeasured, beneficial treatment effects. We sought to identify and categorize clinically recognizable effects of donepezil treatment in Alzheimer's disease. METHODS: A list of potential effects was developed using clinical trials data and the experience of an expert panel. These were incorporated in a questionnaire, which was tested with a focus group, revised and then used in a postal survey of physicians. Data were classified by cognitive domain, and reviewed by a second panel. RESULTS: Items that were most often rated as being improved were related to frontal systems function, including attentional capacity and initiative. Behavioral symptoms that were among the highest rated items were apathy, mood, and agitation. The top two other items were social interactions and involvement in domestic activities. Of the top ten symptomatic treatment effects, only four appeared to be readily identified by current standard measures. CONCLUSIONS: Physicians recognize as important several treatment effects that are not well captured by current standard measures. New methods are needed to capture such effects, which also have the potential to offer insight into the neurobiology of the human cholinergic system.

Visual retinocortical function in dementia of the Alzheimer type.

BACKGROUND: Some histological investigations have reported anomalies in the primary visual pathways of individuals with dementia of the Alzheimer type (DAT), while others have suggested that these visual structures are spared by the disease process. OBJECTIVES: This study was conducted to address this issue of substantial controversy. We determined in vivo whether DAT alters the functioning of the primary visual pathways by evaluating pattern-reversal electroretinograms (ERGs) and cortical visual evoked potentials (VEPs). METHODS: Twenty-seven individuals with mild to moderate DAT and 27 age- and sex-matched control subjects were included in the investigation. ERG and VEP recordings were obtained from all participants with the use of a clinical electrodiagnostic system. Stimulus conditions were biased towards a preferential response from the magnocellular and parvocellular subdivisions of the visual system. RESULTS: Amplitude and latency of the ERG were not affected by DAT. The VEP amplitude was not attenuated in DAT individuals, but there was a delay in the latency of the VEPs arising from both magnocellular and parvocellular streams of visual processing. CONCLUSION: Our results indicate that while the inner retina appears to be spared by the disease process, the visual function is altered upstream in the retinocortical visual pathways of individuals with DAT.