Protocol for the Brain Health Support Program Study of the Canadian Therapeutic Platform Trial for Multidomain Interventions to Prevent Dementia (CAN-THUMBS UP): A Prospective 12-Month Intervention Study.

BACKGROUND/OBJECTIVES: CAN-THUMBS UP is designed as a comprehensive and innovative fully remote program to 1) develop an interactive and compelling online Brain Health Support Program intervention, with potential to positively influence dementia literacy, self-efficacy and lifestyle risk factors; 2) enroll and retain a community-dwelling Platform Trial Cohort of individuals at risk of dementia who will participate in the intervention; 3) support an open platform trial to test a variety of multidomain interventions that might further benefit individuals at risk of dementia. This manuscript presents the Brain Health Support Program Study protocol. DESIGN/SETTING: Twelve-month prospective multi-center longitudinal study to evaluate a fully remote web-based educational intervention. Participants will subsequently be part of a Platform Trial Cohort and may be eligible to participate in further dementia prevention clinical trials. PARTICIPANTS: Three hundred fifty older adults who are cognitively unimpaired or have mild cognitive impairment, with at least 1 well established dementia risk factor. INTERVENTION: Participants engage in the Brain Health Support Program intervention for 45-weeks and complete pre/post intervention measures. This intervention is designed to convey best available evidence for dementia prevention, consists of 181 chapters within 8 modules that are progressively delivered, and is available online in English and French. The program has been developed as a collaborative effort by investigators with recognized expertise in the program's content areas, along with input from older-adult citizen advisors. MEASUREMENTS: This study utilizes adapted remote assessments with accessible technologies (e.g. videoconferencing, cognitive testing via computer and mobile phone, wearable devices to track physical activity and sleep, self-administered saliva sample collection). The primary outcome is change in dementia literacy, as measured by the Alzheimer's Disease Knowledge Scale. Secondary outcomes include change in self-efficacy; engagement using the online program; user satisfaction ratings; and evaluation of usability and acceptance. Exploratory outcomes include changes in attitudes toward dementia, modifiable risk factors, performance on the Neuropsychological Test Battery, performance on self-administered online cognitive assessments, and levels of physical activity and sleep; success of the national recruitment plan; and the distribution of age adjusted polygenic hazard scores. CONCLUSIONS: This fully remote study provides an accessible approach to research with all study activities being completed in the participants' home environment. This approach may reduce barriers to participation, provide an easier and less demanding participant experience, and reach a broader geography with recruitment from all regions of Canada. CAN-THUMBS UP represents a Canadian contribution to the global World-Wide FINGERS program (alz.org/wwfingers).

Donepezil for gait and falls in mild cognitive impairment: a randomized controlled trial.

BACKGROUND AND PURPOSE: Cognitive enhancers are commonly prescribed to people with Alzheimer's disease and related dementias to improve cognition and function. However, their effectiveness for individuals in the pre-stages of dementia, particularly in functional motor outcomes, remains unknown. We aimed to determine the efficacy of donepezil, a cognitive enhancer that improves cholinergic neurotransmission, on gait performance in mild cognitive impairment (MCI). METHODS: This was a double-blind, placebo-controlled trial including 60 older adults with MCI, randomized to receive donepezil (10 mg/daily, maximal dose) or placebo. Primary outcome was gait speed (cm/s) under single and three dual-task conditions (counting backwards by 1 or 7 and naming animals) measured using an electronic walkway. Dual-task gait cost (DTC), a valid measure of motor-cognitive interaction, was calculated as the percentage change between single (S) and dual-task (D) gait speeds: [(S - D)/S] × 100. Secondary outcomes included attention, executive function, balance and falls. RESULTS: After 6 months, the donepezil group experienced an improvement in dual-task gait speed (range 4-11 cm/s), although this was not statistically significant. The donepezil group showed a significant reduction in DTC (improvement) by counting backwards by 1 and 7 compared with placebo (10.25% vs. 1.75%, P = 0.048; 21.38% vs. 14.64%, P = 0.037, intention-to-treat analysis). Per-protocol analyses showed that all three DTCs improved in the donepezil group, along with a non-significant reduction of rate of falls. CONCLUSIONS: Donepezil treatment improved dual-task gait speed and DTC in elderly patients with MCI. Our results support the concept of reducing falls in MCI by targeting the motor-cognitive interface.

An Action Plan to Face the Challenge of Dementia: INTERNATIONAL STATEMENT ON DEMENTIA from IAP for Health.

An international committee set up through the IAP for Health met to develop an action plan for dementia. Comprehensive international and national initiatives should move forward with calls for action that include increased public awareness regarding brain health and dementia, support for a broad range of dementia research objectives, and investment in national health care systems to ensure timely competent person-centred care for individuals with dementia. The elements of such action plans should include: 1) Development of national plans including assessment of relevant lifecourse risk and protective factors; 2) Increased investments in national research programs on dementia with approximately 1% of the national annual cost of the disease invested; 3) Allocating funds to support a broad range of biomedical, clinical, and health service and systems research; 4) Institution of risk reduction strategies; 5) Building the required trained workforce (health care workers, teachers, and others) to deal with the dementia crisis; 6) Ensuring that it is possible to live well with dementia; and 7) Ensuring that all have access to prevention programs, care, and supportive living environments.

Progressive supranuclear palsy in a family with TDP-43 pathology.

UNLABELLED: A member of a family with an autosomal dominant pattern of frontotemporal dementia (FTD) with a TDP-43 pathological substrate in other members and no mutations in FTD-associated genes developed behavioral variant FTD followed by Progressive Supranuclear Palsy. Autopsy revealed a pure tauopathy of PSP pattern. CONCLUSIONS: The findings raise the possibility of shared pathogenic pathways and a proximal genetic abnormality between PSP and FTLD-43.

False recognition in Lewy-body disease and frontotemporal dementia.

The primary goal of this study was to evaluate the false recognition phenomenon in persons with frontotemporal dementia (FTD) and those with Lewy-body disease (LBD). Patients with LBD (n=10) or FTD (n=15) and their corresponding controls (n=30) were subjected to the Deese-Roediger-McDermott (DRM) paradigm to induce false recognition. Patients were first presented with items semantically related to a nonpresented critical target. The critical target was later included in a word list shown to patients to assess level of recognition. Both groups of patients showed a reduced level of false recognition of the critical target when controlling for their overall level of false alarms. This reduction was greater in persons with LBD than in those with FTD. Correlational analyses of performance on neuropsychological tests and the DRM variables indicated that the reduced DRM effect was associated with inhibition deficits in patients with LBD and with inhibition deficits and verbal memory in those with FTD. Our results support current models suggesting that these cognitive components contribute to the false recognition effect.

The semantic category effect increases with worsening anomia in Alzheimer's type dementia.

A large number of patients (n=72) with probable Alzheimer's type dementia (DAT) and mild cognitive impairment (MCI) carried out a picture naming task which comprised stimuli from biological and nonbiological categories. The results were stratified into five ranges of overall naming ability. Every group except those with scores within the range of elderly normal individuals demonstrated better nonbiological naming than biological naming, an effect which increased with worsening impairment. In general, patients diagnosed with other dementia (n=15) did not fit well within the pattern of the DAT/MCI participants, except those known to have a significant semantic impairment. A category effect favoring nonbiological items appears to be robust and produce a predictable pattern across progressive levels of impairment in AD.

Dissociable brain regions process object meaning and object structure during picture naming.

Although imaging studies have indicated that the fusiform gyrus is important in tasks of picture naming, whether this region encodes an object's structure or its meaning is not clear. We used positron emission tomography to examine cerebral blood flow (CBF) changes in response to a picture naming task that varied on two dimensions: familiarity (or difficulty: hard vs easy) and category (tools vs animals). Results show that although familiarity effects are present in the frontal and left lateral posterior temporal cortex, they are absent from the fusiform gyrus. This provides strong evidence that the processing carried out in the fusiform gyrus relates to an object's structure, not to its meaning, and that the left posterior middle temporal gyrus instantiates in part the semantic network that represents the object's meaning.

Normal optic nerve head topography in the early stages of dementia of the Alzheimer type.

In view of the existing controversy as to whether or not the optic nerve head (ONH) is altered in Alzheimer disease, we used modern imaging technology to evaluate the ONH structure in individuals with dementia of the Alzheimer type (DAT). Real-time topographical images of the ONH were obtained with a Heidelberg retina tomograph from individuals in the early stages of DAT and age-matched controls. The various ONH parameters examined in this study did not differ significantly between DAT and age-matched subjects. These results suggest that the deficits in visual function that are known to occur in DAT are not related to ONH structural anomalies, at least in the earlier stages of the disease.

The spectrum of category effects in object and action knowledge in dementia of the Alzheimer's type.

The validity and origin of category effects in the anomia demonstrated by individuals with dementia of the Alzheimer's type (DAT) remains controversial. Twenty DAT subjects were tested with picture naming and semantic association judgment tests. Picture and word stimuli were drawn from biological, nonbiological, and actions-verbs categories, all of equal difficulty and previously normed on elderly controls. DAT subjects made significantly more naming and semantic judgment errors in the biological category than in the nonbiological category. They were relatively more accurate in naming and making judgments for actions-verbs when presented as words or as 5-s animations. When line drawings of actions were shown for naming, performance deteriorated significantly. Converging results from these 2 tasks provide strong evidence for a semantic memory impairment preferentially affecting biological items to a greater extent than nonbiological items or action verbs in DAT.

Neuroretinal function is normal in early dementia of the Alzheimer type.

We recently demonstrated that retinal ganglion cell function, optic nerve head parameters and the retinal nerve fiber layer thickness are not altered in early dementia of the Alzheimer type (DAT). Our current objective was to assess whether the function of cells located more distally in the retina is also unaffected by the disease. We evaluated 23 individuals with early to moderate DAT and 23 healthy age-matched subjects, all displaying clinically normal visual function. Scotopic and photopic flash electroretinograms (fERGs) and oscillatory potentials (OPs) were recorded. The amplitude and latency of the retinal potentials did not differ between DAT and control subjects. Our current results showing normal fERGs and OPs in early DAT indicate that the underlying neurons giving rise to these signals are not impaired by the disease process. These data support and extend our recent findings suggesting that visual deficits in DAT do not stem from neuroretinal dysfunction.

An evaluation of the retinal nerve fiber layer thickness by scanning laser polarimetry in individuals with dementia of the Alzheimer type.

PURPOSE: To determine, using scanning laser polarimetry, whether or not the retinal nerve fiber layer (RNFL) is altered in dementia of the Alzheimer type (DAT). METHODS: Thirty individuals with mild to moderate DAT and 30 healthy age-matched controls participated in the study. Fundus images were acquired with a Nerve Fiber Analyzer. RNFL thickness measurements were obtained under an ellipse located 1.75 disc diameter from the optic nerve head (ONH) center. RESULTS: No differences in RNFL thickness were observed between DAT and healthy subjects. The regional distribution of RNFL thickness was similar between the two test groups, with the RNFL being thickest in the superior and inferior retinal segments relative to the nasal and temporal regions. CONCLUSIONS: Our data indicate that the RNFL is not altered in DAT, at least in the earlier stages of the disease.

Recommendations of the Canadian Consensus Conference on Dementia--dissemination, implementation, and evaluation of impact.

BACKGROUND: Subsequent to the development of consensus statements on a clinical topic, it is vital to establish a plan for dissemination, implementation and evaluation of impact. Consensus statements can be used for both guiding continuing medical education (CME) and producing clinical practice guidelines (CPGs). Insufficient attention to dissemination can lead to a failure to change physician behaviour and improve patient outcomes. METHODS: A plan to disseminate the conclusions of the Canadian Consensus Conference on Dementia (CCCD) was developed. This plan was based on a literature review of CME and CPGs. A Medline search was performed on the dissemination and evaluation of the 1989 Canadian Consensus Conference on the Assessment of Dementia (CCCAD) and other published guides for physicians on dementia care. CCCD dissemination that has occurred to date (June, 2000) was reviewed in this paper. RESULTS: Lectures and unsolicited printed material are weak forms of CME. Small-group interactive CME that provides practice opportunities appears to be the most effective way to change physician behaviour. The ability of CPGs to change physician behaviour is uncertain. It appears that inadequate attention has been placed on CPG dissemination and implementation. The CCCAD had a modest impact on clinical practice in Canada. While dissemination of the conclusions of the CCCD has taken place, evaluation of the impact of the CCCD has yet to be done. Local initiatives utilizing the conclusions of the CCCD are on-going. CONCLUSIONS: Further work is needed on how to optimize the impact of consensus statements and CPGs. While dissemination of the CCCD has occurred, it is currently unknown whether it has led to any change in physician practices.

Assessment of suspected dementia.

At the Second Canadian Consensus Conference on Dementia (CCCD) (February, 1998), a group of neurologists, geriatricians, and psychiatrists met to consider guidelines for evaluation of dementia in Canada. This review paper formed a background paper for their discussion of dementia diagnosis. These experts from across the country concluded that diagnosis of suspected dementia cases continued to rest on skilled clinical assessment. Mental status exam, preferably in some quantifiable form, has become an essential part of the assessment. Selected laboratory tests are advisable in all cases (CBC, TSH, electrolytes, calcium, and glucose), but the CCCD continued to advise that CT scanning was mandatory only in selected cases where clinical findings pointed to another possibility besides Alzheimer's disease. The growing list of other diagnostic measures with potential usefulness in diagnosis of Alzheimer's disease or dementia in general was reviewed, but the evidence was judged as insufficient to support routine use of these tests by physicians. As new treatments for Alzheimer's disease become available, neurologists face new diagnostic challenges--differentiating Mild Cognitive Impairment, Frontotemporal dementias and Mixed dementias, and Lewy Body Dementia. Guidelines to aid in differential diagnosis are presented.

The impact of semantic impairment on word stem completion in Alzheimer's disease.

Both the extent of semantic memory impairment and the level of processing attained during encoding might constitute critical factors in determining the amount of word-stem completion (WSC) priming encountered in Alzheimer's disease (AD) subjects. We investigated the impact of varying encoding level in AD and elderly normal subjects, using a set of stimuli ranked as "intact" or "degraded" in terms of each subject's semantic knowledge on probe questions. For both shallow and deep encoding conditions, overall priming in the two subject groups was equivalent. However, for the deep encoding condition, consisting of a semantic judgment task performed on each target word, the priming effect noted in AD subjects was significantly smaller for semantically degraded items than for semantically intact items. Results indicate that the degree of semantic impairment represents one important variable affecting the amount of WSC priming which results when deep encoding procedures are used at study.

Pattern of semantic memory impairment in dementia of Alzheimer's type.

The specific pattern of semantic memory impairment in patients with dementia of Alzheimer's type (DAT) remains unclear. Specifically, the presence of a category-specific deficit for biological concepts (reflected in anomia for these concepts) has been questioned. We studied 9 DAT patients using a semantic association judgement test in which they had to decide which of the two given words was most like a target word (e.g., lamb: goat, sheep). The 150 target words were drawn from 6 categories: animals, clothing and furniture, fruits and vegetables, tools, action verbs, and abstract nouns. Age- and education-matched control subjects performed equivalently (between 86 and 90% correct) in all categories. Compared to control subjects, DAT patients made significantly more errors in abstract and biological nouns, but not in verbs and man-made artifacts. This pattern of semantic memory impairment--a sparing of verbs and a selective deficit of nouns in the biological category--has been documented in patients with temporal lobe damage, suggesting a critical dysfunction in the temporal lobes of DAT.