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The field of neuromodulation has progressed significantly over the past two decades. It is evident that application of electrical (via tDCS, transcranial direct current stimulation) or magnetic (via rTMS, repetitive transcranial magnetic stimulation) brain stimulation over the skull surface can effect change in brain function, which appears sufficiently robust to have a therapeutic effect. Sometimes the neuromodulation is best coupled with other forms of training or rehabilitation for best efficacy. What are the most promising approaches? What conditions appear to benefit? What are the situations/diseases/ disease states where neuromodulation is sufficiently well-proven now (or may be so in the future) that clinicians should start to consider its use in their psychogeriatric practice? We will review studies showing that tDCS can have a therapeutic effect in dementia, stroke, depression, and a range of other psychiatric conditions. Recent work is showing that with tDCS one can achieve improvement in picture naming, executive function, and memory in Alzheimer Disease and Frontotemporal dementia (Howard Chertkow presentation, Baycrest Health Sciences, Toronto). In stroke rehabilitation, rTMS treatment has been shown to aid in motor and language recovery (Alex Thiel, McGill University). There is now sufficient evidence that tDCS and Magnetic Seizure therapy are beneficial in depression, that these can now become part of the therapeutic armamentarium in selected cases (Jeff Daskalakis, University of Toronto). A range of other neuropsychiatric conditions can also be considered for neuromodulation therapy with rTMS (Daniel Blumberger, University of Toronto, CAMH).By attending this symposium, a physician or health care professional will become familiar with the latest research into neuromodulation and its role in current therapy of neurological and psychiatric diseases.
The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams.
The COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here.
The CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020.
Availability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years.
The magnitude of the problems faced by an aging Canadian society has been clearly identified. Perhaps the single most important problem is the increasing incidence of dementia. Alzheimer's disease (AD) accounts for 50-60% of the dementias in later life within a spectrum of other contributing dementias. Regulatory approval has been given to Acetylcholinesterase inhibitors for the symptomatic treatment of mild to moderate AD, and conditional approval to memantine for the symptoms of moderate to severe AD. There has been no regulatory approval for the treatment of the degenerative dementias beyond AD. The very rapid progress in the past decade in biotechnology and in the molecular biology of the dementias is supporting a new generation of innovative treatment strategies that will more directly target the underlying disease pathogenic mechanisms. Such treatments will foreseeably include immunotherapies, anti-aggregants that may prevent misfolding and deposition of proteins, and neuroregenerative interventions. These Guidelines follow the 2nd Canadian Conference on the Development of Antidementia Therapies, held in 2004, which covered a range of design, methodological and ethical issues facing clinical researchers and regulatory authorities. They are intended to provide a common point of reference and guidance in Canada for therapeutic development of the dementias.
To determine whether clinical data obtained by history and physical examination can predict eventual progression to dementia in a cohort of elderly people with mild cognitive impairment.
A prospective, longitudinal study of a cohort of elderly subjects with amnestic Mild Cognitive Impairment (MCI). Ninety subjects meeting the criteria for amnestic MCI were recruited and followed annually for an average of 3.3 years. Main outcome measure was the development of dementia determined by clinical assessment with confirmatory neuropsychological evaluation.
Fifty patients (56%) developed dementia on follow-up. They were older, had lower Mini-mental status exam (MMSE) scores and a shorter duration of symptoms at the time of first assessment. Multivariate logistic regression analysis identified age at symptom onset as the only clinical parameter which distinguished the group that deteriorated to dementia from the group that did not. The odds ratio for age was 1.1 (confidence interval 1.04 - 1.18).
Patients presenting with amnestic MCI insufficient for the diagnosis of dementia are at high risk of developing dementia on follow-up. In our cohort, 56% were diagnosed with dementia over an average period of 5.9 years from symptom onset. The only clinical predictor for the eventual development of dementia was older age at symptom onset. Clinical features alone were insufficient to predict development of dementia.
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.
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.
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.
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.
The status of Mild Cognitive Impairment (MCI) as a valid construct is controversial. The term encompasses people with heterogeneous clinical profiles, and invites sub-classifications that still require validation. Still, much evidence suggests that, properly selected, many people with MCI - especially Amnestic MCI - are at a high risk of dementia. This paper considers the validity of the construct of MCI as a high-risk state for progression and a target for treatment. We conclude that the status of MCI as an entity remains controversial. On the one hand, it can be argued that the careful section of cases at high risk of developing dementia means that it is a valid target, with the goal being the prevention of dementia. Advocates of this view see a linear progression that they are trying to arrest, but studies have yet to show that this can be done. On the other hand, it can be argued that the patients who progressed did not develop dementia: they actually had a very early form of it. By this view, people without the progressive form will be needlessly exposed to antidementia drugs, and the others should be treated anyway. Why some people progress and others do not is not clear, but the variable rates of progression - between clinic-based and population-based samples and between very similar clinical trials with slightly different inclusion criteria - suggests that MCI is a heterogeneous entity. The phenomenon of slowing or non-progression itself should be investigated, and such investigations likely should extend to people now classified as having mild dementia.
There are five potential major roles for neuroimaging with respect to dementia; 1) as a cognitive neuroscience research tool, 2) for prediction of which normal or slightly impaired individuals will develop dementia and over what time frame, 3) for early diagnosis of Alzheimer's disease (AD) in demented individuals, (sensitivity) and separation of AD from other forms of dementia (specificity), 4) for monitoring of disease progression, and 5) for monitoring response to therapies. Focusing on the last role, no single imaging approach is yet ideal, as all trade-off speed, cost, and accuracy. Functional imaging (SPECT and PET) is best suited to tracking symptomatic therapy response, and anatomic (MRI volumetric) imaging or amyloid PET are more suited to reflect dementia modulation studies. The potential for imaging with respect to pharmacological studies of dementia - to provide surrogate markers for drug studies, to improve diagnosis, to speed evaluation of outcomes, and to decrease sample sizes - is huge. At the present time, however, no single measure has sufficient proven reliability, replicability, or robustness, to replace clinical primary outcome measures.
Amnestic mild cognitive impairment (aMCI) represents a group of individuals who are highly likely to develop Alzheimer's disease (AD). Although aMCI is typically conceptualized as involving predominantly deficits in episodic memory, recent studies have demonstrated that deficits in executive functioning may also be present, and thorough categorization of cognitive functioning in MCI may improve early diagnosis and treatment of AD. We first provide an extensive review of neuropsychology studies that examined executive functioning in MCI. We then present data on executive functioning across multiple sub-domains (divided attention, working memory, inhibitory control, verbal fluency, and planning) in 40 aMCI patients (single or multiple domain) and 32 normal elderly controls (NECs). MCI patients performed significantly worse than NECs in all 5 sub-domains, and there was impairment (>1.0 SD below the mean of NECs) in all sub-domains. Impairment on each test was frequent, with 100% of MCI patients exhibiting a deficit in at least one sub-domain of executive functioning. Inhibitory control was the most frequently and severely impaired. These results indicate that executive dysfunction in multiple sub-domains is common in aMCI and highlights the importance of a comprehensive neuropsychological evaluation for fully characterizing the nature and extent of cognitive deficits in MCI. (JINS, 2012, 18, 541–555)
Semantic deficits have been documented in the prodromal phase of Alzheimer's disease, but it is unclear whether these deficits are associated with non-cognitive manifestations. For instance, recent evidence indicates that cognitive deficits in elders with amnestic mild cognitive impairment (aMCI) are modulated by concomitant depressive symptoms. The purposes of this study were to (i) investigate if semantic memory impairment in aMCI is modulated according to the presence (aMCI-D group) or absence (aMCI group) of depressive symptoms, and (ii) compare semantic memory performance of aMCI and aMCI-D groups to that of patients with late-life depression (LLD). Seventeen aMCI, 16 aMCI-D, 15 LLD, and 26 healthy control participants were administered a semantic questionnaire assessing famous person knowledge. Results showed that performance of aMCI-D patients was impaired compared to the control and LLD groups. However, in the aMCI group performance was comparable to that of all other groups. Overall, these findings suggest that semantic deficits in aMCI are somewhat associated with the presence of concomitant depressive symptoms. However, depression alone cannot account solely for the semantic deficits since LLD patients showed no semantic memory impairment in this study. Future studies should aim at clarifying the association between depression and semantic deficits in older adults meeting aMCI criteria. (JINS, 2011, 17, 865–874)
We investigated the sensitivity of the P300 event-related brain
potential (ERP) recorded during a memory-demanding task to memory
function in subjects with dementia of the Alzheimer's type (DAT),
those with mild cognitive impairment (MCI), and normal elderly
controls. We also explored the ability of neuropsychological (delayed
verbal memory), neuroanatomical (MRI-based hippocampal volume), and
electrophysiological (memory search P300 amplitude) memory measures to
distinguish between the three subject groups using discriminant
function analyses. Fourteen patients with DAT, 16 with MCI, and 15 age-
and education-matched controls were tested. P300 amplitude was reduced
in DAT subjects at all levels of memory load; however, it did not
differ between MCI and control subjects. Delayed verbal memory
performance best discriminated DAT from MCI and control subjects, while
delayed verbal memory and hippocampal volume best discriminated MCI
subjects from controls. These results support the utility of
neuropsychological and neuroanatomical measures in diagnosing dementia
and do not support the notion that P300 amplitude is sensitive to
mild memory dysfunction when measured using the current task.
(JINS, 2004, 10, 200–210.)
Findings of category-specific impairments have suggested that
human semantic memory may be organized around a
living/nonliving dichotomy. In order to assess implicit
memory performance for living and nonliving concepts, one group
of neurologically intact individuals participated in a cross-form
conceptual priming paradigm. In Block 1, pictures primed words
while in Block 2 words were used to prime pictures. Across all
phases of the experiment, subjects decided whether items
represented something which was living or nonliving, and response
times were recorded. Results revealed greater priming for living
concepts across both blocks. Greater priming for living concepts
may have occurred because of increased or prolonged conceptual
activation of these concepts. Results are discussed in the context
of theoretical accounts of the category-specific impairments
observed in brain-damaged populations. (JINS, 2003,
Performance variability on neuropsychological measures is not
a unitary phenomenon, and different measures (consistency,
dispersion, diversity) evaluate separate elements of variability.
It has been suggested that increased variability may be a specific
attribute of frontal lobe pathology. This hypothesis was tested
in 2 matched groups of demented subjects, 8 with dementia of
the Alzheimer type (DAT), 5 with frontal lobe dementia (FLD),
compared with 10 elderly normal controls (ENC). A Stroop test
and Reaction Time measures were administered weekly for 5 weeks
to all subjects. Both measures contained three subtests varying
in degree of complexity. The results from the Stroop task indicated
that the FLD group showed significantly greater variability
on measures of consistency (fluctuations over time) and diversity
(between participant variability) regardless of the complexity
of the subtest. For the Reaction Time subtests, measures of
consistency and diversity showed significantly greater variability
in FLD, but were affected in a different pattern. Greater
variability in terms of consistency of performance was manifested
only in the more attentionally demanding of the Reaction Time
subtests (Choice Reaction Time, CRT). On the measure of diversity,
variable performance was found to be greater on the Simple Reaction
Time (SRT) subtest than on the more effortful CRT. Dispersion
(within participant variability) was only assessed on the reaction
time subtests. The results indicate no significant evidence
for an increase in dispersion for the FLD patients. The hypothesis
that variability will be increased in frontal lobe dementia
is thus confirmed, and the independence of the three forms of
variability measurement is demonstrated in dementia subjects.
(JINS, 2002, 8, 360–372.)
Identification deficits in dementia of the Alzheimer
Type (DAT) often target specific classes of objects, sparing
others. Using line drawings to uncover the etiology of
such category-specific deficits may be untenable because
the underlying shape primitives used to differentiate one
line drawing from another are unspecified, and object form
is yoked to object meaning. We used computer generated
stimuli with empirically specifiable properties in a paradigm
that decoupled form and meaning. In Experiment 1 visually
similar or distinct blobs were paired with semantically
close or disparate labels, and participants attempted to
learn these pairings. By having the same blobs stand for
semantically close and disparate objects and looking at
shape–label confusion rates for each type of set,
form and meaning were independently assessed. Overall,
visual similarity of shapes and semantic similarity of
labels each exacerbated object confusions. For controls,
the effects were small but significant. For DAT patients
more substantial visual and semantic proximity effects
were obtained. Experiment 2 demonstrated that even small
changes in semantic proximity could effect significant
changes in DAT task performance. Labeling 3 blobs with
“lion,” “tiger,” and “leopard”
significantly elevated DAT confusion rates compared to
exactly the same blobs labeled with “lion,”
“tiger,” and “zebra.” In conclusion
both visual similarity and semantic proximity
contributed to the identification errors of DAT patients.
(JINS, 1999, 5, 330–345.)
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