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 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.

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, 9, 796–805.)

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.)