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1.  Neurology in Canada: History of the Canadian Neurological Society 
Neurology  2013;80(4):406-408.
In the 19th and early 20th century, Canadian physicians interested in neurology focused on this area as part of their broader clinical practices. The most renowned was William Osler, often called Canada's first neurologist because one-third of his writing was devoted to neurology. Until the mid-20th century, most Canadian neurologists trained at the National Hospital, Queen Square, London, and in Paris. The majority returned to academic centers and after World War II every Canadian medical school and major center had consultant neurologists.
doi:10.1212/WNL.0b013e31827f0788
PMCID: PMC3589243  PMID: 23339206
2.  Clinical, imaging, and pathological heterogeneity of the Alzheimer's disease syndrome 
With increasing knowledge of clinical in vivo biomarkers and the pathological intricacies of Alzheimer's disease (AD), nosology is evolving. Harmonized consensus criteria that emphasize prototypic illness continue to develop to achieve diagnostic clarity for treatment decisions and clinical trials. However, it is clear that AD is clinically heterogeneous in presentation and progression, demonstrating variable topographic distributions of atrophy and hypometabolism/hypoperfusion. AD furthermore often keeps company with other conditions that may further nuance clinical expression, such as synucleinopathy exacerbating executive and visuospatial dysfunction and vascular pathologies (particularly small vessel disease that is increasingly ubiquitous with human aging) accentuating frontal-dysexecutive symptomatology. That some of these atypical clinical patterns recur may imply the existence of distinct AD variants. For example, focal temporal lobe dysfunction is associated with a pure amnestic syndrome, very slow decline, with atrophy and neurofibrillary tangles limited largely to the medial temporal region including the entorhinal cortex. Left parietal atrophy and/or hypometabolism/hypoperfusion are associated with language symptoms, younger age of onset, and faster rate of decline - a potential 'language variant' of AD. Conversely, the same pattern but predominantly affecting the right parietal lobe is associated with a similar syndrome but with visuospatial symptoms replacing impaired language function. Finally, the extremely rare frontal variant is associated with executive dysfunction out of keeping with degree of memory decline and may have prominent behavioural symptoms. Genotypic differences may underlie some of these subtypes; for example, absence of apolipoprotein E e4 is often associated with atypicality in younger onset AD. Understanding the mechanisms behind this variability merits further investigation, informed by recent advances in imaging techniques, biomarker assays, and quantitative pathological methods, in conjunction with standardized clinical, functional, neuropsychological and neurobehavioral evaluations. Such an understanding is needed to facilitate 'personalized AD medicine', and eventually allow for clinical trials targeting specific AD subtypes. Although the focus legitimately remains on prototypic illness, continuing efforts to develop disease-modifying therapies should not exclude the rarer AD subtypes and common comorbid presentations, as is currently often the case. Only by treating them as well can we address the full burden of this devastating dementia syndrome.
doi:10.1186/alzrt155
PMCID: PMC3580331  PMID: 23302773
3.  Predictors of Patient Self-Ratings of Quality of Life in Alzheimer’s Disease: Cross-Sectional Results from the Canadian Alzheimer’s Disease Quality of Life (CADQOL) Study 
Objectives
To assess whether the core symptoms of Alzheimer’s disease (AD) consistently predict patient self-rated quality of life (QOL) as assessed by a variety of QOL measures in a large national sample of AD patients.
Design
Cross-sectional.
Setting
Fifteen dementia and geriatric clinics across Canada.
Participants
Community-living patients with AD (n = 370) with Mini-Mental State Examination (MMSE) scores > 10.
Measurements
Patients rated their QOL using two utility indexes, the EQ-5D, the Quality of Well-Being Scale, a global QOL visual analogue scale, and the disease-specific QOL-AD instrument. Cognition was assessed with the AD Assessment Scale-Cognitive subscale and MMSE, function with the Disability Assessment for Dementia, and behavioral and psychological symptoms with the Neuropsychiatric Inventory (NPI) and the Geriatric Depression Scale (GDS). One-way analysis of variance and fully adjusted multiple linear regression were used to assess the relationship between core dementia symptoms and QOL ratings.
Results
The QOL measures had only small to moderate correlations with each other. For all QOL measures, patient ratings were significantly lower among patients with more depressive symptoms. In multivariable analyses, the GDS score was the only significant independent predictor of patient self-ratings for all four QOL measures.
Conclusions
Self-rated symptoms of depression were a consistent independent predictor of patient-rated QOL across diverse QOL measures, while performance-based measures of cognition and informant-based functional status were not. These findings confirm the importance of identifying and treating depression in patients with AD and endorse the use of measures of self-rated depressive symptoms and QOL as outcomes in AD clinical trials.
doi:10.1097/JGP.0b013e3182006a67
PMCID: PMC3267777  PMID: 21946804 CAMSID: cams2069
Alzheimer’s disease; dementia; quality of life; utility; depression
4.  Predictors of Family Caregiver Ratings of Patient Quality of Life in Alzheimer’s Disease: Cross-Sectional Results from the Canadian Alzheimer’s Disease Quality of Life (CADQOL) Study 
Objectives
To assess whether the core symptoms of Alzheimer’s disease (AD) and caregiver factors consistently predict family caregiver ratings of patient quality of life (QOL) as assessed by a variety of QOL measures in a large national sample.
Design
Cross-sectional.
Setting
Fifteen dementia and geriatric clinics across Canada.
Participants
Family caregivers (n = 412) of community-living patients with AD of all severities.
Measurements
Caregiver ratings of patient QOL using three utility indexes, the EQ-5D, Quality of Well-Being Scale and Health Utilities Index, a global QOL visual analogue scale, a disease-specific measure, the QOL-AD, and a generic health status measure, the Short Form-36. Patient cognition was assessed with the AD Assessment Scale-Cognitive Subscale and Mini-Mental State Examination, function with the Disability Assessment for Dementia, and behavioral and psychological symptoms with the Neuropsychiatric Inventory and the Geriatric Depression Scale. Caregiver burden was assessed with the Zarit Burden Interview and caregiver depression with the Center for Epidemiologic Studies-Depression scale. One-way analysis of variance and fully adjusted multiple linear regression were used to assess the relationship between patient dementia symptom and caregiver variables with QOL ratings.
Results
In multivariable analyses, caregiver ratings of patient function and depressive symptoms were the only consistent independent predictors of caregiver-rated QOL across the QOL measures.
Conclusions
Caregiver ratings of patient function and depression were consistent independent predictors of caregiver-rated QOL using a spectrum of QOL measures, while measures of patient cognition and caregiver burden and depression were not. These findings support the continued use of caregiver ratings as an important source of information about patient QOL and endorse the inclusion in AD clinical trials of caregiver-rated measures of patient function, depression and QOL.
doi:10.1097/JGP.0b013e3182006a7f
PMCID: PMC3267778  PMID: 21946805 CAMSID: cams2070
Alzheimer’s disease; dementia; quality of life; utility; family caregiver; depression; function
5.  Delaying the onset of Alzheimer disease 
Neurology  2010;75(19):1726-1729.
Objectives:
There is strong epidemiologic evidence to suggest that older adults who maintain an active lifestyle in terms of social, mental, and physical engagement are protected to some degree against the onset of dementia. Such factors are said to contribute to cognitive reserve, which acts to compensate for the accumulation of amyloid and other brain pathologies. We present evidence that lifelong bilingualism is a further factor contributing to cognitive reserve.
Methods:
Data were collected from 211 consecutive patients diagnosed with probable Alzheimer disease (AD). Patients' age at onset of cognitive impairment was recorded, as was information on occupational history, education, and language history, including fluency in English and any other languages. Following this procedure, 102 patients were classified as bilingual and 109 as monolingual.
Results:
We found that the bilingual patients had been diagnosed 4.3 years later and had reported the onset of symptoms 5.1 years later than the monolingual patients. The groups were equivalent on measures of cognitive and occupational level, there was no apparent effect of immigration status, and the monolingual patients had received more formal education. There were no gender differences.
Conclusions:
The present data confirm results from an earlier study, and thus we conclude that lifelong bilingualism confers protection against the onset of AD. The effect does not appear to be attributable to such possible confounding factors as education, occupational status, or immigration. Bilingualism thus appears to contribute to cognitive reserve, which acts to compensate for the effects of accumulated neuropathology.
GLOSSARY
= Alzheimer disease;
= Mini-Mental State Examination.
doi:10.1212/WNL.0b013e3181fc2a1c
PMCID: PMC3033609  PMID: 21060095
6.  Occupation attributes relate to location of atrophy in frontotemporal lobar degeneration 
Neuropsychologia  2010;48(12):3634-3641.
Frontotemporal lobar degeneration (FTLD) often presents with asymmetric atrophy. We assessed whether premorbid occupations in FTLD patients were associated with these hemispheric asymmetries. In a multi-center chart review of 588 patients, occupation information was related to location of tissue loss or dysfunction. Patients with atrophy lateralized to the right had professions more dependent on verbal abilities than patients with left-lateralized or symmetrical atrophy. In a subgroup of 96 well-characterized patients with quantified neuroimaging data, the lateralization effect was localized to the temporal lobes and included verbal and mathematical ability. Patients whose professions placed high demands on language and mathematics had relatively preserved left temporal relative to right temporal volumes. Thus, occupation selection occurring in early adulthood is related to lateralized brain asymmetry in patients who develop FTLD decades later in the relatively deficient hemisphere. The finding suggests that verbal and mathematical occupations may have been pursued due to developmental right-lateralized functional impairment that precedes the neurodegenerative process. Alternatively, long-term engagement of activities associated with these occupations contributed to left-lateralized reserve, right-lateralized dysfunction, or both.
doi:10.1016/j.neuropsychologia.2010.08.020
PMCID: PMC2957479  PMID: 20800604
Frontotemporal dementia; laterality; reserve
8.  Open-label study of the short-term effects of memantine on FDG-PET in frontotemporal dementia 
Background
Memantine has shown effects on cortical metabolism in Alzheimer’s disease (AD), and the mechanism of action may not be specific to AD alone. We hypothesized that participants with frontotemporal dementia taking memantine would show an increased cortical metabolic activity in frontal regions, temporal regions, or in salience network hubs.
Methods
Sixteen participants with behavioral or language variant frontotemporal dementia syndromes (FTD) were recruited from tertiary FTD clinics and treated with memantine hydrochloride 10 mg twice daily in this fixed-dose, open-label pilot study. The primary endpoint was enhancement of cortical metabolic activity after 7–8 weeks of treatment. Secondary endpoints were measures of mood and behavior disturbance, frontal executive function, and motor disturbance.
Results
Voxel-wise parametric image analysis of positron emission tomography (PET) data from seven behavioral variant FTD patients, eight semantic dementia patients, and one progressive nonfluent aphasia patient, of mean age 64.3 years, mean duration of illness 4.25 years, and baseline mean sum of boxes Clinical Dementia Rating score 6.59, revealed an increase in [18F]-fluorodeoxyglucose (FDG) normalized metabolic activity in bilateral insulae and the left orbitofrontal cortex (P < 0.01). The increase on FDG-PET did not correlate with changes on behavioral inventories. Post hoc analysis indicated that semantic dementia participants drove this finding.
Conclusion
This open-label clinical PET study suggests that memantine induces an increase in metabolism in the salience network in FTD. A placebo-controlled follow-up study is warranted.
doi:10.2147/NDT.S22635
PMCID: PMC3140294  PMID: 21792308
Alzheimer’s disease; frontotemporal dementia; metabolism; PET scan; semantic dementia
9.  Apathy is not Associated with Basal Ganglia Atrophy in Frontotemporal Dementia 
Objective
To determine whether basal ganglia atrophy known to be associated with apathy in non-dementia populations was associated with presence of apathy in patients with frontotemporal dementia (FTD).
Methods
A cross-sectional case study was conducted at two tertiary dementia care clinics in Toronto, Ontario. Striatal and thalamic grey matter volumes and apathy measures were collected from 21 subects with FTD; 6 of whom did not show apathy on the Neuropsychatric Inventory (NPI).
Results
No significant differences in grey matter volumes were found between apathetic and non-apathetic groups for the striatum or for the thalamus.
Conclusions
Our findings imply that the etiology of apathy seen in FTD patients differs from that of patients with apathy after acquired injuries to the basal ganglia. Further study is needed to determine whether posterior thalamic atrophy correlates with apathy in FTD, or functional imaging techniques might successfully find a relationship between basal ganglia dysfunction and apathy.
doi:10.1097/JGP.0b013e3181b047ff
PMCID: PMC2747035  PMID: 19700954
frontotemporal dementia; basal ganglia; apathy; atrophy
10.  Apathy Symptom Profile and Behavioral Associations in Frontotemporal Dementia vs. Alzheimer's Disease 
Archives of neurology  2009;66(7):888-893.
Objective:
Apathy is a very common and significant problem in patients with dementia, regardless of etiology. Observations on frontosubcortical circuit (FSC) syndromes indicate that apathy may have affective, behavioral or cognitive manifestations. We explored whether the apathy manifested in frontotemporal dementia (FTD) with its predominantly anterior brain neuropathology differs from the apathy in Alzheimer's disease (DAT) with its predominantly hippocampal and temporoparietal-based neuropathology. We also sought to determine whether other behavioral disturbances reported in FSC syndromes correlate with apathy.
Design:
Survey. Analyses included individual items within Neuropsychiatric Inventory (NPI) subscale items. Items of the Apathy/Indifference subscale were designated by consensus as: A) affective = lacking in emotions, B) behavioral = inactive, chores abandoned or C) cognitive = no interest in others' activities. Proportions of correlated non-apathy NPI items were calculated and displayed using Chernoff faces to facilitate comparison of apathy domains and dementia diagnoses.
Setting and Patients:
Several neurology specialty clinics contributed to our dataset of 92 participants with FTD and 457 with DAT.
Results:
Apathy was more prevalent in FTD than DAT, but when present, the specific apathy symptoms in both dementias were rarely restricted to one of the three domains of apathy. Dysphoria concurrent with apathy was unique to the DAT group and negatively correlated in FTD. Participants with affective apathy more frequently co-presented with an orbitofrontosubcortical syndrome in FTD (impulsivity and compulsions). Affective apathy also co-presented with uncooperative agitation, anger, and physical agitation in both dementias.
Conclusions:
Apathy is common in FTD and in DAT, although it is more common in FTD. When present, it usually involves changes in affect, behavior, and cognition. It is associated with behaviors that have previously been shown to impact on patient safety, independence and quality of life.
doi:10.1001/archneurol.2009.92
PMCID: PMC2875777  PMID: 19597092
Alzheimer's Disease; Apathy; Frontotemporal Dementia; Frontotemporal Degeneration
11.  Episodic Memory and Regional Atrophy in Frontotemporal Lobar Degeneration 
Neuropsychologia  2007;46(1):127-136.
It has been unclear to what extent memory is affected in frontotemporal lobar degeneration (FTLD). Since patients usually have atrophy in regions implicated in memory function, the frontal and/or temporal lobes, one would expect some memory impairment, and that the degree of atrophy in these regions would be inversely related to memory function. The purposes of this study were 1) to assess episodic memory function in FTLD, and more specifically patients' ability to episodically re-experience an event, and determine its source; 2) to examine whether memory performance is related to quantified regional brain atrophy. FTLD patients (n=18) and healthy comparison subjects (n=14) were assessed with cued recall, recognition, “remember/know” (self-reported re-experiencing) and source recall, at 30 min and 24 hr after encoding. Regional gray matter volumes were assessed with high resolution structural MRI concurrently to testing. Patients performed worse than comparison subjects on all memory measures. Gray matter volume in the left medial temporal lobe was positively correlated with recognition, re-experiencing, and source recall. Gray matter volume in the left posterior temporal lobe correlated significantly with recognition, at 30 min and 24 hr, and with source recall at 30 min. Estimated familiarity at 30 min was positively correlated with gray matter volume in the left inferior parietal lobe. In summary, episodic memory deficits in FTLD may be more common than previously thought, particularly in patients with left medial and posterior temporal atrophy.
doi:10.1016/j.neuropsychologia.2007.08.003
PMCID: PMC2267109  PMID: 17888461
episodic memory; recollection; familiarity; frontotemporal dementia; MRI; temporal lobe; parietal lobe; atrophy
12.  Diagnosis and treatment of dementia: 3. Mild cognitive impairment and cognitive impairment without dementia 
Background
Mild cognitive impairment and cognitive impairment, no dementia, are emerging terms that encompass the clinical state between normal cognition and dementia in elderly people. Controversy surrounds their characterization, definition and application in clinical practice. In this article, we provide physicians with practical guidance on the definition, diagnosis and treatment of mild cognitive impairment and cognitive impairment, no 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 had mild cognitive impairment or cognitive impairment, no dementia, as the outcome. Subsequent to the conference, we searched for additional articles published between January 2006 and January 2008. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care.
Results
We identified 2483 articles, of which 314 were considered to be relevant and of good or fair quality. From a synthesis of the evidence in these studies, we made 16 recommendations. In brief, family physicians should be aware that most types of dementia are preceded by a recognizable phase of mild cognitive decline. They should be familiar with the concepts of mild cognitive impairment and of cognitive impairment, no dementia. Patients with these conditions should be closely monitored because of their increased risk for dementia. Leisure activities, cognitive stimulation and physical activity could be promoted as part of a healthy lifestyle in elderly people and those with mild cognitive impairment. Vascular risk factors should be treated optimally. No other specific therapies can yet be recommended.
Interpretation
Physicians will increasingly see elderly patients with mild memory loss, and learning an approach to diagnosing states such as mild cognitive impairment is now warranted. Close monitoring for progression to dementia, promotion of a healthy lifestyle and treatment of vascular risk factors are recommended for the management of patients with mild cognitive impairment.
Articles to date in this seriesChertkow H. Diagnosis and treatment of dementia: Introduction. Introducing a series based on the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. CMAJ 2008;178:316-21.Patterson C, Feightner JW, Garcia A, et al. Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease. CMAJ 2008;178:548-56.Feldman HH, Jacova C, Robillard A, et al. Diagnosis and treatment of dementia: 2. Diagnosis. CMAJ 2008;178:825-36.
doi:10.1503/cmaj.070797
PMCID: PMC2335177  PMID: 18458258
13.  Atypical antipsychotic drugs in the treatment of behavioural and psychological symptoms of dementia: systematic review 
BMJ : British Medical Journal  2004;329(7457):75.
Objective To review the role of oral atypical antipsychotic drugs in the management of the behavioural and psychological symptoms of dementia (BPSD).
Data sources Medline, Embase, and the Cochrane Library. Reference lists were reviewed and experts were contacted to identify additional trials.
Study selection Double blind randomised controlled trials that evaluated the four oral atypical antipsychotic therapies for BPSD.
Review methods Two reviewers assessed trial validity independently.
Data extraction Demographics of patients, study duration, dose of antipsychotic, primary end points, adverse events.
Results 77 abstracts were reviewed. Five randomised trials (1570 patients) evaluating risperidone and olanzapine were identified. The quality of trials was generally good. Most participants were in an institution (> 96%), elderly (weighted mean 82.3 years), and had Alzheimer's disease (76.3%). Trials lasted 6-12 weeks. Treatment with atypical antipsychotic drugs was superior to placebo for the primary end point in three of the five trials. Two trials comparing risperidone with haloperidol did not find any differences in the primary measures of efficacy. Adverse events were common and included extrapyramidal symptoms, somnolence, and abnormal gait.
Conclusions Although atypical antipsychotic drugs are being used with increasing frequency, few randomised trials have evaluated their use for BPSD. Limited evidence supports the perception of improved efficacy and adverse event profiles compared with typical antipsychotic drugs.
doi:10.1136/bmj.38125.465579.55
PMCID: PMC449807  PMID: 15194601

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