Correction to: The Toronto cognitive assessment (TorCA): normative data and validation to detect amnestic mild cognitive impairment.

Upon publication of this article [1], it was brought to our attention that one of the 303 participants in the normative study should have been deleted from the database.

The Toronto Cognitive Assessment (TorCA): normative data and validation to detect amnestic mild cognitive impairment.

BACKGROUND: A need exists for easily administered assessment tools to detect mild cognitive changes that are more comprehensive than screening tests but shorter than a neuropsychological battery and that can be administered by physicians, as well as any health care professional or trained assistant in any medical setting. The Toronto Cognitive Assessment (TorCA) was developed to achieve these goals. METHODS: We obtained normative data on the TorCA (n = 303), determined test reliability, developed an iPad version, and validated the TorCA against neuropsychological assessment for detecting amnestic mild cognitive impairment (aMCI) (n = 50/57, aMCI/normal cognition). For the normative study, healthy volunteers were recruited from the Rotman Research Institute registry. For the validation study, the sample was comprised of participants with aMCI or normal cognition based on neuropsychological assessment. Cognitively normal participants were recruited from both healthy volunteers in the normative study sample and the community. RESULTS: The TorCA provides a stable assessment of multiple cognitive domains. The total score correctly classified 79% of participants (sensitivity 80%; specificity 79%). In an exploratory logistic regression analysis, indices of Immediate Verbal Recall, Delayed Verbal and Visual Recall, Visuospatial Function, and Working Memory/Attention/Executive Control, a subset of the domains assessed by the TorCA, correctly classified 92% of participants (sensitivity 92%; specificity 91%). Paper and iPad version scores were equivalent. CONCLUSIONS: The TorCA can improve resource utilization by identifying patients with aMCI who may not require more resource-intensive neuropsychological assessment. Future studies will focus on cross-validating the TorCA for aMCI, and validation for disorders other than aMCI.

Small vessel disease is linked to disrupted structural network covariance in Alzheimer's disease.

INTRODUCTION: Cerebral small vessel disease (SVD) is thought to contribute to Alzheimer's disease (AD) through abnormalities in white matter networks. Gray matter (GM) hub covariance networks share only partial overlap with white matter connectivity, and their relationship with SVD has not been examined in AD. METHODS: We developed a multivariate analytical pipeline to elucidate the cortical GM thickness systems that covary with major network hubs and assessed whether SVD and neurodegenerative pathologic markers were associated with attenuated covariance network integrity in mild AD and normal elderly control subjects. RESULTS: SVD burden was associated with reduced posterior cingulate corticocortical GM network integrity and subneocorticocortical hub network integrity in AD. DISCUSSION: These findings provide evidence that SVD is linked to the selective disruption of cortical hub GM networks in AD brains and point to the need to consider GM hub covariance networks when assessing network disruption in mixed disease.

Amyloid deposition in semantic dementia: a positron emission tomography study.

BACKGROUND: Pittsburgh compound B ([11C]-PIB) identifies amyloid-ß (Aß) deposition in vivo. Asymptomatic Aß deposition has been reported consistently in some healthy older subjects. Of patients with frontotemporal dementia, those who have later onset have a higher potential for Aß deposition. OBJECTIVE: Comparison of Aß deposition in Alzheimer's disease (AD), healthy older controls, and patients with early- and late-onset semantic dementia (SD), a subtype of frontotemporal dementia. METHODS: Subjects were recruited from tertiary academic care centers specializing in assessment and management of patients with neurodegenerative disease. We used the radiotracer [11C]-PIB in a high-resolution positron emission tomography scanner to evaluate 11 participants with SD (six with onset before age 65 and five with later onset), 9 with probable AD, and 10 controls over age 60. The main outcome measures were frontal, temporal, parietal, and total [11C]-PIB standardized uptake value ratios to establish PIB-positive (PIB+) cutoff. RESULTS: The five patients with late-onset SD were PIB-negative. Two of six with early-onset SD, seven of nine with AD, and 1 of 10 controls were PIB+. The SD participants who were PIB+ did not have memory or visuospatial deficits that are typical in AD. CONCLUSIONS: Aß deposition does not seem to be associated with late-onset SD. Future larger studies might confirm whether a significant minority of early-onset SD patients exhibit Aß deposition. Copyright © 2016 John Wiley & Sons, Ltd.

Trajectories of Behavioural Disturbances Across Dementia Types.

OBJECTIVE: To replicate a previous finding that the trajectory of the Neuropsychiatric Inventory (NPI) shifts in the sixth year of behavioural variant frontotemporal dementia (bvFTD). We evaluated longitudinal tracking with both the Frontal Behavioural Inventory (FBI) and NPI, comparing bvFTD against other dementias. METHODS: Chart reviews over two to five years for patients with bvFTD (n=30), primary progressive aphasia (PPA, n=13) and Alzheimer's disease (AD, n=118) at an urban Canadian tertiary clinic specializing in dementia. Linear regressions of the longitudinal data tested predictors of annualized rates of change (ROC) in NPI and FBI total and subscales for apathy and disinhibition among dementia groups. RESULTS: The mode of the overall sample for the most advanced duration of illness observed was 5 years, with the median at 7 years. We did not find a crescendo-decrescendo pattern in scores although, for bvFTD and AD, high initial scores correlated with ensuing downward ROCs on the NPI and FBI. Educational level showed an influence on disinhibition ROCs. The FBI was no more revealing than the NPI for apathy and disinhibition scores in these dementias. CONCLUSIONS: A cognitive reserve effect on behavioural disturbance was supported but it may take longer than our 4 years of observing the clinical sample to record inflection points in the behavioural and psychiatric symptoms seen in bvFTD. The current data only imply that both apathy and disinhibition will diminish over the course of dementia.

Alzheimer's disease, cerebrovascular disease, and the ß-amyloid cascade.

Alzheimer's disease (AD), considered the commonest neurodegenerative cause of dementia, is associated with hallmark pathologies including extracellular amyloid-ß protein (Aß) deposition in extracellular senile plaques and vessels, and intraneuronal tau deposition as neurofibrillary tangles. Although AD is usually categorized as neurodegeneration distinct from cerebrovascular disease (CVD), studies have shown strong links between AD and CVD. There is evidence that vascular risk factors and CVD may accelerate Aß 40-42 production/ aggregation/deposition and contribute to the pathology and symptomatology of AD. Aß deposited along vessels also causes cerebral amyloid angiopathy. Amyloid imaging allows in vivo detection of AD pathology, opening the way for prevention and early treatment, if disease-modifying therapies in the pipeline show safety and efficacy. In this review, we review the role of vascular factors and Aß, underlining that vascular risk factor management may be important for AD prevention and treatment.

Frontotemporal dementia and pharmacologic interventions.

Frontotemporal lobar degeneration is comprised of three syndromes: frontotemporal dementia (FTD), semantic dementia, and progressive nonfluent aphasia, with FTD being the most prevalent. FTD is characterized predominantly by character change and disordered social conduct. A variety of pathologies may underlie these syndromes, yet it is the location of the pathology rather than the type that dictates the clinical features of the disease. Several medications have been investigated to measure efficacy of treatment in FTD, often with mixed results. The authors review these findings and comment on future directions.

Alzheimer's disease and infection: do infectious agents contribute to progression of Alzheimer's disease?

Infection with several important pathogens could constitute risk factors for cognitive impairment, dementia, and Alzheimer's disease (AD) in particular. This review summarizes the data related to infectious agents that appear to have a relationship with AD. Infections with herpes simplex virus type 1, picornavirus, Borna disease virus, Chlamydia pneumoniae, Helicobacter pylori, and spirochete were reported to contribute to the pathophysiology of AD or to cognitive changes. Based on these reports, it may be hypothesized that central nervous system or systemic infections may contribute to the pathogenesis or pathophysiology of AD, and chronic infection with several pathogens should be considered a risk factor for sporadic AD. If this hypothesis holds true, early intervention against infection may delay or even prevent the future development of AD.

Functional outcome in delusional Alzheimer disease patients. A systematic review.

BACKGROUND: In spite of the prevalence of delusions in Alzheimer's disease (AD) and their association with poor outcomes, there has been little study of the impact of delusions on real-world functioning. METHOD: A number of databases, including Psychlit and Medline, were searched using the keywords: delusions, functional outcomes, activities of daily living, dementia, and Alzheimer's disease. Studies were included in the review if they were in English, restricted to patients with AD, and addressed delusions and function. RESULTS: The review yielded a total of 6 studies, 3 of which showed a correlation between delusions and real-world functioning and 3 of which did not. CONCLUSION: A critical analysis of the existing studies suggests that there may be an association between delusions and impaired real-world functioning. We believe that 2 of the 3 negative studies did not show an association due to issues relating to study design and the use of measures insensitive to executive impairment. This review highlights the future need for more scientifically rigorous studies to clarify this association, so as to ultimately improve treatment outcomes for patients.

Comparison of manual and semi-automated delineation of regions of interest for radioligand PET imaging analysis.

BACKGROUND: As imaging centers produce higher resolution research scans, the number of man-hours required to process regional data has become a major concern. Comparison of automated vs. manual methodology has not been reported for functional imaging. We explored validation of using automation to delineate regions of interest on positron emission tomography (PET) scans. The purpose of this study was to ascertain improvements in image processing time and reproducibility of a semi-automated brain region extraction (SABRE) method over manual delineation of regions of interest (ROIs). METHODS: We compared 2 sets of partial volume corrected serotonin 1a receptor binding potentials (BPs) resulting from manual vs. semi-automated methods. BPs were obtained from subjects meeting consensus criteria for frontotemporal degeneration and from age- and gender-matched healthy controls. Two trained raters provided each set of data to conduct comparisons of inter-rater mean image processing time, rank order of BPs for 9 PET scans, intra- and inter-rater intraclass correlation coefficients (ICC), repeatability coefficients (RC), percentages of the average parameter value (RM%), and effect sizes of either method. RESULTS: SABRE saved approximately 3 hours of processing time per PET subject over manual delineation (p < .001). Quality of the SABRE BP results was preserved relative to the rank order of subjects by manual methods. Intra- and inter-rater ICC were high (>0.8) for both methods. RC and RM% were lower for the manual method across all ROIs, indicating less intra-rater variance across PET subjects' BPs. CONCLUSION: SABRE demonstrated significant time savings and no significant difference in reproducibility over manual methods, justifying the use of SABRE in serotonin 1a receptor radioligand PET imaging analysis. This implies that semi-automated ROI delineation is a valid methodology for future PET imaging analysis.

In-vivo imaging of Alzheimer disease beta-amyloid with [11C]SB-13 PET.

OBJECTIVE: In-vivo imaging of beta-amyloid plaques (Abeta) may improve both early detection of Alzheimer disease (AD) and efficacy assessment of new treatments for AD. The authors' aim was to develop a novel Abeta-specific positron-emission tomography (PET) tracer. METHODS: Five female AD patients (54-77 years old) and six healthy female comparison subjects (53-74 years old), completed 2-hour PET scans after intravenous injection of 10 mCi of both the stilbene [11C]SB-13 and the benzothiazole [11C]6-OH-BTA-1 (also known as [11C]PIB). Kinetic analyses were performed on the resulting time-activity curves to derive Abeta binding-potential estimates, using as input function either the unmetabolized tracer concentration in venous plasma from a two-tissue compartment model or the density of radioactivity in the cerebellum. Authors compared the binding characteristics of the two radiotracers. RESULTS: The two radiotracers demonstrated similar binding properties with respect to regional distribution of retention (increased retention in the frontal and posterior temporal-inferior parietal association cortices in the AD patients, but not in the comparison subjects). Our preliminary PET data indicate that [11C]SB-13 may be similar to [11C]PIB in discriminating AD patients from comparison subjects. CONCLUSIONS: [11C]SB-13 is an effective PET tracer for fibrillar Abeta imaging in vivo, with similar performance as [11C]PIB. Future research directions include evaluation of tracer in larger AD patient samples and in subjects with amnestic mild cognitive impairment, evaluation of arterial input function, and comparison with other tracers, such as [18F]FDG as they relate to cognitive functioning.

Cerebral benzodiazepine receptors in depressed patients measured with [123I]iomazenil SPECT.

BACKGROUND: A recent magnetic resonance spectroscopy (MRS) study revealed low gamma-aminobutyric acid (GABA) levels in the occipital cortex of depressed patients. No in vivo study has been reported to measure postsynaptic GABA receptors in the patients. METHODS: Cortical benzodiazepine (BZ) binding to GABA(A) receptors was measured with [(123)I]iomazenil and single photon emission computed tomography in unmedicated patients with unipolar major depression (n = 13) and healthy subjects (n = 19). Group differences were evaluated by means of statistical parametric mapping (SPM) with partial volume correction for gray matter. Occipital GABA levels were determined by proton MRS in a subgroup (n = 6) of the patients. RESULTS: No evidence of altered BZ binding was found in patients with depression compared with healthy control subjects in the SPM analysis. Although reduction in gray matter volume was observed in the frontal cortex and amygdala of the patients, partial volume correction of the atrophy did not change the result of unaltered BZ binding. GABA levels were found lower in the occipital cortex; however, BZ binding did not show significant relationship to GABA levels. CONCLUSIONS: GABA(A) receptor binding measured in vivo with BZ radioligand binding are not altered in patients with depression.

Effects of catecholamine depletion on D2 receptor binding, mood, and attentiveness in humans: a replication study.

The effect of catecholamine depletion, achieved by per-oral administration of 5250 mg alpha-methyl-para-tyrosine (AMPT) given in the 29 h prior to [11C]raclopride positron emission tomography (PET) was studied on measures of dopamine (DA) release, mood, and attention. Neostriatal DA levels in vivo were estimated by comparing the neostriatal DA D(2) receptor binding potential (D(2)RBP) before and after catecholamine depletion using PET and the radiotracer [11C]raclopride. Six healthy subjects completed the protocol. The AMPT treatment increased D(2)RBP significantly by 13.3+/-5.9% (average+/-standard deviation) and decreased plasma levels of the DA metabolite homovanillic acid (HVA) by 62+/-17%, and levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) by 66+/-5%. Catecholamine depletion resulted in decreased happiness, euphoria, energy, talkativeness, vigor, and attentiveness, and in increased sleepiness, fatigue, sedation, and eye blink rate (EBR). These changes were not correlated with the D(2)RBP increments. The results of this study are overall consistent with previous findings by our group using the same methodology in a different cohort of six healthy subjects.

Pharmacotherapy of agitation and psychotic symptoms in Alzheimer's disease.

Behavioral disorders, such as agitation and psychosis, are the main reasons for nursing home placement of Alzheimer's disease patients. This review article discusses the efficacy and adverse effects rates of antipsychotics, the most effective and widely-used medications for psychosis in elderly patients and the most commonly prescribed class of psychotropic medicines in long-term care institutions. In addition, the efficacy of selective serotonin reuptake inhibitors is discussed. Recommendations are provided regarding these existing and potential new clinical strategies. A future perspective is provided, taking into consideration prospective developments in preventative treatments of Alzheimer's disease over the next 5 years.