Alzheimer Disease: Black SE

Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL, Black SE, Powers WJ, DeCarli C, Merino JG, Kalaria RN, Vinters HV, Holtzman DM, Rosenberg GA, Wallin A, Dichgans M, Marler JR, Leblanc GG. · London Health Sciences Centre, University Campus, London, Ontario, Canada. · Stroke. · Pubmed #16917086 links to  free full text

Abstract: BACKGROUND AND PURPOSE: One in 3 individuals will experience a stroke, dementia or both. Moreover, twice as many individuals will have cognitive impairment short of dementia as either stroke or dementia. The commonly used stroke scales do not measure cognition, while dementia criteria focus on the late stages of cognitive impairment, and are heavily biased toward the diagnosis of Alzheimer disease. No commonly agreed standards exist for identifying and describing individuals with cognitive impairment, particularly in the early stages, and especially with cognitive impairment related to vascular factors, or vascular cognitive impairment. METHODS: The National Institute for Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network (CSN) convened researchers in clinical diagnosis, epidemiology, neuropsychology, brain imaging, neuropathology, experimental models, biomarkers, genetics, and clinical trials to recommend minimum, common, clinical and research standards for the description and study of vascular cognitive impairment. RESULTS: The results of these discussions are reported herein. CONCLUSIONS: The development of common standards represents a first step in a process of use, validation and refinement. Using the same standards will help identify individuals in the early stages of cognitive impairment, will make studies comparable, and by integrating knowledge, will accelerate the pace of progress.

Herrmann N, Black SE. · No affiliation provided · Neurology. · Pubmed #11087763 No free full text.

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Black SE. · No affiliation provided · Neurology. · Pubmed #10331672 No free full text.

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Behl P, Stefurak TL, Black SE. · Linda Campbell Cognitive Neurology Research Unit, Sunnybrook and Women's Research Institute, Toronto, ON, Canada. · Can J Neurol Sci. · Pubmed #16018149 No free full text.

Abstract: The objective of this review is to summarize the literature on Alzheimer's disease progression utilizing cognitive batteries to track change over time. Studies published in English and obtained through PubMed searches (1983-2004) were included (i) if they had a longitudinal design and followed probable Alzheimer's patients diagnosed by National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association or Diagnostic and Statistical Manual III/IV criteria, and (ii) if the techniques used for serial assessment were well-established in terms of validity and reliability. Longitudinal studies examining Alzheimer's disease progression report highly variable annual rates of change in decline rate. It remains unclear if this reflects disease subgroups or stage-related rate of decline. In conclusion a combination of stage-appropriate cognitive tests such as the Mattis Dementia Rating Scale and the Severe Impairment Battery, along with appropriate statistical methods to account for individual variability in decline rates, can capture the progression of Alzheimer disease and may be useful in further investigation.

Black SE. · Department of Medicine, Sunnybrook and Women's College Health Sciences Centre, University of Toronto Faculty of Medicine, Ontario, Canada. · Postgrad Med. · Pubmed #15672887 No free full text.

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Black SE, Patterson C, Feightner J. · Department of Medicine, Neurology, University of Toronto, Ontario, Canada. · Can J Neurol Sci. · Pubmed #11237312 No free full text.

Abstract: Primary prevention will become increasingly important as dementia prevalence increases and effective retardive therapies are developed. To date, only one randomized controlled trial (involving treatment of systolic hypertension) has demonstrated that the incidence of dementia can be reduced. Physicians should remain alert to possible secondary causes of dementia and correct these whenever possible. Primary and secondary prevention of stroke should reduce dementia related to cerebrovascular disease either directly or as a comorbid factor in Alzheimer's disease (AD). Epidemiological studies have revealed a number of risk factors for AD including genetic mutation, susceptibility genes, positive family history, Down's syndrome, age, sex, years of education, head trauma and neurotoxins. In case-control studies non-steroidal anti-inflammatory medication and estrogen replacement therapy appear to decrease the relative risk of developing AD. Further research to develop and test preventative therapies in AD and other dementias should be strongly encouraged.

Swartz RH, Black SE, St George-Hyslop P. · Cognitive Neurology Unit, Sunnybrook Health Science Centre, University of Toronto, Ontario, Canada. · Can J Neurol Sci. · Pubmed #10352866 No free full text.

Abstract: Alzheimer's disease (AD) is the most common cause of dementia in the elderly and an increasingly significant health concern in our aging population. In the past 10 years, our understanding of this disease has increased dramatically. While the discovery of three rare genetic mutations that can cause AD has provided much information about the causes and progression of the disease, a great deal of attention has been focused on apolipoprotein (ApoE) because of its involvement in the more common, later onset form of AD. Due to the rapid pace of recent advances, it has not been easy for health care professionals, researchers and the general public to keep abreast of these developments. This paper reviews recent research in ApoE and late-onset AD, emphasizing molecular neuropathological, genetic and neuroimaging findings and highlighting current controversies that remain to be addressed.

Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA, Anonymous00037. · University of Oxford, John Radcliffe Hospital, Oxford, UK. · Lancet Neurol. · Pubmed #18450517 No free full text.

Abstract: BACKGROUND: The amyloid-beta peptide Abeta(42) has been implicated in the pathogenesis of Alzheimer's disease (AD). We aimed to test the effects of tarenflurbil, a selective Abeta(42)-lowering agent (SALA), on cognition and function in patients with mild to moderate AD. METHODS: 210 patients living in the community who had a mini-mental state examination (MMSE) score of 15-26 were randomly assigned to receive tarenflurbil twice per day (400 mg [n=69] or 800 mg [n=70]) or placebo (n=71) for 12 months in a phase II, multicentre, double-blind study. Primary efficacy outcomes were the AD assessment scale cognitive subscale (ADAS-cog), the Alzheimer's Disease Cooperative Study activities of daily living scale (ADCS-ADL), and the clinical dementia rating sum of boxes (CDR-sb). In a 12-month extended treatment phase, patients who had received tarenflurbil continued to receive the same dose, and patients who had received placebo were randomly assigned to tarenflurbil at 800 mg or 400 mg twice per day. Primary efficacy analyses were done by intention to treat. This trial is registered with Health Canada (084527) and the Medicines and Healthcare products Regulatory Agency in the UK (20365/0001/A 69316). FINDINGS: A prespecified interaction analysis revealed that patients with mild AD (baseline MMSE 20-26) and moderate AD (baseline MMSE 15-19) responded differently to tarenflurbil in the ADAS-cog and the ADCS-ADL (p>or=0.10); therefore, these groups were analysed separately. Patients with mild AD in the 800 mg tarenflurbil group had lower rates of decline than did those in the placebo group in activities of daily living (ADCS-ADL difference in slope 3.98 [95% CI 0.33 to 7.62] points per year, effect size [reduction from placebo decline rate] 46.4%, Cohen's d 0.45; p=0.033) and global function (CDR-sb difference -0.80 [-1.57 to -0.03] points per year, effect size 35.7%, Cohen's d 0.42; p=0.042); slowing of cognitive decline did not differ significantly (ADAS-cog difference -1.36 [-4.07 to 1.36] points per year, effect size 33.7%, Cohen's d 0.20; p=0.327). In patients with moderate AD, 800 mg tarenflurbil twice per day had no significant effects on ADCS-ADL and ADAS-cog and had a negative effect on CDR-sb (-52%, Cohen's d -1.08; p=0.003). The most common adverse events were diarrhoea (in seven, nine, and five patients in the 800 mg, 400 mg, and placebo groups, respectively), nausea (in seven, seven, and four patients), and dizziness (in five, nine, and four patients). Patients with mild AD who were in the 800 mg tarenflurbil group for 24 months had lower rates of decline for all three primary outcomes than did patients who were in the placebo group for months 0-12 and a tarenflurbil group for months 12-24 (all p<0.001), and had better outcomes than did patients who were in the placebo group for months 0-12 and the 800 mg tarenflurbil group for months 12-24 (all p<0.05). INTERPRETATION: 800 mg tarenflurbil twice per day was well tolerated for up to 24 months of treatment, with evidence of a dose-related effect on measures of daily activities and global function in patients with mild AD. FUNDING: Myriad Pharmaceuticals.

Behl P, Bocti C, Swartz RH, Gao F, Sahlas DJ, Lanctot KL, Streiner DL, Black SE. · Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, 160 Russell Jarvis Drive, Toronto, Ontario, Canada. · Arch Neurol. · Pubmed #17296844 links to  free full text

Abstract: OBJECTIVE: To investigate changes in cognition, function, and behavior after 1 year in patients with Alzheimer disease being treated with cholinesterase inhibitors, in relation to the presence or absence of subcortical hyperintensities involving the cholinergic pathways. DESIGN: One-year prospective cohort study. SETTING: Memory Clinic, Sunnybrook Health Sciences Centre, University of Toronto. Patients Ninety patients with possible/probable Alzheimer disease who were being treated with cholinesterase inhibitors at baseline. INTERVENTIONS: Yearly standardized neuropsychological testing and brain magnetic resonance imaging (MRI). The Cholinergic Pathways Hyperintensities Scale (CHIPS) was applied to baseline MRIs to rate the severity of subcortical hyperintensities in cholinergic pathways. The consensus-derived Age-Related White Matter Changes (ARWMC) Rating Scale was used as a general measure of white matter disease burden. MAIN OUTCOME MEASURES: Tests of global cognition, function, and behavior and specific cognitive and functional domains. RESULTS: Patients in the low CHIPS group were equivalent to those in the high CHIPS group with regard to baseline demographic characteristics, cognitive severity, and vascular risk factors. After covarying age and education, no differences were found after 1 year in overall cognition, function, and behavior or on memory, language, and visuospatial tasks. Patients in the high CHIPS group showed improvement on executive function and working memory tasks compared with those in the low CHIPS group. For the ARWMC scale, groups with and without white matter abnormalities were equivalent on baseline demographics and in cognitive, functional, and behavioral outcomes. CONCLUSION: Cerebrovascular compromise of the cholinergic pathways may be a factor that contributes more selectively than does total white matter lesion burden to response to cholinergic therapy in Alzheimer disease, particularly on frontal/executive tasks.

Swartz RH, Black SE, Sela G, Bronskill MJ. · No affiliation provided · Brain Cogn. · Pubmed #15259397 No free full text.

Abstract: This project assessed the contributions of atrophy and cerebrovascular disease (CVD) to cognitive impairment in dementia. Ten individuals with clinically diagnosed pure VaD were age-, sex-, and education-matched to individuals with AD. All participants underwent neuropsychological testing and MRI which were processed to generate quantitative indices of atrophy and CVD. A linear regression, including thalamic lesion and vCSF volumes, predicted cognitive status (R2 = .74; p < .0005). Three VaD subgroups were identified: thalamic lesion (n = 4), hippocampal infarcts (n = 3), and other (n = 3). In participants without thalamic lesion, vCSF predicted general cognition (R2 = .48), hippocampal atrophy predicted memory impairment (R2 = .33), and white matter lesions predicted executive dysfunction (R2 = .48). Both atrophy and CVD burden correlated highly with cognitive impairment and should be simultaneously assessed in studies of brain-behaviour relations in dementia.

Deshpande NA, Gao FQ, Bakshi SN, Leibovitch FS, Black SE, Anonymous00326. · Department of Medicine (Neurology), Sunnybrook & Women's College, Health Sciences Centre, University of Toronto, Ont, Canada. · Brain Cogn. · Pubmed #15025054 No free full text.

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Westmacott R, Black SE, Freedman M, Moscovitch M. · Department of Psychology, University of Toronto, Ont., Canada. · Neuropsychologia. · Pubmed #14615074 No free full text.

Abstract: In a previous study [Memory Cognit., in press], we demonstrated that some semantic concepts are more likely than others to be associated with specific personal memories, and that this autobiographical significance gives these concepts special status in long-term memory. In this paper, we explore the possible neural correlates of autobiographically significant semantic knowledge and examine whether or not autobiographical significance is a factor in determining patterns of semantic memory loss caused by brain damage. Using famous names that were rated on various attributes, including autobiographical significance, by control participants in a norming study [Memory Cognit., in press], we found that semantic dementia (SD) patients were more likely to recognize, identify and remember autobiographically significant episodes involving famous names that were rated high in autobiographical significance as compared to equally familiar names that were rated low. By contrast, people with Alzheimer's disease (AD) and people with medial temporal lobe (MTL) amnesia did not exhibit this preference for names rated high in autobiographical significance. Furthermore, in tests of free recall, recognition, fame judgment and speeded reading, semantic dementia patients demonstrated a performance advantage for autobiographically significant famous names, whereas the other patient groups did not. These findings suggest a critical role for medial temporal regions in the mediation of autobiographical memory and the interaction between personal experience and semantic memory. Theoretical implications are discussed.

Grady CL, McIntosh AR, Beig S, Keightley ML, Burian H, Black SE. · Rotman Research Institute, Baycrest Center for Geriatric Care, Toronto, Ontario, Canada M6A 2E1. · J Neurosci. · Pubmed #12574428 links to  free full text

Abstract: Previous experiments have found that individuals with Alzheimer's disease (AD) show increased activity in prefrontal regions compared with healthy age-matched controls during cognitive tasks. This has been interpreted as compensatory reallocation of cognitive resources, but direct evidence for a facilitating effect on performance has been lacking. To address this we measured neural activity during semantic and episodic memory tasks in mildly demented AD patients and healthy elderly controls. Controls recruited a left hemisphere network of regions, including prefrontal and temporal cortices in both the semantic and episodic tasks. Patients engaged a unique network involving bilateral dorsolateral prefrontal and posterior cortices. Critically, activity in this network of regions was correlated with better performance on both the semantic and episodic tasks in the patients. This provides the most direct evidence to date that AD patients can use additional neural resources in prefrontal cortex, presumably those mediating executive functions, to compensate for losses attributable to the degenerative process of the disease.

Callen DJ, Black SE, Caldwell CB. · Institute of Medical Science, Research Program in Aging, Imaging, Sunnybrook & Women's University of Toronto, Canada. · Eur J Nucl Med Mol Imaging. · Pubmed #12111130 No free full text.

Abstract: The goal of this study was to perform a systematic, semi-quantitative analysis of limbic perfusion in patients with Alzheimer's disease (AD) using coregistered single-photon emission tomography (SPET) images aligned to magnetic resonance (MR) images. Limbic perfusion in 40 patients with mild to moderate AD was compared with that of 17 age-, sex-, and education-matched normal controls (NC). HMPAO SPET scans and 3D T1-weighted MR images were acquired for each subject. Structures of the limbic system (i.e. hippocampus, amygdala, anterior thalamus, hypothalamus, mamillary bodies, basal forebrain, septal area and cingulate, orbitofrontal and parahippocampal cortices) were traced on the MR images and transferred to the coregistered SPET scans. Perfusion ratios for all limbic regions were calculated relative to cerebellar perfusion. General linear model multivariate analysis revealed that, overall, limbic structures showed significant hypoperfusion (F=7.802, P<0.00001, eta (2)=0.695 ) in AD patients compared with NC. Greatest differences (d > or = 0.8) were found in the hippocampus, as well as all areas of the cingulate cortex. Significant relative hypoperfusion was also apparent in the parahippocampal cortex, amygdala/entorhinal cortex, septal area and anterior thalamus, all of which showed medium to large effect sizes (d=0.6-0.8). No significant relative perfusion differences were detected in the basal forebrain, hypothalamus, mamillary bodies or orbitofrontal cortex. Logistic regression indicated that posterior cingulate cortex perfusion was able to discriminate AD patients from NC with 93% accuracy (95% sensitivity, 88% specificity). The current results suggest that most, but not all, limbic structures show significant relative hypoperfusion in AD. These findings validate previous post-mortem studies and could be useful in improving diagnostic accuracy, monitoring disease progression and evaluating potential treatment strategies in AD.

Ismail Z, Herrmann N, Francis PL, Rothenburg LS, Lobaugh NJ, Leibovitch FS, Black SE, Lanctôt KL. · Centre for Addiction and Mental Health, Toronto, Ont., Canada. · Dement Geriatr Cogn Disord. · Pubmed #19246910 No free full text.

Abstract: BACKGROUND/AIMS: This study aimed to investigate the possible association of regional cerebral perfusion and sleep loss in Alzheimer's disease (AD). METHODS: 55 AD patients were characterized as having (SL) or not having (NSL) nocturnal sleep loss based on standard AD scales assessing sleep over the previous 4 weeks. (99m)Tc-ethylcysteinate dimer SPECT scans were performed in a relaxed, wakeful state. Whole-brain analysis using Statistical Parametrical Mapping (SPM5) was performed to compare perfusion across groups. In addition, the AD groups were compared to normal control (NC) subjects of comparable age and gender to provide a context for interpretation of findings. RESULTS: SPM analysis showed increased perfusion in the right middle frontal gyrus (R-MFG, Brodman area 9, p = 0.016, familywise-error-corrected) in SL versus NSL patients. Comparison with NC subjects confirmed that perfusion in the R-MFG among SL patients did not exceed that found in NCs (relative rather than absolute hyperperfusion). CONCLUSIONS: In this sample of mild-to-moderate AD patients, relative hyperperfusion in the R-MFG is associated with reports of SL. This region may play a role in regulating sleep.

Schwindt GC, Black SE. · Institute of Medical Science, University of Toronto, Canada. · Neuroimage. · Pubmed #19103293 No free full text.

Abstract: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder, rapidly increasing in prevalence as the population ages. As the potential for disease-modifying therapy grows, a large body of literature has aimed at finding reliable, noninvasive biomarkers of AD, to allow for early intervention and sensitive tracking of therapeutic response. Task-related functional brain imaging techniques have been increasingly used to examine episodic memory function in AD. In the present study we completed a quantitative meta-analysis of this growing literature, to establish consensus and elucidate consistent patterns across this important research area. Results from encoding and retrieval paradigms were analyzed using the activation likelihood estimation (ALE) technique for patient and control groups. Second-level ALE analyses directly compared activation between these two groups. Results indicated a number of consistent findings across the included studies. Controls showed consistently greater activity than patients in a number of regions including the MTL and frontal pole across encoding and retrieval paradigms. Patients demonstrated increased activation likelihood in areas of the ventral lateral prefrontal cortex and other regions. Our findings quantitatively confirm the widely-cited deficits in MTL activity among AD patients, and also bring to light a pattern of differential prefrontal involvement, which may be implicated in compensatory changes occurring in AD. On the whole, this study quantitatively demonstrates that functional imaging studies show consistent, if complex, patterns of brain activation differences between patients and controls. These findings support the continued evaluation of functional neuroimaging for clinical use.

Tippett WJ, Black SE. · L.C. Campbell Cognitive Neurology Research Unit, Toronto, Ontario, Canada. · J Int Neuropsychol Soc. · Pubmed #18954483 No free full text.

Abstract: This study investigated the role of visuospatial tasks in identifying cognitive decline in patients with Alzheimer's disease (AD), by correlating neuropsychological performance with cerebral perfusion measures. There were 157 participants: 29 neurologically healthy controls (age: 70.3 +/- 6.6, MMSE > or = 27), 86 patients with mild AD (age: 69.18 +/- 8.28, MMSE > or = 21) and 42 patients moderate/severe AD (age: 68.86 +/- 10.69, MMSE 8-20). Single Photon Emission Computerized Tomography (SPECT) was used to derive regional perfusion ratios, and correlated using partial least squares (PLS) with neuropsychological test scores from the Benton Line Orientation (BLO) and the Rey-Osterrieth Complex Figure (RO). Cross-sectional analysis demonstrated that mean scores differed in accordance with disease status: control group (BLO 25.5, RO 33.3); mild AD (BLO 20.1, RO 25.5); moderate/severe AD (BLO 10.7, RO 16). Correlations were observed between BLO/RO and right parietal SPECT regions in the AD groups. Visuospatial performance, often undersampled in cognitive batteries for AD, is clearly impaired even in mild AD and correlates with functional deficits as indexed by cerebral perfusion ratios on SPECT implicating right hemisphere circuits. Furthermore, PLS reveals that usual spatial tasks probe a distributed brain network in both hemispheres including many areas targeted by early AD pathology.

Fernandez-Duque D, Baird JA, Black SE. · Psychology Department, Villanova University, Villanova, PA 19085, USA. · J Clin Exp Neuropsychol. · Pubmed #18686116 No free full text.

Abstract: The ability to understand other people's behavior in terms of mental states, such as beliefs, desires, and intentions, is central to social interaction. It has been argued that the interpersonal problems of patients with behavioral variant of frontotemporal dementia (FTD-b) are due to a dysfunction of that system. We used first- and second-order false-belief tasks to assess theory-of-mind reasoning in a group of patients with FTD-b and a cognitively matched group of patients with Alzheimer's disease (AD). Both patient groups were equally impaired relative to a healthy elderly group in the cognitively demanding second-order false-belief tasks, revealing that cognitive demands are an important factor in false-belief task performance. Both patient groups reached ceiling performance in the first-order false-belief tasks with minimal cognitive demands, despite the striking difference in their social graces. These results suggest that a conceptual deficit in theory of mind-as measured by the false-belief task-is not at the core of the differences between FTD-b and AD.

Behl P, Lanctôt KL, Streiner DL, Black SE. · Linda C. Campbell Cognitive Neurology Research Unit, University of Toronto, Canada. · Int Psychogeriatr. · Pubmed #18606043 No free full text.

Abstract: BACKGROUND: Despite widespread use of second-generation cholinesterase inhibitors (CHEIs) for the symptomatic treatment of Alzheimer's disease (AD), little is known about possible long-term effects in different functional domains. This study seeks to assess change in activities of daily living (ADLs) over two years in AD patients treated with CHEIs matched to untreated patients in the same longitudinal cohort study. METHODS: This study is based on the two-year prospective cohort study at the Memory Clinic in Sunnybrook Health Sciences Centre, University of Toronto. Probable AD patients (N = 130: untreated = 65, treated = 65) underwent standardized neuropsychological assessments including the Disability Assessment for Dementia Scale (DAD), at baseline, one-year and two-year follow-up. Groups received a careful evaluation of comorbid illnesses, concomitant medication use, and vascular risk factors. RESULTS: At baseline, there were no significant differences in demographics and characteristics. Treated patients showed less decline in overall function and in instrumental and basic ADLs. Furthermore, less decline was seen in the overall scores for initiation and planning over two years with moderate to large effect sizes. CONCLUSION: These findings have clinical relevance since functional ability has been increasingly recognized as a key outcome variable in AD treatment. It is also of note that the subscores reflecting executive functioning appear to drive these beneficial differences.

Levy-Cooperman N, Burhan AM, Rafi-Tari S, Kusano M, Ramirez J, Caldwell C, Black SE. · Linda C. Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, Ontario. · J Psychiatry Neurosci. · Pubmed #18592038 links to  free full text

Abstract: BACKGROUND: Depressive symptoms of varying severity are prevalent in up to 63% of Alzheimer disease (AD) patients and often result in greater cognitive decline and increased caregiver burden. The current study aimed to determine the neural correlates of depressive symptoms in a sample of AD patients. METHODS: Using the Cornell Scale for Depression in Dementia, we assessed 56 patients who met criteria for probable AD. Data obtained from Technetium-99m ethyl cysteinate dimer single photon emission computed tomography (SPECT) were analyzed with the use of a magnetic resonance imaging-derived region of interest (ROI) anatomic template before and after atrophy correction and statistical parametric mapping (SPM). The following 4 frontal ROIs were investigated bilaterally: middle frontal gyrus (Brodmann's area [BA] 46), orbitofrontal cortex (BA 11), superior prefrontal (BA 8/9) and anterior cingulate (BA 24/25/32/33). RESULTS: Depressive symptoms were present in 27 of the AD patients (48%). Patients with depressive symptoms showed less perfusion in the right superior and bilateral middle frontal gyri (p < 0.005), left superior frontal (p < 0.05) and anterior cingulate gyri (p < 0.005) before atrophy correction. SPM analyses revealed significantly lower perfusion in bilateral dorsolateral and superior prefrontal cortex of patients with depressive symptoms (right, p < 0.005; left, p < 0.05). SPECT ROI analyses with atrophy correction revealed trends similar to data without atrophy correction but did not reach statistical significance. CONCLUSION: In this study, depressive symptoms in AD patients were associated with relative hypoperfusion in the prefrontal cortex when they were compared with AD patients without depressive symptoms. These findings are consistent with previous reports in studies of primary depression suggesting that these regions are involved in affect and emotional regulation.

Lanctôt KL, Herrmann N, Black SE, Ryan M, Rothenburg LS, Liu BA, Busto UE. · Department of Psychiatry, University of Toronto, Toronto, Canada. · Am J Geriatr Psychiatry. · Pubmed #18591575 No free full text.

Abstract: OBJECTIVE: To assess the role of the dopaminergic brain reward system (BRS) in apathy associated with Alzheimer disease (AD). DESIGN: BRS function was probed in 20 AD patients using dextroamphetamine (d-amph) challenge. After baseline behavioral testing, patients were given a single 10 mg dose of d-amph. The time course of the subjective response to d-amph was assessed at hourly intervals for 4 hours. SETTING: Three outpatient dementia clinics associated with a university-affiliated hospital. PARTICIPANTS: Twenty AD patients aged 77 +/- 8 years with Neuropsychiatric Inventory (NPI) apathy scores of 3.4 +/- 3.5 and Mini-Mental State Examination scores of 20.4 +/- 5.1. MEASUREMENTS: Patients were classified as apathetic based on an NPI apathy subscore of > or =4. Apathy severity was assessed using the Apathy Evaluation Scale (AES). The subjective and behavioral responses to d-amph were assessed using computerized versions of the Addiction Research Centre Inventory (ARCI), Profile of Mood States and Connor's Continuous Performance Task. RESULTS: Repeated measures ANOVA revealed a significant interaction between the presence of apathy and the peak subjective response to d-amph on the ARCI, such that while nonapathetic AD patients were responsive to the rewarding effects of d-amph, apathetic patients were not (F(1,17) = 4.93, p = 0.04). Continuous AES scores were predicted by peak ARCI positive effects scores and baseline overall behavioral disturbances (NPI total) in a backward linear regression analysis using the entire study sample (F(2,17) = 10.00, p = 0.01, R(2) = 0.49). CONCLUSIONS: Apathy in AD is associated with a blunted subjective response to d-amph, which may be indicative of dysfunction in the BRS.

Pettersen JA, Sathiyamoorthy G, Gao FQ, Szilagyi G, Nadkarni NK, St George-Hyslop P, Rogaeva E, Black SE. · Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, A421-2075 Bayview Ave, Toronto, ON M4N 3M5, Canada. · Arch Neurol. · Pubmed #18541799 links to  free full text

Abstract: BACKGROUND: Microbleeds are hemosiderin deposits around small vessels and are well visualized with T2*-weighted gradient-recalled echo (GRE) imaging. OBJECTIVES: To determine frequency and topography of microbleeds in Alzheimer disease (AD) and to assess their association with leukoaraiosis and cognition. DESIGN: Case-control cross-sectional analysis. Microbleeds were counted using GRE imaging. Leukoaraiosis was rated on T2-weighted and proton density-weighted scans using the Age-Related White Matter Changes Rating Scale (ARWMC). Neuropsychological tests indexed cognition. SETTING: The Cognitive Neurology Clinic, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. PATIENTS: Individuals with probable AD (n = 80) and healthy controls (n = 25) from a longitudinal cohort with GRE sequences as part of standard imaging protocol (2002-2006). RESULTS: Microbleeds occurred in 29% of patients with AD and 12% of controls and were multiple (> 1) in 48% of patients with AD and 33% of controls. There was lobar (vs centrencephalic) predominance in 92% of AD patients, with occipital lobes accounting for 57% of these microbleeds. The ARWMC scores (P < .005) were significantly higher in AD patients with microbleeds than in those without, and microbleeds correlated with total (r = 0.39, P = .01) and parietooccipital (r = 0.28, P < .01) ARWMC scores. We were unable to demonstrate an association between microbleeds (or leukoaraiosis) and cognitive performance. CONCLUSIONS: Occipital predominance of microbleeds with corresponding parietooccipital leukoaraiosis has not been well described in prior imaging studies of AD. Microbleeds were frequent, often multiple, and predicted greater leukoaraiosis. These findings illustrate the complexity of AD vasculopathy and the need for additional studies in dementia and stroke populations.

Ismail Z, Herrmann N, Rothenburg LS, Cotter A, Leibovitch FS, Rafi-Tari S, Black SE, Lanctôt KL. · Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. · J Neurol Sci. · Pubmed #18495162 No free full text.

Abstract: BACKGROUND: Alzheimer's Disease (AD) is frequently associated with changes in appetite. This study investigated the relationship between regional cerebral perfusion and appetite loss in AD. METHODS: 64 patients with possible or probable AD were characterized as being with (n=22) or without (n=44) appetite loss based on the Neuropsychiatric Inventory (NPI) Appetite subscale. 99mTc-ECD SPECT scans were coregistered to a standardized template in Talairach space generating mean ratios of uptake referenced to the cerebellum. Regions of interest (ROIs) included anterior cingulate cortex (ACC), middle mesial temporal cortex (MTC-m), inferior mesial temporal cortex (MTC-i), insula (INS), orbitofrontal cortex (OFC) and thalamus-hypothalamus (THAL). RESULTS: Backward stepwise logistic regression analysis of these ROIs showed hypoperfusion in the L-ACC (p=0.015) and L-OFC (p=0.015), relative sparing of perfusion in the R-ACC (p=0.010), R-OFC (p=0.010) and L-MTC-m (p=0.006), and greater anxiety (p=0.005) independently predicted loss of appetite (chi(2)=22.24, p=0.001, Nagelkerke R(2)=0.41). CONCLUSIONS: Hypoperfusion in the left anterior cingulate and left orbitofrontal cortices, and relative sparing of perfusion in the right anterior cingulate, right orbitofrontal and left middle mesial temporal cortices emerged as predictors of appetite loss in this sample of patients. These findings are consistent with impairments in the extrinsic motivational pathways of eating and impaired reward value of food as components of appetite loss in AD.

Herrmann N, Rothenburg LS, Black SE, Ryan M, Liu BA, Busto UE, Lanctôt KL. · Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. · J Clin Psychopharmacol. · Pubmed #18480686 No free full text.

Abstract: Apathy is a common behavioral symptom of Alzheimer's disease (AD), being present in up to 70% of patients. Apathy in AD and non-AD populations has been associated with dysfunction in the dopaminergic brain reward system, suggesting that pharmacotherapeutic targeting of this system may be an effective treatment for apathy in AD. We therefore performed a randomized, double-blind, placebo-controlled crossover trial of methylphenidate in a sample of 13 apathetic AD patients (6 men, 7 women; age mean 77.9 years [SD, 7.8 years]; Mini Mental Status Examination score, 19.9 [SD, 4.7]). Patients were treated with methylphenidate (10 mg PO twice a day) or an identical placebo in two 2-week phases separated by a 1-week placebo washout. All patients participated in a dextroamphetamine challenge test (one 10-mg oral dose) before treatment with methylphenidate to gauge the functional integrity of the dopamine brain reward system. Overall, patients demonstrated greater improvement with methylphenidate compared with placebo according to Apathy Evaluation Scale total change scores (end of treatment - baseline: Wilcoxon Z = -2.00; P = 0.047). However, a significantly greater proportion of patients experienced at least 1 adverse event with methylphenidate compared with placebo (3 vs 1; chi = 4.33, P = 0.038). Two patients experienced serious adverse events with methylphenidate, consisting of delusions, agitation, anger, irritability, and insomnia, which resolved upon discontinuation of the medication. Response to methylphenidate was associated with increases in inattention on a continuous performance task after dextroamphetamine challenge. Psychostimulants may be effective in treating features of apathy in AD, and dopaminergic changes may predict response.

Hsiung GY, Alipour S, Jacova C, Grand J, Gauthier S, Black SE, Bouchard RW, Kertesz A, Loy-English I, Hogan DB, Rockwood K, Feldman HH. · Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. · Dement Geriatr Cogn Disord. · Pubmed #18417973 links to  free full text

Abstract: BACKGROUND: Patients with cognitive impairment no dementia (CIND) are at an increased risk of progression to Alzheimer's disease (AD). Whether subtle impairments in functional or social abilities at the CIND stage can predict progression to AD is not yet fully determined. We evaluated whether impairments on the Disability Assessment for Dementia (DAD) and Functional Rating Scale (FRS) can predict progression to AD. METHODS: We examined 70 patients with CIND from the ACCORD cohort having complete DAD and FRS baseline and 2-year follow-up data. MANCOVA adjusted for age, sex, education and baseline MMSE score compared the baseline and 2-year change in DAD and FRS scores in CIND patients who progressed to AD versus non-progressors. RESULTS: There were no significant differences between CIND progressors and non-progressors in baseline total DAD or FRS scores. FRS domain analysis revealed that greater impairment in social/occupational functioning significantly predicted progression, while there were no predictive DAD domains. In progressors, both DAD and FRS scores significantly declined over time with the largest changes in instrumental activities of daily living (IADL). CONCLUSION: While changes in IADL characterize the progression from CIND to AD, impairment in complex social-cognitive competency significantly predicts risk of progression and may mark early AD.