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Background Cardiovascular risk factors co‐occur with one another, and little is known about the extent of their clustering and risk of Alzheimer disease (AD). We identify groups of cardiovascular risk factors in cognitively normal individuals and investigate between‐group differences in incident AD and death. Methods and Results Cognitively normal individuals were recruited from the National Alzheimer's Coordinator Center. A latent class analysis was conducted with hypertension, hypercholesterolemia, heart condition, stroke, smoking history, diabetes, and high body mass index. Between‐group differences in the incidence of AD, mortality, and mortality‐adjusted AD were investigated. This study included 12 412 cognitively normal individuals (average follow‐up, 65 months). Three groups were identified: (1) low probabilities of cardiovascular risk factors (reference; N=5398 [43%]), (2) hypertension and hypercholesterolemia (vascular‐dominant; N=5721 [46%]), and (3) hypertension, hypercholesterolemia, diabetes, and high body mass index (vascular‐metabolic; N=1293 [10%]). Both vascular groups were significantly older, had more men, were slightly less educated, and were slightly more cognitively impaired than the reference group (all P P P P P =0.02). Mortality‐adjusted AD was greater in the vascular‐dominant (OR, 1.54; P =0.02) and vascular‐metabolic groups (OR, 1.46; P =0.04). Conclusions Three distinct cardiovascular risk factor groups were identified in cognitively normal elderly individuals. Only the vascular‐dominant group was associated with a greater incidence of AD. Selective mortality may contribute to the attenuated association between the vascular‐metabolic group and incident AD.

Background and ObjectivesTo determine whether cognitive reserve attenuates the association of vascular brain injury with cognition.MethodsCross-sectional data were analyzed from 2 harmonized studies: the Canadian Alliance for Healthy Hearts and Healthy Minds (CAHHM) and the Prospective Urban and Rural Epidemiology (PURE) study. Markers of cognitive reserve were education, involvement in social activities, marital status, height, and leisure physical activity, which were combined into a composite score. Vascular brain injury was defined as nonlacunar brain infarcts or high white matter hyperintensity (WMH) burden on MRI. Cognition was assessed using the Montreal Cognitive Assessment Tool (MoCA) and the Digit Symbol Substitution Test (DSST).ResultsThere were 10,916 participants age 35–81. Mean age was 58.8 years (range 35–81) and 55.8% were female. Education, moderate leisure physical activity, being in a marital partnership, being taller, and participating in social groups were each independently associated with higher cognition, as was the composite cognitive reserve score. Vascular brain injury was associated with lower cognition (β –0.35 [95% confidence interval [CI] –0.53 to −0.17] for MoCA and β −2.19 [95% CI −3.22 to −1.15] for DSST) but the association was not modified by the composite cognitive reserve variable (interactionp= 0.59 for MoCA andp= 0.72 for DSST).ConclusionsBoth vascular brain injury and markers of cognitive reserve are associated with cognition. However, the effects were independent such that the adverse effects of covert vascular brain injury were not attenuated by higher cognitive reserve. To improve cognitive brain health, interventions to both prevent cerebrovascular disease and promote positive lifestyles are needed.

Author(s): Pilotto, Andrea; Romagnolo, Alberto; Scalvini, Andrea; Masellis, Mario; Shimo, Yasushi; Bonanni, Laura; Camicioli, Richard; Wang, Lily L; Dwivedi, Alok K; Longardner, Katherine; Rodriguez-Porcel, Federico; DiFrancesco, Mark; Vizcarra, Joaquin A; Montanaro, Elisa; Maule, Simona; Lupini, Alessandro; Ojeda-Lopez, Carmen; Black, Sandra E; Delli Pizzi, Stefano; Gee, Myrlene; Tanaka, Ryota; Yamashiro, Kazuo; Hatano, Taku; Borroni, Barbara; Gasparotti, Roberto; Rizzetti, Maria C; Hattori, Nobutaka; Lopiano, Leonardo; Litvan, Irene; Espay, Alberto J; Padovani, Alessandro; Merola, Aristide | Abstract: ObjectiveTo evaluate whether orthostatic hypotension (OH) or supine hypertension (SH) is associated with brain atrophy and white matter hyperintensities (WMH), we analyzed clinical and radiologic data from a large multicenter consortium of patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB).MethodsSupine and orthostatic blood pressure (BP) and structural MRI data were extracted from patients with PD and DLB evaluated at 8 tertiary-referral centers in the United States, Canada, Italy, and Japan. OH was defined as a systolic/diastolic BP fall ≥20/10 mm Hg within 3 minutes of standing from the supine position (severe ≥30/15 mm Hg) and SH as a BP ≥140/90 mm Hg with normal sitting BP. Diagnosis-, age-, sex-, and disease duration-adjusted differences in global and regional cerebral atrophy and WMH were appraised with validated semiquantitative rating scales.ResultsA total of 384 patients (310 with PD, 74 with DLB) met eligibility criteria, of whom 44.3% (n = 170) had OH, including 24.7% (n = 42) with severe OH and 41.7% (n = 71) with SH. OH was associated with global brain atrophy (p = 0.004) and regional atrophy involving the anterior-temporal (p = 0.001) and mediotemporal (p = 0.001) regions, greater in severe vs nonsevere OH (p = 0.001). The WMH burden was similar in those with and without OH (p = 0.49). SH was not associated with brain atrophy (p = 0.59) or WMH (p = 0.72).ConclusionsOH, but not SH, was associated with cerebral atrophy in Lewy body disorders, with prominent temporal region involvement. Neither OH nor SH was associated with WMH.

Rationale We evaluated K-means clustering to classify amyloid brain PETs as positive or negative. Patients and methods Sixty-six participants (31 men, 35 women; age range, 52-81 years) were recruited through a multicenter observational study: 19 cognitively normal, 25 mild cognitive impairment, and 22 dementia (11 Alzheimer disease, 3 subcortical vascular cognitive impairment, and 8 Parkinson-Lewy Body spectrum disorder). As part of the neurocognitive and imaging evaluation, each participant had an 18F-flutemetamol (Vizamyl, GE Healthcare) brain PET. All studies were processed using Cortex ID software (General Electric Company, Boston, MA) to calculate SUV ratios in 19 regions of interest and clinically interpreted by 2 dual-certified radiologists/nuclear medicine physicians, using MIM software (MIM Software Inc, Cleveland, OH), blinded to the quantitative analysis, with final interpretation based on consensus. K-means clustering was retrospectively used to classify the studies from the quantitative data. Results Based on clinical interpretation, 46 brain PETs were negative and 20 were positive for amyloid deposition. Of 19 cognitively normal participants, 1 (5%) had a positive 18F-flutemetamol brain PET. Of 25 participants with mild cognitive impairment, 9 (36%) had a positive 18F-flutemetamol brain PET. Of 22 participants with dementia, 10 (45%) had a positive 18F-flutemetamol brain PET; 7 of 11 participants with Alzheimer disease (64%), 1 of 3 participants with vascular cognitive impairment (33%), and 2 of 8 participants with Parkinson-Lewy Body spectrum disorder (25%) had a positive 18F-flutemetamol brain PET. Using clinical interpretation as the criterion standard, K-means clustering (K = 2) gave sensitivity of 95%, specificity of 98%, and accuracy of 97%. Conclusions K-means clustering may be a powerful algorithm for classifying amyloid brain PET.

Background and Purpose: Many patients with ischemic stroke present with multiple comorbidities that threaten survival and recovery. This study sought to determine the risks of adverse long-term stroke outcomes associated with multimorbid diabetes mellitus and depression. Methods: Retrospective analysis of prospectively collected data on consecutive patients without premorbid dementia admitted from the community for a first-ever acute ischemic stroke to comprehensive stroke centers across Ontario, Canada (2003–2013). Premorbid histories of diabetes mellitus and depression were ascertained within 5 years before stroke admission. Adjusted hazard ratios (aHR [95% CI]) of admission to long-term care, incident dementia, readmission for stroke or transient ischemic attack and all-cause mortality, over time among those discharged back into the community poststroke. Results: Among 23 579 stroke admissions, n=20 201 were discharged back into the community. Diabetes mellitus and depression were associated with synergistic hazards of admission to long-term care (X 2 =5.4; P =0.02) over a median follow-up of 5.6 years. This interaction was observed among women specifically; depression multimorbidity showed particularly high hazards of admission to long-term care (aHR Depression =1.57 [1.24–1.98]) and incident dementia (aHR Depression =1.85 [1.40–2.44]) among women with diabetes mellitus. In the whole cohort, diabetes mellitus and depression were associated individually with long-term care admission (aHR Diabetes =1.20 [1.12–1.29]; aHR Depression =1.19 [1.04–1.37]), incident dementia (aHR Diabetes =1.14 [1.06–1.23]; aHR Depression =1.27 [1.08–1.49]), stroke/transient ischemic attack readmission (aHR Diabetes =1.18 [1.10–1.26]; aHR Depression =1.24 [1.07–1.42]), and all-cause mortality (aHR Diabetes =1.29 [1.23–1.36]; aHR Depression =1.16 [1.05–1.29]). Conclusions: The risks of dementia and needing long-term care in the years after surviving a stroke were particularly elevated among women when premorbid diabetes mellitus and depression occurred together. Long-term stroke recovery strategies might target high-risk patients with mood and metabolic multimorbidity.

Background The incidence of ischemic stroke has increased among adults aged 18 to 64 years, yet little is known about relationships between specific risk factors and outcomes. This study investigates in‐hospital and long‐term outcomes in patients with stroke aged Methods and Results Consecutive patients aged Conclusions Focused secondary prevention and risk factor management may be needed to address poor long‐term outcomes for patients with stroke aged

ObjectiveTo determine ifAPOEε4 influences the association between white matter hyperintensities (WMH) and cognitive impairment in Alzheimer disease (AD) and dementia with Lewy bodies (DLB).MethodsA total of 289 patients (AD = 239; DLB = 50) underwent volumetric MRI, neuropsychological testing, andAPOEε4 genotyping. Total WMH volumes were quantified. Neuropsychological test scores were included in a confirmatory factor analysis to identify cognitive domains encompassing attention/executive functions, learning/memory, and language, and factor scores for each domain were calculated per participant. After testing interactions between WMH andAPOEε4 in the full sample, we tested associations of WMH with factor scores using linear regression models inAPOEε4 carriers (n = 167) and noncarriers (n = 122). We hypothesized that greater WMH volume would relate to worse cognition more strongly inAPOEε4 carriers. Findings were replicated in 198 patients with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI-I), and estimates from both samples were meta-analyzed.ResultsA significant interaction was observed between WMH andAPOEε4 for language, but not for memory or executive functions. Separate analyses inAPOEε4 carriers and noncarriers showed that greater WMH volume was associated with worse attention/executive functions, learning/memory, and language inAPOEε4 carriers only. In ADNI-I, greater WMH burden was associated with worse attention/executive functions and language inAPOEε4 carriers only. No significant associations were observed in noncarriers. Meta-analyses showed that greater WMH volume was associated with worse performance on all cognitive domains inAPOEε4 carriers only.ConclusionAPOEε4 may influence the association between WMH and cognitive performance in AD and DLB.

To evaluate random forests (RFs) as a supervised machine learning algorithm to classify amyloid brain PET as positive or negative for amyloid deposition and identify key regions of interest for stratification.The data set included 57 baseline F-florbetapir (Amyvid; Lilly, Indianapolis, IN) brain PET scans in participants with severe white matter disease, presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter, and clinically read by 2 nuclear medicine physicians with interpretation based on consensus (35 negative, 22 positive). SUV ratio data and clinical reads were used for supervised training of an RF classifier programmed in MATLAB.A 10,000-tree RF, each tree using 15 randomly selected cases and 20 randomly selected features (SUV ratio per region of interest), with 37 cases for training and 20 cases for testing, had sensitivity = 86% (95% confidence interval [CI], 42%-100%), specificity = 92% (CI, 64%-100%), and classification accuracy = 90% (CI, 68%-99%). The most common features at the root node (key regions for stratification) were (1) left posterior cingulate (1039 trees), (2) left middle frontal gyrus (1038 trees), (3) left precuneus (857 trees), (4) right anterior cingulate gyrus (655 trees), and (5) right posterior cingulate (588 trees).Random forests can classify brain PET as positive or negative for amyloid deposition and suggest key clinically relevant, regional features for classification.

Purpose/background Loss of gray matter after stroke has been associated with cognitive impairment. This pilot study aimed to investigate the therapeutic potential of lithium, a putative neurotrophic agent, in the stroke recovery process within a year of stroke occurrence. Methods Twelve stroke patients (mean ± SD age, 71.1 ± 11.9 years) were recruited to the study, and eligible participants were prescribed open-label lithium for 60 days. Magnetic resonance imaging was used to assess global gray matter at baseline and end of treatment; global cognition was assessed using the standardized Mini-Mental State Examination and Montreal Cognitive Assessment, and verbal memory was evaluated using the Hopkins Verbal Learning Test-Revised. Findings/results There was no difference in global gray matter volume between baseline and follow-up (t = 1.977, P = 0.074). There was a significant interaction between higher lithium dose and increased global gray matter volume (F = 14.25, P = 0.004) and a correlation between higher lithium dose and improved verbal memory (r = 0.576, P = 0.05). Implications/conclusions Lithium pharmacotherapy may be associated with gray matter volume change and verbal memory improvement in stroke patients, providing a rationale for future trials assessing therapeutic potential of lithium in a poststroke population.

Background: The thalamus is globally connected to many brain regions. Previous work highlights thalamic contributions to multiple cognitive functions, but few studies have measured thalamic volume changes or explored correlates of such changes with post-stroke cognition. Hence this study investigates possible associations of thalamic volumes with post-stroke cognitive functions. Methods: Participants with brain infarcts (6-42 months) underwent volumetric brain MRI and cognitive testing, including the Montreal Cognitive Assessment (MoCA). Focal Brain infarcts and thalami were traced manually. If the patient had bilateral infarcts, the side of the primary infarct volume defined the hemisphere involved. Brain parcellation and volumetrics used our comprehensive semi-automatic brain region and vascular lesion extraction pipeline (Ramirez, Neuroimage, 2011). MRI in 24 age and gender-matched healthy people provided normal comparative thalamic volumes. Thalamic atrophy was defined by percent thalamic volume loss in the stroke hemisphere compared to the other side. Spearman correlation assessed relationships between thalamic and infarct volumes and MoCA scores. Logistic regression analysis assessed whether thalamic atrophy correlated with MoCA score. Results: Thalami volumes ipsilateral to the infarct in stroke patients (n=55) were smaller than left (4.4 ± 1.4 vs. 5.4 ± 0.8 cc, p = 0.012) and right (4.4 ± 1.4 vs. 5.3 ± 0.7 cc, p = 0.024) thalamic volumes in the controls. Thalamic volumes were inversely correlated with ipsilateral infarct volumes (r = -0.384, p = 0.004). After controlling for head-size and brain atrophy, infarct volume independently correlated with ipsilateral thalamic volume s (β= -0.068, P=0.026), and only frontal infarcts (β = 2.300, p = 0.021) independently contributed to > 15% ipsilateral thalamic atrophy. Left thalamic atrophy of > 10% correlated significantly with poorer MoCA performance (β = 3.139, p = 0.023), after controlling for demographics and infarct volumes. Conclusions: Our results suggest that remote effects of infarction on ipsilateral thalamic volume, presumably related to disrupted thalamic-cortical interconnectivity, is associated with a commonly used metric of post-stroke cognitive impairment.

Background: Studies evaluating endothelial injury after EVT have been done by means of retrieved human thrombus, MR vessel-wall imaging, and animal histopathologic studies. These techniques have limitations, as MR imaging has insufficient spatial resolution to directly visualize endothelium, and histopathologic examinations are ex-vivo and unable to provide real-time patterns of injury. Objective: Endovascular imaging after EVT using optical coherence tomography (OCT) to examine for vessel injury in real-time. Methodology: Three swine weighing 35-40kg were selected for the animal model. Autologous venous whole-blood was used to create thrombus. A second-generation stent retriever was used for EVT. Next, three consecutive patients with basilar artery occlusion underwent EVT and endovascular OCT imaging. Results: In the animal model, revascularization and OCT imaging was successful for all 9 vessels. Endothelial injury was observed in 4/9 (44%) of vessels, and residual thrombus was observed in 4/9 (44%) of vessels despite complete angiographic revascularization. All vessels undergoing EVT after 6 hours had evidence of endothelial injury, and 2/3 (66%) had residual thrombus. Two basilar stroke patients (2/3) 66% had significant residual thrombus despite complete angiographic revascularization. The residual thrombus was also not visible on CT angiography or MR imaging done within 24 hours of EVT. Conclusions: Endothelial injury and residual thrombus despite complete revascularization is present after EVT and can be observed in real-time using OCT. It is possible that the longer occlusive thrombus is present, the more endothelial injury will occur during EVT.

ObjectiveTo determine the relationship between white matter hyperintensities (WMH) presumed to indicate disease of the cerebral small vessels, temporal lobe atrophy, and verbal memory deficits in Alzheimer disease (AD) and other dementias.MethodsWe recruited groups of participants with and without AD, including strata with extensive WMH and minimal WMH, into a cross-sectional proof-of-principle study (n = 118). A consecutive case series from a memory clinic was used as an independent validation sample (n = 702; Sunnybrook Dementia Study; NCT01800214). We assessed WMH volume and left temporal lobe atrophy (measured as the brain parenchymal fraction) using structural MRI and verbal memory using the California Verbal Learning Test. Using path modeling with an inferential bootstrapping procedure, we tested an indirect effect of WMH on verbal recall that depends sequentially on temporal lobe atrophy and verbal learning.ResultsIn both samples, WMH predicted poorer verbal recall, specifically due to temporal lobe atrophy and poorer verbal learning (proof-of-principle −1.53, 95% bootstrap confidence interval [CI] −2.45 to −0.88; and confirmation −0.66, 95% CI [−0.95 to −0.41] words). This pathway was significant in subgroups with (−0.20, 95% CI [−0.38 to −0.07] words, n = 363) and without (−0.71, 95% CI [−1.12 to −0.37] words, n = 339) AD. Via the identical pathway, WMH contributed to deficits in recognition memory (−1.82%, 95% CI [−2.64% to −1.11%]), a sensitive and specific sign of AD.ConclusionsAcross dementia syndromes, WMH contribute indirectly to verbal memory deficits considered pathognomonic of Alzheimer disease, specifically by contributing to temporal lobe atrophy.

Objective:To compare the diffusion and perfusion MRI metrics of normal-appearing white matter (NAWM) with and without impaired cerebrovascular reactivity (CVR).Methods:Seventy-five participants with moderate to severe leukoaraiosis underwent blood oxygen level–dependent CVR mapping using a 3T MRI system with precise carbon dioxide stimulus manipulation. Several MRI metrics were statistically compared between areas of NAWM with positive and negative CVR using one-way analysis of variance with Bonferroni correction for multiple comparisons.Results:Areas of NAWM with negative CVR showed a significant reduction in fractional anisotropy by a mean (SD) of 3.7% (2.4), cerebral blood flow by 22.1% (8.2), regional cerebral blood volume by 22.2% (7.0), and a significant increase in mean diffusivity by 3.9% (3.1) and time to maximum by 10.9% (13.2) (p < 0.01), compared to areas with positive CVR.Conclusions:Impaired CVR is associated with subtle changes in the tissue integrity of NAWM, as evaluated using several quantitative diffusion and perfusion MRI metrics. These findings suggest that impaired CVR may contribute to the progression of white matter disease.

Background and Purpose— Poststroke cognitive impairment is typified by prominent deficits in processing speed and executive function. However, the underlying neuroanatomical substrates of executive deficits are not well understood, and further elucidation is needed. There may be utility in fractionating executive functions to delineate neural substrates. Methods— One test amenable to fine delineation is the Trail Making Test (TMT), which emphasizes processing speed (TMT-A) and set shifting (TMT-B-A difference, proportion, quotient scores, and TMT-B set-shifting errors). The TMT was administered to 2 overt ischemic stroke cohorts from a multinational study: (1) a chronic stroke cohort (N=61) and (2) an acute–subacute stroke cohort (N=45). Volumetric quantification of ischemic stroke and white matter hyperintensities was done on magnetic resonance imaging, along with ratings of involvement of cholinergic projections, using the previously published cholinergic hyperintensities projections scale. Damage to the superior longitudinal fasciculus, which colocalizes with some cholinergic projections, was also documented. Results— Multiple linear regression analyses were completed. Although larger infarcts ( β =0.37, P β =0.39, P β =0.17, P =0.03). These findings were replicated in both cohorts. Patients with ≥2 TMT-B set-shifting errors also had greater cholinergic hyperintensities projections scale severity. Conclusions— In this multinational stroke cohort study, damage to lateral cholinergic pathways and the superior longitudinal fasciculus emerged as significant neuroanatomical correlates for executive deficits in set shifting.

Background and Purpose— The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Vascular Cognitive Impairment Harmonization working group proposed a brief cognitive protocol for screening of vascular cognitive impairment. We investigated the validity, reliability, and feasibility of the Montreal Cognitive Assessment 5-minute protocol (MoCA 5-minute protocol) administered over the telephone. Methods— Four items examining attention, verbal learning and memory, executive functions/language, and orientation were extracted from the MoCA to form the MoCA 5-minute protocol. One hundred four patients with stroke or transient ischemic attack, including 53 with normal cognition (Clinical Dementia Rating, 0) and 51 with cognitive impairment (Clinical Dementia Rating, 0.5 or 1), were administered the MoCA in clinic and a month later, the MoCA 5-minute protocol over the telephone. Results— Administration of the MoCA 5-minute protocol took 5 minutes over the telephone. Total score of the MoCA 5-minute protocol correlated negatively with age ( r =−0.36; P r =0.41; P P =0.773). Total scores of the MoCA and MoCA 5-minute protocol were highly correlated ( r =0.87; P P >0.05 for difference; Cohen d for group difference, 0.80–1.13). It differentiated cognitively impaired patients with executive domain impairment from those without (areas under receiver operating characteristics curve, 0.89; P d =1.7 for group difference). Thirty-day test–retest reliability was excellent (intraclass correlation coefficient, 0.89). Conclusions— The MoCA 5-minute protocol is a free, valid, and reliable cognitive screen for stroke and transient ischemic attack. It is brief and highly feasible for telephone administration.

Background and Purpose— A role of neural networks in the development of poststroke dementia has not been clearly established. We hypothesized that stroke-mediated disruption of subcortical cholinergic pathway or large-scale neural networks contributes to poststroke dementia. Methods— A matched case–control study was conducted in a predetermined cohort with acute ischemic stroke. Cases were defined as newly developed dementia diagnosed >3 months after stroke using the Korean Vascular Cognitive Impairment Harmonization Standards. Each case was matched to 2 controls for age, education, and initial stroke severity. The Cholinergic Pathways HyperIntensities Scale was applied with some modifications to characterize disruption of cholinergic pathways by acute stroke lesions. Involvement of major cortical hub locations of the default mode network, central executive network, and salience network was also investigated. Results— After matching, 38 cases and 66 matched controls were included. Cholinergic Pathways HyperIntensities Scale scores were significantly higher in cases than in controls (2.2±2.9 versus 0.9±1.4). Acute ischemic lesions affecting the default mode and central executive networks were more frequently observed in cases compared with controls (36.8% versus 7.6% and 26.3% versus 6.1%, respectively). These findings remained significant in the multiple logistic regression models adjusted for various sets of potential confounders. Lesion location analysis revealed that cases were more likely to have acute lesions in the left corona radiata, hippocampal formation, and posterior parietal cortex. Conclusions— Disruption of cholinergic pathways and major hubs of large-scale neural networks might contribute to newly developed dementia after acute ischemic stroke.

Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, ¹⁸F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured ("metric": visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR-), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR- between 0.25 and 0.08, whereas prognostic LR+ and LR- were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR- from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR-. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR-. Within markers, the largest proportion of diagnostic LR+ and LR- variability was within ¹⁸F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.

Current literature suggests that theory of mind (ToM) and recognition of facial emotion are impaired in behavioral variant frontotemporal dementia (bvFTD). In contrast, studies suggest that ToM is spared in Alzheimer disease (AD). However, there is controversy whether recognition of emotion in faces is impaired in AD. This study challenges the concepts that ToM is preserved in AD and that recognition of facial emotion is impaired in bvFTD. ToM, recognition of facial emotion, and identification of emotions associated with video vignettes were studied in bvFTD, AD, and normal controls. ToM was assessed using false-belief and visual perspective-taking tasks. Identification of facial emotion was tested using Ekman and Friesen's pictures of facial affect. After adjusting for relevant covariates, there were significant ToM deficits in bvFTD and AD compared with controls, whereas neither group was impaired in the identification of emotions associated with video vignettes. There was borderline impairment in recognizing angry faces in bvFTD. Patients with AD showed significant deficits on false belief and visual perspective taking, and bvFTD patients were impaired on second-order false belief. We report novel findings challenging the concepts that ToM is spared in AD and that recognition of facial emotion is impaired in bvFTD.

Subcortical hyperintensities (SHs) on brain magnetic resonance imaging are associated with cognitive and gait impairment in elderly but their impact on dual-tasking (performing cognitive tasks while walking) in patients with Alzheimer disease (AD) is unknown. This study explored the costs of dual-tasking in relation to SH severity in AD and normal controls (NCs). Cadence while walking on a treadmill, and speed-accuracy-tradeoff (SAT), on 3 working memory tasks, were measured during single-task and dual-task conditions. Dual-task costs (DTC) on SAT, cadence, and overall DTC were measured for each of these tasks. On visual rating of SH severity, AD and NC groups were subdivided into high-SH and low-SH subgroups. Compared with the NC, the AD group performed poorly on all working memory tasks across both conditions, decreased cadence on dual-tasking, and showed a decrement in overall DTC (all P

Background and Purpose— We sought to assess the efficacy and safety of donepezil in patients with vascular dementia (VaD) fulfilling National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences criteria. Methods— This international, multicenter, 24-week trial was conducted from March 2003 to August 2005. Patients (N=974; mean age, 73.0 years) with probable or possible VaD were randomized 2:1 to receive donepezil 5 mg/d or placebo. Coprimary outcome measures were scores on the Vascular-Alzheimer Disease Assessment Scale–Cognitive Subscale and Clinician’s Interview–Based Impression of Change, plus carer interview. Analyses were performed for the intent-to-treat population with the last-observation-carried-forward method. Results— Compared with placebo, donepezil-treated patients showed significant improvement from baseline to end point on the Vascular-Alzheimer Disease Assessment Scale–Cognitive Subscale (least-squares mean difference, −1.156; 95% CI, −1.98 to −0.33; P Conclusions— Patients treated with donepezil 5 mg/d demonstrated significant improvement in cognitive, but not global, function. Donepezil was relatively well tolerated; adverse events were consistent with current labeling. Mortality in the placebo group was unexpectedly low. The differential treatment response of VaD patients by hippocampal size suggests that hippocampal imaging warrants further investigation for understanding VaD.

Background and Purpose— Intravenous tissue plasminogen activator for ischemic stroke is approved for eligible patients who can be treated within a 3-hour window, but treatment rates remain disappointingly low, often Methods— We compared consecutive patients with stroke arriving to our stroke center during the first 4 months of this new triage protocol (February 14 to June 14, 2005) versus the same 4-month period in 2004. Results— The protocol resulted in an immediate doubling in the number of patients with acute stroke arriving to our regional stroke center within 2.5 hours of symptom onset. We observed a 4-fold increase in patients who were eligible for and treated with tissue plasminogen activator. The tissue plasminogen activator treatment rate for ischemic stroke patients increased from 9.5% to 23.4% ( P =0.01), and one in 2 patients with ischemic stroke arriving within 2.5 hours received thrombolysis during this period (one in 5 of patients with ischemic stroke overall). The median onset-to-needle time for tissue plasminogen activator-treated patients was significantly reduced. Many implementation challenges were identified and addressed. Conclusions— This prehospital triage was immediately successful in improving tissue plasminogen activator access for patients with ischemic stroke, enabling our center to achieve one of the highest tissue plasminogen activator treatment rates in North America and underscoring the need for coordinated systems of acute stroke care. Sustainability of such an initiative will be dependent on interdisciplinary teamwork, ongoing paramedic training, adequate hospital staffing, bed availability, and repatriation agreements with community hospitals.

Normal aging leads to frontocortical atrophy. The degree to which this complicates the use of frontotemporal atrophy as a diagnostic criterion for the frontotemporal dementias (FTDs) has not been reported. The present case-control study compared frontotemporal volumes delineated with semi-automatic brain region extraction [n=30 controls vs. 16 behavioral variant FTD (bvFTD) vs. 14 primary progressive aphasia]. Logistic regression identified those regions least helpful for distinguishing bvFTD and primary progressive aphasia from controls. Linear regression tested the correlation of duration of illness to atrophy severity. The control group showed high variance in volumes. Controls had right frontal lobe volumes that overlapped considerably with bvFTD volumes, but, as anticipated, the left anterior temporal volumes of interest showed 91% accuracy in distinguishing the aphasic subgroup from controls. Left-sided and not right-sided atrophy in the medial middle frontal region distinguished the bvFTD group from controls. The relegation of structural imaging to a supportive criterion for diagnosis is reasonable in the context of the range of atrophy due to normal aging. While volumetry identified left-sided atrophy as useful for identifying FTD cases, future studies should determine whether clinicians could make these distinctions on viewing routine diagnostic magnetic resonance imaging scans.

Background and Purpose— The prevalence of stroke in elderly patients has been increasing in recent years. However, limited information is available about the burden of stroke in individuals over 80. We sought to evaluate differences in clinical outcomes in Canadians over 80 years old hospitalized for an acute ischemic stroke. Methods— The authors conducted a multicenter cohort study including all hospital admissions for ischemic stroke identified from the Canadian Hospital Morbidity and Mortality Database from April 2003 to March 2004. The Hospital Morbidity and Mortality Database contains a national database that contains patient-level sociodemographic, diagnostic, procedural, and administrative information from across Canada. Multivariable analysis was performed using logistic regression. The primary outcome was 7-day case fatality and fatality at discharge. Secondary end points included intensive care unit admissions, medical complications, gender differences, length of hospital stay, and discharge disposition. Results— We analyzed 26 676 patients with ischemic stroke admitted to 606 hospitals across Canada. Mean age (SD) was 74±13 years. Overall, 10 171 (38%) were aged 80 years or older. Case fatality at discharge was 5.7% (age P P P P Conclusions— Aging of the population is a growing reality in Western societies and this translates into an increasing demand on healthcare systems. In our study, patients with stroke over 80 had higher risk-adjusted fatality, longer hospitalization, and were less likely to be discharged to their original place of residence. Strategies need to be implemented to facilitate equal access to specialized stroke care for the elderly.

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.

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.

Objective To determine the sensitivity of the Gambling Test (GT) to the neurocognitive effects of traumatic brain injury (TBI) and to examine the cognitive, neural, and psychosocial correlates of impaired GT performance in patients with TBI. Background The GT is sensitive to behavioral deficits in patients with prefrontal brain damage, especially in ventral regions. Patients with TBI and behavioral deficits often have focal ventral prefrontal damage as well as diffuse damage. Analysis of the correlates of the GT in this population has implications for interpretation of the GT in other groups. Method Seventy-one TBI patients were administered the GT, neuropsychological tests, and psychosocial outcome questionnaires. Patients also had high-resolution structural magnetic resonance imaging analyzed for both lesion location and tissue compartment volumes. Results The GT was sensitive to TBI in general, but not to TBI severity or quantified chronic phase atrophy. Marked impairment was observed in (but not limited to) patients with large frontal lesions. There were modest correlations between the GT and tests of working memory and executive functioning as well as between self- and other-rated real-life memory, executive, and emotional problems. Conclusions The GT can be a useful adjunct to assessment of patients with TBI. Interpretation of GT performance in patients with complex neuropsychological deficits such as TBI should consider the influence of domain-general resources in addition to specific ventral prefrontal function.

Several studies indicate semantic fluency more sensitively discriminates patients with Alzheimer disease (AD) from normal elderly persons, with disproportionate impairment of semantic over phonemic fluency.To determine the ability of abbreviated fluency measures in the clinic setting (1-minute letter F and animal fluency tests) to detect AD, and to assess whether difference scores between these measures discriminate patients with AD and vascular dementia (VaD) from normal elderly persons.The authors studied patients with AD (n = 98) meeting National Institute of Neurological Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, VaD patients (n = 18) meeting National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria, cognitively impaired but not demented patients (CIND; n = 25), vascular CIND patients (VCIND; n = 24), and normal control subjects (NCs; n = 46).Analysis of covariance controlling for age, education, and overall impairment indicated all groups generated fewer animal names compared with NCs, whereas only VaD patients generated fewer letter F words compared with NCs. On standardized scores, patients with AD and CIND, unlike those with VCIND and VaD, scored significantly worse on the animal fluency test than on the letter F fluency test. The animal fluency test was superior in discriminating all patient groups from NCs. Positive likelihood ratios (PLRs) revealed animal fluency scores15 were 20 times more likely in a patient with AD than in an NC (sensitivity = 0.88; specificity = 0.96). Letter F scores4 discriminated VaD from AD patients (PLR = 4.0; sensitivity = 0.44; specificity = 0.90). Difference scores0 (i.e., fewer animal than letter F words) discriminated patients with VCIND from those with CIND (PLR = 2.5; sensitivity = 0.32; specificity = 1.00).A 1-minute semantic fluency test can assist in early detection of dementia in the memory clinic setting.

To examine volumetric changes in limbic structures in patients with probable AD using planimetric measures on MRI.Limbic structures (i.e., hippocampus, amygdala, anterior thalamus, hypothalamus, mamillary bodies, basal forebrain, septal area, fornix, and cingulate, orbitofrontal, and parahippocampal cortices) were traced on 3D T1-weighted MR images of 40 patients with mild to moderate AD and 40 age-, sex-, and education-matched normal control subjects. Limbic volumes were compared between groups and the predictive ability was assessed.Overall, limbic structures showed significant atrophy in AD patients compared with normal control subjects. Differences (p0.05) were found in all limbic regions except the anterior cingulate cortex. The greatest percentage volumetric losses occurred in the septal area (34%), hippocampus (28%), amygdala (21%), parahippocampal cortex (21%), and posterior cingulate cortex (20%). Combining volumetric measures of amygdala and septal area distinguished patients with AD from normal control subjects with 93% accuracy.These results verify that system-wide limbic degeneration occurs in patients with AD. In addition, atrophy in selected limbic structures was used to distinguish patients with AD from normal elderly individuals with over 90% accuracy in this select clinical sample. The measures require further exploration in samples more representative of those seen by primary care physicians before their utility can be accurately assessed.

Background —Postpartum cerebral angiopathy as a cause of hemorrhagic stroke in young women is not well recognized. It is unknown whether this disorder represents a true inflammatory vasculitis or transient vasoconstriction related to the hormonal events of pregnancy and the postpartum period. Case Description —A 39-year-old woman presented with postpartum intracranial hemorrhage and, 32 months later, with subarachnoid hemorrhage, following normal pregnancies. Cerebral angiography obtained after each stroke demonstrated diffuse irregularity of branches of the middle cerebral arteries consistent with a diffuse vasospastic process or classic vasculitis. Neurological deficits resolved and results of a transcranial Doppler study normalized after a short course of high-dose corticosteroids following the second stroke. Conclusions —Postpartum cerebral angiopathy should be considered in the differential diagnosis of recurrent intracranial hemorrhagic stroke in young women. Recognition of this condition may preclude treatment with potentially toxic therapies for vasculitis and will have important implications for counseling women on subsequent pregnancies.

Structural and functional lesion localization in patients with hemispatial neglect.Location and severity of brain damage on CT and SPECT correlated with neglect performance as assessed with a battery of drawings, line bisection, and line and shape cancellation subtests.Participants included 120 consecutive stroke patients with a single right-hemisphere-damaged lesion on CT who were admitted to the Acute Stroke Care Unit at Sunnybrook Health Science Centre. Of these, 88 also had a SPECT.On CT, 82 patients with neglect (compared with 38 without neglect) had more extensive damage in the parietal and sensorimotor cortex and white matter fiber bundles, including the posterior-superior longitudinal and inferior-frontal fasciculi (p0.05). Parietal and anterior cingulate damage best predicted neglect score using the CT data (p0.05), and regional blood flow in the parietal cortex best predicted neglect score using the SPECT data (p0.05) after controlling for the influence of age and lesion size on multiple linear regression.Damage in the parietal and anterior cingulate cortex and posterior white matter fiber bundles correlated with hemispatial neglect. Combining structural- and functional-imaging techniques with neurobehavioral analysis can elucidate brain-behavior relationships.

Background and Purpose —To assess the prevalence of depressive symptoms, their clinical correlates, and the effects of depressive symptoms on stroke recovery, a relatively unselected, well-diagnosed cohort of consecutive stroke survivors was followed prospectively. Methods —Consecutive admissions to a regional stroke center who met World Health Organization and National Institute of Neurological Disorders and Stroke criteria for stroke were eligible. Subarachnoid hemorrhage and brain stem strokes were excluded. Patients underwent CT, single-photon emission CT, and standardized neurological and cognitive examinations at entry. At 3 months and 1 year after stroke, depressive symptoms were assessed with the Montgomery Asberg Depression Rating Scale (MADRS) and the Zung Self-Rating Depression Scale (SDS). Functional outcome was measured with the Functional Independence Measure, and handicap was assessed by the Oxford Handicap Scale. Results —We assessed 436 patients at entry (mean±SD age, 74.9±11.6 years). There were 150 patients available for assessment at 3 months and 136 at 1 year. Marked depressive symptoms were noted in 22% (SDS) to 27% (MADRS) at 3 months and 21% (SDS) to 22% (MADRS) at 1 year. Patents with marked depressive symptoms had more neurological impairment ( P P P r =−.31, P r =.41, P r =−.28, P r =.35, P Conclusions —Depressive symptoms and functional outcome are correlated. In view of the prevalence of depressive symptoms in this population, diagnosis and treatment of depression are important in optimizing recovery.

Background and Purpose Single-photon emission computed tomography (SPECT) is used in patients with acute stroke but as yet is of controversial value. We investigated an association of brain perfusion changes in stroke patients with stroke severity, volume of brain damage, and recovery. Methods Consecutive patients with hemispheric stroke were studied prospectively with serial neurological examinations using the Canadian Neurological Scale (CNS), CT, and 99m Tc–hexamethylpropyleneamine oxime (HMPAO) SPECT. Visual SPECT patterns of brain perfusion (normal, high, mixed, low, and absent) were correlated with the severity of stroke, lesion volume, and short-term outcome. Results SPECT studies were performed in a total of 458 consecutive acute stroke patients within 2 weeks after the onset (mean time, 5 days; range, 1 to 12 days). SPECT perfusion patterns correlated with stroke severity (CNS score) during the first 2 weeks ( P P P =.0001). SPECT had its own prognostic value independent of clinical judgment ( P =.03). SPECT statistically improved predictive power of the CNS score (+1% receiver operating characteristic curve area, [χ 2 ] 2 =20, P Conclusions Visual brain perfusion patterns correlate with the extent, severity, and short-term outcome of hemispheric stroke. HMPAO SPECT may improve the prognostic value of clinical examination if performed during the first 72 hours of stroke.

Most strokes are covert and observed incidentally on brain scans, but their presence increases risk of overt stroke and dementia. Amyloid angiopathy, associated with Alzheimer Disease (AD) causes stroke, and when even small strokes coexist with AD, they lower the threshold for dementia. Diffuse ischemic white matter disease impairs executive functioning, information processing speed, and gait. Neuroimaging techniques, such as tissue segmentation, Diffusion Tensor Imaging, MR Spectroscopy, functional MRI and amyloid PET, probe microstructural integrity, molecular biology, and activation patterns, providing new insights into brain-behavior relationships. MR-pathological studies of periventricular hyperintensity (leukoaraiosis) in aging and dementia reveal arteriolar tortuosity, reduced vessel density, and occlusive venous collagenosis which causes venous insufficiency and vasogenic edema. Activated microglia, oligodendroglial apoptosis, clasmatodendritic astrocytosis, and upregulated hypoxia-markers are seen on immunohistochemistry. Further research is needed to understand and treat this chronic subcortical vascular disease, which is epidemic in our aging population.

Response: We thank Dr Toni and colleagues for their insightful comments. We acknowledge that no clinical stroke syndrome is pathophysiologically pure, that the TOAST classification of stroke mechanism is imperfect, and that a better system is needed, …

Objective: To examine the relationship between temporal lobe (TL) SH volumes and CVLT performance in a group of AD patients [n=139, mean age(SD)=73.8(9.2)] and normal elderly [NC; n=69, mean age(SD)=70(8.2)]. Background Subcortical hyperintensities (SH) are commonly observed on Proton Density (PD) and T2-weighted (T2) MRIs in the elderly and are believed to indicate cerebral small vessel disease (Wolf et al. 2000), often associated with decreased performance on various neuropsychological tests (DeGroot et al. 2000), particularly in speed of information processing (Nordahl et al. 2006). The California Verbal Learning Test (CVLT; Delis et al. 1986) is commonly used to measure verbal learning and memory and has been shown to predict conversion from mild cognitive impairment (MCI) to Alzheimer9s Disease (AD; Lekeu et al. 2010). Design/Methods: The Lesion Explorer (LE; Ramirez et al. 2011) processing pipeline was used to quantify SH and the Semi-Automated Brain Region Extraction (SABRE; Dade et al. 2004) parcellation method was used to obtain standardized regional tissue compartment volumes. Linear regression using backwards elimination of non-significant variables was used to analyze the relationship between volumetric data and neuropsychological scores. Age, years of education and brain parenchymal fraction were included as covariates. Non-parametric tests (Mann-Whitney) were used for group comparisons as required. Results: When comparing left and right TL SH, a significant inverse relationship was found between the total acquisition CVLT score and left TL SH (β=-0.211, p Conclusions: The cerebrovascular contribution to the expression of dementia has been increasingly recognized in AD and cognitive aging and in the conversion from MCI to dementia (Carmichael et. al, 2010). This study suggests that SH are associated with learning deficits in AD and NC and should be accounted for when studying brain behaviour relationships in these groups. Disclosure: Dr. Black has received personal compensation for activities with Novartis Pharmaceuticals, Pfizer, GlaxoSmithKline, Roche Pharmaceuticals, and Bristol-Myers Squibb. Dr. Black has received research support from Novartis Pharmaceuticals, Pfizer, Roche, and GlaxoSmithKline. Dr. McNeely has nothing to disclose. Dr. Ramirez has received personal compensation for activities with Pfizer as a speaker. Dr. Scorrano has received personal compensation for activities with Pfizer as a speaker. Dr. Szilagyi has received personal compensation for activities with Pfizer, Inc as a speaker. Dr. Kiss has nothing to disclose. Dr. Stuss has nothing to disclose.

Objective: To explore the association of nocturnal limb movements (LMs) and sleep quality with cerebral white matter hyperintensities (WMH). Background Nocturnal LMs are associated with transient but significant increases in night-time blood pressure and autonomic hyperactivity; emerging evidence suggests a link with vascular disease. While obstructive sleep apnea is linked with WMH, the relationship between nocturnal LMs and WMH remains to be clarified. Design/Methods: Patients evaluated in a tertiary care behavioral neurology clinic were assessed with polysomnography for various sleep problems. Polysomnography was scored according to criteria from the American Academy of Sleep Medicine. WMH were rated using the Age Related White Matter Changes Score (ARWMC) from FLAIR MRI. Polysomnographic (transformed where necessary) and ARWMC data were compared using Pearson correlations. Results: Forty-five participants were assessed (69% male, mean age 64 years) and vascular risk factors were as follows: hypertension (27%), hyperlipidemia (18%) and diabetes (9%). Prior cerebrovascular disease (7%), obstructive sleep apnea (49%) and restless legs syndrome (33%) were also present. The mean ARWMC score was 3.84 (range 0-25, standard deviation 4.73). When controlling for hypertension, the total ARWMC score was correlated with total LMs per hour of sleep (r=0.66, p=0.01). There were no differences in the ARWMC score between hemispheres, but more LMs were noted on the left side (66.3 vs. 24.1, p Conclusions: LM counts strongly correlated with the presence of WMH. In addition, sleep efficiency was negatively correlated with WMH. In keeping with developing evidence, our findings suggest that nocturnal LMs associated with poor quality sleep may contribute to episodes of nocturnal hypertension, which have been implicated in the development of WMH, even after controlling for the presence of daytime hypertension. Supported by: Dr. Mark Boulos is supported by a Focus on Stroke Research Fellowship, which is funded by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, and the Canadian Stroke Network. Disclosure: Dr. Boulos has nothing to disclose. Dr. Pettersen has nothing to disclose. Dr. Jewell has nothing to disclose. Dr. Black has received personal compensation for activities with Novartis Pharmaceuticals, Pfizer, GlaxoSmithKline, Roche Pharmaceuticals, and Bristol-Myers Squibb. Dr. Black has received research support from Novartis Pharmaceuticals, Pfizer, Roche, and GlaxoSmithKline. Dr. Murray has received personal compensation for activities with Pfizer and Valeant as a consultant.

Allow us to set the stage. You have a serious but common problem that has major emotional and financial implications for patients, caregivers, and society. There are a variety of therapeutic approaches, none of which has been extensively researched or studied “head-to-head.” You assemble a formidable team of experienced investigators and design a model study to compare three of the most highly recommended approaches against placebo. These investigators recruit a sufficient number of subjects and analyze the data appropriately. Finally, the results provide clinicians with firm, evidence-based recommendations for treatment. Sound too good to be true? Unfortunately, it is. The Alzheimer’s Disease Cooperative Study (ADCS) of the treatment of agitation in AD1 followed the plot exactly, right up to but not including the punch line. Behavioral and psychological symptoms in dementia (BPSD) are common, serious problems that affect the quality of life of both patient and caregiver, and frequently result in premature institutionalization. BPSD include agitation, aggression, delusions, hallucinations, depression, apathy, sleep disturbance, and sexually inappropriate behaviors. These difficulties occur in up to 90% of patients at some point in …

To the Editor: We read with interest the review article on stroke and encephalopathy after cardiac surgery1 and the related editorial.2 We agree that assessing these complications provides a unique clinical opportunity for evaluating preventive strategies because patients at higher risk can be identified before surgery. We would like to add to the list of potential cerebroprotective agents proposed (gangliosides, glutamate receptor antagonists, antioxidants) the angiotensin AT1 receptor blockers (AT1RB). Both …

To the Editor: In the above titled article,1 the authors reviewed 7 published studies that compared cerebral blood flow (CBF) measurements with a diagnostic gold standard (follow-up brain CT/MRI) and reported CBF thresholds for the differentiation between ischemic penumbra and infarct core. They found that the “reported CBF thresholds varied widely, from 14.1 to 35.0 and from 4.8 to 8.4 mL/100 g per minute for penumbra and infarct core, respectively.” They concluded that “the use of CBF thresholds… for imaging methods …

With the advent of symptomatic treatment and the prospect of stabilizing therapies for AD, the race for reliable disease and progression markers has picked up speed. Two hot contenders are described in this issue of Neurology: CSF measures of β-amyloid(1-42) (Aβ-42) and tau levels as diagnostic markers1 and MRI quantification of brain atrophy changes for monitoring progression.2 How good are these biomarkers, and how far away are they from routine use in clinical practice? The desired sensitivity and specificity of a proposed biomarker depends on its purpose: for example, screening at-risk populations, differentiating AD from aging and other dementias, or monitoring progression and therapeutic response.3 One biomarker is unlikely to serve all these purposes. The current “bronze standard” for diagnosis—namely, expert clinical assessment that meets the criteria for probable AD of the National Institute for Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association—uses a combination of history, physical, and cognitive examination, as well as blood tests and neuroimaging, to exclude secondary causes. The diagnostic accuracy achieved in research centers when these criteria are followed is 85% to 90%.4 In “gold standard” …

Three models of human language processing can be discerned in contemporary neurobiology: the Wernicke-Broca model, primarily derived from studies of stroke and other brain lesions; the model developed by Dr. George Ojemann from electrical stimulation mapping of the cerebral cortex; and the linguistic model, evolved from Noam Chomsky's linguistic theories. The Wernicke-Broca model employs a posterior-sensory anterior-motor conception of brain language processing that is substantially different from the more modular conception developed from electrical stimulation mapping. The linguistic model attempts to explain language in terms of hierarchical mental function.

We measured the MRI area of corpus callosum in 104 normal adults, 51 men, 53 women, 52 right- and 52 left-handers. There were no significant sex or handedness differences. Callosal areas did not correlate with brain size nor with measures of lateralization for hand performance, dichotic listening, or visual field preference. The results are contrary to the notion of increased callosal connectivity in left-handers, women, or individuals with less-lateralized function.

We compared MRI and CT in a study of 175 patients; 87 infarcts within a week, 40 from 1 to 40 weeks, 25 a year after onset, and 23 hemorrhages, 18 within 2 weeks and 5 in 4 to 8 weeks. Fifty-nine infarcts and eight hemorrhages had sequential scanning. MRI is more sensitive than CT in the early detection of cerebral infarcts. CT is the method of choice to rule out intracerebral bleeding, but MRI is more specific in later stages of hemorrhage. Periventricular hyperintensity is seen more frequently with diabetes than without. Hyperintense white matter patches are often unrelated to clinical events. MRI is useful in following the evolution of strokes and distinguishing acute and chronic infarcts without contrast agents.

Fifteen patients with right hemispheric subcortical infarcts localized by CT or MRI were evaluated with a neglect testing battery. Trimodal extinction was present in one case, visual extinction in three, tactile in three, and auditory in six. Although frequent (10 cases), hemispatial neglect was rarely severe (3 cases). Three cases recovered completely. Large posterior internal capsule lesions were associated with more frequent impairment on a cancellation test. The probable mechanism of hemispatial neglect was attentional in one case and intentional in six. Visual and auditory extinction is explained by striatonigral mechanisms. Although subcortical structures participate in attentional and intentional behavior, cortical structures can substitute for their functions.