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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.

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.

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.

ObjectiveTo study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD).MethodsThe sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions.ResultsThere were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all p < 0.001). T2DM was associated with lower baseline cortical thickness (p = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = −0.17, p = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, p = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis.ConclusionsIn an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.

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.

Objective:To underline the importance of blood pressure regulation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to describe changes that occur in the veins in this condition, specifically venous collagenosis associated with leukoaraiosis.Methods:Case report with neuroimaging and pathologic data.Results:A 61-year-old man with genetically confirmed CADASIL was initially lucid following a motor vehicle accident but subsequently became hypotensive (60/40 mm Hg) due to an open femur fracture and required intubation. Multiple new white matter infarcts appeared on brain imaging. A second hypotensive episode days later was associated with new coin-sized infarcts in the bilateral corona radiata and cerebellar peduncles, and resulted in quadriplegia. No embolic source was found on cardiac or vascular imaging. He died 5 weeks post trauma. Autopsy revealed extensive subcortical and periventricular leukoencephalopathy and multiple cavitations involving deep subcortical gray and white matter. Small arteries had thickened walls, disruption of the muscularis, and intimal periodic acid–Schiff (PAS)–positive material. Both larger periventricular and small caliber veins had thickened walls that were PAS-negative and trichrome-positive, consistent with venous collagenosis. There was no pathologic evidence of global hypoxia or diffuse axonal injury.Conclusions:The findings suggest rapid acceleration of CADASIL pathology from acute hypotension in the setting of impaired vasoreactivity. In addition, collagenosis of veins in the affected white matter regions suggests that the veins may play an important, though largely overlooked, role in maintaining white matter integrity.

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.

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.

Objective: To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD). Methods: The Alzheimer9s Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI. Results: CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ 42 . Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD. Conclusion: The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.

This article provides a classification of primary progressive aphasia (PPA) and its 3 main variants to improve the uniformity of case reporting and the reliability of research results. Criteria for the 3 variants of PPA--nonfluent/agrammatic, semantic, and logopenic--were developed by an international group of PPA investigators who convened on 3 occasions to operationalize earlier published clinical descriptions for PPA subtypes. Patients are first diagnosed with PPA and are then divided into clinical variants based on specific speech and language features characteristic of each subtype. Classification can then be further specified as "imaging-supported" if the expected pattern of atrophy is found and "with definite pathology" if pathologic or genetic data are available. The working recommendations are presented in lists of features, and suggested assessment tasks are also provided. These recommendations have been widely agreed upon by a large group of experts and should be used to ensure consistency of PPA classification in future studies. Future collaborations will collect prospective data to identify relationships between each of these syndromes and specific biomarkers for a more detailed understanding of clinicopathologic correlations.

Objective: To assess the relationship between regional brain volume changes and traumatic brain injury (TBI) severity in patients with and without focal lesions. Methods: Sixty-nine chronic-phase TBI patients spanning the full range of severity were recruited from consecutive hospital admissions. Patients received high-resolution structural MRI a minimum of 1 year after injury. Multivariate statistical analyses assessed covariance patterns between volumes of gray matter, white matter, and sulcal/subdural and ventricular CSF across 38 brain regions and TBI severity as assessed by depth of coma at the time of injury. Patients with diffuse and diffuse plus focal injury were analyzed both separately and together. Results: There was a stepwise, dose–response relationship between parenchymal volume loss and TBI severity. Patients with moderate and severe TBI were differentiated from those with mild TBI, who were in turn differentiated from noninjured control subjects. A spatially extensive pattern of volume loss covaried with TBI severity, with particularly widespread effects in white matter volume and sulcal/subdural CSF. The most reliable effects were observed in the frontal, temporal, and cingulate regions, although effects were observed to varying degrees in nearly every brain region. Focal lesions were associated with greater volume loss in frontal and temporal regions, but volume loss remained marked even when analyses were restricted to patients with diffuse injury. Conclusions: Patterns of parenchymal volumetric changes can differentiate among levels of traumatic brain injury (TBI) severity, even in mild TBI. TBI causes a spatially extensive pattern of volume loss that reflects independent but overlapping contributions of focal and diffuse injury.

Objective: To evaluate the efficacy and safety of donepezil for severe Alzheimer disease (AD). Methods: Patients with severe AD (Mini-Mental State Examination [MMSE] scores 1 to 12 and Functional Assessment Staging [FAST] scores ≥6) were enrolled in this multinational, double-blind, placebo-controlled trial at 98 sites. Patients were randomized to donepezil 10 mg daily or placebo for 24 weeks. Primary endpoints were the Severe Impairment Battery (SIB) and Clinician9s Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus). Secondary endpoints included the MMSE, the Alzheimer Disease Cooperative Study-Activities of Daily Living-severe version (ADCS-ADL-sev), the Neuropsychiatric Inventory (NPI), the Caregiver Burden Questionnaire (CBQ), and the Resource Utilization for Severe Alzheimer Disease Patients (RUSP). Efficacy analyses were performed in the intent-to-treat (ITT) population using last post-baseline observation carried forward (LOCF). Safety assessments were performed for patients receiving ≥1 dose of donepezil or placebo. Results: Patients were randomized to donepezil (n = 176) or placebo (n = 167). Donepezil was superior to placebo on SIB score change from baseline to endpoint (least squares mean difference 5.32; p = 0.0001). CIBIC-Plus and MMSE scores favored donepezil at endpoint (p = 0.0473 and p = 0.0267). Donepezil was not significantly different from placebo on the ADCS-ADL-sev, NPI, CBQ, or RUSP. Adverse events reported were consistent with the known cholinergic effects of donepezil and with the safety profile in patients with mild to moderate AD. Conclusion: Patients with severe AD demonstrated greater efficacy compared to placebo on measures of cognition and global function.

Objective: To characterize the neuropsychiatric symptoms (NPS) of subjects classified as not cognitively impaired (NCI), cognitively impaired–not demented (CIND), and dementia. Methods: A Canadian Cohort Study of Cognitive Impairment and Related Dementias (ACCORD) is a longitudinal investigation of individuals referred to eight Canadian dementia centers for evaluation of cognitive impairment and neurobehavioral symptoms. Of the inception cohort of 804 subjects for whom the informant-based Neuropsychiatric Inventory (NPI) was completed at study entry, 35 were classified as NCI, 193 as CIND, and 576 as dementia. The three diagnostic groups were compared on each of the 12 NPI items. Within each diagnostic group, comparisons were also made between symptomatic (NPS+; total score > 1) and asymptomatic (NPS−; total score = 0) subjects on measures of general cognitive status and functional disability. A subset of the NCI and CIND individuals were also compared on a comprehensive neuropsychological test battery. Results: There was at least one NPI item reported in 60% of subjects with NCI, 74% with CIND, and 89% with dementia. The item scores for delusions, hallucinations, agitation, apathy, disinhibition, aberrant motor behavior, and problems with appetite were greater in dementia subjects than in NCI or CIND. There were no significant differences between subjects with NCI and CIND on any NPI item. For each diagnostic group, NPS+ subjects were more impaired on functional but not neuropsychological measures. Conclusions: Across all levels of cognition, neuropsychiatric symptoms (NPS) are an important feature in individuals referred to dementia clinics. The current data suggest that NPS may precede cognitive deficits in individuals classified as not cognitively impaired and cognitively impaired–not demented.

Objective: To improve clinical recognition and provide research diagnostic criteria for three clinical syndromes associated with frontotemporal lobar degeneration. Methods: Consensus criteria for the three prototypic syndromes-frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia-were developed by members of an international workshop on frontotemporal lobar degeneration. These criteria build on earlier published clinical diagnostic guidelines for frontotemporal dementia produced by some of the workshop members. Results: The consensus criteria specify core and supportive features for each of the three prototypic clinical syndromes and provide broad inclusion and exclusion criteria for the generic entity of frontotemporal lobar degeneration. The criteria are presented in lists, and operational definitions for features are provided in the text. Conclusions: The criteria ought to provide the foundation for research work into the neuropsychology, neuropathology, genetics, molecular biology, and epidemiology of these important clinical disorders that account for a substantial proportion of cases of primary degenerative dementia occurring before the age of 65 years.

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 …

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” …

We studied motor impersistence with a standardized clinical test of sustained actions, both in patients with acute focal stroke lesions, who were matched for age and size of lesion, and normal controls. Patients with right-sided lesions had significantly more impersistence than did those with left-sided lesions. The most discriminating tests were eye-closure, mouth-opening, tongue-protrusion, and gaze to the left. Right central and frontal lesions seemed to be more responsible for motor impersistence than were posterior or left-sided lesions. Although motor impersistence is sometimes seen with diffuse cerebral disease, it is also a sign of right-hemisphere lesions; the phenomenon is probably related to mechanisms of directed attention that are necessary to sustain motor activity.

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.