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1.  Effect of Working Memory and Spatial Attention Tasks on Gait in Healthy Young and Older Adults 
Motor control  2010;14(2):195-210.
Changes gait parameters induced by the concomitant performance of one of two cognitive tasks activating working memory and spatial attention, was examined in healthy young adults (YA) and older adults (OA). There was a main effect of task condition on gait-speed (p= 0.02), stride-length (p<0.001) and double-support time (p=0.04) independent of the group. There were no significant differences between working memory and spatial attention associated gait changes. Working-memory and spatial-attention dual-tasking led to a decrease in gait-speed (p=0.09 and 0.01) and stride-length (p=0.04 and 0.01) and increase in double-support time (p=0.01 and 0.03) in YA and decrease in stride-length (p=0.04 and 0.01) alone in OA. Cognitive task associated changes in gait may be a function of limited attentional resources irrespective of the type of cognitive task.
PMCID: PMC3897230  PMID: 20484770
2.  Functional correlates of instrumental activities of daily living in mild Alzheimer's disease 
Neurobiology of aging  2010;33(1):53-60.
Execution of instrumental-activities of daily-living (IADL) requires the integration of its subcomponents namely, task-initiation, -planning and -performance. Research on their neuroanatomical correlates in Alzheimer's disease (AD) is sparse. Regional cerebral perfusion was measured using Single-Photon-Emission Computed Tomography in 13 bilateral regions-of-interest (ROI). The perfusion ratios obtained in 121 patients with AD were compared to that of 42 age-matched normal controls (NC). The perfusion correlates of IADL components, rated on the Disability Assessment in Dementia scale, were explored in the AD group. AD patients had lower perfusion in the posterior-cingulate and parietal regions bilaterally (p<0.01). Significant correlations were noted between IADL-initiation and bilateral fronto-striatal-anterior cingulate ROI (p<0.01), IADL-planning and right occipital ROI (p<0.05), and IADL-performance and right parietal ROI (p<0.05). Right lateral temporal perfusion was a common correlate of all three components (p<0.05). MMSE score and left anterior-cingulate perfusion explained 21% of the variance in IADL-initiation (R= 0.46; F=15.4; p<0.01). Perfusion correlates of various components of IADL differ in keeping with the heterogenous nature of cognitive processes involved in IADL.
PMCID: PMC3897231  PMID: 20359778
Alzheimer's disease; instrumental activities of daily living (IADL); cerebral perfusion
3.  Impact of Subcortical Hyperintensities on Dual-tasking in Alzheimer’s Disease and Aging 
Alzheimer disease and associated disorders  2012;26(1):10.1097/WAD.0b013e3182172c58.
Subcortical hyperintensities (SH) on brain MRI are associated with cognitive and gait impairment in elderly but their impact on dual-tasking (performing cognitive tasks while walking) in patients with Alzheimer’s disease (AD) is unknown. This study explored the costs of dual-tasking in relation to SH severity in AD and normal controls (NC). Cadence while walking on a treadmill, and speed-accuracy-tradeoff (SAT), on three working memory tasks, were measured during single- 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- and low-SH subgroups. Compared to 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< 0.01). When grouped according to SH severity, the low-SH-NC group performed superiorly on working-memory tasks (p<0.001) and the high-SH-AD group (p=0.001) showed a decrease in dual task costs of cadence. While the AD group showed a decrement in overall DTC (p<0.01) compared to NC, when assessed in terms of SH severity, the high-SH-AD group showed the largest decrement in DTC (p<0.01). Greater SH severity is associated with a decrement in overall dual-tasking ability in AD.
PMCID: PMC3874593  PMID: 21502852
Alzheimer’s Disease; subcortical; hyperintensities; gait; working memory; white matter disease; white matter hyperintensities; dual-tasking; cadence; cognition; walking; treadmill
4.  Differentiating between visual hallucination-free dementia with Lewy bodies and corticobasal syndrome on the basis of neuropsychology and perfusion single-photon emission computed tomography 
Dementia with Lewy bodies (DLB) and Corticobasal Syndrome (CBS) are atypical parkinsonian disorders with fronto-subcortical and posterior cognitive dysfunction as common features. While visual hallucinations are a good predictor of Lewy body pathology and are rare in CBS, they are not exhibited in all cases of DLB. Given the clinical overlap between these disorders, neuropsychological and imaging markers may aid in distinguishing these entities.
Prospectively recruited case–control cohorts of CBS (n =31) and visual hallucination-free DLB (n =30), completed neuropsychological and neuropsychiatric measures as well as brain perfusion single-photon emission computed tomography and structural magnetic resonance imaging (MRI). Perfusion data were available for forty-two controls. Behavioural, perfusion, and cortical volume and thickness measures were compared between the groups to identify features that serve to differentiate them.
The Lewy body with no hallucinations group performed more poorly on measures of episodic memory compared to the corticobasal group, including the delayed and cued recall portions of the California Verbal Learning Test (F (1, 42) =23.1, P <0.001 and F (1, 42) =14.0, P =0.001 respectively) and the delayed visual reproduction of the Wechsler Memory Scale-Revised (F (1, 36) =9.7, P =0.004). The Lewy body group also demonstrated reduced perfusion in the left occipital pole compared to the corticobasal group (F (1,57) =7.4, P =0.009). At autopsy, the Lewy body cases all demonstrated mixed dementia with Lewy bodies, Alzheimer’s disease and small vessel arteriosclerosis, while the corticobasal cases demonstrated classical corticobasal degeneration in five, dementia with agyrophilic grains + corticobasal degeneration + cerebral amyloid angiopathy in one, Progressive Supranuclear Palsy in two, and Frontotemporal Lobar Degeneration-Ubiquitin/TAR DNA-binding protein 43 proteinopathy in one. MRI measures were not significantly different between the patient groups.
Reduced perfusion in the left occipital region and worse episodic memory performance may help to distinguish between DLB cases who have never manifested with visual hallucinations and CBS at earlier stages of the disease. Development of reliable neuropsychological and imaging markers that improve diagnostic accuracy will become increasingly important as disease modifying therapies become available.
PMCID: PMC4256921  PMID: 25484929
5.  Aging, the Central Nervous System, and Mobility 
Mobility limitations are common and hazardous in community-dwelling older adults but are largely understudied, particularly regarding the role of the central nervous system (CNS). This has limited development of clearly defined pathophysiology, clinical terminology, and effective treatments. Understanding how changes in the CNS contribute to mobility limitations has the potential to inform future intervention studies.
A conference series was launched at the 2012 conference of the Gerontological Society of America in collaboration with the National Institute on Aging and the University of Pittsburgh. The overarching goal of the conference series is to facilitate the translation of research results into interventions that improve mobility for older adults.
Evidence from basic, clinical, and epidemiological studies supports the CNS as an important contributor to mobility limitations in older adults without overt neurologic disease. Three main goals for future work that emerged were as follows: (a) develop models of mobility limitations in older adults that differentiate aging from disease-related processes and that fully integrate CNS with musculoskeletal contributors; (b) quantify the contribution of the CNS to mobility loss in older adults in the absence of overt neurologic diseases; (c) promote cross-disciplinary collaboration to generate new ideas and address current methodological issues and barriers, including real-world mobility measures and life-course approaches.
In addition to greater cross-disciplinary research, there is a need for new approaches to training clinicians and investigators, which integrate concepts and methodologies from individual disciplines, focus on emerging methodologies, and prepare investigators to assess complex, multisystem associations.
PMCID: PMC3805295  PMID: 23843270
Motor control; Central nervous system; Mobility.
6.  Kynurenine and depressive symptoms in a poststroke population 
Background and purpose
Depression is a commonly occurring and persistent sequel of stroke affecting approximately 29% of patients. An immunological hypothesis has been put forward, and synthesis of kynurenine from tryptophan has been proposed to link inflammatory activity with neurotoxicity and neurotransmitter dysfunction. This study assessed the relationship between peripheral blood kynurenine and poststroke depressive symptoms.
Patients and methods
This was a multisite cross-sectional observational cohort study of patients with ischemic stroke. Depressive symptoms were assessed using the Center for Epidemiological Studies Depression (CES-D) scale and divided into high, medium, and low depressive symptom tertiles. Concentrations of kynurenine and tryptophan were assayed from fasting serum samples, and the kynurenine/tryptophan ratio was compared between tertiles. Serum cytokine concentrations were assayed in a subgroup of patients, and the ratio of proinflammatory (IL-6, IL-18, IFNγ, TNF, IL-1β) to anti-inflammatory (IL-10) cytokines compared.
NLM identifier
In these patients (n=86, 52.3% male, mean age 71.7±14.2 years), there were no differences in kynurenine/tryptophan ratios between CES-D scale tertiles (F2,76=0.04, P=0.96) controlling for relevant covariates. For cytokines (n=53), serum IL-1β concentrations (F2,52=3.55, P=0.037) and serum ratios of IL-18/IL-10 (F2,52=3.30, P=0.046), IFNγ/IL-10 (F2,52=4.02, P=0.025), and IL-1β/IL-10 (F2,52=4.34, P=0.019) were elevated in the middle CES-D tertile. Post hoc analyses suggested that serum ratios of IL-18/IL-10 (ρ=0.28, P=0.04), and IL-1β/IL-10 (ρ=0.43, P=0.001), as well as IL-1β (ρ=0.29, P=0.04), were significantly associated with fatigue.
Peripheral kynurenine/tryptophan ratios were not associated with depressive symptoms in a poststroke population. However, in exploratory analyses a proinflammatory bias was identified specifically in patients with mild depressive symptoms and associated with poststroke fatigue, suggesting an avenue for future research.
PMCID: PMC4181733  PMID: 25285006
kynurenine; tryptophan; cytokine; inflammation; stroke; depression
7.  Differences in Cerebral Perfusion Deficits in Mild Traumatic Brain Injury and Depression Using Single-Photon Emission Computed Tomography 
Background: Numerous studies have shown decreased perfusion in the prefrontal cortex following mild traumatic brain injury (mTBI). However, similar hypoperfusion can also be observed in depression. Given the high prevalence of depressive symptoms following mTBI, it is unclear to what extent depression influences hypoperfusion in TBI.
Methods: Mild TBI patients without depressive symptoms (mTBI-noD, n = 39), TBI patients with depressive symptoms (mTBI-D, n = 13), and 15 patients with major depressive disorder (MDD), but no TBI were given 99m T-ECD single-photon emission computed tomography (SPECT) scans within 2 weeks of injury. All subjects completed tests of information processing speed, complex attention, and executive functioning, and a self-report questionnaire measuring symptoms of psychological distress. Between-group comparisons of quantified SPECT perfusion were undertaken using univariate and multivariate (partial least squares) analyses.
Results: mTBI-D and mTBI-noD groups did not differ in terms of cerebral perfusion. However, patients with MDD showed hypoperfusion compared to both TBI groups in several frontal (orbitofrontal, middle frontal, and superior frontal cortex), superior temporal, and posterior cingulate regions. The mTBI-D group showed poorer performance on a measure of complex attention and working memory compared to both the mTBI-noD and MDD groups.
Conclusion: These results suggest that depressive symptoms do not affect SPECT perfusion in the sub-acute phase following a mild TBI. Conversely, MDD is associated with hypoperfusion primarily in frontal regions.
PMCID: PMC4138441  PMID: 25191305
TBI; depression; SPECT; neuropsychology; attention; partial least squares
8.  Treatment effects in multiple cognitive domains in Alzheimer’s disease: a two-year cohort study 
Despite widespread use of second-generation cholinesterase inhibitors for the symptomatic treatment of Alzheimer’s disease (AD), little is known about the long term effects of cholinergic treatment on global cognitive function and potential specific effects in different cognitive domains. The objectives of this study were to determine the association between cholinergic treatment and global cognitive function over one and two years in a cohort of patients with mild or moderate AD and identify potential differences in domain-specific cognitive outcomes within this cohort.
A cohort of patients meeting the revised National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for mild or moderate AD, including patients both on treatment with a cholinesterase inhibitor and untreated controls (treated = 65, untreated = 65), were recruited from the Cognitive Neurology Clinic at Sunnybrook Health Sciences Centre, as part of the Sunnybrook Dementia Study. Patients were followed for one to two years and underwent standardized neuropsychological assessments to evaluate global and domain-specific cognitive function. Associations between cholinesterase inhibitor use and global and domain-specific cognitive outcome measures at one and two years of follow-up were estimated using mixed model linear regression, adjusting for age, education, and baseline mini mental state examination (MMSE).
At one year, treated patients showed significantly less decline in global cognitive function, and treatment and time effects across tests of executive and visuospatial function. At two years, there was a significant trend towards less decline in global cognition for treated patients. Moreover, treated patients showed significant treatment and time effects across tests of executive functioning, memory, and visuospatial function.
The present study offers two important contributions to knowledge of the effectiveness of cholinesterase inhibitor treatment in patients with mild-moderate AD: 1) that second-generation cholinesterase inhibitors demonstrate long-term effectiveness for reducing global cognitive decline over one to two years of follow-up, and 2) that decline in function for cognitive domains, including executive function, memory, and visuospatial skill that are primarily mediated by frontal networks and by the cholinergic system, rather than memory, may be slowed by treatment targeting the cholinergic system.
PMCID: PMC4255390  PMID: 25484926
9.  Subcortical hyperintensity volumetrics in Alzheimer’s disease and normal elderly in the Sunnybrook Dementia Study: correlations with atrophy, executive function, mental processing speed, and verbal memory 
Subcortical hyperintensities (SHs) are radiological entities commonly observed on magnetic resonance imaging (MRI) of patients with Alzheimer’s disease (AD) and normal elderly controls. Although the presence of SH is believed to indicate some form of subcortical vasculopathy, pathological heterogeneity, methodological differences, and the contribution of brain atrophy associated with AD pathology have yielded inconsistent results in the literature.
Using the Lesion Explorer (LE) MRI processing pipeline for SH quantification and brain atrophy, this study examined SH volumes of interest and cognitive function in a sample of patients with AD (n = 265) and normal elderly controls (n = 100) from the Sunnybrook Dementia Study.
Compared with healthy controls, patients with AD were found to have less gray matter, less white matter, and more sulcal and ventricular cerebrospinal fluid (all significant, P <0.0001). Additionally, patients with AD had greater volumes of whole-brain SH (P <0.01), periventricular SH (pvSH) (P <0.01), deep white SH (dwSH) (P <0.05), and lacunar lesions (P <0.0001). In patients with AD, regression analyses revealed a significant association between global atrophy and pvSH (P = 0.02) and ventricular atrophy with whole-brain SH (P <0.0001). Regional volumes of interest revealed significant correlations with medial middle frontal SH volume and executive function (P <0.001) in normal controls but not in patients with AD, global pvSH volume and mental processing speed (P <0.01) in patients with AD, and left temporal SH volume and memory (P <0.01) in patients with AD.
These brain-behavior relationships and correlations with brain atrophy suggest that subtle, yet measurable, signs of small vessel disease may have potential clinical relevance as targets for treatment in Alzheimer’s dementia.
PMCID: PMC4255416  PMID: 25478020
10.  Overcoming obstacles to repurposing for neurodegenerative disease 
Repurposing Food and Drug Administration (FDA)-approved drugs for a new indication may offer an accelerated pathway for new treatments to patients but is also fraught with significant commercial, regulatory, and reimbursement challenges. The Alzheimer’s Drug Discovery Foundation (ADDF) and the Michael J. Fox Foundation for Parkinson’s Research (MJFF) convened an advisory panel in October 2013 to understand stakeholder perspectives related to repurposing FDA-approved drugs for neurodegenerative diseases. Here, we present opportunities on how philanthropy, industry, and government can begin to address these challenges, promote policy changes, and develop targeted funding strategies to accelerate the potential of FDA-approved repurposed drugs.
PMCID: PMC4184781  PMID: 25356422
11.  Spatial and temporal gait parameters in Alzheimer’s disease and aging 
Gait & posture  2009;30(4):452-454.
This study compared spatial and temporal gait parameters in patients with mild stage of Alzheimer’s Disease [AD] and matched normal controls [NC]. Forty patients with mild AD and 34 NC were asked to walk over-ground, and subsequently on a (harness-secured) treadmill, both at preferred speed. Overground gait-velocity, cycle-time, cadence, stride-length, stride-width and double-support time were averaged over a minimum of three traverses on an automated walkway [GAITRite]. Cadence, cycle-time and double-support time was obtained on the treadmill using footswitches. The groups were well matched on baseline characteristics. The AD group were significantly slower on the Timed-up-and-go task compared to NC [p<0.05]. AD patients differed significantly from the NC on their over-ground gait velocity [99±19 cm/sec vs 119+15 cm/sec, p<0.0001], cadence [101±9 steps/min vs 109±9 steps/min, p<0.001] and stride-length [118±18cm vs 131±17cm, p<0.01]. Preferred speed on the treadmill was significantly slower in the AD group than the NC group [60±20 cm/sec vs 74±23 cm/sec, p=0.01], but at their preferred constant belt speed, no significant differences were observed in gait parameters collected on the treadmill. Patients with mild AD may have subtle changes in gait compared to NC which relate to temporal gait characteristics. At a steady belt-speed on the treadmill, these differences in temporal measures are no longer seen suggesting that early gait changes in AD relate to step-timing and gait-speed.
PMCID: PMC4030705  PMID: 19740661
12.  Executive deficits detected in mild Alzheimer's disease using the antisaccade task 
Brain and Behavior  2012;2(1):15-21.
The antisaccade task, a hands- and language-free metric, may provide a functional index of the dorsolateral prefrontal cortex (DLPFC), a region damaged in the later stages of Alzheimer's disease (AD). Our objective was to determine if patients with mild AD made more errors relative to age-matched controls. Thirty patients with mild AD (Mini Mental Status Exam [MMSE] ≥ 17) and 31 age-matched controls completed a laptop version of the prosaccades and antisaccades tasks. Patients with AD made more antisaccade errors, and corrected fewer errors, than age-matched controls. Error rates, corrected or uncorrected, were not correlated with AD MMSE or Dementia Rating Scale scores. Our findings indicate that antisaccade impairments exist in mild AD, suggesting clinically detectable DLPFC pathology may be present earlier than suggested by previous studies.
PMCID: PMC3343295  PMID: 22574270
Alzheimer's disease; dementia; executive control; saccades
13.  A Direct Morphometric Comparison of Five Labeling Protocols for Multi-Atlas Driven Automatic Segmentation of the Hippocampus in Alzheimer’s Disease 
NeuroImage  2012;0:50-70.
Hippocampal volumetry derived from structural MRI is increasingly used to delineate regions of interest for functional measurements, assess efficacy in therapeutic trials of Alzheimer’s disease (AD) and has been endorsed by the new AD diagnostic guidelines as a radiological marker of disease progression. Unfortunately, morphological heterogeneity in AD can prevent accurate demarcation of the hippocampus. Recent developments in automated volumetry commonly use multitemplate fusion driven by expert manual labels, enabling highly accurate and reproducible segmentation in disease and healthy subjects. However, there are several protocols to define the hippocampus anatomically in vivo, and the method used to generate atlases may impact automatic accuracy and sensitivity – particularly in pathologically heterogeneous samples. Here we report a fully automated segmentation technique that provides a robust platform to directly evaluate both technical and biomarker performance in AD among anatomically unique labeling protocols. For the first time we test head-to-head the performance of five common hippocampal labeling protocols for multi-atlas based segmentation, using both the Sunnybrook Longitudinal Dementia Study and the entire Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI-1) baseline and 24-month dataset. We based these atlas libraries on the protocols of (Haller et al., 1997; Killiany et al., 1993; Malykhin et al., 2007; Pantel et al., 2000; Pruessner et al., 2000), and a single operator performed all manual tracings to generate de facto “ground truth” labels. All methods distinguished between normal elders, mild cognitive impairment (MCI), and AD in the expected directions, and showed comparable correlations with measures of episodic memory performance. Only more inclusive protocols distinguished between stable MCI and MCI-to-AD converters, and had slightly better associations with episodic memory. Moreover, we demonstrate that protocols including more posterior anatomy and dorsal white matter compartments furnish the best voxel-overlap accuracies (Dice Similarity Coefficient = 0.87–0.89), compared to expert manual tracings, and achieve the smallest sample sizes required to power clinical trials in MCI and AD. The greatest distribution of errors was localized to the caudal hippocampus and alveus-fimbria compartment when these regions were excluded. The definition of the medial body did not significantly alter accuracy among more comprehensive protocols. Voxel-overlap accuracies between automatic and manual labels were lower for the more pathologically heterogeneous Sunnybrook study in comparison to the ADNI-1 sample. Finally, accuracy among protocols appears to significantly differ the most in AD subjects compared to MCI and normal elders. Together, these results suggest that selection of a candidate protocol for fully automatic multi-template based segmentation in AD can influence both segmentation accuracy when compared to expert manual labels and performance as a biomarker in MCI and AD.
PMCID: PMC3606906  PMID: 23142652
Automatic Hippocampal Segmentation; Multi-atlas; Alzheimer’s disease; Hippocampal Tracing Protocol
14.  Investigation of C9orf72 in 4 Neurodegenerative Disorders 
Archives of neurology  2012;69(12):1583-1590.
To estimate the allele frequency of C9orf72 (G4C2) repeats in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer disease (AD), and Parkinson disease (PD).
The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained APOE genotypes and MAPT H1/H2 haplotypes.
Hospitals specializing in neurodegenerative disorders.
We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the LRRK2 G2019S mutation.
Main Outcome Measure
The expansion frequency.
Based on a prior cutoff (>30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly associated with family history of ALS or FTLD and age at onset of FTLD. Phenotype variation (ALS vs FTLD) was not associated with MAPT, APOE, or variability in the repeat flanking regions. Two patients with PD were carriers of 39 and 32 repeats with questionable pathological significance, since the 39-repeat allele does not segregate with PD. No expansion or intermediate alleles (20–29 repeats) were found among the G2019S carriers and AD cases with TAR DNA-binding protein 43–positive inclusions. Surprisingly, the frequency of the 10-repeat allele was marginally increased in all 4 neurodegenerative diseases compared with controls, indicating the presence of an unknown risk variation in the C9orf72 locus.
The C9orf72 expansion is a common cause of ALS and FTLD, but not of AD or PD. Our study raises concern about a reliable cutoff for the pathological repeat number, which is important in the utility of genetic screening.
PMCID: PMC4005900  PMID: 22964832
15.  Lesion Explorer: A Video-guided, Standardized Protocol for Accurate and Reliable MRI-derived Volumetrics in Alzheimer's Disease and Normal Elderly 
Obtaining in vivo human brain tissue volumetrics from MRI is often complicated by various technical and biological issues. These challenges are exacerbated when significant brain atrophy and age-related white matter changes (e.g. Leukoaraiosis) are present. Lesion Explorer (LE) is an accurate and reliable neuroimaging pipeline specifically developed to address such issues commonly observed on MRI of Alzheimer's disease and normal elderly. The pipeline is a complex set of semi-automatic procedures which has been previously validated in a series of internal and external reliability tests1,2. However, LE's accuracy and reliability is highly dependent on properly trained manual operators to execute commands, identify distinct anatomical landmarks, and manually edit/verify various computer-generated segmentation outputs.
LE can be divided into 3 main components, each requiring a set of commands and manual operations: 1) Brain-Sizer, 2) SABRE, and 3) Lesion-Seg. Brain-Sizer's manual operations involve editing of the automatic skull-stripped total intracranial vault (TIV) extraction mask, designation of ventricular cerebrospinal fluid (vCSF), and removal of subtentorial structures. The SABRE component requires checking of image alignment along the anterior and posterior commissure (ACPC) plane, and identification of several anatomical landmarks required for regional parcellation. Finally, the Lesion-Seg component involves manual checking of the automatic lesion segmentation of subcortical hyperintensities (SH) for false positive errors.
While on-site training of the LE pipeline is preferable, readily available visual teaching tools with interactive training images are a viable alternative. Developed to ensure a high degree of accuracy and reliability, the following is a step-by-step, video-guided, standardized protocol for LE's manual procedures.
PMCID: PMC4168739  PMID: 24797507
Medicine; Issue 86; Brain; Vascular Diseases; Magnetic Resonance Imaging (MRI); Neuroimaging; Alzheimer Disease; Aging; Neuroanatomy; brain extraction; ventricles; white matter hyperintensities; cerebrovascular disease; Alzheimer disease
16.  FDG-PET in Semantic Dementia after 6 Months of Memantine: an Open-Label Pilot Study 
To follow up on the increases we reported in normalized metabolic activity in salience network hubs from a 2-month open label study of memantine in frontotemporal dementia (FTD).
We repeated fluoro-deoxyglucose positron emission tomography (PET) after 6 months of drug use and subjected the data to an SPM analysis to reveal clusters of significant change from baseline. We also sought correlations between changes in behavioral disturbances on the Frontal Behavioral Inventory (FBI).
Recruitment of one progressive nonfluent aphasia and one behavioral variant FTD precluded statistical analysis for any FTD subtype other than semantic dementia. The baseline-to-6-month interval showed increased normalized metabolic activity in the left orbitofrontal cortex (p<0.002) for 5 participants with semantic dementia. The 2–6 month interval revealed a late increase in normalized metabolic activity in the left insula (p<0.013), right insula (p<0.009), and left anterior cingulate (p<0.005). The right anterior cingulate showed both an initial increase and a delayed, further increase (2–6 month, p<0.016). FBI scores worsened by 43.3%. One participant with semantic dementia opted not to continue memantine beyond 2 months yet showed similar FDG-PET increases.
Increases in normalized cortical metabolic activity in salience network hubs were sustained in SD over a 6-month period. Since one participant without medication also showed these changes, further investigation is recommended through a double-blind, placebo-controlled study with FDG-PET as an outcome measure.
PMCID: PMC3467357  PMID: 22674572
frontotemporal dementia; metabolism; PET scan; semantic dementia
17.  Temporal gait symmetry and velocity differ in their relationship to age 
Gait & posture  2012;35(4):590-594.
Measurement of gait is essential for identifying underlying deficits contributing to gait dysfunction, guiding clinical decisions and measuring rehabilitation outcomes. Velocity is commonly used to measure gait, however, its interpretation in patient populations is complicated by the confound of age. Gait symmetry may be an additional and valuable measure since it may not feature the same age-related changes as velocity. The purpose of this study was to determine if gait symmetry is related to age.
Spatiotemporal gait parameters were recorded for 172 individuals with stroke and 81 healthy adults walking across a pressure sensitive mat at their preferred speed. Swing time, stance time and step length symmetry ratios were calculated. The relationship of age to velocity and symmetry was examined using Pearson correlations.
There was a significant negative association between velocity and age in the healthy group (r=−0.57, p<0.01). There were no significant relationships between age and any of the three symmetry ratios for either the stroke or healthy groups.
The main finding of the current study is that gait symmetry ratios are not significantly associated with age in either a healthy or a post-stroke group. Gait symmetry ratios may therefore, allow the clinician and the researcher to make judgments about the effects of disease (such as stroke) on the control of an individual’s gait without the confound of age.
PMCID: PMC3914537  PMID: 22300728
18.  Early-onset dementias: diagnostic and etiological considerations 
Alzheimer's Research & Therapy  2013;5(Suppl 1):S7.
This paper summarizes the body of literature about early-onset dementia (EOD) that led to recommendations from the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. A broader differential diagnosis is required for EOD compared with late-onset dementia. Delays in diagnosis are common, and the social impact of EOD requires special care teams. The etiologies underlying EOD syndromes should take into account family history and comorbid diseases, such as cerebrovascular risk factors, that may influence the clinical presentation and age at onset. For example, although many EODs are more likely to have Mendelian genetic and/or metabolic causes, the presence of comorbidities may drive the individual at risk for late-onset dementia to manifest the symptoms at an earlier age, which contributes further to the observed heterogeneity and may confound diagnostic investigation. A personalized medicine approach to diagnosis should therefore be considered depending on the age at onset, clinical presentation, and comorbidities. Genetic counseling and testing as well as specialized biochemical screening are often required, especially in those under the age of 40 and in those with a family history of autosomal dominant or recessive disease. Novel treatments in the drug development pipeline for EOD, such as genetic forms of Alzheimer's disease, should target the specific pathogenic cascade implicated by the mutation or biochemical defect.
PMCID: PMC3936399  PMID: 24565469
19.  A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies 
JAMA neurology  2013;70(6):10.1001/jamaneurol.2013.1925.
While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders.
To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB).
We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity.
Eleven centers from sites around the world performing genotyping.
Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity.
Main Outcome Measures
Frequency of GBA1 mutations in cases and controls.
We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78–14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53–15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P<.001), with higher disease severity scores.
Conclusions and Relevance
Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.
PMCID: PMC3841974  PMID: 23588557
20.  Vascular Contributions to Cognitive Impairment and Dementia 
Background and Purpose
This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment and dementia of later life are common. Definitions of vascular cognitive impairment (VCI), neuropathology, basic science and pathophysiological aspects, role of neuroimaging and vascular and other associated risk factors, and potential opportunities for prevention and treatment are reviewed. This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment.
Writing group members were nominated by the writing group co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council Scientific Statement Oversight Committee, the Council on Epidemiology and Prevention, and the Manuscript Oversight Committee. The writing group used systematic literature reviews (primarily covering publications from 1990 to May 1, 2010), previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. After peer review by the American Heart Association, as well as review by the Stroke Council leadership, Council on Epidemiology and Prevention Council, and Scientific Statements Oversight Committee, the statement was approved by the American Heart Association Science Advisory and Coordinating Committee.
The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury—not solely stroke—ranging from mild cognitive impairment through fully developed dementia. Dysfunction of the neurovascular unit and mechanisms regulating cerebral blood flow are likely to be important components of the pathophysiological processes underlying VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage of the brain, and VCI. The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment. In this regard, magnetic resonance imaging and other neuroimaging techniques play an important role in the definition and detection of VCI and provide evidence that subcortical forms of VCI with white matter hyperintensities and small deep infarcts are common. In many cases, risk markers for VCI are the same as traditional risk factors for stroke. These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease. Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI. Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration. However, detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of VCI, even in older people.
Vascular contributions to cognitive impairment and dementia are important. Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies. Transdisciplinary, translational, and transactional approaches are recommended to further our understanding of this entity and to better characterize its neuropsychological profile. There is a need for prospective, quantitative, clinical-pathological-neuroimaging studies to improve knowledge of the pathological basis of neuroimaging change and the complex interplay between vascular and Alzheimer disease pathologies in the evolution of clinical VCI and Alzheimer disease. Long-term vascular risk marker interventional studies beginning as early as midlife may be required to prevent or postpone the onset of VCI and Alzheimer disease. Studies of intensive reduction of vascular risk factors in high-risk groups are another important avenue of research.
PMCID: PMC3778669  PMID: 21778438
AHA Scientific Statements; vascular dementia; Alzheimer disease; risk factors; prevention; treatment
21.  Quantified MRI and cognition in TBI with diffuse and focal damage☆ 
NeuroImage : clinical  2013;2:534-541.
In patients with chronic-phase traumatic brain injury (TBI), structural MRI is readily attainable and provides rich anatomical information, yet the relationship between whole-brain structural MRI measures and neurocognitive outcome is relatively unexplored and can be complicated by the presence of combined focal and diffuse injury. In this study, sixty-three patients spanning the full range of TBI severity received high-resolution structural MRI concurrent with neuropsychological testing. Multivariate statistical analysis assessed covariance patterns between volumes of grey matter, white matter, and sulcal/subdural and ventricular CSF across 38 brain regions and neuropsychological test performance. Patients with diffuse and diffuse + focal injury were analyzed both separately and together. Tests of speeded attention, working memory, and verbal learning and memory robustly covaried with a distributed pattern of volume loss over temporal, ventromedial prefrontal, right parietal regions, and cingulate regions. This pattern was modulated by the presence of large focal lesions, but held even when analyses were restricted to those with diffuse injury. Effects were most consistently observed within grey matter. Relative to regional brain volumetric data, clinically defined injury severity (depth of coma at time of injury) showed only weak relation to neuropsychological outcome. The results showed that neuropsychological test performance in patients with TBI is related to a distributed pattern of volume loss in regions mediating mnemonic and attentional processing. This relationship holds for patients with and without focal lesions, indicating that diffuse injury alone is sufficient to cause significant neuropsychological disability in relation to regional volume loss. Quantified structural brain imaging data provides a highly sensitive index of brain integrity that is related to cognitive functioning in chronic phase TBI.
PMCID: PMC3773881  PMID: 24049744
Structural MRI; Neuropsychological assessment; Executive Function; Attention; Memory; Traumatic Brain Injury
22.  Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration 
Lancet Neurology  2013;12(8):822-838.
Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).
PMCID: PMC3714437  PMID: 23867200
23.  Are there long-term benefits of donepezil in Alzheimer's disease? 
PMCID: PMC524947  PMID: 15559925
25.  Clinical, imaging, and pathological heterogeneity of the Alzheimer's disease syndrome 
With increasing knowledge of clinical in vivo biomarkers and the pathological intricacies of Alzheimer's disease (AD), nosology is evolving. Harmonized consensus criteria that emphasize prototypic illness continue to develop to achieve diagnostic clarity for treatment decisions and clinical trials. However, it is clear that AD is clinically heterogeneous in presentation and progression, demonstrating variable topographic distributions of atrophy and hypometabolism/hypoperfusion. AD furthermore often keeps company with other conditions that may further nuance clinical expression, such as synucleinopathy exacerbating executive and visuospatial dysfunction and vascular pathologies (particularly small vessel disease that is increasingly ubiquitous with human aging) accentuating frontal-dysexecutive symptomatology. That some of these atypical clinical patterns recur may imply the existence of distinct AD variants. For example, focal temporal lobe dysfunction is associated with a pure amnestic syndrome, very slow decline, with atrophy and neurofibrillary tangles limited largely to the medial temporal region including the entorhinal cortex. Left parietal atrophy and/or hypometabolism/hypoperfusion are associated with language symptoms, younger age of onset, and faster rate of decline - a potential 'language variant' of AD. Conversely, the same pattern but predominantly affecting the right parietal lobe is associated with a similar syndrome but with visuospatial symptoms replacing impaired language function. Finally, the extremely rare frontal variant is associated with executive dysfunction out of keeping with degree of memory decline and may have prominent behavioural symptoms. Genotypic differences may underlie some of these subtypes; for example, absence of apolipoprotein E e4 is often associated with atypicality in younger onset AD. Understanding the mechanisms behind this variability merits further investigation, informed by recent advances in imaging techniques, biomarker assays, and quantitative pathological methods, in conjunction with standardized clinical, functional, neuropsychological and neurobehavioral evaluations. Such an understanding is needed to facilitate 'personalized AD medicine', and eventually allow for clinical trials targeting specific AD subtypes. Although the focus legitimately remains on prototypic illness, continuing efforts to develop disease-modifying therapies should not exclude the rarer AD subtypes and common comorbid presentations, as is currently often the case. Only by treating them as well can we address the full burden of this devastating dementia syndrome.
PMCID: PMC3580331  PMID: 23302773

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