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Objectives: Recent evidence suggests attention-deficit/hyperactivity disorder (ADHD) is a risk factor for cognitive impairment in later life. Here, we investigated cerebrovascular burden, quantified using white matter hyperintensity (WMH) volumes, as a potential mediator of this relationship., Design: This was a cross-sectional observational study., Setting: Participants were recruited from a cognitive neurology clinic where they had been referred for cognitive assessment, or from the community., Participants: Thirty-nine older adults with clinical ADHD and 50 age- and gender-matched older adults without ADHD., Measurements: A semiautomated structural MRI pipeline was used to quantify periventricular (pWMH) and deep WMH (dWMH) volumes. Cognition was measured using standardized tests of memory, processing speed, visuo-construction, language, and executive functioning. Mediation models, adjusted for sex, were built to test the hypothesis that ADHD status exerts a deleterious impact on cognitive performance via WMH burden., Results: Results did not support a mediated effect of ADHD on cognition. Post hoc inspection of the data rather suggested a moderated effect, which was investigated as an a posteriori hypothesis. These results revealed a significant moderating effect of WMH on the relationship between ADHD memory, speed, and executive functioning, wherein ADHD was negatively associated with cognition at high and medium levels of WMH, but not when WMH volumes were low., Conclusions: ADHD increases older adults' susceptibility to the deleterious cognitive effects of WMH in the brain. Older adults with ADHD may be at risk for cognitive impairment if they have deep WMH volumes above 61 mm 3 and periventricular WMH above 260 mm 3 ., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Interactions between subcortical vascular disease and dementia due to Alzheimer's disease (AD) are unclear, and clinical overlap between the diseases makes diagnosis challenging. Existing studies have shown regional microstructural changes specific to each disease, and that textures in fluid-attenuated inversion recovery (FLAIR) MRI images may characterize abnormalities in tissue microstructure. This work aims to investigate regional FLAIR biomarkers that can differentiate dementia cohorts with and without subcortical vascular disease. FLAIR and diffusion MRI (dMRI) volumes were obtained in 65 mild cognitive impairment (MCI), 21 AD, 44 subcortical vascular MCI (scVMCI), 22 Mixed etiology, and 48 healthy elderly patients. FLAIR texture and intensity biomarkers were extracted from the normal appearing brain matter (NABM), WML penumbra, blood supply territory (BST), and white matter tract regions of each patient. All FLAIR biomarkers were correlated to dMRI metrics in each region and global WML load, and biomarker means between groups were compared using ANOVA. Binary classifications were performed using Random Forest classifiers to investigate the predictive nature of the regional biomarkers, and SHAP feature analysis was performed to further investigate optimal regions of interest for differentiating disease groups. The regional FLAIR biomarkers were strongly correlated to MD, while all biomarker regions but white matter tracts were strongly correlated to WML burden. Classification between Mixed disease and healthy, AD, and scVMCI patients yielded accuracies of 97%, 81%, and 72% respectively using WM tract biomarkers. Classification between scVMCI and healthy, MCI, and AD patients yielded accuracies of 89%, 84%, and 79% respectively using penumbra biomarkers. Only the classification between AD and healthy patients had optimal results using NABM biomarkers. This work presents novel regional FLAIR biomarkers that may quantify white matter degeneration related to subcortical vascular disease, and which indicate that investigating degeneration in specific regions may be more important than assessing global WML burden in vascular disease groups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Magnetic resonance imaging (MRI) scanner-specific geometric distortions may contribute to scanner induced variability and decrease volumetric measurement precision for multi-site studies. The purpose of this study was to determine whether geometric distortion correction increases the precision of brain volumetric measurements in a multi-site multi-scanner study., Methods: Geometric distortion variation was quantified over a one-year period at 10 sites using the distortion fields estimated from monthly 3D T1-weighted MRI geometrical phantom scans. The variability of volume and distance measurements were quantified using synthetic volumes and a standard quantitative MRI (qMRI) phantom. The effects of geometric distortion corrections on MRI derived volumetric measurements of the human brain were assessed in two subjects scanned on each of the 10 MRI scanners and in 150 subjects with cerebrovascaular disease (CVD) acquired across imaging sites., Results: Geometric distortions were found to vary substantially between different MRI scanners but were relatively stable on each scanner over a one-year interval. Geometric distortions varied spatially, increasing in severity with distance from the magnet isocenter. In measurements made with the qMRI phantom, the geometric distortion correction decreased the standard deviation of volumetric assessments by 35% and distance measurements by 42%. The average coefficient of variance decreased by 16% in gray matter and white matter volume estimates in the two subjects scanned on the 10 MRI scanners., Conclusion: Geometric distortion correction using an up-to-date correction field is recommended to increase precision in volumetric measurements made from MRI images., (Copyright © 2022 Elsevier Inc. All rights reserved.)

For many years there has been uncertainty regarding how apolipoprotein E (APOE) E2 and E4 variants may influence overlapping features of neurodegeneration, such as cognitive impairment. We aimed to identify whether the APOE variants are associated with cognitive function across various neurodegenerative and cerebrovascular diagnoses (n = 513). Utilizing a comprehensive neuropsychology battery, multivariate multiple regression was used to assess the influence of APOE carrier status and disease cohort on performance across five cognitive domains. Irrespective of disease cohort, E4 carriers had significantly lower performance in verbal memory and visuospatial domains than those with E3/3, while E2 carriers' cognitive performance was not significantly different. However, E2 carriers with frontotemporal dementia (FTD) performed significantly worse than those with E3/3 in the attention/working memory, executive function, and visuospatial domains. Our results highlight that the influence of APOE variation on cognition is complex, in some cases varying based on diagnosis and possibly underlying disease pathology., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Some studies suggest that angiotensin II type 1 receptor blockers (ARBs) may protect against memory decline more than angiotensin-converting enzyme inhibitors (ACE-Is), but few have examined possible mechanisms. We assessed longitudinal differences between ARB versus ACE-I users in global and sub-regional amyloid-β accumulation by 18 F-florbetapir. In cognitively normal older adults (n= 142), propensity-weighted linear mixed-effects models showed that ARB versus ACE-I use was associated with slower amyloid-β accumulation in the cortex, and specifically in the caudal anterior cingulate and precuneus, and in the precentral and postcentral gyri. In amyloid-positive participants with Alzheimer's disease dementia or mild cognitive impairment (n = 169), ARB versus ACE-I use was not associated with different rates of amyloid-β accumulation. Apolipoprotein E ε4 carrier status explained some heterogeneity in the different rates of amyloid-β accumulation between users of ARBs versus ACE-Is in the study. Replicative studies and clinical trials are warranted to confirm potential benefits of ARBs on rates of amyloid-β accumulation in the contexts of Alzheimer's disease prevention and treatment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: ICU survivors can experience both cognitive dysfunction and persistent sleep disturbances after hospitalization. Sleep disturbances have been linked with cognitive impairment in various patient populations, and the apolipoprotein E (APOE) genotype has been linked to sleep-related impairments in cognition., Research Question: Is there an association between sleep, long-term cognition, and APOE status in ICU survivors?, Study Design and Methods: We enrolled 150 patients from five centers who had been mechanically ventilated for at least 3 days; 102 patients survived to ICU discharge. Actigraphy and cognitive testing were undertaken at 7 days, 6 months, and 12 months after ICU discharge, and sleep duration, quality, and timing were estimated by actigraphy. APOE single nucleotide polymorphisms were assessed for each patient., Results: Actigraphy-estimated sleep fragmentation, but not total sleep time or interdaily stability (estimate of circadian rhythmicity), was associated with worse cognitive impairment at 7 days of ICU discharge. No actigraphy-estimated variable of sleep estimation at 7 days post-ICU discharge predicted cognitive impairment or persistent sleep abnormalities at 6 and 12 months of follow-up in subsequently assessed survivors. Possessing the APOE ε4 allele was not significantly associated with sleep disturbances and its presence did not modify the risk of sleep-related cognitive impairment at follow-up., Interpretation: Sleep fragmentation estimated by actigraphy was associated with worse cognitive performance in hospital, but not at later time intervals. Further research is needed to better delineate the relationship between persistent sleep disturbances and cognition in larger numbers of ICU survivors., Trial Registry: ClinicalTrials.gov; No.: NCT02086877; URL: www.clinicaltrials.gov., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

In the present study, we tested the hypothesis that higher amyloid-beta (Aβ) burden at baseline is associated with greater longitudinal decline in body mass index (BMI) in clinically normal adults. Participants from the Harvard Aging Brain Study (n = 312) and the Alzheimer's Disease Neuroimaging Initiative (n = 336) underwent Aβ positron emission tomography at baseline. BMI was assessed longitudinally over a median of >4 years. Linear mixed models showed that higher baseline Aβ burden was significantly associated with greater decline in BMI in both the Harvard Aging Brain Study (t = -1.93; p = 0.05) and Alzheimer's Disease Neuroimaging Initiative cohorts (t = -2.54; p = 0.01), after adjusting for covariates, including cognitive performance and depressive symptoms. In addition, the association of Aβ burden with longitudinal decline in BMI persisted in both cohorts after excluding participants with diabetes/endocrine disturbances and participants classified as underweight or obese (BMI <18.5 or >30). These findings suggest that decline in BMI in clinically normal adults may be an early manifestation related to cerebral amyloidosis that precedes objective cognitive impairment. Therefore, unintentional BMI decline in otherwise healthy individuals might alert clinicians to increased risk of Alzheimer's disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Stroke lesions in non-auditory areas may affect higher-order central auditory processing. We sought to characterize auditory functions in chronic stroke survivors with unilateral arm/hand impairment using auditory evoked responses (AERs) with lesion and perception metrics., Methods: The AERs in 29 stroke survivors and 14 controls were recorded with single tones, active and passive frequency-oddballs, and a dual-oddball with pitch-contour and time-interval deviants. Performance in speech-in-noise, mistuning detection, and moving-sound detection was assessed. Relationships between AERs, behaviour, and lesion overlap with functional networks, were examined., Results: Despite their normal hearing, eight patients showed unilateral AER in the hemisphere ipsilateral to the affected hand with reduced amplitude compared to those with bilateral AERs. Both groups showed increasing attenuation of later components. Hemispheric asymmetry of AER sources was reduced in bilateral-AER patients. The N1 wave (100 ms latency) and P2 (200 ms) were delayed in individuals with lesions in the basal-ganglia and white-matter, while lesions in the attention network reduced the frequency-MMN (mismatch negativity) responses and increased the pitch-contour P3a response. Patients' impaired speech-in-noise perception was explained by AER measures and frequency-deviant detection performance with multiple regression., Conclusion: AERs reflect disruption of auditory functions due to damage outside of temporal lobe, and further explain complexity of neural mechanisms underlying higher-order auditory perception., Significance: Stroke survivors without obvious hearing problems may benefit from rehabilitation for central auditory processing., Competing Interests: Declaration of Competing Interest None of the authors have potential conflicts of interest to be disclosed., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the efficacy and safety of nabilone for agitation in patients with moderate-to-severe Alzheimer's disease (AD)., Design: This 14-week randomized double-blind crossover trial compared nabilone to placebo (6 weeks each) with a 1-week washout between phases., Setting: Patients were recruited from a long-term care facility and geriatric psychiatry clinics., Participants: Patients had AD (standardized Mini-Mental State Examination [sMMSE ≤24]) and agitation (Neuropsychiatric Inventory-Nursing Home version [NPI-NH]-agitation/aggression subscore ≥3)., Intervention: Nabilone (target 1-2 mg) versus placebo., Measurements: The primary outcome was agitation (Cohen Mansfield Agitation Inventory [CMAI]). Secondary outcomes included NPI-NH total, NPI-NH caregiver distress, cognition (sMMSE and Severe Impairment Battery [SIB] or Alzheimer's Disease Assessment Scale of Cognition), global impression (Clinician's Global Impression of Change [CGIC]), and adverse events., Results: Thirty-nine patients (mean ± SD age = 87 ± 10, sMMSE = 6.5 ± 6.8, CMAI = 67.9 ± 17.6, NPI-NH total = 34.3 ± 15.8, 77% male, nabilone dose = 1.6 ± 0.5 mg) were randomized. There were no crossover or treatment-order effects. Using a linear mixed model, treatment differences (95% CI) in CMAI (b = -4.0 [-6.5 to -1.5], t(30.2) = -3.3, p = 0.003), NPI-NH total (b = -4.6 [-7.5 to -1.6], t(32.9) = -3.1, p = 0.004), NPI-NH caregiver distress (b = -1.7 [-3.4 to -0.07, t(33.7) = -2.1, p = 0.041), and sMMSE (b = 1.1 [0.1-2.0], t(22.6) = 2.4, p = 0.026) all favored nabilone. However, in those who completed the SIB (n = 25) treatment differences favored placebo (b = -4.6 [-7.3 to -1.8], t(20.7) = -4.8, p = 0.003). CGIC improvement during nabilone (47%) and placebo (23%) was not significantly different (McNemar's test, exact p = 0.09). There was more sedation during nabilone (45%) compared to placebo (16%) phases (McNemar's test, exact p = 0.02), but treatment-limiting sedation was not significantly different (McNemar's test, exact p = 0.22)., Conclusions: Nabilone may be an effective treatment for agitation. However, sedation and cognition should be closely monitored., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Some degree of ischemic injury to white matter tracts occurs naturally with age and is visible on magnetic resonance imaging as focal or confluent white matter hyperintensities. Its relationship to cognition, however, remains unclear. To explore this, community-dwelling adults between the ages 55 and 80 years completed structural imaging, neuropsychological testing, and questionnaires to provide objective measures and subjective experience of executive functioning. Volumetric lesion burden derived from structural MRI identified those with significant white matter hyperintensity burden (∼10 cm 3 ). Half of those recruited met this criterion and were designated as the cerebral small vessel disease (CSVD) group. Subjective cognitive complaints but not objective test scores differentiated adults with and without CSVD. Hierarchical clustering revealed 2 CSVD subgroups that differentiated those with impaired versus preserved executive function relative to controls. Overall these results provide some explanation for behavioral heterogeneity often observed in studies of age-related white matter changes. They also support the use of questionnaires to assess subjective cognitive complaints that may point to subtle effects of vascular pathology not evident on standardized cognitive scores., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The harmonized Canadian Dementia Imaging Protocol (CDIP) has been developed to suit the needs of a number of co-occurring Canadian studies collecting data on brain changes across adulthood and neurodegeneration. In this study, we verify the impact of CDIP parameters compliance on total brain volume variance using 86 scans of the same individual acquired on various scanners. Data included planned data collection acquired within the Consortium pour l'identification précoce de la maladie Alzheimer - Québec (CIMA-Q) and Canadian Consortium on Neurodegeneration in Aging (CCNA) studies, as well as opportunistic data collection from various protocols. For images acquired from Philips scanners, lower variance in brain volumes were observed when the stated CDIP resolution was set. For images acquired from GE scanners, lower variance in brain volumes were noticed when TE/TR values were within 5% of the CDIP protocol, compared to values farther from that criteria. Together, these results suggest that a harmonized protocol like the CDIP may help to reduce neuromorphometric measurement variability in multi-centric studies., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The relationships between cholinergic system damage and cerebrovascular disease are not entirely understood. Here, we investigate associations between atrophy of the substantia innominata (SI; the origin of cortical cholinergic projections) and measures of large and small vessel disease; specifically, elongation of the juxtaposed internal carotid artery termination and Cholinergic Pathways Hyperintensity scores (CHIPS). The study (n = 105) consisted of patients with Alzheimer's disease (AD) and/or subcortical ischemic vasculopathy, and elderly controls. AD and subcortical ischemic vasculopathy groups showed greater impingement of the carotid termination on the SI and smaller SI volumes. Both carotid termination elongation and CHIPS were associated independently with smaller SI volumes in those with and without AD. Atrophy of the SI mediated effects of carotid termination elongation on language and memory functions and the effect of CHIPS on attention/working memory. In conclusion, SI atrophy was related to cerebrovascular disease of the large and small vessels and to cognitive deficits in people with and without AD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The World Alzheimer Report 2016 estimated that 47 million people are living with dementia worldwide (Alzheimer's Disease International, 2016). In the inaugural World Health Organization Ministerial Conference on Global Action against Dementia, six of the top ten research priorities were focused on prevention, identification, and reduction of dementia risk, and on delivery and quality of care for people with dementia and their carers (Shah et al., 2016). While the Lancet Neurology Commission has suggested that even minor advances to delay progression or ameliorate symptoms might have substantial financial and societal benefits (Winblad et al., 2016), advances have been slow.

Background: New onset of mood and behavioral changes in middle-aged patients are frequently the first manifestations of an unrecognized neurocognitive disorder. Impairment of social cognition, the cognitive ability to process social information coming from others, such as emotions, to attribute mental states to others, and to respond appropriately to them, is often at the origin of behavioral manifestations in neurodegenerative disorders., Methods: This paper reviews the current literature on social cognition impairment in neurocognitive disorders, particularly in prodromal stages of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer's disease (AD), idiopathic Parkinson's disease (IPD), and Lewy body dementia (LBD). The concepts of social cognition will be reviewed, including its impairment and neural basis, its clinical assessment, and the different therapeutic interventions available clinically., Results: Socially inappropriate behaviors, such as loss of empathy, inappropriateness of affect, and disinhibition are frequently reported in prodromal bvFTD and in prodromal AD. Lack of self-control, reduced perception of social cues, such as recognition of facial emotions and sarcastic speech, and impaired Theory of Mind all contribute to the neuropsychiatric symptoms and are secondary to neurodegeneration in specific brain regions. In contrasts to bvFTD and AD, deficits in social cognition in IPD occur later in the course of the disease and are often multifactorial in origin., Conclusions: Through various manifestations, social inappropriateness is frequently the first clinical sign of a neurodegenerative process, especially in AD and bvFTD, years before noticeable impairment on classical neuropsychological assessment and brain atrophy on imaging.

Movement is traditionally viewed as a process that involves motor brain regions. However, movement also implicates non-motor regions such as prefrontal and parietal cortex, regions whose integrity may thus be important for motor recovery after stroke. Importantly, focal brain damage can affect neural functioning within and between distinct brain networks implicated in the damage. The aim of this study is to investigate how resting state connectivity (rs-connectivity) within and between motor and frontoparietal networks are affected post-stroke in correlation with motor outcome. Twenty-seven participants with chronic stroke with unilateral upper limb deficits underwent motor assessments and magnetic resonance imaging. Participants completed the Chedoke-McMaster Stroke Assessment as a measure of arm (CMSA-Arm) and hand (CMSA-Hand) impairment and the Action Research Arm Test (ARAT) as a measure of motor function. We used a seed-based rs-connectivity approach defining the motor (seed=contralesional primary motor cortex (M1)) and frontoparietal (seed=contralesional dorsolateral prefrontal cortex (DLPFC)) networks. We analyzed the rs-connectivity within each network (intra-network connectivity) and between both networks (inter-network connectivity), and performed correlations between: a) intra-network connectivity and motor assessment scores; b) inter-network connectivity and motor assessment scores. We found: a) Participants with high rs-connectivity within the motor network (between M1 and supplementary motor area) have higher CMSA-Hand stage (z=3.62, p=0.003) and higher ARAT score (z=3.41, p=0.02). Rs-connectivity within the motor network was not significantly correlated with CMSA-Arm stage (z=1.83, p>0.05); b) Participants with high rs-connectivity within the frontoparietal network (between DLPFC and mid-ventrolateral prefrontal cortex) have higher CMSA-Hand stage (z=3.64, p=0.01). Rs-connectivity within the frontoparietal network was not significantly correlated with CMSA-Arm stage (z=0.93, p=0.03) or ARAT score (z=2.53, p=0.05); and c) Participants with high rs-connectivity between motor and frontoparietal networks have higher CMSA-Hand stage (r s =0.54, p=0.01) and higher ARAT score (r s =0.54, p=0.009). Rs-connectivity between the motor and frontoparietal networks was not significantly correlated with CMSA-Arm stage (r s =0.34, p=0.13). Taken together, the connectivity within and between the motor and frontoparietal networks correlate with motor outcome post-stroke. The integrity of these regions may be important for an individual's motor outcome. Motor-frontoparietal connectivity may be a potential biomarker of motor recovery post-stroke., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Context: Despite a large literature on psi, which encompasses a range of experiences including putative telepathy (mind-mind connections), clairvoyance (perceiving distant objects or events), precognition (perceiving future events), and mind-matter interactions, there has been insufficient focus on the brain in relation to this controversial phenomenon. In contrast, our research is based on a novel neurobiological model suggesting that frontal brain systems act as a filter to inhibit psi and that the inhibitory mechanisms may relate to self-awareness., Objective: To identify frontal brain regions that may inhibit psi., Design: We used mind-matter interactions to study psi in two participants with frontal lobe damage. The experimental task was to influence numerical output of a Random Event Generator translated into movement of an arrow on a computer screen to the right or left. Brain MRI was analyzed to determine frontal volume loss., Results: The primary area of lesion overlap between the participants was in the left medial middle frontal region, an area related to self-awareness, and involved Brodmann areas 9, 10, and 32. Both participants showed a significant effect in moving the arrow to the right, i.e., contralateral to the side of primary lesion overlap. Effect sizes were much larger compared to normal participants., Conclusions: The medial frontal lobes may act as a biological filter to inhibit psi through mechanisms related to self-awareness. Neurobiological studies with a focus on the brain may open new avenues of research on psi and may significantly advance the state of this poorly understood field., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Subcortical white matter hyperintensities (WMH), presumed to indicate small vessel ischemic vascular disease, are found commonly in elderly individuals with and without Alzheimer's disease (AD). Oxidative stress may instigate or accelerate the development of vascular disease, and oxidative stress markers are elevated in AD. Here, we assess independent relationships between three serum lipid peroxidation markers (lipid hydroperoxides [LPH], 8-isoprostane, and 4-hydroxynonenal) and the presence of extensive subcortical WMH and/or AD. Patients were recruited from memory and stroke prevention clinics into four groups: minimal WMH, extensive WMH, AD with minimal WMH, and AD with extensive WMH. Extensive WMH, but not AD, was associated with higher serum concentrations of 8-isoprostane and LPH. Peripheral LPH concentrations mediated the effect of hypertension on deep, but not periventricular, WMH volumes. 4-hydroxynonenal was associated with hyperlipidemia and cerebral microbleeds, but not with extensive WMH or AD. We conclude that lipid peroxidation mediates hypertensive injury to the deep subcortical white matter and that peripheral blood lipid peroxidation markers indicate subcortical small vessel disease regardless of an AD diagnosis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the relationship between both dynamic and steady-state measures of cerebrovascular reactivity (CVR) and the progression of age-related white matter disease., Methods: Blood oxygen level-dependent (BOLD) MRI CVR scans were acquired from forty-five subjects (age range: 50-90 years, 25 males) with moderate to severe white matter disease, at baseline and one-year follow-up. To calculate the dynamic (τ) and steady-state (ssCVR) components of the BOLD signal response, the PETCO2 signal waveform was convolved with an exponential decay function. The τ corresponding to the best fit between the convolved PETCO2 and BOLD signal defined the speed of response, and the slope of the regression between the convolved PETCO2 and BOLD signal defined ssCVR. ssCVR and τ were compared between normal-appearing white matter (NAWM) that remains stable over time and NAWM that progresses to white matter hyperintensities (WMHs)., Results: In comparison to contralateral NAWM, NAWM that progressed to WMH had significantly lower ssCVR values by mean (SD) 46.5 (7.6)%, and higher τ values by 31.9 (9.6)% (both P < 0.01)., Conclusions: Vascular impairment in regions of NAWM that progresses to WMH consists not only of decreased magnitude of ssCVR, but also a pathological decrease in the speed of vascular response. These findings support the association between cerebrovascular dysregulation and the development of WMH.

Objective: Coronary artery disease (CAD) is associated with an increased risk of cognitive decline. Although cerebral white matter (WM) damage predicts cognitive function in CAD, conventional neuroimaging measures only partially explain the effect of CAD on cognition. The purpose of this study was to determine if WM microstructural integrity and CAD using diffusion tensor imaging (DTI) correlates with cognitive function in older adults with CAD., Methods: Forty-nine CAD patients (66 ± 7 years old, 86% male) underwent neurocognitive assessments using the cognitive battery recommended by the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network for the study of vascular cognitive impairment. Composite scores for each cognitive domain were calculated. Microstructural integrity in normal-appearing WM was quantified as fractional anisotropy (FA) using DTI in nine bilateral and two interhemispheric WM tracts from the Johns Hopkins University WM Tractography Atlas. Linear regression models examined associations between FA and cognitive performance, controlling for age, sex, and education, with correction for multiple comparisons using a false discovery rate of 5%., Results: Executive function was most significantly associated with FA in the left parahippocampal cingulum (β = 0.471, t = 3.381, df = 44, p = 0.002) and left inferior fronto-occipital fasciculus (β = 0.430, t = 2.984, df = 44, p = 0.005). FA was not associated with memory in any of the WM tracts examined., Conclusion: These results suggest that WM microstructural integrity may be an important neural correlate of executive function even in cognitively intact CAD patients. This study suggests WM damage may be relevant to subtle cognitive decline in a population that may have early neural risk for dementia., (Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Little is known about the effect of methylphenidate (MPH) on attention in Alzheimer's disease (AD). MPH has shown to improve apathy in AD, and both apathy and attention have been related to dopaminergic function. The goal was to investigate MPH effects on attention in AD and assess the relationship between attention and apathy responses., Methods: MPH (10 mg PO twice daily) or placebo was administered for six weeks in a randomized, double-blind trial in mild-to-moderate AD outpatients with apathy (Neuropsychiatric Inventory (NPI) Apathy ≥ 4). Attention was measured with the Wechsler Adult Intelligence Scale--Digit Span (DS) subtest (DS forward, selective attention) and apathy with the Apathy Evaluation Scale (AES). A mixed effects linear regression estimated the difference in change from baseline between treatment groups, defined as δ (MPH (DS week 6-DS baseline)) - (placebo (DS week 6-DS baseline))., Results: In 60 patients (37 females, age = 76 ± 8, Mini-Mental State Examination (MMSE) = 20 ± 5, NPI Apathy = 7 ± 2), the change in DS forward (δ = 0.87 (95% CI: 0.06-1.68), p = 0.03) and DS total (δ = 1.01 (95% CI: 0.09-1.93), p = 0.03) favored MPH over placebo. Of 57 completers, 17 patients had improved apathy (≥3.3 points on the AES from baseline to end point) and 40 did not. There were no significant associations between AES and NPI Apathy with DS change scores in the MPH, placebo, AES responder, or non-responder groups. DS scores did not predict apathy response to MPH treatment., Conclusion: These results suggest MPH can improve attention and apathy in AD; however, the effects appear independent in this population.

The internal carotid artery termination (CAT) ends in a T-shaped bifurcation just below the substantia innominata (SI), which contains cognitively strategic cholinergic neurons and undergoes atrophy in Alzheimer's disease (AD). This study investigated whether an elongated CAT with possible resulting encroachment into the SI would correlate with SI atrophy and with cognitive dysfunction in AD. We rated the degree of CAT encroachment upon the SI and measured SI volume on magnetic resonance imaging in 30 AD patients, 30 AD patients with subcortical small vessel disease, and 30 age-matched controls. CAT encroachment significantly correlated with SI volume after adjusting for age within the overall group and the groups with dementia. AD patients with higher CAT encroachment scores had lower SI volumes and lower attention, memory, and executive test scores. These data suggest that CAT encroachment may mechanically injure the SI, exacerbating cholinergic damage and contributing to cognitive impairment. This process may represent a possible previously underappreciated mechanism for interaction between large-vessel cerebrovascular disease and AD., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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.

Atherosclerosis exacts a large toll on society in the form of cardiovascular morbidity, mortality, and resource use and is exacerbated by the epidemics of obesity and diabetes. Consequently, there is a critical need for more-effective methods of diagnosis, treatment, and prevention of the complications of atherosclerosis. Careful and well-conducted large population studies are needed in order to truly understand the natural history of the disease, its imaging biomarkers, and their links to patient outcomes. The Canadian Atherosclerosis Imaging Network (CAIN) is a unique research network funded by the Canadian Institutes of Health Research and the Canada Foundation for Innovation and designed to address these needs and to enable large population-based imaging studies. The central objective of CAIN is to move innovations in imaging toward their broad application in clinical research and clinical practice for the improved evaluation of cardiac and neurologic vascular disease. CAIN is established as an international resource for studying the natural history, progression, and regression of atherosclerosis, as well as novel therapeutic interventions aimed at atherosclerosis. The network represents Canada's leading atherosclerosis imaging experts, embodying both basic imaging science and clinical imaging research. The network is improving methods of detection and treatment of atherosclerosis and, through a better understanding of the underlying disease itself, improving strategies for disease prevention. The benefits are expected to appear in the next 2 to 3 years. CAIN will drive innovation in imaging technology within the field of cardiology and neurology and improve health outcomes in Canada and worldwide., (Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The purposes of this study were first, to evaluate the effectiveness of citalopram in treating behavioral disturbances in frontotemporal dementia (FTD) subjects and second, to determine whether an association exists between serotonergic function, as determined by a neuroendocrine challenge, and treatment response., Design: Single-dose citalopram (30 mg per os) challenge followed by a 6-week open-label study., Setting: Outpatients referred to memory clinics., Participants: Fifteen patients suffering from FTD with severe behavioral and psychological symptoms of dementia., Intervention: Following citalopram challenge, all patients were treated with citalopram titrated to a target dose of 40 mg once daily., Measurements: Behavioral disturbances, using the Neuropsychiatric Inventory (NPI) (primary outcome) and Frontal Behavioural Inventory (secondary outcome), were assessed. Change in prolactin concentration following citalopram challenge was used as an index of central serotonergic response., Results: Citalopram treatment was effective in treating behavioral symptoms, with significant decreases in NPI total score (F[2, 28] = 6.644, p = 0.004), disinhibition (F[2, 28] = 4.030, p = 0.029), irritability (F[2, 28] = 7.497, p = 0.003) and depression (F[2, 28] = 3.467, p = 0.045) scores over the 6 weeks. Significant improvement in Frontal Behavioural Inventory scores suggested that citalopram was also effective in the treatment ofbehaviors specific to FTD. A lower change score in concentration of prolactin was significantly positively correlated with greater improvement in the total NPI score from baseline to endpoint (r = 0.687, p = 0.005). A blunted response to a citalopram challenge, implying a dysfunctional serotonergic system, predicted a more positive treatment outcome., Conclusions: The results suggest that despite the endogenous serotonin deficiency of FTD, citalopram treatment may be effective in targeting the behavioral disturbances characteristic of FTD.

Instrumental activities of daily living (IADL) includes the integration of task-initiation, -planning, and -performance. Little is known on the cerebral perfusion correlates of these subcomponents of IADL in Alzheimer's disease (AD). In 121 AD patients, cerebral perfusion, using single-photon emission computed tomography, in 13 bilateral regions of interest (ROI) and the perfusion correlates of IADL subcomponents, rated on the Disability Assessment in Dementia scale, were explored. Significant correlations were observed between IADL initiation and multiple bilateral prefrontal-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). Multiple regression, accounting for age, cognitive impairment, and depression severity, revealed significant relationship between right basal ganglia perfusion and IADL-initiation (R = 0.6, R(2) = 0.39, F(4,117) = 17.8, SE = 1.56; p < 0.001) and right occipital perfusion and IADL-planning (R = 0.6, R(2) = 0.34, F(4,117) = 19.5, SE = 1.47; p < 0.001). In AD, perfusion correlates of these subcomponents may be linked to the heterogenous cognitive processes involved in IADL., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: To assess whether the core symptoms of Alzheimer disease (AD) consistently predict patient self-rated quality of life (QOL) as assessed by a variety of QOL measures in a large national sample of AD patients., Design: Cross-sectional., Setting: Fifteen dementia and geriatric clinics across Canada., Participants: Community-living patients with AD (n = 370) with Mini-Mental State Exam (MMSE) scores greater than 10., Measurements: Patients rated their QOL by using two utility indexes, the European QOL-5 Dimensions and the Quality of Well-Being Scale, a global QOL Visual Analog Scale, and the disease-specific QOL-AD instrument. Cognition was assessed with the AD Assessment Scale-Cognitive subscale and MMSE, function with the Disability Assessment for Dementia, and behavioral and psychological symptoms with the Neuropsychiatric Inventory and the Geriatric Depression Scale (GDS). One-way analysis of variance and fully adjusted multiple linear regression were used to assess the relationship between core dementia symptoms and QOL ratings., Results: The QOL measures had only small-to-moderate correlations with each other. For all QOL measures, patient ratings were significantly lower among patients with more depressive symptoms. In multivariable analyses, the GDS score was the only significant independent predictor of patient self-ratings for all four QOL measures., Conclusions: Self-rated symptoms of depression were a consistent independent predictor of patient-rated QOL across diverse QOL measures, while performance-based measures of cognition and informant-based functional status were not. These findings confirm the importance of identifying and treating depression in patients with AD and endorse the use of measures of self-rated depressive symptoms and QOL as outcomes in AD clinical trials.

Objectives: To assess whether the core symptoms of Alzheimer disease (AD) and caregiver factors consistently predict family caregiver ratings of patient quality of life (QOL) as assessed by a variety of QOL measures in a large national sample., Design: : Cross-sectional., Setting: Fifteen dementia and geriatric clinics across Canada., Participants: : Family caregivers (n = 412) of community-living patients with AD of all severities., Measurements: Caregiver ratings of patient QOL using three utility indexes, the European Quality of Life-5 Dimensions, Quality of Well-Being Scale and Health Utilities Index; a global QOL visual analogue scale; a disease-specific measure, the Quality of Life-Alzheimer's Disease; and a generic health status measure, the Short Form-36. Patient cognition was assessed with the cognitive subscale of the Alzheimer's Disease Assessment Scale and Mini-Mental State Examination, function with the Disability Assessment for Dementia, and behavioral and psychological symptoms with the Neuropsychiatric Inventory and the Geriatric Depression Scale. Caregiver burden was assessed with the Zarit Burden Interview and caregiver depression with the Center for Epidemiologic Studies Depression scale. One-way analysis of variance and fully adjusted multiple linear regression were used to assess the relationship between patient dementia symptom and caregiver variables with QOL ratings., Results: In multivariable analyses, caregiver ratings of patient function and depressive symptoms were the only consistent independent predictors of caregiver-rated QOL across the QOL measures., Conclusions: Caregiver ratings of patient function and depression were consistent independent predictors of caregiver-rated QOL, using a spectrum of QOL measures, while measures of patient cognition and caregiver burden and depression were not. These findings support the continued use of caregiver ratings as an important source of information about patient QOL and endorse the inclusion in AD clinical trials of caregiver-rated measures of patient function, depression, and QOL.

Background: Cholinesterase inhibitors (ChEIs) are being used for increasingly long periods of time, even in patients with severe Alzheimer's disease. Because there is little data to help clinicians to decide on when it is safe and appropriate to discontinue ChEIs after long-term use, practices may vary widely., Methods: An internet-based survey was undertaken of Canadian dementia experts (geriatric psychiatrists, neurologists, geriatricians) involved in clinical trial research. Recommendations for ChEI discontinuation were determined based on responses to questions dealing with patient/caregiver preference, administrative considerations, effectiveness, and adverse events., Results: There was reasonable consensus that ChEIs should be discontinued based on patient and caregiver preference, and in the presence of severe bothersome adverse events. There was much less consensus on issues related to effectiveness - in particular, what constitutes greater than expected decline. There was a general reluctance to rely on any single measure of cognition, function and/or behavior, and in particular, the MMSE was seen as unhelpful for making decisions about discontinuation., Conclusion: Recommendations for discontinuing ChEIs after long-term use from a survey of dementia experts are presented. Ideally, clinical practice guidelines based on controlled discontinuation trials are needed.

Objective: To determine whether basal ganglia atrophy, known to be associated with apathy in nondementia populations, was associated with presence of apathy in patients with frontotemporal dementia (FTD)., Methods: A cross-sectional case study was conducted at two tertiary dementia care clinics in Toronto, Ontario, Canada. Striatal and thalamic gray matter volumes and apathy measures were collected from 21 subjects with FTD, 6 of whom did not show apathy on the Neuropsychiatric Inventory., Results: No significant differences in gray matter volumes were found between apathetic and nonapathetic groups for the striatum or the thalamus., Conclusions: Our findings imply that the etiology of apathy seen in patients with FTD differs from that of patients with apathy after acquired injuries to the basal ganglia. Further study is needed to determine whether posterior thalamic atrophy correlates with apathy in FTD or functional imaging techniques might successfully find a relationship between basal ganglia dysfunction and apathy.

Behaviour and fMRI brain activation patterns were compared during encoding and recognition tasks in mild cognitive impairment (MCI) (n=14) and normal controls (NC) (n=14). Deep (natural vs. man-made) and shallow (color vs. black and white) decisions were made at encoding and pictures from each condition were presented for yes/no recognition 20 min later. MCI showed less inferior frontal activation during deep (left only) and superficial encoding (bilaterally) and in both medial temporal lobes (MTL). When performance was equivalent (recognition of words encoded superficially), MTL activation was similar for the two groups, but during recognition testing of deeply encoded items NC showed more activation in both prefrontal and left MTL region. In a region of interest analysis, the extent of activation during deep encoding in the parahippocampi bilaterally and in left hippocampus correlated with subsequent recognition accuracy for those items in controls but not in MCI, which may reflect the heterogeneity of activation responses in conjunction with different degrees of pathology burden and progression status in the MCI group.

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

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

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

Objective: Previous research has shown that cognitively-impaired-not-demented (CIND) individuals with at least one neuropsychiatric symptom (NPS) have more functional disability than individuals without any NPSs. The objectives of the present study were to determine whether there are consistent clusters of NPS in CIND individuals and whether certain NPS clusters are more strongly associated with measures of functional disability than other NPS clusters in this population., Methods: This was a cross-sectional baseline study of NPS using the Neuropsychiatric Inventory (NPI) in a national clinic-based observational cohort study (the Canadian Cohort Study of Cognitive Impairment and Related Dementias study). The present investigation focuses on a subset of CIND subjects (73%) whose informant endorsed the presence of at least one NPI item., Results: A hierarchical cluster analysis identified two NPS clusters. One consisted of mood factors (i.e., depression, anxiety, apathy, irritability, and problems with sleep) and the other cluster captured frontal symptoms (i.e., aberrant motor behavior, disinhibition, agitation, and problems with appetite). NPSs grouped within the mood cluster were more common than the frontal cluster (95% of subjects had at least one NPS within the mood cluster versus 53% in the frontal cluster). However, the frontal cluster was more strongly associated with functional disability measures even after controlling for cognitive status (i.e., the Mini-Mental State Exam) and the mood cluster score., Conclusion: The frontal cluster of NPSs was more strongly associated with functional disability than the mood cluster.

Objective: The important role of serotonin-1A (5-hydroxytryptamine-1A [5-HT(1A)]) receptors in cognition, behavior, and drug response is increasingly being recognized. Postmortem studies suggest decreased 5-HT(1A) receptors in patients with Alzheimer disease (AD), but this has not been confirmed in vivo. Our primary objective was to assess the extent of 5-HT(1A) receptor losses in mild to moderate AD., Methods: The authors examined 5-HT(1A) receptors in 10 patients with mild to moderate AD and 10 healthy volunteers with the same sex and similar age using positron emission tomography imaging with the selective 5-HT(1A) receptor radioligand, [(11)C]WAY-100635. Regions of interest (ROIs) were manually drawn on coregistered magnetic resonance images for the frontal, lateral temporal, medial temporal (MTC), parietal, and cerebellar cortices. Using the simplified reference tissue model, 5-HT(1A) binding potentials (BPs) were calculated relative to the cerebellum., Results: After adjusting for partial volume effects, ROI analysis showed a significant group effect (AD versus comparison group) on BP. Analysis of between-subjects factors showed significantly decreased 5-HT(1A) BP in the right MTC, but not in the other ROIs., Conclusion: Given the strategic role of these receptors, loss of right medial temporal 5-HT(1A) receptors might play an important role in AD symptomatology.

Background and Purpose: There is a need for empirical studies to define criteria for vascular cognitive impairment (VCI) subtypes. In this paper, we report the predictive validity of a subtype classification scheme based on clinical and radiographic features., Methods: Nine Canadian memory clinics participated in the Consortium to Investigate Vascular Impairment of Cognition. This cohort consisted of 1347 patients, of whom 324 had VCI, and was followed for up to 30 months., Results: Clinical and neuroimaging features defined three subtypes: vascular cognitive impairment, no dementia, (n=97), vascular dementia (n=101) and mixed neurodegenerative/vascular dementia (n=126). Any ischemic lesion on neuroimaging increased the odds (odds ratio=9.31; 95% confidence interval 6.46, 13.39) of a VCI diagnosis. No VCI subtype, however, was associated with a specific neuroimaging abnormality. Compared to those with no cognitive impairment, patients with each VCI subtype had higher rates of death and institutionalization (hazard ratio for combined adverse events=6.08, p<0.001)., Conclusions: Both clinical features and radiographic features help establish a diagnosis of VCI. The outcomes of VCI subtypes, however, are more strongly associated with clinical features than with radiographic ones.

The goal of the current study was to determine whether Alzheimer's disease (AD) pathology affects the limbic system of men and women differently as measured by in vivo neuroimaging. Magnetic resonance imaging (MRI) and coregistered single photon emission computed tomography (SPECT) were used to examine the limbic system in 20 men and 20 women with probable AD compared to 40 age- and education-matched normal controls (20 men, 20 women). Limbic volumes and relative perfusion values were obtained from the MR images and coregistered SPECT scans, respectively. No significant differences were found between sexes in limbic volumes or relative perfusion values in the normal controls. Many limbic regions were significantly affected in both men and women with AD compared to normal controls. However, only the men with AD displayed atrophy in the orbitofrontal cortex, middle and posterior cingulate cortices, hypothalamus, and mamillary bodies, and relative hypoperfusion in the anterior and middle cingulate cortices. Women with AD exclusively showed anterior thalamic atrophy. Separating men and women did not substantially improve diagnostic classification.

To discriminate Alzheimer's disease (AD) from healthy controls, the thinnest medial temporal lobe (tMTL) width on 3D-MRI was measured according to a newly developed method at the inter-collicular sulcus (ICS) level with scans aligned to the long axis of the hippocampus in 22 mild, 27 moderate probable AD patients and 41 healthy controls. For comparison, MTL width replicating the technique of Jobst et al. (jMTL) as well as hippocampal and parahippocampal volumes, were also measured. Using logistic regression taking into account age, sex, and education, tMTL width classified mild AD from controls with a sensitivity of 86%, specificity of 95% and accuracy of 92%. Similar values were obtained for moderate or total AD group versus controls. By comparison, jMTL width was only useful in distinguishing moderate AD from controls, and volumetric measures were equally sensitive in classifying mild and moderate AD in our sample. This quick, reliable, and standardized measurement of tMTL can be helpful in differentiating even mild AD from controls with reasonable accuracy.

We studied the hippocampal angle and spatial relationships of medial temporal lobe (MTL) structures, using midbrain colliculi and inter-collicular sulcus (ICS) as landmarks, and measured MTL width on axial 3D-T1-weighted MRI at ICS level in 41 normal, aged participants. Mean hippocampal angle was 29 degrees (range 17-42 degrees ) caudal to the anterior-posterior commissure (AC-PC) line. The slice at the ICS, parallel to the long axis of the hippocampus, best revealed a longitudinal view of hippocampus and parahippocampal gyrus in 76% of participants, compared to only 7% when slices were 20 degrees caudal to orbitomeatal line (OML), an accepted technique used to examine MTL width in previous CT studies. The MTL width measured midway and at its thinnest between the anterior-posterior borders of the midbrain was highly reproducible (intraclass correlation coefficients >0.98) using these new methods. These simple decision rules, individualized orientation along the hippocampus and using a standardized landmark like the ICS, make these measures more comparable across subjects, and hence more useful in detecting and monitoring MTL atrophy in dementia.

This case report documents the partial recovery, over a 12-month period, of pure alexia in an adult female following a left occipital infarction. Measures of speed and accuracy were obtained on an oral reading and a lexical decision task immediately postonset and then on 10 subsequent occasions. Explicit letter-by-letter reading was observed only during the first week poststroke but a significant effect of word length was seen in all testing sessions. Reading accuracy was relatively good at all stages and reading latency showed a remarkable decrease over time but did not reach normal reading rates. The inability to use higher-order orthographic knowledge, as manifest in the absence of a word superiority effect, was still noted at one year postonset. We therefore concluded that the change in behavior was attributable to increased proficiency in the use of the adaptive letter-by-letter procedure rather than to the resolution of the underlying deficit. It is suggested that longitudinal neurobehavioral studies add to our understanding of the alexic deficit and provide insight into the recovery process.