Correlation of White Matter Lesions, Cerebral Blood Flow, and Cognitive Decline in Patients With Alzheimer's Disease and Vascular Dementia.

How far is arterial spin labeling MRI from a clinical reality? Insights from arterial spin labeling comparative studies in Alzheimer's disease and other neurological disorders.

Changes in regional cerebral blood flow and functional connectivity in the cholinergic pathway associated with cognitive performance in subjects with mild Alzheimer's disease after 12-week donepezil treatment

Patent foramen ovale (PFO) is a prevalent cardiac remnant of fetal anatomy that may pose a risk factor for stroke in some patients, while others can present with asymptomatic white matter (WM) lesions. The current study aimed to test the hypothesis that patients with a PFO who have a history of stroke or transient ischemic attack, compared to those without such a history, have a different burden and distribution of cerebral WM hyperintensities. Additionally, we tested the association between PFO morphological characteristics and severity of shunt, and their impact on the occurrence of ischemic cerebral vascular events and on the burden of cerebral WM lesions. Retrospective, case-control study that included patients with PFO confirmed by transesophageal echocardiography. Right-to-left shunt size was assessed using transcranial Doppler ultrasound. Cerebral MRIs were analyzed for all participants using the semi-automated Quantib NDTM software for the objective quantification of WM lesions. WM lesions volume was compared between patients with and without a history of stroke. Additionally, the anatomical characteristics of PFOs were assessed to explore their relation to stroke occurrence and WM lesions volume. Of the initial 264 patients diagnosed with PFO, 67 met the inclusion criteria and were included in the analysis. Of them, 62% had a history of PFO-related stroke/TIA. Overall burden of WM lesions, including stroke volume, was not significantly different (p = 0.103). However, after excluding stroke volume, WM lesions volume was significantly higher in patients without stroke (0.27 cm3, IQR 0.03-0.60) compared to those with stroke/TIA (0.08 cm3, IQR 0.02-0.18), p = 0.019. Patients with a history of PFO-related stroke/TIA had a tendency to larger PFO sizes by comparison to those without, in terms of length and height, and exhibited greater right-to-left shunt volumes. We suggest that PFO may be associated with the development of two distinct cerebrovascular conditions (stroke and "silent" WM lesions), each characterized by unique imaging patterns. Further studies are needed to identify better the "at-risk" PFOs and gain deeper insights into their clinical implications.

Vascular cognitive impairment is common and represents a spectrum of cognitive dysfunction associated with stroke and cardiovascular risk factors which may be slight, moderate or severe.1 Recently and as a major advance, the National Institute of Neurological Disorders and Stroke—Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards Working Group published clinical and research standards for the description and study of vascular cognitive impairment.2 In this update we report advances in vascular cognitive impairment in the following areas: clinical trials and treatment, new risk factors, white matter disease, and genetics. Cardiovascular risk factors such as blood pressure elevation and hyperglycemia are prime targets for clinical trial study because they are believed to cause negative effects on brain structure and cognitive function and may even influence risk of Alzheimer disease (AD).3 Results of recently published observational epidemiological studies have fueled controversy in relation to the role of blood pressure on cognition because some studies such as the Honolulu Asia Aging Study4 and Cache County Study5 suggest that antihypertensive therapy may reduce risk of dementia and cognitive decline or reduce incidence of AD, respectively, whereas the Religious Orders Study6 did not find an association between blood pressure and risk of AD or cognitive decline. Meta-analysis of patients with cardiovascular and/or cerebrovascular disease who received blood pressure-lowering treatment show a trend toward prevention of dementia and/or cognitive decline;7 however, a systematic analysis of 3 studies comprising 12 091 patients with hypertension who were treated with either medication or lifestyle strategies for at least 6 months show no evidence that blood pressure-lowering prevents dementia or cognitive impairment.8 Lack of definitive results in some of these trials may be explained by insufficient power to detect treatment effects, measurement error in cognitive end points, variation in treatment effects between …

Cerebral blood flow in ischemic vascular dementia and Alzheimer's disease, measured by arterial spin-labeling magnetic resonance imaging

Introduction: Brain health is dependent upon maintenance of stable cerebral blood flow in part through the interplay of blood pressure variability (BPV) and cerebrovascular reactivity (CVR). Consistent with this conceptualization, both BPV and CVR have been separately implicated in cerebral hypoperfusion and white matter lesion (WML) burden. However, the interactive effect of BPV and CVR on WML burden has yet to be investigated. Hypothesis: Older adults with elevated BPV and deficient CVR will exhibit greater WML volume. Aims: Determine the relationship between elevated beat-to-beat BPV and WML volume across varying levels of whole brain CVR. Methods: Independently living older adults without history of major neurological/psychiatric history were recruited from the community and underwent continuous blood pressure monitoring and pseudo-continuous arterial spin labeling MRI. Whole brain perfusion was quantified during 5 minutes of rest with simultaneous monitoring of end-tidal CO2 (ETCO2) levels. BPV was quantified as beat-to-beat systolic average real variability and spontaneous CVR was quantified as %change in CBF/change in ETCO2 at rest. WML volume was quantified from T1-weighted fluid attenuated inversion recovery and segmented with the lesion growth algorithm implemented in the LST toolbox version 3.0.0 for SPM12. Results: Eighty-five older adults were studied (mean age = 69.3 years; SD = 6.56; age range 55–89 years; 61.4% female). Resting whole brain CVR moderated the relationship between BPV and WML volume ( B= -.12, P= .01). Specifically, in individuals with impaired whole brain CVR, elevated BPV was independently associated with increased white matter lesion volume (Fig. 1). Conclusion: The present findings show that the relationship between BPV and WML volume is dependent upon whole brain CVR. This suggests that the cerebral vasculature’s ability to respond to vasoactive stimuli determines whether elevated BPV is associated with white matter lesions. Future studies of blood pressure variability and cerebral small vessel disease should account for this interactive effect.

BackgroundBoth hypertension and the E4 allele of the APOE gene are known risk factors for Alzheimer’s disease (AD). We investigated the influence of these factors on global cerebral blood flow (CBF) and four prespecified areas (angular gyrus, hippocampus, posterior cingulate, temporal lobe) using arterial spin labeling (ASL) MRI both in fasting state and after ingestion of a high fat drink.MethodAfter fasting, 29 older adults (age 66.8 ± 4.1) underwent baseline and 1, 2, 3‐hour ASL MRI after ingestion of 1/2 cup heavy cream with comparable total and saturated fat to a high fat breakfast. We used pCASL MRI with background suppression to measure CBF in ml/100g/min. Imaging parameters were in accordance with the recommendations of ISMRM: label duration = 1.8 s, postlabeling delay = 2 s, labeling offset = 25‐30 mm, slices = 20, resolution = 3.5×3.5×5 mm3, SENSE‐factor = 2, TR/TE= 5000/18 ms. Finally, we acquired a reference scan (M0, 1 minute) identical to above scan but with TR = 10,000 ms and no labeling or background suppression. Statistical analyses included repeated measures ANOVA as well as cross‐sectional multiple regressions with robust estimators adjusting for age, E4 status, BMI, heart rate, systolic and diastolic blood pressure (DBP).ResultGlobal CBF decreased at 1‐, 2‐, and 3‐hours post‐lipid drink, compared to time 0 (RM ANOVA F=5.57, p=0.002). These findings were recapitulated in the posterior cingulate (F=3, p=0.036) and hippocampus (F=3.3, p= 0.025); this difference was not seen in the temporal lobe or angular gyrus. E4 genotype was significantly associated with lower global CBF at hour 2 and in three areas examined (Table). Additionally, higher DBP was associated with lower CBF globally and in all four areas (Table).ConclusionCBF decreased in response to lipid ingestion, both globally and in regions known to be important in AD, and this was exaggerated in individuals with the E4+ genotype and with elevated DBP. Further examination of E4 and blood pressure interactions are ongoing, as well as how these findings relate to cognitive performance.

INTRODUCTIONChronic cerebral hypoperfusion is one of the assumed pathophysiological mechanisms underlying vascular cognitive impairment (VCI). We investigated the association between baseline cerebral blood flow (CBF) and cognitive decline after 2 years in patients with VCI and reference participants.METHODSOne hundred eighty‐one participants (mean age 66.3 ± 7.4 years, 43.6% women) underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) and neuropsychological assessment at baseline and at 2‐year follow‐up. We determined the association between baseline global and lobar CBF and cognitive decline with multivariable regression analysis.RESULTSLower global CBF at baseline was associated with more global cognitive decline in VCI and reference participants. This association was most profound in the domain of attention/psychomotor speed. Lower temporal and frontal CBF at baseline were associated with more cognitive decline in memory.DISCUSSIONOur study supports the role of hypoperfusion in the pathophysiological and clinical progression of VCI.HighlightsImpaired cerebral blood flow (CBF) at baseline is associated with faster cognitive decline in VCI and normal aging.Our results suggest that low CBF precedes and contributes to the development of vascular cognitive impairment.CBF determined by ASL might be used as a biomarker to monitor disease progression or treatment responses in VCI.

Background: White matter lesions (WML) and brain atrophy are important biomarkers in stroke and dementia. Stroke lesions, either acute or old, symptomatic or silent, are common in older people. Such stroke lesions can have similar signals to WML and cerebrospinal fluid (CSF) on magnetic resonance (MR) images, and may be classified accidentally as WML or CSF by MR image processing algorithms, distorting WML and brain atrophy volume from the true volume. We evaluated the effect that acute or old stroke lesions at baseline, and new stroke lesions occurring during follow-up, could have on measurement of WML volume, cerebral atrophy and their longitudinal progression. Methods: We used MR imaging data from patients who had originally presented with acute lacunar or minor cortical ischaemic stroke symptoms, recruited prospectively, who were scanned at baseline and about 3 years later. We measured WML and CSF volumes (ml) semi-automatically. We manually outlined the acute index stroke lesion (ISL), any old stroke lesions present at baseline, and new lesions appearing de novo during follow-up. We compared baseline and follow-up WML volume, cerebral atrophy and their longitudinal progression excluding and including the acute ISL, old and de novo stroke lesions. A non-parametric test (Wilcoxon’s signed rank test) was used to compare the effects. Results: Among 46 patients (mean age 72 years), 33 had an ISL visible on MR imaging (median volume 2.05 ml, IQR 0.88–8.88) and 7 of the 33 had old lacunes at baseline: WML volume was 8.54 ml (IQR 5.86–15.80) excluding versus 10.98 ml (IQR 6.91–24.86) including ISL (p < 0.001). At follow-up, median 39 months later (IQR 30–45), 3 patients had a de novo stroke lesion; total stroke lesion volume had decreased in 11 and increased in 22 patients: WML volume was 12.17 ml (IQR 8.54–19.86) excluding versus 14.79 ml (IQR 10.02–38.03) including total stroke lesions (p < 0.001). Including/excluding lacunes at baseline or follow-up also made small differences. Twenty-two of the 33 patients had tissue loss due to stroke lesions between baseline and follow-up, resulting in a net median brain tissue volume loss (i.e. atrophy) during follow-up of 24.49 ml (IQR 12.87–54.01) excluding versus 24.61 ml (IQR 15.54–54.04) including tissue loss due to stroke lesions (p < 0.001). Including stroke lesions in the WML volume added substantial noise, reduced statistical power, and thus increased sample size estimated for a clinical trial. Conclusions: Failure to exclude even small stroke lesions distorts WML volume, cerebral atrophy and their longitudinal progression measurements. This has important implications for design and sample size calculations for observational studies and randomised trials using WML volume, WML progression or brain atrophy as outcome measures. Improved methods of discriminating between stroke lesions and WML, and between tissue loss due to stroke lesions and true brain atrophy are required.

BackgroundBehavioral and psychological symptoms of dementia (BPSD) are highly prevalent in Alzheimer’s disease (AD) and associated with adverse outcomes. There is increasing interest in identifying the risk factors for developing BPSD among AD patients. However, the pathophysiological mechanisms underlying BPSD remain poorly understood. Here we evaluated whether BPSD are associated with WMLs volume, brain atrophy and brain metabolism in AD subjects.Method130 AD subjects form the Evaluating Liraglutide in Alzheimer's Disease (ELAD) trial (NCT01843075) were enrolled. The presence of BPSD was evaluated with the Neuropsychiatric Inventory Questionnaire (NPI). FLAIR and T1‐weighted imaging were performed on 3T scans. WMLs was determined on FLAIR images using the Lesion Segmentation Tool (LST) in SPM12. Hippocampal and grey matter volumes were estimated using the FreeSurfer analysis on T1 MRI. Glucose metabolism (rCMRGlc) was calculated by parametric images generated using spectral analysis with an arterial plasma input function.ResultIn this AD population, NPI scores were correlated with WMLs volume (Spearman's rho=.197, p=.02), also after correcting for age. NPI scores were not correlated to hippocampal or grey matter volume and to rCMRGlc in frontal, temporal, parietal or occipital lobes. When looking at the NPI sub‐scores, WMLs volume was significantly associated with agitation/aggression (Spearman's rho=.177, p=.05) and with appetite and eating disorders (Spearman's rho=.233, p=.00).ConclusionIn this study of a clinical AD population, BPSD were associated with WMLs but not with brain atrophy and hypometabolism. This suggests that vascular changes and the prevention of vascular risk factors might play an important role in reducing the impact of BPSD in AD dementia.

Alzheimer's disease and vascular dementia are the two most common types of dementia, with significant overlap of clinical symptoms and pathology. Previous results from a 6-month, double-blind, placebo-controlled, international, multicentre study of the cholinomimetic galantamine in patients with probable vascular dementia or mixed dementia (Alzheimer's disease with cerebrovascular disease) showed significant cognitive, behavioural and functional benefits in these patients. Furthermore, results of a 6-month, open-label extension of this study confirmed that patients with vascular dementia or Alzheimer's disease with cerebrovascular disease may benefit from galantamine therapy for at least 1 year. The objective of the current analysis was to determine if the long-term cognitive benefits of galantamine seen in the above-mentioned study are influenced by dementia type (probable vascular dementia vs Alzheimer's disease with cerebrovascular disease). A post hoc sub-analysis of a 6-month, multicentre, randomised, double-blind, placebo-controlled study and a subsequent 6-month, open-label extension. Patients diagnosed with probable vascular dementia or Alzheimer's disease with cerebrovascular disease were treated with galantamine (Reminyl) 24 mg/day for 12 months (6 months double-blind and 6 months open-label) or placebo for 6 months (double-blind) followed by galantamine 24 mg/day for 6 months (open-label). Changes in scores on the 11-item Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog/11) were assessed at months 6, 7.5 and 12. Mean changes from baseline were analysed. Patients with probable vascular dementia treated with galantamine for 6 or 12 months showed significant improvements in ADAS-cog/11 scores versus baseline, which were maintained at the end of the 12-month study. Patients who had Alzheimer's disease with cerebrovascular disease continuously treated with galantamine maintained the cognitive abilities seen at baseline for at least 12 months. Additionally, patients who had Alzheimer's disease with cerebrovascular disease who were switched from placebo to open-label galantamine therapy for 6 months demonstrated cognitive benefits, but these benefits were significantly less than those observed in patients treated with galantamine continuously for the 12-month period. Galantamine was well tolerated throughout the entire 12-month study. These findings suggest that the drug is efficacious for such common forms of dementia as vascular dementia and Alzheimer's disease with cerebrovascular disease. Moreover, some patients benefit from galantamine therapy that is initiated early, soon after diagnosis, and continued for at least 1 year.

Background: White matter lesions (WMLs) increase with age and are associated with stroke, cognitive decline and dementia. WMLs can be quantified by visual rating scores, or by computational measurement of WML volume, but the concurrence between these two methods has not been widely studied. We compared WML visual ratings and computed volumes to determine agreement and sources of disagreement. Methods: We used subjects from the Lothian Birth Cohort 1936 who had brain MRI. We rated WMLs visually on FLAIR using the Fazekas scale and measured WML volume using a validated multispectral image fusion technique: MCMxxxVI ( sourceforge.net/projects/bric1936 ). We summed the deep and periventricular Fazekas scores and calculated the correlation between the total Fazekas score (0-6) and WML volume (Spearman's ρ). We sought explanations for outliers, such as stroke lesions. Results: Amongst 672 subjects with full brain imaging data, the median Fazekas score was 2 and the median WML volume was 7.7 ml (IQR 13.6ml). The Fazekas score and WML volume were highly correlated (Spearman ρ=0.73, p&lt;0.001). Including stroke lesions, most of which were small but which can inflate WML volume values, gave a similar correlation (Spearman ρ=0.75, p&lt;0.001). In 114 subjects (17% of the total) the z-scores of WML volume and Fazekas rating differed by &gt;1, most of whom had a total Fazekas score of 1 (n=26, WML volume:0-14.8ml) or 2 (n=63, WML volume:0-34.37ml). The main reasons for disagreements were: 1) subtle WMLs visually identified which were omitted from the WML volume; 2) prominent periventricular caps with thin ventricular body lining obtaining a Fazekas periventricular score of 1 or 2 but a large WML volume; and 3) small deep white matter focal lesions which increase disproportionally the score obtained in the rating scale if they are beginning to coalesce but add little to the WML volume which may range from &lt;0.5 to &gt;12ml. Conclusions: WML visual rating and volumes show high correlation, but subtle WMLs and two features that are not well differentiated in the WML score weakened the agreement. Methods to improve computational WML quantification (e.g. adaptive filtering) would improve measurement of subtle WML areas. Consideration should be given to modifying WML scores to differentiate ventricular caps from other periventricular lesions and small but early coalescent from larger deep WMLs.

HOW TO MANAGE OVERACTIVE BLADDER IN ELDERLY INDIVIDUALS WITH DEMENTIA? A COMBINED USE OF DONEPEZIL, A CENTRAL ACETYLCHOLINESTERASE INHIBITOR, AND PROPIVERINE, A PERIPHERAL MUSCARINE RECEPTOR ANTAGONIST

Associations between cerebral blood flow and structural and functional brain imaging measures in individuals with neuropsychologically defined mild cognitive impairment

This study aims to examine the role of neurovascular coupling (NVC) in vascular cognitive impairment (VCI) by investigating the relationship between white matter lesion (WML) burden, NVC, and cognitive deficits. Additionally, we aim to explore the potential of NVC as a tool for understanding the neural mechanisms underlying VCI. This study included thirty-eight small vessel disease cognitive impairment (SVCI) patients, 34 post-stroke cognitive impairment (PSCI) patients, and 43 healthy controls (HC). Comprehensive assessments, including neuroimaging and neuropsychological testing, were conducted to evaluate cognitive function. WML burden was measured and correlated with NVC coefficients to examine the relationship between white matter pathology and NVC. Mediation analysis was employed to explore the link relationship between NVC, WML burden, and cognitive function. The present study showed that NVC was significantly reduced in the SVCI and PSCI groups compared with HCs at both whole-brain and brain region level. The analysis revealed notable findings regarding NVC in relation to WML burden and cognitive function in VCI patients. Specifically, reduced NVC coefficients were observed within higher order brain systems responsible for cognitive control and emotion regulation. Mediation analysis demonstrated that NVC played a mediating role in the relationship between WML burden and cognitive impairment. This study reveals the mediating role of NVC in the relationship between WML burden and cognitive function in VCI patients. The results demonstrate the potential of the NVC as an accurate measure of cognitive impairment and its ability to identify specific neural circuits affected by WML burden.