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1.  Differences in Prefrontal, Limbic, and White Matter Lesion Volumes According to Cognitive Status in Elderly Patients with First-Onset Subsyndromal Depression 
PLoS ONE  2014;9(1):e87747.
The purpose of this preliminary study was to test the hypothesis that subsyndromal depression is associated with the volume of medial prefrontal regional gray matter and that of white matter lesions (WMLs) in the brains of cognitively normal older people. We also explored the relationships between subsyndromal depression and medial prefrontal regional gray matter volume, limbic regional gray matter volume, and lobar WMLs in the brains of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). We performed a cross-sectional study comparing patients with subsyndromal depression and nondepressed controls with normal cognition (n = 59), MCI (n = 27), and AD (n = 27), adjusting for sex, age, years of education, and results of the Mini-Mental State Examination. Frontal WML volume was greater, and right medial orbitofrontal cortical volume was smaller in cognitively normal participants with subsyndromal depression than in those without subsyndromal depression. No volume differences were observed in medial prefrontal, limbic, or WML volumes according to the presence of subsyndromal depression in cognitively impaired patients. The absence of these changes in patients with MCI and AD suggests that brain changes associated with AD pathology may override the changes associated with subsyndromal depression.
doi:10.1371/journal.pone.0087747
PMCID: PMC3909227  PMID: 24498184
2.  The association between cognitive function and white matter lesion location in older adults: a systematic review 
BMC Neurology  2012;12:126.
Background
Maintaining cognitive function is essential for healthy aging and to function autonomously within society. White matter lesions (WMLs) are associated with reduced cognitive function in older adults. However, whether their anatomical location moderates these associations is not well-established. This review systematically evaluates peer-reviewed evidence on the role of anatomical location in the association between WMLs and cognitive function.
Methods
In accordance with the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement, databases of EMBASE, PUBMED, MEDLINE, and CINAHL, and reference lists of selected papers were searched. We limited our search results to adults aged 60 years and older, and studies published in the English language from 2000 to 2011. Studies that investigated the association between cognitive function and WML location were included. Two independent reviewers extracted: 1) study characteristics including sample size, sample characteristic, and study design; 2) WML outcomes including WML location, WML quantification method (scoring or volume measurement), strength of the MRI magnet in Tesla, and MRI sequence used for WML detection; and 3) cognitive function outcomes including cognitive tests for two cognitive domains of memory and executive function/processing speed.
Results
Of the 14 studies included, seven compared the association of subcortical versus periventricular WMLs with cognitive function. Seven other studies investigated the association between WMLs in specific brain regions (e.g., frontal, parietal lobes) and cognitive function. Overall, the results show that a greater number of studies have found an association between periventricular WMLs and executive function/processing speed, than subcortical WMLs. However, whether WMLs in different brain regions have a differential effect on cognitive function remains unclear.
Conclusions
Evidence suggests that periventricular WMLs may have a significant negative impact on cognitive abilities of older adults. This finding may be influenced by study heterogeneity in: 1) MRI sequences, WML quantification methods, and neuropsychological batteries; 2) modifying effect of cardiovascular risk factors; and 3) quality of studies and lack of sample size calculation.
doi:10.1186/1471-2377-12-126
PMCID: PMC3522005  PMID: 23110387
White matter lesions; Distribution; Cognition; Aging
3.  Spatial Distribution of Cerebral White Matter Lesions Predicts Progression to Mild Cognitive Impairment and Dementia 
PLoS ONE  2013;8(2):e56972.
Context
White matter lesions (WML) increase the risk of dementia. The relevance of WML location is less clear. We sought to determine whether a particular WML profile, based on the density and location of lesions, could be associated with an increased risk of mild cognitive impairment (MCI) or dementia over the following 7 years.
Methods
In 426 healthy subjects from a cohort of community-dwelling people aged 65 years and over (ESPRIT Project), standardized cognitive and neurological evaluations were repeated after 2, 4 and 7 years. Patterns of WML were computed with a supervised data mining approach (decision trees) using the regional WML volumes (frontal, parietal, temporal, and occipital regions) and the total WML volume estimated at baseline. Cox proportional hazard models were then constructed to study the association between WML patterns and risk of MCI/dementia.
Results
Total WML volume and percentage of WML in the temporal region proved to be the best predictors of progression to MCI and dementia. Specifically, severe total WML load with a high proportion of lesions in the temporal region was significantly associated with the risk of developing MCI or dementia.
Conclusions
Above a certain threshold of damage, a pattern of WML clustering in the temporal region identifies individuals at increased risk of MCI or dementia. As this WML pattern is observed before the onset of clinical symptoms, it may facilitate the detection of patients at risk of MCI/dementia.
doi:10.1371/journal.pone.0056972
PMCID: PMC3572965  PMID: 23457645
4.  Structural MRI correlates of apathy symptoms in older persons without dementia 
Neurology  2014;82(18):1628-1635.
Objective:
We aimed to investigate the relation between apathy symptoms and structural brain changes on MRI, including white matter lesions (WMLs) and atrophy, in a large cohort of older persons.
Methods:
Cross-sectional analyses are based on 4,354 persons without dementia (aged 76 ± 5 years) participating in the population-based Age, Gene/Environment Susceptibility–Reykjavik Study. Apathy symptoms were assessed with 3 items from the 15-item Geriatric Depression Scale. Brain volumes and total WML volume were estimated on 1.5-tesla MRI using an automated segmentation program; regional WML load was calculated using a semiquantitative scale. Regression analyses were adjusted for age, sex, education, intracranial volume, vascular risk factors, physical activity, brain infarcts, depressive symptoms, antidepressants, and cognitive status.
Results:
Compared to those with <2 apathy symptoms, participants with ≥2 apathy symptoms (49% of the cohort) had significantly smaller gray matter volumes (mean adjusted difference −3.6 mL, 95% confidence interval [CI] −6.2 to −1.0), particularly in the frontal and temporal lobes; smaller white matter volumes (mean adjusted difference −1.9 mL, 95% CI −3.6 to −0.3), mainly in the parietal lobe; and smaller thalamus volumes. They were also more likely to have WMLs in the frontal lobe (adjusted odds ratio = 1.08, 95% CI 0.9–1.3). Excluding participants with a depression diagnosis did not change the associations.
Conclusions:
In this older population without dementia, apathy symptoms are associated with a more diffuse loss of both gray and white matter volumes, independent of depression.
doi:10.1212/WNL.0000000000000378
PMCID: PMC4013817  PMID: 24739783
5.  Influences of lobar gray matter and white matter lesion load on cognition and mood 
Psychiatry research  2010;181(2):90.
Depressed mood is a frequent co-morbidity of dementia suggesting that they might share a common neuropathological substrate. Gray matter (GM) atrophy and white matter lesions (WML) have been described in both conditions. Our aims were to determine the relationship of GM and WML with cognition and depressed mood in the same population. Structural brain images were obtained from 42 controls, 20 Alzheimer’s disease (AD) patients and 32 subjects with cognitive impairment/dementia due to subcortical cerebrovascular disease (vascCIND/IVD) and segmented to obtain lobar GM, white matter and WML volumes. Lobar WML had a negative effect on GM in all lobes in controls, on frontal, parietal and occipital GM in AD and on frontal GM in vascCIND/IVD. Frontal, temporal and hippocampal GM were associated with cognitive functions and frontal WML load with depressed mood. Cognitive function is associated with GM atrophy and depressed mood is associated with frontal WML. This indicates that although both often occur together depressed mood and cognitive impairment are caused by different pathological correlates.
doi:10.1016/j.pscychresns.2009.08.002
PMCID: PMC2814971  PMID: 20074914
white matter lesion; gray matter atrophy; depression; mood; cognition; MRI
6.  Differences between suicide attempters and non-attempters in depressed older patients: Depression severity, white matter lesions, and cognitive functioning 
Objectives
Older adults with major depressive disorder (MDD) have the highest population-rate of suicide. White matter brain lesions (WML) are a potential biological marker for suicidality in young and middle-age adults and are correlated with cognitive impairment (CI) in older adults. In the current study of older patients with MDD, we examined 1) if a history of suicide attempts was associated with a more severe course of MDD; 2) if WML are a biological marker for suicide; and 3) if suicide attempt history is associated with CI mediated by WML.
Setting
Data from the Neurocognitive Outcomes of Depression in the Elderly.
Participants
Depressed patients (60+) who had ever attempted suicide (n=23) were compared to depressed patients (60+) who had not attempted suicide (n=223).
Measurements
Baseline and follow-up assessments were obtained for depressive symptoms (every 3 months) and cognitive functioning (every six months) over two years. Three MRI scans were conducted.
Results
At baseline, suicide attempters reported more severe past and present symptoms (e.g., depressive symptoms, current suicidal thoughts, psychotic symptoms, earlier age of onset, and more lifetime episodes) than non-attempters. Suicide attempters had more left WML at baseline, and suicide attempt history predicted a greater growth in both left and right WML. WML predicted cognitive decline; nonetheless, history of suicide attempt was unrelated to cognitive functioning.
Conclusions
Severity of depressive symptoms and WML are associated with suicide attempts in geriatric depressed patients. Suicide attempts predicted neurological changes, which may contribute to poorer long-term outcomes in elder attempters.
doi:10.1016/j.jagp.2013.01.063
PMCID: PMC4155401  PMID: 23933424
Geriatric; major depression; white matter lesions
7.  Depressive Symptoms, Symptom Dimensions and White Matter Lesion Volume in Older Adults: A Longitudinal Study 
Objectives
White matter lesions (WMLs) are associated with depressive symptoms in older adults. However, it is not clear whether different symptom dimensions of depression have distinct associations with WMLs. We assessed the longitudinal relationships of the Center for Epidemiologic Studies Depression Scale (CES-D) total score and subscale scores with WML volume in the Baltimore Longitudinal Study of Aging (BLSA).
Design
Prospective observational design with examination of WML volume and depressive symptoms at 1–2 year intervals for up to 9 years.
Setting
Neuroimaging substudy of the BLSA.
Participants
116 dementia-free participants (mean age = 68.78 ± 7.68).
Measurements
At each visit, depressive symptoms were measured with the CES-D and WML volumes were quantified from structural magnetic resonance imaging scans.
Results
Higher CES-D full scale scores were associated with greater WML volume and with a faster rate of volume increases over time in women, especially at older ages. Higher depressed mood and somatic symptoms subscale scores were associated with greater increases in WML volume over time at older ages. In men, depressed mood and somatic symptoms were associated with larger WML volume at baseline.
Conclusions
Findings confirm an association between WMLs and depressive symptoms and suggest that depressed mood and somatic symptoms may be stronger predictors of depression-related brain changes than lack of well-being. Age and sex may moderate the relationships between depressive symptoms and WMLs. Understanding particular symptom dimensions of depressive symptoms has implications for treatment and may lead to targeted interventions and more precise knowledge of mechanisms underlying depression.
doi:10.1016/j.jagp.2013.10.005
PMCID: PMC3984387  PMID: 24211028
depression; WML; symptom dimensions; aging; MRI
8.  Impact of White Matter Lesions on Depression in the Patients with Alzheimer's Disease 
Psychiatry Investigation  2015;12(4):516-522.
Objective
Comorbid depression is common in patients with Alzheimer's disease (AD). An increase in white matter lesions (WMLs) has been associated with depression in both elderly individuals with normal cognition and patients with Alzheimer's disease. We investigated whether the severity and location of WMLs influence the association between WMLs and comorbid depression in AD.
Methods
We enrolled 93 AD patients from Seoul National University Bundang Hospital. We administered both the Mini International Neuropsychiatric Inventory (MINI) and the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD-K) clinical and neuropsychological battery. Subjects also underwent brain magnetic resonance imaging (MRI). We diagnosed AD according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. We diagnosed depressive disorders according to the DSM-IV diagnostic criteria, and evaluated the severity of depressive symptoms using the Korean version of the Geriatric Depression Scale (GDS-K). We quantified the WML volumes from the brain MRI using a fully automated segmentation algorithm.
Results
The log of the WML volume in the frontal lobe was significantly associated with depressive disorders (odds ratio=1.905, 95% CI=1.027-3.533, p=0.041), but not with the severity of depressive symptoms as measured by the GDS-K.
Conclusion
The WML volume in the frontal lobe conferred a risk of comorbid depressive disorders in AD, which implies that comorbid depression in AD may be attributed to vascular causes.
doi:10.4306/pi.2015.12.4.516
PMCID: PMC4620309  PMID: 26508963
Alzheimer's disease; White matter lesions; Depression
9.  Influence of the MTHFR C677T polymorphism on MRI hyperintensity volume and cognition in geriatric depression 
Objective
The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) has been linked to unipolar major depressive disorder (MDD) and MRI hyperintensities. We examined the relationship between the MTHFR C677T polymorphism (C677T) and a) geriatric depression, b) MRI hyperintense lesion volume, and c) neurocognitive test performance.
Design
Cross-sectional.
Setting
Duke University Medical Center.
Participants
Depressed (N=178) and comparison (N=85) elderly subjects.
Measurements
Subjects had blood drawn to assess MTHFR genotype, were imaged by MRI to determine their white (WML) and gray (GML) matter hyperintense lesion volume, and assessed using a comprehensive neurocognitive battery evaluating multiple domains of function. Linear regression models were fit to test the effect of genotype, a depression by genotype interaction, and an age by genotype interaction on both hyperintense lesion volume measures and neurocognitive task performance.
Results
The MTHFR C677T genotype by age interaction term was significantly associated with MRI WML volume (p=0.0175), however this relationship was no longer statistically significant when WML volumes underwent a log transformation to produce a more normal distribution. The 677T allele was neither more frequent in depressed subjects nor associated with either gray matter hyperintensity volume or neurocognitive test performance.
Conclusions
MTHFR genotype affects the relationship between age and WML volume, where individuals who carry the 677T allele exhibit greater WML volume by age, although this relationship should be verified given the failure to replicate the finding using transformed WML volumes. Genotype was not related to GML volume, cognitive function, or presence of depression, although demographic differences could account for this negative finding.
doi:10.1097/JGP.0b013e3181aad5b2
PMCID: PMC2805265  PMID: 19910873
MTHFR polymorphism; depression; white matter lesion; folate; homocysteine; elderly
10.  White Matter Lesions and Brain Gray Matter Volume in Cognitively Normal Elders 
Neurobiology of Aging  2011;33(4):834.e7-834.e16.
Objectives
Cerebral white matter lesions (WMLs) reflect small vessel disease, are common in elderly individuals and are associated with cognitive impairment. We sought to determine the relationships between WMLs, age, gray matter (GM) volume, and cognition in the Cardiovascular Health Study (CHS).
Methods
From the CHS we selected 740 cognitively normal controls with a 1.5 T MRI scan of the brain and a detailed diagnostic evaluation. WML severity was determined using a standardized visual rating system. GM volumes were analyzed using voxel-based morphometry implemented in the Statistical Parametric Mapping software.
Results
WMLs were inversely correlated with GM volume, with the greatest volume loss in the frontal cortex. Age related atrophy was observed in the hippocampus and posterior cingulate cortex. Regression analyses revealed links among age, APOE*4 allele, hypertension, WMLs, GM volume, and digit symbol substitution test scores.
Conclusions
Both advancing age and hypertension predict higher WML load, which is itself associated with GM atrophy. Longitudinal data are needed to confirm the temporal sequence of events leading to a decline in cognitive function.
doi:10.1016/j.neurobiolaging.2011.08.010
PMCID: PMC3248984  PMID: 21943959
White matter lesions; age; gray matter volume; cognition
11.  Association between Carotid Plaque Characteristics and Cerebral White Matter Lesions: One-Year Follow-Up Study by MRI 
PLoS ONE  2011;6(2):e17070.
Objective
To prospectively assess the relation between carotid plaque characteristics and the development of new cerebral white matter lesions (WMLs) at MRI.
Methods
Fifty TIA/stroke patients with ipsilateral 30–69% carotid stenosis underwent MRI of the plaque at baseline. Total plaque volume and markers of vulnerability to thromboembolism (lipid-rich necrotic core [LRNC] volume, fibrous cap [FC] status, and presence of intraplaque hemorrhage [IPH]) were assessed. All patients also underwent brain MRI at baseline and after one year. Ipsilateral cerebral WMLs were quantified with a semiautomatic method.
Results
Mean WML volume significantly increased over a one-year period (6.52 vs. 6.97 mm3, P = 0.005). WML volume at baseline and WML progression did not significantly differ (P>0.05) between patients with 30–49% and patients with 50–69% stenosis. There was a significant correlation between total plaque volume and baseline ipsilateral WML volume (Spearman ρ = 0.393, P = 0.005). There was no significant correlation between total plaque volume and ipsilateral WML progression. There were no significant associations between LRNC volume and WML volume at baseline and WML progression. WML volume at baseline and WML progression did not significantly differ between patients with a thick and intact FC and patients with a thin and/or ruptured FC. WML volume at baseline and WML progression also did not significantly differ between patients with and without IPH.
Conclusion
The results of this study indicate that carotid plaque burden is significantly associated with WML severity, but that there is no causal relationship between carotid plaque vulnerability and the occurrence of WMLs.
doi:10.1371/journal.pone.0017070
PMCID: PMC3039645  PMID: 21347225
12.  Effect of white matter lesions on manual dexterity in healthy middle-aged persons 
Neurology  2015;84(19):1920-1926.
Objectives:
We hypothesized that integrated motor-visual functions measured by manipulative manual dexterity are affected by white matter lesion (WML) burden as measured on cranial MRI across relevant brain regions in subjects at risk of preclinical occult vascular disease.
Methods:
A real-time cross-sectional study of healthy subjects aged 29 to 74 years with a family history of early-onset coronary artery disease (n = 714; mean age, 51 ± 11 years; mean education, 14 ± 3 years; 42% male; 38% black) were identified from probands with coronary artery disease diagnosed before age 60 years. WMLs on 3-tesla brain MRI and Grooved Pegboard scores were measured.
Results:
WMLs were observed at all ages. Mean pegboard scores were 108 ± 18, similar to normal populations. In unadjusted analysis, WMLs and pegboard scores were significantly correlated by region (total WMLs, r = 0.34, p = 0.0001; frontal [r = 0.34, p < 0.0001], insula [r = 0.31, p < 0.0001], parietal [r = 0.31, p < 0.0001], and temporal [r = 0.17, p < 0.0001]). In multivariate analysis predicting (log) pegboard score adjusted for age, sex, race, education, regional or total volumes, and familial nonindependence, total WML volume (p = 5.79E − 05) and regional WML volumes (p < 0.01) retained statistical significance in all but the youngest age quartile (29–43 years).
Conclusions:
Greater WML volumes in different brain regions are associated with higher pegboard scores (worse performance) independent of age, sex, race, education, and total or regional volumes. This suggests that small vessel cerebrovascular disease may be present in healthy individuals in a preclinical state with measurable impact on complex integrative functions in individuals with excess risk of clinical vascular disease.
doi:10.1212/WNL.0000000000001557
PMCID: PMC4433457  PMID: 25862800
13.  Relationship between systemic and cerebral vascular disease and brain structure integrity in normal elderly individuals 
Cerebral white matter lesions (WMLs) are considered a reflection of cerebral and systemic small vessel disease (SVD), and are associated with reductions in brain volume. Like the brain, the kidney is also sensitive to factors that affect vasculature. Glomerular dysfunction due to renal vascular damage can be measured with different biochemical parameters, such as creatinine or cystatin C, although cystatin C is considered to be more accurate than creatinine in the elderly. The purpose of the study was to determine whether manifestations of SVD in the kidney can predict SVD-based damage to the brain. We examined the relationship between glomerular dysfunction as a measure of SVD on WMLs, gray matter (GM) volume, and cognition in 735 cognitively normal participants from the Cardiovascular Health Study Cognition Study. The multivariate analyses controlled for demographic characteristics, hypertension, heart disease, diabetes, Apolipoprotein 4 allele, C reactive protein, lipids, physical activity, smoking, and body mass index (BMI). Elevated cystatin C levels were associated with lower neuropsychological test scores, the presence of MRI-identified brain infarcts, the severity of WMLs, and GM atrophy five years later. In adjusted models, GM volume was significantly associated with cystatin-C only until BMI and severity of WMLs were added to the model, meaning that the effect of SVD on GM volume is mediated by these two variables. These findings suggest that age-related SVD is a process that leads to altered brain structure, and creates a vulnerability state for cognitive decline.
doi:10.3233/JAD-141077
PMCID: PMC4297227  PMID: 25213770
Cystatin C; gray matter volume; cognitive impairment; white matter lesions
14.  White matter lesion progression: A genome-wide search for genetic influences 
Background and Purpose
White matter lesion (WML) progression on magnetic resonance imaging (MRI) is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
Methods
Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in seven cohorts risk models including demographics, vascular risk factors plus single nucleotide polymorphisms (SNPs) that have been shown to be associated cross-sectionally with WML in the current and previous association studies.
Results
A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no SNPs achieved genome-wide significance (p-value < 5×10−8). Four loci were suggestive (p-value < 1×10−5) of an association with WML progression: 10q24.32 (rs10883817, p=1.46×10−6); 12q13.13 (rs4761974, p=8.71×10−7); 20p12.1 (rs6135309, p=3.69×10−6); and 4p15.31 (rs7664442, p=2.26×10−6). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors and baseline WML burden.
Conclusions
Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, life-style or host-related biological factors.
doi:10.1161/STROKEAHA.115.009252
PMCID: PMC4749149  PMID: 26451028
magnetic resonance imaging; aging; cerebral small vessel disease
15.  ANGIOTENSIN RECEPTOR GENE POLYMORPHISMS AND TWO-YEAR CHANGE IN HYPERINTENSE LESION VOLUME IN MEN 
Molecular psychiatry  2009;15(8):816-822.
This longitudinal study examined the relationship between 2-year change in white matter hyperintense lesion (WML) volume and polymorphisms in genes coding for the angiotensin-II type 1 and type 2 receptors, AGTR1 A1166C and AGTR2 C3123A. 137 depressed and 94 nondepressed subjects age 60 years or older were enrolled. Standard clinical evaluations were performed on all subjects and blood samples obtained for genotyping. 1.5T MRI was obtained at baseline and approximately two years later. These scans were processed using a semi-automated segmentation process which allowed for the calculation of WML volume at each time point. Statistical models tested for the relationship between change in WML volume and genotype, while also controlling for age, sex, diagnostic strata, baseline WML volume, and comorbid cerebrovascular risk factors. In men, AGTR1 1166A allele homozygotes exhibited significantly less change in WML volume than 1166C carriers. We also found that men reporting hypertension with the AGTR2 3123C allele exhibit less change in WML volume than hypertensive men with the 3123A allele, or men without hypertension. There were no significant relationships between these polymorphisms and change in WML volume in women. No significant gene-gene or gene-depression interactions were observed. Our results parallel previously observed gender differences of the relationship between other renin-angiotensin system polymorphisms and hypertension. Further work is needed to determine if these observed relationships are secondary to polymorphisms affecting response to antihypertensive medication, and if antihypertensive medications can slow WML progression and lower the risk of morbidity associated with WMLs.
doi:10.1038/mp.2009.26
PMCID: PMC2891956  PMID: 19274051
MRI; Major Depressive Disorder; Volumetric Study; Cerebrovascular Disease; Renin-Angiotensin System; Genetic Polymorphisms
16.  Prefrontal Lobe Brain Reserve Capacity with Resistance to Higher Global Amyloid Load and White Matter Hyperintensity Burden in Mild Stage Alzheimer’s Disease 
PLoS ONE  2016;11(2):e0149056.
Background
Amyloid deposition and white matter lesions (WMLs) in Alzheimer's disease (AD) are both considered clinically significant while a larger brain volume is thought to provide greater brain reserve (BR) against these pathological effects. This study identified the topography showing BR in patients with mild AD and explored the clinical balances among BR, amyloid, and WMLs burden.
Methods
Thirty patients with AD were enrolled, and AV-45 positron emission tomography was conducted to measure the regional standardized uptake value ratio (SUVr) in 8 cortical volumes-of- interests (VOIs). The quantitative WMLs burden was measured from magnetic resonance imaging while the normalized VOIs volumes represented BR in this study. The cognitive test represented major clinical correlates.
Results
Significant correlations between the prefrontal volume and global (r = 0.470, p = 0.024), but not regional (r = 0.264, p = 0.223) AV-45 SUVr were found. AD patients having larger regional volume in the superior- (r = 0.572, p = 0.004), superior medial- (r = 0.443, p = 0.034), and middle-prefrontal (r = 0.448, p = 0.032) regions had higher global AV-45 SUVr. For global WML loads, the prefrontal (r = -0.458, p = 0.019) and hippocampal volume (r = -0.469, p = 0.016) showed significant correlations while the prefrontal (r = -0.417, p = 0.043) or hippocampal volume (r = -0.422, p = 0.04) also predicted better composite memory scores. There were no interactions between amyloid SUVr and WML loads on the prefrontal volume.
Conclusions
BR of the prefrontal region might modulate the adverse global pathological burden caused by amyloid deposition. While prefrontal volume positively associated with hippocampal volume, WMLs had an adverse impact on the hippocampal volume that predicts memory performance in mild stage AD.
doi:10.1371/journal.pone.0149056
PMCID: PMC4752238  PMID: 26872386
17.  Cerebral white matter lesions – associations with Aβ isoforms and amyloid PET 
Scientific Reports  2016;6:20709.
Small vessel disease (SVD) and amyloid deposition may promote each other, with a potential association between SVD and altered production or clearance of β-amyloid (Aβ) affecting its cleavage products. We investigated the relationship between SVD, multiple isoforms of Aβ in cerebrospinal fluid (CSF) and cortical Aβ in 831 subjects with cognitive performance ranging from normal to Alzheimer’s disease (AD) (the Swedish BioFINDER study). SVD was estimated as white matter lesions (WML) and lacunes. 18F-flutemetamol PET was performed in 321 subjects. Lower CSF levels of Aβ38 and Aβ40 were consistently associated with increased WML in all subgroups, while lower levels of CSF Aβ42 were associated with WML mainly in AD. CSF Aβ38 and Aβ40 were associated with regional WML in all regions, while CSF Aβ42 was associated with temporal WML only. A composite measure of 18F-flutemetamol uptake was not associated with WML, and regional 18F-flutemetamol uptake only with temporal WML. Lacunes were not associated with Aβ isoforms nor 18F-flutemetamol uptake. Our results suggest that WML may be associated with alterations in the production or clearance of Aβ species, particularly of Aβ38 and Aβ40. However, in AD cases, Aβ42 pathology might be associated with WML, especially in the temporal lobe.
doi:10.1038/srep20709
PMCID: PMC4746584  PMID: 26856756
18.  Neuroprotective Pathways: Lifestyle activity, brain pathology and cognition in cognitively normal older adults 
Neurobiology of aging  2014;35(8):1873-1882.
This study used path analysis to examine effects of cognitive activity and physical activity on cognitive functioning in older adults, through pathways involving beta-amyloid (Aβ) burden, cerebrovascular lesions, and neural injury within brain regions affected in Alzheimer’s disease (AD). Ninety-two cognitively normal older adults (75.2±5.6 years) reported lifetime cognitive activity and current physical activity using validated questionnaires. For each participant, we evaluated cortical Aβ burden (using PIB-PET), cerebrovascular lesions (using MRI-defined white matter lesion (WML)), and neural integrity within AD regions (using a multimodal biomarker). Path models (adjusted for age, gender, and education) indicated that higher lifetime cognitive activity and higher current physical activity was associated with fewer WMLs. Lower WML volumes were in turn related to higher neural integrity and higher global cognitive functioning. As shown previously, higher lifetime cognitive activity was associated with lower PIB retention, which itself moderated the impact of neural integrity on cognitive functioning. Lifestyle activity may thus promote cognitive health in aging by protecting against cerebrovascular pathology and Aβ pathology thought to be relevant to AD development.
doi:10.1016/j.neurobiolaging.2014.02.015
PMCID: PMC4019766  PMID: 24656834
Cognitive activity; Physical activity; Cognitive aging; Beta-amyloid; PIB-PET; white matter lesion
19.  How Much Do Focal Infarcts Distort White Matter Lesions and Global Cerebral Atrophy Measures? 
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.
doi:10.1159/000343226
PMCID: PMC3566554  PMID: 23154746
White matter disease; Infarcts; Lacunes; Atrophy; Magnetic resonance imaging
20.  Education modulates the impact of white matter lesions on the risk of mild cognitive impairment and dementia 
Objectives
Conflicting results have been reported regarding the association between white matter lesions (WML) and cognitive impairment. We hypothesized that education, a marker of cognitive reserve (CR), could modulate the effects of WML on the risk of Mild Cognitive Impairment (MCI) or dementia.
Methods
We followed 500 healthy subjects from a cohort of community-dwelling persons aged 65 years and over (ESPRIT Project). At baseline, WML volume was measured using a semi-automatic method on T2-weighted MRI. Standardized cognitive and neurological evaluations were repeated after 2, 4 and 7 years. The sample was dichotomized according to education level into low (≤8 years) and high (>8 years) education groups. Cox proportional hazard models were constructed to study the association between WML and risk of MCI/dementia.
Results
The interaction between education level and WML volume reached significance (p=0.017). After adjustment for potential confounders, the association between severe WML and increased MCI/dementia risk was significant in the low education group (≤8 years) (p=0.02, HR= 3.77 [1.29–10.99]), but not in the high education group (>8 years) (p=0.82, HR=1.07 [0.61–1.87]).
Conclusions
Severe WML significantly increases the risk of developing MCI/dementia over a 7-year period in low educated participants. Subjects with higher education levels were seen to be more likely to be resilient to the deleterious effects of severe WML. The CR hypothesis suggests several avenues for dementia prevention.
doi:10.1016/j.jagp.2013.06.002
PMCID: PMC4143478  PMID: 24021219
Alzheimer’s disease; dementia; mild cognitive impairment (MCI); white matter lesions; Magnetic Resonance Imaging (MRI); cognitive reserve; cohort studies
21.  Reduced glucose uptake and Aβ in brain regions with hyperintensities in connected white matter 
NeuroImage  2014;100:684-691.
Interstitial concentration of amyloid beta (Aß) is positively related to synaptic activity in animal experiments. In humans, Aß deposition in Alzheimer's disease overlaps with cortical regions highly active earlier in life. White matter lesions (WML) disrupt connections between gray matter (GM) regions which in turn changes their activation patterns. Here, we tested if WML are related to Aß accumulation (measured with PiB-PET) and glucose uptake (measured with FDGPET) in connected GM. WML masks from 72 cognitively normal (age 61.7±9.6 years, 71% women) individuals were obtained from T2-FLAIR. MRI and PET images were normalized into common space, segmented and parcellated into gray matter (GM) regions. The effects of WML on connected GM regions were assessed using the Change in Connectivity (ChaCo) score. Defined for each GM region, ChaCo is the percentage of WM tracts connecting to that region that pass through the WML mask. The regional relationship between ChaCo, glucose uptake and Aß was explored via linear regression. Subcortical regions of the bilateral caudate, putamen, calcarine, insula, thalamus and anterior cingulum had WM connections with the most lesions, followed by frontal, occipital, temporal, parietal and cerebellar regions. Regional analysis revealed that GM with more lesions in connecting WM and thus impaired connectivity had lower FDG-PET (r=0.20, p<0.05 corrected) and lower PiB uptake (r=0.28, p<0.05 corrected). Regional regression also revealed that both ChaCo (β=0.045) and FDG-PET (β=0.089) were significant predictors of PiB. In conclusion, brain regions with more lesions in connecting WM had lower glucose metabolism and lower Aß deposition.
doi:10.1016/j.neuroimage.2014.06.060
PMCID: PMC4138232  PMID: 24999038
Magnetic Resonance Imaging; Positron Emission Tomography; amyloid beta; aging; cerebrovascular disorders
22.  Cerebral Blood Flow in Ischemic Vascular Dementia and Alzheimer's Disease By Arterial Spin Labeling MRI 
Background
The objectives were first to compare the effects of subcortical ischemic vascular dementia (SIVD) and Alzheimer's disease (AD) on cerebral blood flow (CBF) and second to analyze the relationship between CBF and subcortical vascular disease, measured as volume of white matter lesions (WML).
Methods
Eight mildly demented patients with SIVD (77 ± 8 years, 26 ± 3 MMSE) and 14 patients with AD were compared to 18 cognitively normal elderly. All subjects had CBF measured using arterial spin labeling MRI and brain volumes assessed using structural MRI.
Results
AD and SIVD showed marked CBF reductions in frontal (p = 0.001) and parietal (p = 0.001) cortex. In SIVD, increased subcortical WML were associated with reduced CBF in frontal cortex (p = 0.04) in addition to cortical atrophy (frontal: p = 0.05; parietal: p = 0.03).
Conclusions
Subcortical vascular disease is associated with reduced CBF in the cortex, irrespective of brain atrophy.
doi:10.1016/j.jalz.2009.04.1233
PMCID: PMC2802181  PMID: 19896584
Magnetic Resonance Imaging; Cerebral blood flow; Subcortical ischemic vascular dementia; Alzheimer's disease; Cortex; Segmentation; White matter lesions
23.  Early-Stage White Matter Lesions Detected by Multispectral MRI Segmentation Predict Progressive Cognitive Decline 
White matter lesions (WML) are the main brain imaging surrogate of cerebral small-vessel disease. A new MRI tissue segmentation method, based on a discriminative clustering approach without explicit model-based added prior, detects partial WML volumes, likely representing very early-stage changes in normal-appearing brain tissue. This study investigated how the different stages of WML, from a “pre-visible” stage to fully developed lesions, predict future cognitive decline. MRI scans of 78 subjects, aged 65–84 years, from the Leukoaraiosis and Disability (LADIS) study were analyzed using a self-supervised multispectral segmentation algorithm to identify tissue types and partial WML volumes. Each lesion voxel was classified as having a small (33%), intermediate (66%), or high (100%) proportion of lesion tissue. The subjects were evaluated with detailed clinical and neuropsychological assessments at baseline and at three annual follow-up visits. We found that voxels with small partial WML predicted lower executive function compound scores at baseline, and steeper decline of executive scores in follow-up, independently of the demographics and the conventionally estimated hyperintensity volume on fluid-attenuated inversion recovery images. The intermediate and fully developed lesions were related to impairments in multiple cognitive domains including executive functions, processing speed, memory, and global cognitive function. In conclusion, early-stage partial WML, still too faint to be clearly detectable on conventional MRI, already predict executive dysfunction and progressive cognitive decline regardless of the conventionally evaluated WML load. These findings advance early recognition of small vessel disease and incipient vascular cognitive impairment.
doi:10.3389/fnins.2015.00455
PMCID: PMC4667087  PMID: 26696814
executive functions; cognition; image analysis; MRI; neuropsychology; white matter lesions; small vessel disease
24.  Association between Subcortical Vascular Lesion Location and Cognition: A Voxel-Based and Tract-Based Lesion-Symptom Mapping Study. The SMART-MR Study 
PLoS ONE  2013;8(4):e60541.
Introduction
Lacunar lesions (LLs) and white matter lesions (WMLs) affect cognition. We assessed whether lesions located in specific white matter tracts were associated with cognitive performance taking into account total lesion burden.
Methods
Within the Second Manifestations of ARTerial disease Magnetic Resonance (SMART-MR) study, cross-sectional analyses were performed on 516 patients with manifest arterial disease. We applied an assumption-free voxel-based lesion-symptom mapping approach to investigate the relation between LL and WML locations on 1.5 Tesla brain MRI and compound scores of executive functioning, memory and processing speed. Secondly, a multivariable linear regression model was used to relate the regional volume of LLs and WMLs within specific white matter tracts to cognitive functioning.
Results
Voxel-based lesion-symptom mapping identified several clusters of voxels with a significant correlation between WMLs and executive functioning, mostly located within the superior longitudinal fasciculus and anterior thalamic radiation. In the multivariable linear regression model, a statistically significant association was found between regional LL volume within the superior longitudinal fasciculus and anterior thalamic radiation and executive functioning after adjustment for total LL and WML burden.
Conclusion
These findings identify the superior longitudinal fasciculus and anterior thalamic radiation as key anatomical structures in executive functioning and emphasize the role of strategically located vascular lesions in vascular cognitive impairment.
doi:10.1371/journal.pone.0060541
PMCID: PMC3620525  PMID: 23593238
25.  MRI predictors of cognition in subcortical ischemic vascular disease and Alzheimer’s disease 
Neurology  2001;57(12):2229-2235.
Background
Causes of cognitive impairment in subcortical ischemic vascular disease (SIVD) are less well understood than in AD, but have been thought to result from direct effects of subcortical lacunes and white matter lesions, perhaps related to disruption of important cortical-subcortical pathways.
Objective
To examine the relation between cognitive abilities and quantitative MRI measures of subcortical cerebrovascular disease and cortical and hippocampal atrophy.
Methods
Subjects were 157 participants in a multicenter study of SIVD and AD who included cognitively normal, cognitively impaired, and demented individuals with and without subcortical lacunar infarcts. Dependent variables were neuropsychological tests of global cognitive function, memory, language, and executive function. Independent variables were quantitative MRI measures of volume of lacunar infarcts in specific subcortical structures, volume of white matter lesion (WML), volume of cortical gray matter (cGM), and total hippocampal volume (HV). Multiple regression analyses were used to identify MRI predictors of cognition.
Results
Subcortical lacunes were not related to cognitive measures independent of effects of other MRI variables. WML was independently related to selected, timed measures. HV and cGM were strong and independent predictors of cognitive variables, with effects that did not differ in subjects with and without subcortical lacunes.
Conclusions
Results suggest that cognitive impairment associated with subcortical ischemic vascular disease is primarily a result of associated hippocampal and cortical changes.
PMCID: PMC1862483  PMID: 11756602

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