Brain MRI white matter hyperintensities and one-carbon cycle metabolism in non-geriatric outpatients with major depressive disorder (Part I)

The objective of the present work was to study the interrelationship between white matter hyperintensities (WMHs), cardiovascular risk factors and elements of the one-carbon cycle including serum folate, vitamin B12, and homocysteine levels in a relatively young sample of outpatients with major depressive disorder (MDD), and to compare the severity of white matter hyperintensities in MDD patients and healthy volunteers. Fifty MDD outpatients (34% women, age 40.6 ± 10.3 years), free of psychotropic medications for at least 2 weeks before enrollment, underwent magnetic resonance imaging (MRI) scans of the brain to detect T2 WMHs and also had (1) serum folate, vitamin B12, homocysteine and cholesterol levels measured, and (2) cardiovascular risk factors assessed during the same study visit. Thirty-five healthy comparison subjects (40% women, age 39.2 ± 9.8 years) also underwent brain MRI scans. Hypofolatemia, hypertension and age independently predicted a greater severity of total brain WMHs. Separately, the same factors also predicted a greater severity of subcortical WMHs. Hypofolatemic and hypertensive patients had more severe WMHs than normal controls. In light of the adverse impact of WMHs on a number of health-related outcomes later in life, hypofolatemia and hypertension may represent modifiable risk factors to prevent the occurrence of such adverse outcomes.     

Brain MRI white matter hyperintensities and one-carbon cycle metabolism in non-geriatric outpatients with major depressive disorder (Part II)

The objective of this study was to investigate the relative impact of brain white matter hyperintensities (WMHs), cardiovascular risk factors and elements of the one-carbon cycle metabolism (including serum folate, vitamin B12 and homocysteine levels) on the outcome of antidepressant treatment in non-elderly subjects with major depressive disorder (MDD). Fifty MDD subjects were administered brain magnetic resonance imaging (MRI) scans at 1.5 T to detect T2 WMHs. The severity of brain WMHs was classified with the Fazekas scale (range = 0–3). We assessed cardiovascular risk factors in all MDD subjects (age, gender, smoking, diabetes, family history, hypertension, cholesterol). MDD patients also had serum folate, vitamin B12 and homocysteine levels measured. All MDD subjects received treatment with fluoxetine 20 mg/day for 8 weeks. In a logistic regression, the severity of subcortical WMHs and the presence of hypofolatemia were independent predictors of lack of clinical response to antidepressant treatment. Separately, hypofolatemia also predicted lack of remission to antidepressant treatment. These associations were independent of the presence of smoking, diabetes, family history, hypercholesterolemia, hyperhomocysteinemia and low B12 levels. Although preliminary, the results of the present work suggest that subcortical brain WMHs and hypofolatemia may have an independent negative impact on the likelihood of responding to antidepressant treatment in non-geriatric subjects with MDD.     

Major depressive disorder with anger attacks and subcortical MRI white matter hyperintensities

Previous reports of increased rates of cardiovascular risk factors in major depressive disorder (MDD) with anger attacks led the authors to hypothesize that MDD with anger attacks may be associated with brain vascular changes (magnetic resonance imaging white matter hyperintensities [WMHs]). Sixty-five subjects meeting DSM-III-R criteria for major depressive disorder were administered brain magnetic resonance imaging scans at 1.5T to detect T2 WMH. The severity of brain WMH was classified with the Fazekas scale. We used standardized scales to assess melancholic MDD, atypical MDD, and MDD with anger attacks. In logistic regression analyses, MDD with anger attacks was associated with higher severity of subcortical WMH and of total WMH, but not with periventricular WMH. Atypical and melancholic MDD subtypes were not significantly associated with brain WMH. In conclusion, subcortical brain vascular lesions may be more prevalent or severe in MDD with anger attacks.     

Prevalence of white matter hyperintensities increases with age

White matter hyperintensities(WMHs) that arise with age and/or atherosclerosis constitute a heterogeneous disorder in the white matter of the brain. However, the relationship between age-related risk factors and the prevalence of WMHs is still obscure. More clinical data is needed to confirm the relationship between age and the prevalence of WMHs. We collected 836 patients, who were treated in the Renmin Hospital, Hubei University of Medicine, China from January 2015 to February 2016, for a case-controlled retrospective analysis. According to T2-weighted magnetic resonance imaging results, all patients were divided into a WMHs group(n = 333) and a non-WMHs group(n = 503). The WMHs group contained 159 males and 174 females. The prevalence of WMHs increased with age and was associated with age-related risk factors, such as cardiovascular diseases, smoking, drinking, diabetes, hypertension and history of cerebral infarction. There was no significant difference in sex, education level, hyperlipidemia and hyperhomocysteinemia among the different age ranges. These findings confirm that age is an independent risk factor for the prevalence and severity of WMHs. The age-related risk factors enhance the occurrence of WMHs.     

White matter hyperintensities and chronicity of depression

OBJECTIVE: White matter hyperintensities (WMHs) on T(2)-weighted magnetic resonance imaging (MRI) of the brain are associated with advanced age and late-life depression. Most investigations predominantly found these lesions in frontal lobe and basal ganglia supporting the hypothesis of a fronto-striatal dysfunction in depression. A prospective study was undertaken to investigate the association between extent of WMHs and clinical outcome in elderly depressed patients. METHODS: Thirty-one non-demented depressed subjects underwent a 1.5 T cranial MRI scan. The MRI scans were analysed in consensus by two experienced radiologists. Each MRI scan was assessed for presence and extent of WMHs, which are differentiated in periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs). A total of 21 patients of the original cohort of 31 patients were re-assessed 5 years after baseline assessment. We ascertained the severity of depressive symptoms, the longitudinal course of depression, the cognitive decline and the global assessment of functioning at follow-up visit. RESULTS: (1) Subjects with greater extent of WMHs had a significant higher Hamilton Depression Rating Scale (HAM-D) score, (2) had more severe longitudinal courses of depression (3) and had a lower Mini-Mental State Examination (MMSE) score. CONCLUSIONS: WMHs on MRI are associated with poorer outcome in elderly depressed subjects. Further studies are needed to evaluate WHMs as prognostic factor for an appropriate treatment decision-making.     

Homocysteine,white matter hyperintensities,and cognition in healthy elderly people

Hyperhomocysteinemia is associated with an increased risk of vascular disease, and recent results suggest that it also could increase the risk of dementia. We examined the relationship between homocysteine and cognitive decline in 1,241 subjects aged 61 to 73 years, followed up over 4 years. Plasma homocysteine levels were determined in all participants as well as cardiovascular risk factors, apolipoprotein E genotype, plasma levels of folate, and vitamin B12. Cognitive performances were assessed repeatedly by using Mini-Mental State Examination, Trail Making Test, Digit Symbol Substitution Test, and Finger Tapping Test. At 2-year follow-up, 841 subjects underwent cerebral magnetic resonance imaging, and white matter hyperintensities were rated visually. Analyses were adjusted for all cardiovascular risk factors. Cross-sectional analyses showed that higher concentrations of homocysteine were significantly related to poorer performances at all neuropsychological tests. Longitudinal analyses confirmed this finding. The odds of cognitive decline was 2.8-fold (p < 0.05) higher in subjects with homocysteine levels above 15 micromol/L compared with those with homocysteine levels below 10 micromol/L. In participants who underwent magnetic resonance imaging, the relationship between homocysteine and cognition was unchanged after taking into account white matter hyperintensities suggesting that white matter hyperintensities do not mediate the association between homocysteine and cognition.     

White matter hyperintensities in the forties: their prevalence and topography in an epidemiological sample aged 44-48

White matter hyperintensities (WMHs) are a frequent finding on T2-weighted MRI of the brain in elderly individuals, but their prevalence and severity in younger asymptomatic populations is less well studied. We report the topography of WMHs on T2-weighted fluid inversion recovery (FLAIR) MRI in 428 individuals aged 44-48 years recruited randomly from a healthy community sample. WMHs were delineated from FLAIR and T1-weighted scans by using a computer algorithm, further verified and then classified using k-nearest neighbor (kNN) algorithm into deep WMH (DWMH), and periventricular WMH (PVWMH), which included extended periventricular "rims" and frontal and occipital "caps". Small caps and pencil-thin rims were not taken as WMHs for this analysis. The new computer algorithm was validated and compared with the scores of visual rating, and the correspondence between the two methods was high. We found that 218 (50.9%) subjects had WMHs. 146 of the 218 (34.1% of whole sample population of 428) subjects had deep white matter hyperintensities (DWMHs). The average number of WMH clusters (occurrences) per brain was 1.37 (0.94 for DWMH and 0.43 for pathological PVWMH) and the mean WMH tissue volume was 0.278 ml. There was no significant sex difference in the severity and distribution of WMHs. The study suggests that small punctate or focal WMHs are common in the brains of individuals in their 40s, and may represent an early stage of development of these lesions.     

Associations of microalbuminuria with brain atrophy and white matter hyperintensities in hypertensive sibships

BACKGROUND: Because of similarities between brain and kidney microvascular disease, there may be a relationship between measures of renal microvascular disease and brain structural changes in middle aged or elderly individuals. OBJECTIVE: To determine whether the urine albumin/creatinine ratio (UACR), a measure of renal microvascular disease, is associated with brain atrophy and white matter hyperintensities. METHODS: As part of a larger study of the genetics of hypertension, we performed brain imaging and assessed microalbuminuria and other vascular risk factors including diabetes, hypertension, hyperlipidemia and hyperhomocysteinemia in 1253 individuals from hypertensive sibships (age mean 63.8 years, range 50 to 91; 65% women; 49% African-American; 78% hypertensive). Semi-automated quantitative measurements of brain atrophy (BA) ventricular volume, and white matter hyperintensities (WMH) were carried out on the brain MR scans. RESULTS: In logistic regression models, elevated UACR was associated with greater BA (odds ratio (OR)=1.70 (95% CI 1.14, 2.54) and burden of WMH (OR=2.06 (95% CI 1.37, 3.10) after controlling for demographic factors, blood glucose, hypertension severity, duration of smoking and serum homocysteine. In contrast to elevated UACR, the associations with elevated creatinine or reduced glomerular filtration rate and WMH were not significant in the fully adjusted models. CONCLUSIONS: In this cohort with an overrepresentation of hypertensives, elevated UACR was independently associated with both brain atrophy and white matter hyperintensities. Brain volume loss and WMH burden might represent expressions of microvascular disease that share common mechanisms with nephrosclerosis.     

Prevalence of White Matter and Periventricular Magnetic Resonance Hyperintensities in Asymptomatic Volunteers

Magnetic resonance imaging (MRI) of 101 asymptomatic volunteers ranging in age from 31 to 84 years (mean, 55 yr) was performed to determine the prevalence and extent of unexpected white matter (WMH) and periventricular hyperintensities (PVH) in the “normal” population. Twenty-nine had followup studies after 11 to 28 months (mean, 15 mo). Predominantly punctate WMHs were present in 48%. Increasing prevalence was associated with aging and was significantly higher in individuals with major cerebrovascular risk factors (P < 0.05). PVH was noted in 45% and consisted mainly of caps and lines. Volunteers with more extensive WMHs (6%) or PVH (4%) had risk factors or were above 60 years of age. The repeat scans exhibited no significant changes.     

Effect of the apolipoprotein E epsilon4 allele on white matter hyperintensities in dementia

BACKGROUND AND PURPOSE: The clinical significance of the apoE epsilon4 allele in white matter changes in patients with dementia has been a subject of debate. We studied the association between the apoE epsilon4 allele and white matter hyperintensities (WMHs) before and after control for (1) potential vascular risk factors and (2) the presence of lacunar infarcts in patients with dementia. METHODS: The subjects were 131 patients with dementia who had either Alzheimer's disease or vascular dementia, or a combination of these 2 types of dementia, with or without WMHs, lacunar infarcts, or both. The association of the epsilon4 allele with WMHs was examined before and after control for age, sex, duration of symptoms, education level, severity of dementia, presence of lacunar infarcts, and potential vascular risk factors, including hypertension, diabetes mellitus, lipid disorders, smoking habit, drinking habit, and cardiac diseases. RESULTS: WMHs were observed in 73 (55.7%) of the patients. Neither the number of apoE epsilon4 alleles nor their presence was significantly associated with WMHs before or after control for the potential confounding factors. Multiple logistic regression analyses revealed that age, the presence of hypertension, and the presence of lacunar infarcts were independently associated with WMHs. CONCLUSIONS: The apoE epsilon4 allele was not associated with WMHs in patients with dementia. The fact that WMHs were significantly associated with hypertension and lacunar infarcts may indicate an ischemic origin of WMHs.     

MRI volumetric correlates of white matter lesions in dementia with Lewy bodies and Alzheimer's disease

The aim of the study was to examine the relationship between white matter changes on magnetic resonance imaging (MRI), brain atrophy and ventricular dilation in late-life dementias. T(1)-weighted, T(2)-weighted, and proton density MRI scans were acquired in subjects with Alzheimer's disease (AD, N=25) and dementia with Lewy bodies (DLB, N=27). Total brain and ventricular volumes were measured and white matter lesions rated using a semi-quantitative scale. Periventricular hyperintensities (PVH) were found to independently correlate with advancing age and increasing ventricular dilatation in all subjects. In contrast, deep white matter hyperintensities (DWMH) did not correlate with measures of brain atrophy, ventricular dilatation or age, but were associated with a history of hypertension. These findings support the hypothesis that PVH and DWMH are pathologically diverse and that white matter change in AD and DLB may be determined by similar processes. In particular, PVH appear to be linked to atrophic processes involving ventricular enlargement and DWMH to ischaemic risk factors.     

Homocysteine levels, MTHFR C677T genotype, and MRI Hyperintensities in late-onset major depressive disorder.

OBJECTIVE: Epidemiological studies suggest that elevated plasma homocysteine is associated with an increased risk of depression and cerebrovascular disease. There are no published reports of homocysteine levels and methylenetetrahydrofolate reductase (MTHFR) C677T genotype in clinical samples of patients with late-onset major depressive disorder (MDD). The purpose of this study was to examine the association of homocysteine levels or MTHFR C677T genotype and late-onset MDD and assess whether this may be affected by brain magnetic resonance imaging (MRI) hyperintensities. METHODS: Authors recruited 39 elderly patients with MDD with first episode occurring after age 50 and 20 comparison subjects and assessed total plasma homocysteine levels, MTHFR genotype, and brain MRIs. RESULTS: Plasma total homocysteine levels were higher in elderly patients with late-onset MDD versus comparison subjects. The association did not change after controlling for MRI hyperintensities, and the distribution of MTHFR C677T genotype was not different between the groups. CONCLUSIONS: In this exploratory study, elevated homocysteine levels were associated with late-onset MDD, and the association did not appear to be mediated by vascular pathology as identified by brain MRI hyperintensities.     

Subcortical hyperintensities on magnetic resonance imaging: a comparison of normal and depressed elderly subjects

Previous studies reported that depressed subjects had more signal hyperintensities on magnetic resonance imaging scans than control subjects, but the subjects had cerebrovascular disease risk factors. This study used subjects with a history of major depression and matched comparison subjects, screened to exclude cerebrovascular risk factors, to determine whether depressed subjects had more white matter hyperintensities and other lesions. We evaluated the prevalence and severity of MRI signal hyperintensities in 30 elderly depressed patients and 20 controls matched for age. Deep matter hyperintensities, periventricular hyperintensities and subcortical gray hyperintensities were rated on a standard 0-3 scale by two radiologists blind to clinical diagnosis. No significant differences were found between groups for the presence of subcortical gray matter, deep white matter and periventricular hyperintensities. These findings suggest that cerebrovascular disease risk factors most likely mediated the relationship between depression and hyperintensities in previous studies.     

Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals

The authors examined the association of total plasma homocysteine (Hcy) levels with measures of atrophy and white matter disease on MRI scans in 36 healthy elderly individuals. Hcy had a significant positive relationship with lateral ventricle-brain ratios in the anterior (r = 0.49) and middle (r = 0.43) ventricular regions as measures of central atrophy, but not with cortical atrophy or white matter hyperintensities. In a logistic regression analysis, elevated Hcy was a significant determinant of increased anterior ventricle-brain ratio (> or =0.34) after controlling for age, folate, B12, creatinine, and white matter disease (OR = 2.3; CI, 1.03-5.09).     

White matter lesions on magnetic resonance imaging in dementia with Lewy bodies, Alzheimer's disease, vascular dementia, and normal aging

OBJECTIVES: Alzheimer's disease and vascular dementia are associated with an increase in changes in white matter on MRI. The aims were to investigate whether white matter changes also occur in dementia with Lewy bodies and to examine the relation between white matter lesions and the cognitive and non-cognitive features of dementia with Lewy bodies, Alzheimer's disease, and vascular dementia. METHODS: Proton density and T2 weighted images were obtained on a 1.0 Tesla MRI scanner in patients with dementia with Lewy bodies (consensus criteria; n=27, mean age=75.9 years), Alzheimer's disease (NINCDS/ADRDA; n=28, mean age=77.4 years), vascular dementia (NINDS/AIREN; n=25, mean age=76.8 years), and normal controls (n=26, mean age=76.2 years). Cognitive function, depressive symptoms, and psychotic features were assessed using a standardised protocol. Periventricular hyperintensities (PVHs), white matter hyperintensities (WMHs) and basal ganglia hyperintensities (BGHs) were visually rated blind to diagnosis using a semiquantitative scale. RESULTS: Periventricular hyperintensities were positively correlated with age and were more severe in all dementia groups than controls. Total deep hyperintensities scores (WMHs plus BGHs) were significantly higher in all dementia groups than controls and higher in patients with vascular dementia than those with dementia with Lewy bodies or Alzheimer's disease. In all patients with dementia, frontal WMHs were associated with higher depression scores and occipital WMHs were associated with an absence of visual hallucinations and delusions. CONCLUSION: In common with Alzheimer's disease and vascular dementia, PVHs and WMHs were significantly more extensive in dementia with Lewy bodies than in controls. This overlap between different dementias may reflect shared pathological mechanisms. The link between frontal WMHs and depression and the absence of occipital WMHs and psychotic symptoms has important implications for understanding the neurobiological basis of these symptoms.     

Relationship of deep white matter hyperintensities and apolipoprotein E genotype to depressive symptoms in older adults without clinical depression

OBJECTIVE: This study examined whether evidence of cerebrovascular disease in the form of magnetic resonance imaging (MRI) signal hyperintensities in white matter was associated with depressive symptoms in a high-functioning group of normal elderly volunteers. METHOD: Ninety-two community-dwelling elderly individuals participating in a study of white matter hyperintensities (WMHs) in normal aging whose apolipoprotein E (APOE) genotype had been determined completed the Geriatric Depression Scale and received an MRI scan. Univariate analyses of variance were used to examine the relationship between depressive symptoms and the location of WMHs (in deep white matter versus in periventricular white matter) and to determine whether WMHs were more likely to be associated with symptoms of impaired motivation and concentration or with mood symptoms. The effect on depressive symptoms of the interaction between severity of cerebrovascular disease as evidenced by WMHs and APOE genotype was also examined. RESULTS: Hyperintensities in the deep white matter, but not in the periventricular white matter, were associated with depressive symptoms, especially symptoms of impaired motivation, concentration, and decision making. The relationship between deep WMHs and depressive symptoms was especially strong in individuals carrying the APOE-4 allele. CONCLUSIONS: The pattern of depressive symptoms associated with WMHs in this study was similar to the pattern described in the literature as characterizing "vascular" depression in older persons with major depression. The results suggest that cerebrovascular disease may also underlie the depressive symptoms often found in older individuals who are not clinically depressed.     

White matter hyperintensities as a predictor of neuropsychological deficits post-stroke

OBJECTIVES: Cerebral white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) are a recognised risk factor for post-stroke dementia. Their specific relations to cognitive impairment are still not well known. The purpose of this study was to explore how the severity and location of WMHs predict neuropsychological test performance in the context of other brain lesions in elderly stroke patients. METHODS: In the Helsinki Stroke Aging Memory Study, 323 patients, aged from 55 to 85 years, completed a detailed neuropsychological test battery and MRI 3 months after an ischaemic stroke. The demographic and MRI predictors of cognition were studied with sequential linear regression analyses. RESULTS: After age, education and total infarct volume were controlled for, the overall degree of WMHs predicted poor performance in tests of mental speed, executive functions, memory, and visuospatial functions, but not in those of short term memory storage or verbal conceptualisation. However, the contribution of separate white matter regions was relatively low. Only the lesions along the bodies of lateral ventricles were independently associated with speed and executive measures. Additionally, general cortical atrophy clearly predicted a wide range of cognitive deficits while infarct volume had less relevance. Further analyses revealed that executive functions act as a strong mediator between the relationship of WMHs to memory and visuospatial functions. CONCLUSIONS: The degree of WMHs is independently related to post-stroke cognitive decline. The most affected cognitive domains seem to be executive functions and speed of mental processing, which may lead to secondary deficits of memory and visuospatial functions.     

Different associations of periventricular and deep white matter lesions with cognition, neuropsychiatric symptoms, and daily activities in dementia

We investigated the associations of periventricular white matter hyperintensities (PWMHs) and deep white matter hyperintensities (DWMHs) with cognition, activities of daily living (ADLs), and neuropsychiatric symptoms in dementia. This was a hospital-based MRI300 study. We recruited patients newly diagnosed with mild-to-moderate dementia caused either by Alzheimer's disease or subcortical ischemic vascular dementia from 13 dementia clinics at university or general hospitals in South Korea. We enrolled 289 patients aged over 50 from August 2007 to March 2008. We compared cognition, ADLs, and neuropsychiatric symptoms among 3 groups according to the severities of PWMHs and DWMHs, respectively, by adjusting for age, vascular risk factors, and level of other WMHs. A higher severity of PWMHs was related to lower cognitive function and severer neuropsychiatric symptoms, whereas basic ADLs were associated with DWMH. Both PWMHs and DWMHs exhibited different associations with cognition, neuropsychiatric symptoms, and daily activities.     

Age-dependent association between cigarette smoking on white matter hyperintensities

Previous reports have shown that cigarette smoking is associated with white matter hyperintensities (WMHs). However, it remains unclear whether this is true for all ages. We investigated the association between cigarette smoking, WMHs, and age. We retrospectively reviewed charts from 595 patients, who presented as outpatients from January 2007 to March 2010. Grading of periventricular WMHs (PVWMHs) and the scores of deep WMHs (DWMHs) was determined based on criteria established by the Rotterdam Scan Study. We compared the degree of WMHs between smokers and non-smokers, and those younger than the age of 65 years versus those above. In younger age group, smokers had higher grades of PVWMHs and more microbleeds than non-smokers. In the older age group, total burden of DWMHs was much greater in smokers than nonsmokers. Multivariate regression analysis showed that cigarette smoking was an independent risk factor for PVWMHs in the younger age group and for DWMHs in the older age group. The location of WMHs in association with smoking seems to differ among age groups. Age should be considered when interpreting the effects of smoking on the brain.     

Review of cerebral microangiopathy and Alzheimer's disease: relation between white matter hyperintensities and microbleeds

Although Alzheimer's disease (AD) is basically considered to be a neurodegenerative disorder, cerebrovascular disease is also involved. The role of vascular risk factors and vascular disease in the progression of AD remains incompletely understood. With the development of brain MRI, it is now possible to detect small-vessel disease, whose prevalence and severity increase with age. The first types of small-vessel disease to be described were white matter hyperintensities (WMHs). More recently, small areas of signal loss on T(2)*-weighted images, also called microbleeds (MBs), have been reported. Cerebral MBs are focal deposits of hemosiderin that indicate prior microhemorrhages around small vessels, related to either ruptured atherosclerotic microvessels or amyloid angiopathy. Consequently, using brain MRI for the detection of microangiopathy may prove useful to improve our understanding of the impact of the vascular burden in AD pathology. The relationship between microangiopathy and the clinical course of AD or the conversion of mild cognitive impairment to AD remains questionable in terms of cognitive or affective symptoms, particularly if we consider MBs.