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Objectives: To investigate spatial heterogeneity of white matter lesions or hyperintensities (WMH)., Methods: MRI scans of 1,836 participants (median age 52.2 ± 13.16 years) encompassing a wide age range (22-84 years) from the cross-sectional Study of Health in Pomerania (Germany) were included as discovery set identifying spatially distinct components of WMH using a structural covariance approach. Scans of 307 participants (median age 73.8 ± 10.2 years, with 747 observations) from the Baltimore Longitudinal Study of Aging (United States) were included to examine differences in longitudinal progression of these components. The associations of these components with vascular risk factors, cortical atrophy, Alzheimer disease (AD) genetics, and cognition were then investigated using linear regression., Results: WMH were found to occur nonuniformly, with higher frequency within spatially heterogeneous patterns encoded by 4 components, which were consistent with common categorizations of deep and periventricular WMH, while further dividing the latter into posterior, frontal, and dorsal components. Temporal trends of the components differed both cross-sectionally and longitudinally. Frontal periventricular WMH were most distinctive as they appeared in the fifth decade of life, whereas the other components appeared later in life during the sixth decade. Furthermore, frontal WMH were associated with systolic blood pressure and with pronounced atrophy including AD-related regions. AD polygenic risk score was associated with the dorsal periventricular component in the elderly. Cognitive decline was associated with the dorsal component., Conclusions: These results support the hypothesis that the appearance of WMH follows age and disease-dependent regional distribution patterns, potentially influenced by differential underlying pathophysiologic mechanisms, and possibly with a differential link to vascular and neurodegenerative changes., (© 2018 American Academy of Neurology.)

Background: In Parkinson's disease cognitive impairment is an early nonmotor feature, but it is still unclear why some patients are able to maintain their cognitive performance at normal levels, as quantified by neuropsychological tests, whereas others cannot. The objectives of this study were to perform a cross-sectional study and analyze the white matter changes in the cognitive and motor bundles in patients with Parkinson's disease., Methods: Sixteen Parkinson's disease patients with normal cognitive performance, 19 with mild cognitive impairment (based on their performance of 1.5 standard deviations below the healthy population mean), and 16 healthy controls were compared with respect to their tractography patterns between the cortical cognitive / motor regions and subcortical structures, using high angular resolution diffusion imaging and constrained spherical deconvolution computation., Results: Motor bundles showed decreased apparent fiber density in both PD groups, associated with a significant increase in diffusivity metrics, number of reconstructed streamlines, and track volumes, compared with healthy controls. By contrast, in the cognitive bundles, decreased fiber density in both Parkinson's groups was compounded by the absence of changes in diffusivity in patients with normal cognition, whereas patients with cognitive impairment had increased diffusivity metrics, lower numbers of reconstructed streamlines, and lower track volumes., Conclusions: Both PD groups showed similar patterns of white matter neurodegeneration in the motor bundles, whereas cognitive bundles showed a distinct pattern: Parkinson's patients with normal cognition had white matter diffusivity metrics similar to healthy controls, whereas in patients with cognitive impairment white matter showed a neurodegeneration pattern. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Adult-onset leukoencephalopathies are clinically and genetically heterogeneous disorders that affect predominantly the cerebral white matter of the central nervous system. Clinical and neuroimaging-based approaches have been developed to improve diagnostic processes for adult-onset leukoencephalopathies. However, the differential diagnosis is often challenging. Recently, knowledge of the genetic basis of leukoencephalopathies has been accumulated rapidly, which provides powerful diagnostic approaches. The article provides an overview of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), focusing on the clinical presentations of cognitive impairment and symptoms of movement disorders. ALSP is a subtype of dominantly inherited leukoencephalopathy caused by CSF1R mutations. ALSP typically develop in adulthood, with cognitive decline, psychiatric symptoms, and motor symptoms of movement disorders. Cognitive symptoms in ALSP are characterized by frontal lobe dysfunctions such as executive dysfunction, attention deficits and indifference. The cardinal motor symptoms of movement disorders ALSP were gait disturbance and bradykinesia, which may appear as the initial symptoms. Thus, ALSP should be recognized as both a cognitive disorder and a movement disorder., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Evidence suggests that cerebral white matter lesions (WML) play a role in cognitive decline., Objective: To assess the impact of cerebral WML on cognitive function relative to absence or presence of medial temporal atrophy (MTA) in a large single-center memory clinic population., Methods: Patients included had subjective cognitive impairment (SCI, n = 333), mild cognitive impairment (MCI, n = 492) and Alzheimer's disease (AD, n = 832). The relationships between visually rated WML (Fazekas scale, 0-3) on brain Computed Tomography and CAMCOG memory and non-memory function were investigated with regression analysis adjusted for age, gender and education in combined patient groups. We assessed possible interaction versus addition effects of these relationships with visually rated MTA (Scheltens scale)., Results: The highly statistical significant relationship between WML and memory function was no longer significant when MTA was taken into account. However, the strong significant relationship between WML and non-memory function remained significant after adjustment for MTA, but the explained variance attributed to WML was only 1.3%. There was no interaction between WML and MTA on CAMCOG test scores. In addition, shown by a 2×2 factorial model by presence versus absence of WML and MTA, WML affected non-memory function only in the presence of MTA., Conclusion: Our data suggest that presence of WML is associated with lower non-memory cognitive function but this effect is conditional on the presence of pre-existing MTA. The very small explained variance suggests little impact of WML to the clinical profile of a memory clinic patient.

Background: The anti-aging protein, α-Klotho, may be involved in cognitive decline and has potential as a surrogate marker that reflects dementia. However, the role of α-Klotho in the brain has not been sufficiently investigated., Objective: Here, we investigated the association between α-Klotho and cognitive decline that is associated with cerebral deep white matter lesions (DWMLs)., Methods: Two hundred-eighty participants (187 males and 93 females, mean age: 70.8 years old) were evaluated for DWMLs, and the Fazekas scale (Grade) was assessed following brain magnetic resonance imaging. A questionnaire concerning lifestyle and neuropsychological tests was administered, and their associations with the blood α-Klotho level were retrospectively investigated., Results: The α-Klotho level was 685.1 pg/mL in Grade 0 (68 subjects), 634.1 in G1 (134), 596.0 in G2 (62), and 571.6 in G3 (16), showing that the level significantly decreased with advanced grades. Significant correlations were noted between the α-Klotho level and higher brain function tests including the Mini-Mental State Examination and word fluency tests (p < 0.05). When a 90th percentile value of the level in the G0 group (400 pg/mL) or lower was defined as a low α-Klotho level, the odds ratio of the high-grade G3 group was 2.9 (95% confidence interval: 1.4-7.8) (after correction for age, sex, hypertension, and chronic kidney disease), which was significant., Conclusion: A reduced blood α-Klotho level was correlated with grading of cerebral DWMLs and was accompanied by cognitive decline as an independent risk factor. The α-Klotho level may serve as a useful clinical index of vascular cognitive impairment.

Subjects with metabolic syndrome (MetS) often show worse cognitive performance compared with the healthy population. We investigated whether microstructural white matter abnormalities are associated with cognitive performance in adults with MetS using diffusion tensor MR imaging. A total of 32 subjects with MetS (age 64.8 ± 7.8, 56.25 % female) and 23 age-, gender-, and education-matched healthy controls completed a battery of neuropsychological tests and diffusion tensor imaging (DTI) at 3-T MRI. Brain global and regional volumes, white matter fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (LD) were calculated. The least-square models adjusted for age, sex, HbA1c, hypertension, body mass index, hyperlipidemia, and white matter hyperintensities were used to evaluate the relationship between cognitive function and DTI. The MetS group had worse performance in verbal fluency (VF) and learning and memory function (total VF: T score (p = 0.01), VF: animals T score (p = 0.0001), Hopkins Verbal Learning Test (HVLT): Total recall T score (p = 0.0001), and HVLT: delayed recall T score (p = 0.002), as compared with controls. In the MetS group, abnormalities in diffusivity measures were associated with worse cognitive performance [VF: animals T score and left post-central gyrus-LD (p = 0.0007, r adj 0.4), R angular gyrus-RD (p = 0.0008, r adj 0.3), L supra-marginal gyrus-RD (p = 0.009, r adj 0.2) after adjusting for age, sex, HbA1c, 24 h mean BP, presence of hyperlipidemia, and global white matter hyperintensities]. Microstructural white matter abnormalities in the MetS group might be the underlying mechanisms of worse verbal learning and memory performance.

White matter hyperintensities (WMHs) in the brain are the consequence of cerebral small vessel disease, and can easily be detected on MRI. Over the past three decades, research has shown that the presence and extent of white matter hyperintense signals on MRI are important for clinical outcome, in terms of cognitive and functional impairment. Large, longitudinal population-based and hospital-based studies have confirmed a dose-dependent relationship between WMHs and clinical outcome, and have demonstrated a causal link between large confluent WMHs and dementia and disability. Adequate differential diagnostic assessment and management is of the utmost importance in any patient, but most notably those with incipient cognitive impairment. Novel imaging techniques such as diffusion tensor imaging might reveal subtle damage before it is visible on standard MRI. Even in Alzheimer disease, which is thought to be primarily caused by amyloid, vascular pathology, such as small vessel disease, may be of greater importance than amyloid itself in terms of influencing the disease course, especially in older individuals. Modification of risk factors for small vessel disease could be an important therapeutic goal, although evidence for effective interventions is still lacking. Here, we provide a timely Review on WMHs, including their relationship with cognitive decline and dementia.

Background: Cognitive and motor performance can be supported, especially in older subjects, by different types of brain activations, which can be accurately studied by functional magnetic resonance imaging (fMRI). Vascular risk factors (VRFs) are extremely important in the development of cognitive impairment, but few studies have focused on the fMRI cortical activation characteristics of healthy subjects with and without silent cerebrovascular disease including white matter hyperintensities (WMH) and carotid stenosis (CS) performing cognitive tasks., Methods: Thirty-five volunteers with and without asymptomatic unilateral carotid stenosis above 70% and variable degrees of WMH underwent performance of a simple motor and cognitive task during an fMRI session., Results: While the performance of the motor task resulted in a cortical activation dependent of age but not of WMH and carotid stenosis, performance of the cognitive task was accompanied by a significantly increased activation independently correlated with age, presence of WMH as well as of carotid stenosis., Conclusions: in this study, cognitive domains regulating attention and working memory appear to be activated with a pattern influenced by the presence of carotid stenosis as well as by white matter hyperintensities. The impairment of these cognitive abilities is of high relevance in Alzheimer's disease pathology. The fMRI pattern shown in patients with asymptomatic but significant carotid stenosis might be related to chronic cerebrovascular hypoperfusion, a critical pathophysiological mechanisms in AD. In these patients, carotid endoarterectomy should be considered also for AD prevention and might be recommended.

Objective: We aimed to quantify the effects of white matter hyperintensities (WMHs) on specific cognitive functions with particular attention to WMH progression and localization., Methods: PubMed (January 1990-July 2013) and bibliographies from included articles were used. Studies that were included (1) used MRI; (2) had a population-based or case-control design with a healthy control group that could be used for analysis; (3) matched/adjusted for age, sex, and education; and (4) addressed ≥1 predefined cognitive domains with ≥1 validated neuropsychological tests. Data were independently extracted by 2 investigators. Pearson r was extracted/calculated and used as the common metric for the effect size across studies., Results: Twenty-three cross-sectional and 14 longitudinal studies were included with a total of 8,685 and 7,731 participants. Presence of WMHs was significantly associated with concurrent cognitive deficits in all examined domains: general intelligence (Fisher z -0.10, 95% confidence interval [CI] -0.19 to -0.04), memory (-0.08, -0.13 to -0.06), processing speed (-0.11, -0.17 to -0.07), attention and executive functions (-0.11, -0.16 to -0.07), and perception/construction (-0.15, -0.21 to -0.07). Similar effect sizes were observed for cognitive decline over time. WMH progression was associated with greater cognitive decline, particularly for general intelligence (Fisher z -0.31, 95% CI -0.5 to -0.02) and attention and executive functions (-0.32, -0.34 to -0.28)., Conclusions: The small but robust and consistent effects of WMHs on all cognitive domains suggest a more global effect on cognition than previously thought. Progression of WMHs was associated with even worse cognitive functioning, most pronounced in attention and executive functioning., (© 2014 American Academy of Neurology.)

Delayed leukoencephalopathy is an uncommon complication of hypoxic-ischemic events of different etiologies, including carbon monoxide intoxication. We present a case of a 40-year-old male patient who was admitted with rapidly progressive neurocognitive and behavioral deficits. There was a history of accidental carbon monoxide intoxication one month before, presenting with loss of consciousness and short hospitalization, followed by a complete clinical recovery. The imaging studies in the delayed phase depicted confluent, symmetric supra-tentorial white matter lesions in keeping with diffuse demyelinization. Restricted diffusion and metabolite abnormalities in magnetic resonance proton spectroscopy were also seen. The diagnosis of CO-mediated delayed post-hypoxic leukoencephalopathy was assumed after exclusion of other mimickers. Hyperbaric oxygen therapy was tentatively performed and the patient had a favorable clinical and radiological evolution.

Cerebral white matter lesions (WMLs) have been consistently related to cognitive dysfunction but the role of white matter (WM) damage in cognitive impairment is not fully determined. Diffusion tensor imaging is a promising tool to explain impaired cognition related to WMLs. We investigated the separate association of high-grade periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs) with fractional anisotropy (FA) in middle-aged individuals. We also assessed the predictive value to cognition of FA within specific WM tracts associated with high-grade WMLs. One hundred participants from the Barcelona-AsIA Neuropsychology Study were divided into groups based on low- and high-grade WMLs. Voxel-by-voxel FA were compared between groups, with separate analyses for high-grade PVHs and DWMHs. The mean FA within areas showing differences between groups was extracted in each tract for linear regression analyses. Participants with high-grade PVHs and participants with high-grade DWMHs showed lower FA in different areas of specific tracts. Areas showing decreased FA in high-grade DWMHs predicted lower cognition, whereas areas with decreased FA in high-grade PVHs did not. The predictive value to cognition of specific WM tracts supports the involvement of cortico-subcortical circuits in cognitive deficits only in DWMHs.

Objectives: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE). Its etiology remains unknown. With diffusion tensor imaging, we have studied cerebral white matter properties and associations with cognitive functioning in children with FLE and healthy controls., Methods: Thirty children aged 8-13 years with FLE of unknown cause and 39 healthy age-matched controls underwent neuropsychological assessment, structural and diffusion-weighted brain MRI. Patients were grouped as cognitively impaired or unimpaired, and their white matter diffusion properties were compared with the controls., Results: Children with FLE had reduced apparent diffusion coefficients in various posteriorly located tract bundles, a reduced fractional anisotropy (FA) of the white matter tract between the right frontal and right occipital lobe, and smaller volumes of several collections of interlobar bundle tracts, compared with controls. The cognitively impaired patient group demonstrated significant increases in FA of the white matter of both occipital lobes, a reduced FA of white matter tract bundles between the right frontal and both left occipital lobe and subcortical white matter area, and smaller volumes of two collections of tract bundles connecting the frontal lobe with the temporal and parietal lobes, compared with controls., Conclusions: Children with FLE had white matter abnormalities mainly in posterior brain regions, not confined to the area of the seizure focus. Cognitively impaired children with FLE showed the most pronounced white matter abnormalities. These possibly reflect disturbed maturation and might be part of the etiology of the cognitive impairment., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

White matter lesions (WMLs) are of considerable research interest because of their high prevalence and serious consequences, such as stroke and dementia. Most existing studies of WMLs have focused on severe WMLs, but mild WMLs, which are clinically and fundamentally significant, have been largely neglected. The present study is a comprehensive investigation on the injury pattern and on the anatomical, functional, and cognitive changes related to mild WMLs. These results may provide better understanding mild WMLs. Fifty-one human subjects with mild WMLs and 49 control participants completed serial neuropsychological tests and underwent a 3-T magnetic resonance imaging (MRI) scan that included diffusion tensor imaging, a resting-state functional MRI, and a structural MRI. We found declines in cognitive functions such as global function, executive function, and episodic memory in mild WMLs subjects. The white matter injuries in the mild WMLs subjects were mainly in the fibers that projected to frontal areas, while gray matter structures were relatively intact. The overall resting state function of the frontal area was significantly increased. The integrity of the neural fibers in the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus was significantly correlated with the cognitive scores in executive function and episodic memory in both the control and the mild WMLs group. These findings demonstrate that mild WMLs subjects exhibit abnormalities in both white matter structure and functional intrinsic brain activity and that such changes are related to several types of cognitive dysfunction.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a young-adult-onset autosomal dominant white matter disease characterized by progressive cognitive dysfunction. We herein report the case of a 20-year-old woman who developed spastic hemiplegia. Brain magnetic resonance imaging revealed increased bilateral T2 signal intensity and bright diffusion-weighted imaging signals with a low apparent diffusion coefficient within the frontoparietal white matter. The lesion gradually expanded for over one year. The patient was initially diagnosed with multiple sclerosis (MS); however, she did not respond to immunosuppressive therapy. DNA sequencing showed a heterozygous c.2381T>C mutation in colony-stimulating factor 1 receptor. HDLS with a pure motor phenotype is sometimes difficult to differentiate from MS.

Purpose of Review: Late-life depression (LLD) presents in older adults as a heterogeneous mood disorder. Because of the diverse outcomes and symptomatology of LLD, several theories, especially the vascular depression hypothesis, have been proposed to identify its cause. This review outlines the features of LLD and explores the recent advances in characterizing this disorder through studies of brain functioning and cognition, with an emphasis on how vascular changes may mediate this disorder., Recent Findings: LLD is associated with brain changes, including atrophy of hippocampus, independent of other neurodegenerative states. White matter lesions (WMLs) are frequently found in patients with LLD. Functional imaging has revealed both distinct characteristics of LLD and overlap of some cognitive symptoms with other dementias. Executive dysfunction and impaired processing speeds are at the core of the cognitive deficits in LLD and are associated with the development of WMLs in specific fiber tracts in the brain., Summary: LLD is associated with brain changes in both gray matter and white matter, including cerebrovascular changes, atrophy, and loss of myelin integrity. These brain changes are associated with age of onset of depression, as well as cumulative life-time depression burden, and can explain the increased dementia risk associated with LLD.

Reductions in mobility and cognitive function linked to accrual of brain microvascular disease related white matter hyperintensities (WMHs) on magnetic resonance imaging can occur in older hypertensive patients in as little as 2 years. We have designed a trial evaluating 2 levels of ambulatory blood pressure (ABP) control in individuals with normal or mildly impaired mobility and cognition who have detectable cerebrovascular disease (>0.5% WMH fraction of intracranial volume) on functional outcomes. The study is a prospective randomized, open-label trial with blinded end points, in patients ages ≥75 years with elevated 24-hour systolic blood pressure (BP) (145 mm Hg in the untreated state) who do not have unstable cardiovascular disease, heart failure, or stroke. The primary and key secondary outcomes in the trial are change from baseline in mobility and cognitive function and damage to brain white matter as demonstrated by accrual of WMH volume and changes in diffusion tensor imaging. Approximately 300 patients will be enrolled, and 200 randomized to 1 of 2 levels of ABP control (intensive to achieve a goal 24-hour systolic BP of ≤130 mm Hg or standard to achieve a goal 24-hour systolic BP of ≤145 mm Hg) for a total of 36 months using similar antihypertensive regimens. The analytical approach provides 85% power to show a clinically meaningful effect in differences in mobility accompanied by quantitative differences in WMH between treatment groups. The INFINITY trial is the first to guide antihypertensive therapy using ABP monitoring rather than clinic BP to reduce cerebrovascular disease., (Copyright © 2013 Mosby, Inc. All rights reserved.)

The association of cerebral white matter lesions (WMLs) with cognitive status is not well understood in middle-aged individuals. Our aim was to determine the specific contribution of periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs) to cognitive function in a community sample of asymptomatic participants aged 50 to 65 years. One hundred stroke- and dementia-free adults completed a comprehensive neuropsychological battery and brain MRI protocol. Participants were classified according to PVH and DWMH scores (Fazekas scale). We dichotomized our sample into low grade WMLs (participants without or with mild lesions) and high grade WMLs (participants with moderate or severe lesions). Analyses were performed separately in PVH and DWMH groups. High grade DWMHs were associated with significantly lower scores in executive functioning (-0.45 standard deviations [SD]), attention (-0.42 SD), verbal fluency (-0.68 SD), visual memory (-0.52 SD), visuospatial skills (-0.79 SD), and psychomotor speed (-0.46 SD). Further analyses revealed that high grade DWMHs were also associated with a three- to fourfold increased risk of impaired scores (i.e.,<1.5 SD) in executive functioning, verbal fluency, visuospatial skills, and psychomotor speed. Our findings suggest that only DWMHs, not PVHs, are related to diminished cognitive function in middle-aged individuals. (JINS, 2012, 18, 1-12).

Recent evidence suggests that age-related impairments in cognition may be mediated by a specific deficit in the ability to maintain goal-relevant information, a critical component of cognitive control dependent on the dorsolateral prefrontal cortex, although the underlying neural mechanism of these deficits remains unclear. To examine white matter hyperintensities as a neurobiological mechanism of these impairments, older individuals with severe white matter hyperintensity burden, older individuals with low white matter hyperintensity burden, and young adults were assessed in an event-related functional imaging scan while performing the 'AX'-continuous performance task. Individuals with severe white matter hyperintensity burden showed a significant reduction in dorsolateral prefrontal cortex activity during the high cognitive control cue condition relative to the low white matter hyperintensity group and young individuals. Conversely, those with severe white matter hyperintensity burden showed greater activity in rostral anterior cingulate cortex compared to young individuals. These results are consistent with impaired cognitive control and a possible failure to deactivate default-mode regions in these subjects. Additionally, those with severe white matter hyperintensity burden showed reduced functional connectivity between dorsolateral prefrontal cortex and task-relevant brain regions including middle frontal gyrus, and supramarginal gyrus relative to young subjects and those with minimal white matter hyperintensity burden. These results suggest that age-related goal maintenance impairments and associated dorsolateral prefrontal cortex dysfunction may partly reflect incipient white matter disease of interconnected cognitive networks.