Cerebral White Matter Lesions Research Articles

Author response: Neuronal intranuclear inclusion disease showing intranuclear inclusions in renal biopsy 12 years earlier.

We thank Lopez-Blanco et al. for the comment on our article.1 Fragile X-associated tremor/ataxia syndrome (FXTAS) is the inherited progressive neurologic disorder showing intention tremor or cerebellar ataxia, and the histopathologic features of FXTAS partially resemble those of neuronal intranuclear inclusion disease (NIID). FXTAS presents substantial cerebellar and cerebral white matter lesions on MRI findings.

Association of Intensive vs Standard Blood Pressure Control With Cerebral White Matter Lesions

The effect of intensive blood pressure lowering on brain health remains uncertain. To evaluate the association of intensive blood pressure treatment with cerebral white matter lesion and brain volumes. A substudy of a multicenter randomized clinical trial of hypertensive adults 50 years or older without a history of diabetes or stroke at 27 sites in the United States. Randomization began on November 8, 2010. The overall trial was stopped early because of benefit for its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. Brain magnetic resonance imaging (MRI) was performed on a subset of participants at baseline (n = 670) and at 4 years of follow-up (n = 449); final follow-up date was July 1, 2016. Participants were randomized to a systolic blood pressure (SBP) goal of either less than 120 mm Hg (intensive treatment, n = 355) or less than 140 mm Hg (standard treatment, n = 315). The primary outcome was change in total white matter lesion volume from baseline. Change in total brain volume was a secondary outcome. Among 670 recruited patients who had baseline MRI (mean age, 67.3 [SD, 8.2] years; 40.4% women), 449 (67.0%) completed the follow-up MRI at a median of 3.97 years after randomization, after a median intervention period of 3.40 years. In the intensive treatment group, based on a robust linear mixed model, mean white matter lesion volume increased from 4.57 to 5.49 cm3 (difference, 0.92 cm3 [95% CI, 0.69 to 1.14]) vs an increase from 4.40 to 5.85 cm3 (difference, 1.45 cm3 [95% CI, 1.21 to 1.70]) in the standard treatment group (between-group difference in change, -0.54 cm3 [95% CI, -0.87 to -0.20]). Mean total brain volume decreased from 1134.5 to 1104.0 cm3 (difference, -30.6 cm3 [95% CI, -32.3 to -28.8]) in the intensive treatment group vs a decrease from 1134.0 to 1107.1 cm3 (difference, -26.9 cm3 [95% CI, 24.8 to 28.8]) in the standard treatment group (between-group difference in change, -3.7 cm3 [95% CI, -6.3 to -1.1]). Among hypertensive adults, targeting an SBP of less than 120 mm Hg, compared with less than 140 mm Hg, was significantly associated with a smaller increase in cerebral white matter lesion volume and a greater decrease in total brain volume, although the differences were small. ClinicalTrials.gov Identifier: NCT01206062.

Optical measures of cerebral arterial stiffness are associated with white matter signal abnormalities and cognitive performance in normal aging

Decline in fluid abilities in normal aging is associated with increased white matter lesions, measured on T1-weighted images as white matter signal abnormalities (WMSAs). WMSAs are particularly evident in hypertensive older adults, suggesting vascular involvement. However, because hypertension is assessed systemically, the specific role of cerebral arterial stiffening in WMSAs has yet to be demonstrated. In 93 cognitively normal adults (aged 18–87 years), we used a novel method to measure cerebral arterial elasticity (pulse relaxation function [PReFx]) with diffuse optical tomography (pulse-DOT) and investigated its association with WMSAs, age, and cognition. PReFx was associated with WMSAs, with older adults with low PReFx showing the greatest WMSA burden. PReFx in brain regions perfused by the middle cerebral artery showed the largest associations with WMSAs and partially mediated the relationship between age and WMSAs. Finally, WMSAs partially mediated the relationship between PReFx and fluid but not crystallized abilities scores. Taken together, these findings suggest that loss of cerebral arterial elasticity is associated with cerebral white matter lesions and age-related cognitive decline.

Intracerebral Transcatheter Laser Photobiomodulation Therapy in the Treatment of Binswanger's Disease and Vascular Parkinsonism: Research and Clinical Experience.

Objective: This research is devoted to intracerebral transcatheter laser photobiomodulation therapy (PBMT) in the treatment of ischemic and neurodegenerative lesions of cerebral white matter in patients with Binswanger's disease (BD) and vascular parkinsonism (VP) in comparison with conservative treatment methods. Background: Recent studies have shown PBMT high potential in the treatment of various cerebral lesions. Materials and methods: Twenty-seven patients with BD, 58-81 years of age (mean age 78), 17 (62.96%) men, and 10 (27.04%) women. Of these, test group 1-14 (51.85%) patients-underwent intracerebral transcatheter laser PBMT, and control group 1-13 (48.15%) patients-had conservative treatment. Besides, 62 patients with VP, 52-80 years of age (mean age 77), 48 (77.42%) men, and 14 (22.58%) women. Of these, test group 2-37 (59.68%) patients-underwent intracerebral transcatheter laser PBMT, and control group 2-25 (40.32%) patients-had conservative treatment. Results: Good and satisfactory clinical results were obtained in Test group 1 and Test group 2 patients in 49 (92.45%) cases, with a persistent decrease of dementia and motor impairment, and recovery of cognitive functions and daily life activity. Control group 1 and Control group 2 patients showed a satisfactory clinical result in 6 (15.79%) cases. Persistent positive dynamics was not observed. Conclusions: Intracerebral transcatheter laser PBMT is a pathogenetically justified, effective treatment for BD and VP; it restores cerebral collateral and capillary blood supply, improves microcirculation, restores cellular and tissue metabolism, stimulates neurogenesis, and causes regenerative processes in the brain.

P2‐277: RAPID PROGRESSIVE DEMENTIA IN HDLS WITH A NOVEL CSF1R MUTATION

Hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia (HDLS) is a hereditary leukodystrophy whose main clinical manifestations include parkinsonism, spasticity, and ataxia. A 39-year old man gradually developed a decline in cognitive functions with spastic gait and parkinsonism. The patient was initially diagnosed with a progressive variant of young-onset dementia or parkinsonism. But gait disturbances and cognitive impairment became more severe, and then the differential diagnosis was made for other causes including genetic testing. Brain MRI showed fronto-temporal atrophy with hyperintense multiple small lesions in the deep cerebral white matter, and deep white matter diffusion abnormalities. The DNA analysis revealed a novel missense mutation c.2349C>A (p.Asn783Gln) of the CSF1R gene. We report a patient with rapid progression of cognitive and gait manifestations of HDLS and a novel CSF1R mutation. Hereditary diffuse leukoencephalopathy with axonal spheroids should be included in the differential diagnosis of young-onset progressive dementia and gait disturbance.

Periventricular White Matter Lesions Influence Gait Functions in Parkinson’s Disease

Objective: We quantitatively evaluated the gait of Parkinson’s disease (PD) patients over a 10-m course during normal walking and during dual-task walking while performing a calculation task, and clarified which parts of white matter lesions (WML) influence gait in PD patients. Methods: Gait parameters, including walking speed, gait cycle, stride length, and left-right instability, were measured in 64 PD patients and 20 controls who walked 10 m with normal gait and as they were performing a calculation task. WML on magnetic resonance imaging (MRI) of PD patients were scored according to Scheltens’ criteria, and associations with gait parameters were investigated. Results: Compared to controls, the PD group showed decreased walking speed and narrowed stride (p < 0.05), and the stride length and step time coefficient of variation changed significantly during the calculation task (p < 0.001). Frontal lobe functions correlated positively with walking speed and stride during the calculation task in patients with PD (p < 0.05). The total score for periventricular hyperintensity (PVH) on MRI correlated with walking speed and stride (p < 0.01). Multiple regression analysis revealed significant correlations between walking speed and frontal cap of PVH, and between stride and occipital cap (p < 0.05). Conclusion: Gait of PD patients deteriorated not only due to motor dysfunction but also due to mental burden in association with frontal lobe function and periventricular lesions of cerebral white matter.

Associated factors of early neurological deterioration in isolated acute lacunar infarction in basal ganglia

Objective:To investigate, in basal ganglia, the factors associated with early neurological deterioration (END) of isolated acute lacunar infarction.Methods:167 patients, in the retrospective group, with isolated acute lacunar infarction in basal ganglia, were defined by magnetic resonance imaging (MRI). The National Institutes of Health Stroke Scale (NIHSS) defined early neurological deterioration as increases of ≥ 2 within 72 hours following admission. Baseline variables predicting END were investigated with multivariate logistic regression analysis.Results:In the study, END occurred in 42 (25.15%) patients. Lesions located in posterior limb of internal capsule were independent risk factors for END (P &lt; 0.01). Associated with END were the age of onset, history of cerebral infarction, history of diabetes, systolic blood pressure at admission and lesions of cerebral white matter. This presented significant differences (P &lt; 0.05). With or without diabetes and different lesion location at varying layers and inter-layers, single-factor and multi-factor analysis revealed no effect on the association between positive ENT and age, history of stroke, white matter. Previous history of stroke, pathological changes of white matter, and age of onset, correlates with END which showed significant difference (P &lt; 0.05).Conclusions:There is a close relationship between the lesion location and other related factors, such as lesions of cerebral white matter, history of cerebral infarction, history of diabetes and age, etc. and END in patients with isolated acute lacunar infarction in basal ganglia. Protective factors of END included age ≥ 65, high systolic pressure, stroke history, cerebral white matter lesions in our study.

The Relationship Between Left Ventricular Systolic Function And Cerebral Blood Flow

PURPOSE: The positive relationship between cardiac output and cerebral blood flow (CBF) has been indicated in healthy individuals and patinets with cardiovascular diseases. Previous studies reported that the reduced cardiac output was related with a low brain volume and an increased risk for Alzheimer’s disease. Also, compromised left ventricular (LV) diastolic function was reported to be associated with a cerebral white matter lesions. Therefore, cardiac function may play an important role for the maintenance of CBF. However, the relationship between LV systolic function and CBF is still unclear. The purpose of this study was to test our hypothesis that the LV systolic function would be associated with CBF. METHODS: Sixty-three outpatients who presented to our hospital due to transient loss of consciousness were enrolled (59 ± 22 years old, rang 17 to 93 years old, 31 females). LV function was assessed by stroke volume (SV), LV ejection fraction (LVEF) and mass (LVmass) by echocardiography, and preejection period (PEP), ejection time (ET) and ET/PEP by phonocardiogram. ET was corrected by heart rate (ETc). On the other hand, CBF was estimated from systolic, diastolic and mean blood flow velocity in middle cerebral artery (MCA), measured by transcranaial Doppler ultrasound. The multiple linear regression analysis was performed using MCA blood flow velocities (MCAv) as independent variables, and age, sex and each LV funtion as dependent variables. RESULTS: SV, LVEF, LVmass and PEP were not correlated with MCAv. In contrast, ETc was significantly correlated with both systolic (β = 0.32, P = 0.01) and mean (β = 0.25, P = 0.02) MCAv. ET/PEP was significantly correlated with systolic MCAv (β = 0.22, P = 0.04) only. CONCLUSIONS: These results indicated that LV systolic function evaluated by phonocardiogram may play more siginifcant role for regulating CBF as compared with that by echocardiography such as LVEF.

Hypertension and Dementia: A comprehensive review from the HOPE Asia Network.

Approximately 365 million people in Asia were classified as elderly in 2017. This number is rising and expected to reach approximately 520 million by 2030. The risk of hypertension and cognitive impairment/dementia increases with age. Recent data also show that the prevalence of hypertension and age-related dementia are rising in Asian countries. Moreover, not many people in Asian countries are aware of the relationship between hypertension and cognitive impairment/dementia. Furthermore, hypertension control is poorer in Asia than in developed countries. Hypertension is known to be a major risk factor for damage to target organs, including the brain. Decreased cognitive function can indicate the presence of target organ damage in the brain. Twenty-four-hour blood pressure profiles and blood pressure variability have been associated with cognitive impairment and/or silent cerebral diseases, such as silent cerebral infarction or white matter lesions, which are predisposing conditions for cognitive impairment and dementia. Hypertension that occurs in midlife also affects the incidence of cognitive impairments in later life. Managing and controlling blood pressure could preserve cognitive functions, such as by reducing the risk of vascular dementia and by reducing the global burden of stroke, which also affects cognitive function.

Transcranial Doppler ultrasound in vascular cognitive impairment-no dementia.

BackgroundAlthough cerebral white matter lesions (WMLs) are considered as a risk factor for vascular dementia, data on their impact on cerebral hemodynamics are scarce. We test and compare transcranial Doppler (TCD) features in WML patients with or without associated cognitive impairment.MethodsA sample of non-demented elderly patients with WMLs was consecutively recruited. Mean blood flow velocity (MBFV), pulsatility index (PI), peak systolic blood flow velocity (PSV), end-diastolic blood flow velocity (EDV), and resistivity index (RI) were recorded from the middle cerebral artery bilaterally. Global cognitive functioning, frontal lobe abilities, functional status, and WML severity were also assessed.Results161 patients satisfying the clinical criteria for vascular cognitive impairment-no dementia (VCI-ND) were age-matched with 97 presenting WMLs without any cognitive deficit. VCI-ND patients exhibited a decrease in MBFV and EDV, as well as an increase in PI, RI, and PSV. Moreover, a significant correlation between all TCD parameters and the severity of executive dysfunction was observed, whereas PI, RI, and EDV were significantly correlated with the WML load.ConclusionsVCI-ND showed a hemodynamic pattern indicative of cerebral hypoperfusion and enhanced vascular resistance. These changes may be considered as the TCD correlate of VCI-ND due to microcirculation pathology. TCD provides useful indices of the occurrence and severity of small vessel disease and executive dysfunction in elderly patients at risk of future dementia.

Determinants of Early Versus Delayed Neurological Deterioration in Intracerebral Hemorrhage.

Background and Purpose- We investigated factors associated with early and delayed neurological deterioration (END and DND, respectively) after acute spontaneous intracerebral hemorrhage in the main INTERACT (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial)-2. Methods- INTERACT-2 was a randomized trial of early intensive versus guideline-recommended blood pressure lowering in hypertensive intracerebral hemorrhage (<6 hours from symptom onset) patients. END and DND were defined as a ≥4-point increase on the National Institutes of Health Stroke Scale or ≥2-point decrease on Glasgow Coma Scale, in periods baseline to 24 hours and 24 hours to 7 days, respectively. Multivariable logistic regression models were used to determine independent predictors of END and DND and 90-day outcomes (death and dependency on the modified Rankin Scale). Results- Of 2598 participants, 450 (17.3%) had either END or DND. Non-China recruitment, higher systolic blood pressure, larger baseline hematoma volume, left hemisphere hematoma location, intraventricular hemorrhage, subarachnoid extension, heterogeneous hematoma density, and cerebral white matter lesions, were predictors of END (all P≤0.045). Higher systolic blood pressure, lower diastolic blood pressure, higher glucose, larger baseline hematoma volume, intraventricular hemorrhage, lobar location, brain atrophy, and heterogeneous hematoma density were predictors of DND (all P≤0.042). END and DND were both related to death, and death or major disability (modified Rankin Scale scores of 3-6), in adjusted analyses ( P<0.001). Conclusions- Common variables, most directly related to the intracerebral hemorrhage morphology and underlying cerebral features, determine END and DND and their influence on poor outcomes of death and major disability. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT00716079.

Mathematical modeling for the prediction of cerebral white matter lesions based on clinical examination data.

Cerebral white matter lesions are ischemic symptoms caused mainly by microangiopathy; they are diagnosed by MRI because they show up as abnormalities in MRI images. Because patients with white matter lesions do not have any symptoms, MRI often detects the lesions for the first time. Generally, head MRI for the diagnosis and grading of cerebral white matter lesions is performed as an option during medical checkups in Japan. In this study, we develop a mathematical model for the prediction of white matter lesions using data from routine medical evaluations that do not include a head MRI. Linear discriminant analysis, logistic discrimination, Naive Bayes classifier, support vector machine, and random forest were investigated and evaluated by ten-fold cross-validation, using clinical data for 1,904 examinees (988 males and 916 females) from medical checkups that did include the head MRI. The logistic regression model was selected based on a comparison of accuracy and interpretability. The model variables consisted of age, gender, plaque score (PS), LDL, systolic blood pressure (SBP), and administration of antihypertensive medication (odds ratios: 2.99, 1.57, 1.18, 1.06, 1.12, and 1.52, respectively) and showed Areas Under the ROC Curve (AUC) 0.805, the model displayed sensitivity of 72.0%, and specificity 75.1% when the most appropriate cutoff value was used, 0.579 as given by the Youden Index. This model has shown to be useful to identify patients with a high-risk of cerebral white matter lesions, who can then be diagnosed with a head MRI examination in order to prevent dementia, cerebral infarction, and stroke.

Prevalence of fascicular hyperintensities in peripheral nerves of healthy individuals with regard to cerebral white matter lesions.

Detection and pattern analysis of fascicular nerve hyperintensities in the T2-weighted image are the backbone of magnetic resonance neurography (MRN) as they may represent lesions of various etiologies. The aim of this study was to assess the prevalence of fascicular nerve hyperintensities in healthy individuals with regard to a potential association with age or cerebral white matter lesions. Sixty volunteers without peripheral nerve diseases between the age of 20 and 80 underwent MRN (high-resolution T2-weighted) of upper (median, ulnar, radial) and lower (sciatic, tibial) extremity nerves and a fluid-attenuated inversion recovery (FLAIR) sequence of the brain. Presence of peripheral nerve hyperintensities and degree of cerebral white matter lesions were independently rated by two blinded readers and related to each other and to age. T test with Welch's correction was used for group comparisons. Spearman's correlation coefficients were reported for correlation analyses. MR neurography revealed fascicular hyperintensities in 10 of 60 subjects (16.7%). Most frequently, they occurred in the sciatic nerve (8/60 subjects, 13.3%), less frequently in the tibial nerve at the lower leg and the median, ulnar, and radial nerves at the upper arm (1.7-5.0%). Mean age of subjects with nerve hyperintensities was higher than that of those without (60.6years vs. 48.0years, p = 0.038). There was only a weak correlation of nerve lesions with age and with cerebral white matter lesions, respectively. Fascicular nerve hyperintensities may occur in healthy individuals and should therefore always be regarded in conjunction with the clinical context. • MR neurography may reveal fascicular hyperintensities in peripheral nerves of healthy individuals. Fascicular hyperintensities occur predominantly in the sciatic nerve and older individuals. • Therefore, fascicular hyperintensities should only be interpreted as clearly pathologic in conjunction with the clinical context.

Correlations of plasma homocysteine with cerebral white matter lesion severity and cognitive impairment in elderly patients with hypertension

Objective To investigate the correlations of plasma homocysteine(Hcy)levels with cerebral white matter lesion(WML)severity and cognitive impairment in elderly hypertension patients. Methods A retrospective case-control study was conducted.Ninty-eight elderly patients with hypertension were enrolled.Based on the presence or absence of hyperhomocysteinemia(hypertension with plasma Hcy levels ≥10 μmol/L was defined as H-type hypertension), patients were divided into two groups: a control group(n=48)and an H-type hypertension group(n=50). The degree of WML was rated by the Fazekas scale using magnetic resonance imaging(MRI)analysis.Neuropsychological examinations including mini-mental state examination(MMSE)and Montreal cognitive assessment(MoCA)were taken to assess cognitive function.The degree of WML and cognitive impairment were compared between the two groups.Correlations of plasma Hcy levels with the degree of WML and cognitive impairment were analyzed. Results Compared with the control group, scores of the Fazekas scale(3.2±1.0 vs.2.5±1.0, P<0.05)and deep white matter hyperintensity on MRI(1.7±0.8 vs.1.3±0.7, P<0.05)increased, and scores of MMSE(24.9±3.3 vs.27.7±1.8, P<0.05)and MoCA(18.6±3.9 vs.25.0±3.0, P<0.05)decreased in the H-type hypertension group.Plasma Hcy levels were positively correlated with the degree of WML(r=0.430, P<0.01)and negatively correlated with cognitive function(r=-0.406 in MMSE and-0.663 in MoCA, P<0.01). Multivariate logistic regression showed that Hcy, fasting blood-glucose, deep WML, low-density lipoprotein cholesterolin, age and systolic pressure were influencing factors for cognitive impairment(P<0.01). Conclusions WML and cognitive function are worse in elderly H-type hypertension patients than in hypertension patients with normal Hcy levels.WML and cognitive impairment are aggravated with increased plasma Hcy levels.The plasma Hcy level may be an effective clinical indicator of cognitive function in elderly people with hypertension. Key words: Hypertension; Cysteine; Leukoencephalopathies; Cognitive disorders

Otras demencias degenerativas. Demencia con cuerpos de Lewy, demencia en la enfermedad de Parkinson, demencia frontotemporal y demencia vascular

Dementia with Lewy bodies is the second most common cause of degenerative dementia. Its clinical features are attentional impairments and visuospatial difficulties, visual hallucinations, parkinsonism and REM sleep behavior disorder. Patients with Parkinson's disease have an increased risk for developing dementia, which, in many cases, share pathological alterations and clinical similarities with dementia with Lewy bodies. So, both are considered the same disease entity with different clinical expressions. Frontotemporal dementia is the most common group of degenerative dementia in young population. Usually begins with behavioral disturbances or with primary aphasias. Behavioral is the most common between both variants. Clinically are characterized by lack of inhibition, apathy, loss of empathy, compulsive behavior and hyperpolarization. In early stages, neuropsychological and neuroimaging tests may appear normal. Vascular dementia, is the second most common type of dementia after Alzheimer's disease. Grounds of suspicion are executive dysfunction, stroke history, vascular risk factors and stepwise progression. Diagnosis is supported by cerebral white matter lesions (stroke and/or ischemic).

The Impact of APOL1 on Chronic Kidney Disease and Hypertension.

Essential hypertension is a clinical diagnosis based on the presence of an elevated systemic blood pressure on physical examination without a clear inciting cause. It has multiple etiologies and is not a homogeneous disorder. Hypertension contributes to the development and progression of atherosclerotic cardiovascular diseases, and antihypertensive treatment reduces the risk of fatal and nonfatal myocardial infarction, stroke, and congestive heart failure. Although hypertension is frequently present in nondiabetic individuals with low levels of proteinuria and chronic kidney disease, reducing blood pressures in this population does not reliably slow nephropathy progression. Many of these patients with recent African ancestry have the primary kidney disease "solidified glomerulosclerosis" that is strongly associated with renal-risk variants in the apolipoprotein L1 gene (APOL1). This kidney disease contributes to secondarily elevated blood pressures. The APOL1-associated spectrum of nondiabetic nephropathy also includes proteinuric kidney diseases, idiopathic focal segmental glomerulosclerosis, collapsing glomerulopathy, severe lupus nephritis, and sickle cell nephropathy. This article reviews relationships between mild to moderate essential hypertension and chronic kidney disease with a focus on the role of APOL1 in development of hypertension. Available evidence strongly supports that APOL1 renal-risk variants associate with glomerulosclerosis in African Americans, which then causes secondary hypertension, not with essential hypertension per se.

The presence of cerebral white matter lesions and lower skin microvascular perfusion predicts lower cognitive performance in type 1 diabetes patients with retinopathy but not in healthy controls-A longitudinal study.

ObjectiveCognitive impairments in type 1 diabetes may result from hyperglycemia‐associated cerebral microangiopathy. We aimed to identify cerebral microangiopathy and skin microvascular dysfunction—as a surrogate marker for generalized microvascular function—as predictors of cognitive performance over time.MethodsIn this prospective cohort study, 25 type 1 diabetes patients with proliferative retinopathy and 25 matched healthy controls underwent neurocognitive testing at baseline and after follow‐up (3.8 ± 0.8 years). At baseline, 1.5‐T cerebral magnetic resonance imaging was used to detect WML and cerebral microbleeds. Skin capillary perfusion was assessed by means of capillary microscopy.ResultsIn type 1 diabetes patients, but not in healthy controls, the presence of WML (ß = −0.419; P = 0.037) as well as lower skin capillary perfusion (baseline: ß = 0.753; P < 0.001; peak hyperemia: ß = 0.743; P = 0.001; venous occlusion: ß = 0.675; P = 0.003; capillary recruitment: ß = 0.549; P = 0.022) at baseline was associated with lower cognitive performance over time, independent of age, sex, HbA1c, and severe hypoglycemia. The relationship between WML and lower cognitive performance was significantly reduced after adjusting for capillary perfusion.ConclusionsThese data fit the hypothesis that cerebral microangiopathy is a manifestation of generalized microvascular dysfunction, leading to lower cognitive performance.

Brain white matter lesions and postoperative cognitive dysfunction: a review

Postoperative cognitive dysfunction (POCD) is a serious complication of anesthesia and surgery, and the major risk factor of POCD is aging. Although the exact pathophysiology of POCD remains unknown, two possible and reliable mechanisms have been proposed: neuroinflammation and neurodegeneration, i.e., amyloid β accumulation and/or tau protein phosphorylation, by surgery and/or general anesthetics. White matter lesions (WML) are produced by chronic cerebral hypoperfusion, frequently observed in elderly people, and closely related to cognitive decline. As recent studies have revealed that WML are a significant risk factor for POCD in humans, and we previously also demonstrated that persistent hypocapnea or hypotension caused neuronal damage in the caudoputamen or the hippocampus in a rat model of chronic cerebral hypoperfusion, which features global cerebral WML without neuronal damage and is recognized as a good model of human vascular dementia especially in elderly people, we hypothesize that in addition to those two previously proposed mechanisms, perioperative vital sign changes that cause reductions in cerebral blood flow might contribute to POCD in patients with WML, whose cerebral blood flow is already considerably decreased.

A Neuroimaging Marker Based on Diffusion Tensor Imaging and Cognitive Impairment Due to Cerebral White Matter Lesions.

Background: The peak width of skeletonized mean diffusivity (PSMD) is a new, fully automated, robust imaging marker for cerebral small vessel disease (SVD), strongly associated with processing speed. However, it has never been applied to cerebral white matter lesions (WMLs). Our study aimed to investigate the correlation between PSMD and cognition, particularly in the executive function of patients with WMLs.Methods: A total of 111 WML patients and 50 healthy controls (HCs) were enrolled, and their demographic information and cardiovascular disease risk factors were recorded. Subjects were divided into three groups: WMLs with normal cognition (WMLs-NC), WMLs with vascular cognitive impairment (WMLs-VCI), and HCs. They underwent conventional head magnetic resonance imaging and diffusion tensor imaging (DTI), followed by neuropsychological and psychological examinations, including the Montreal Cognitive Assessment (MoCA), and the executive function tests. We compared executive function and PSMD among the three groups and analyzed the correlation between PSMD and cognitive function in all subjects.Results: There were no significant differences in demographic characteristics (age, sex, education level, and cardiovascular disease risk factors) among the three groups (P > 0.05), but there were significant differences in global cognition (P < 0.0001), executive function (P < 0.0001), and PSMD (P < 0.0001). The average PSMD value (×10−4 mm2/s) was 2.40 ± 0.23, 2.68 ± 0.30, and 4.51 ± 0.39 in the HC, WMLs-NC, and WMLs-VCI groups, respectively. There was no correlation between PSMD and cognition in the HC group, but PSMD was significantly correlated with MoCA scores (r = −0.3785, P < 0.0001) and executive function (r = −0.4744, P < 0.0001) in the WMLs-NC group and in the WMLs-VCI group (r = −0.4448, P < 0.0001 and r = −0.6279, P < 0.0001, respectively).Conclusions: WML patients have higher PSMD and worse cognitive performance than HCs, and PSMD is strongly associated with global cognition and executive functions in WML patients. This result provides new insights into the pathophysiology of cognitive impairment in WML patients. PSMD could be a surrogate marker for disease progression and could thus be used in therapeutic trials involving WML patients.

Extravascular fibrinogen in the white matter of Alzheimer's disease and normal aged brains: implications for fibrinogen as a biomarker for Alzheimer's disease.

The blood-brain barrier (BBB) regulates cerebrovascular permeability and leakage of blood-derived fibrinogen. Dysfunction of the BBB has been associated with cerebral arteriolosclerosis small vessel disease (SVD) and white matter lesions (WML). Furthermore, BBB dysfunction is associated with the pathogenesis of Alzheimer's disease (AD) with the presence of CSF plasma proteins suggested to be a potential biomarker of AD. We aimed to determine if extravascular fibrinogen in the white matter was associated with the development of AD hallmark pathologies, i.e., hyperphosphorylated tau (HPτ) and amyloid-β (Aβ), as well as SVD, cerebral amyloid angiopathy (CAA) and measures of white matter damage. Using human post-mortem brains, parietal tissue from 20 AD and 22 non-demented controls was quantitatively assessed for HPτ, Aβ, white matter damage severity, axonal density, demyelination and the burden of extravascular fibrinogen in both WML and normal appearing white matter (NAWM). SVD severity was determined by calculating sclerotic indices. WML- and NAWM fibrinogen burden was not significantly different between AD and controls nor was it associated with the burden of HPτ or Aβ pathology, or any measures of white matter damage. Increasing severity of SVD was associated with and a predictor of both higher WML- and NAWM fibrinogen burden (all P<0.05) in controls only. In cases with minimal SVD NAWM fibrinogen burden was significantly higher in the AD cases (P<0.05). BBB dysfunction was present in both non-demented and AD brains and was not associated with the burden of AD-associated cortical pathologies. BBB dysfunction was strongly associated with SVD but only in the non-demented controls. In cases with minimal SVD, BBB dysfunction was significantly worse in AD cases possibly indicating the influence of CAA. In conclusion, extravascular fibrinogen is not associated with AD hallmark pathologies but indicates SVD, suggesting that the presence of fibrinogen in the CSF is not a surrogate marker for AD pathology.