Alzheimer adopted Binswanger’s encephalopathy (BD) in 1902 to describe atherosclerotic subcortical white matter changes. The pathology and clinical manifestations of subcortical white matter dementia are now considered to have multiple causes. Some authors [1] suggested that specific subcortical lacunar infarctions (LI) should be differentiated from leukoaraiosis (LA).Sabri et al [2] suggested that MRI-detected LI and LA can lead to vascular dementia.LA refers to patchy or diffuse changes in bilateral white matter, especially in the hemi-oval center, with a CT LA is common in patients with a history of stroke and dementia, but can also be seen in normal elderly people. The common risk factors are aging, hypertension, diabetes mellitus, and heart disease [2, 3]. Its clinical manifestations, cerebral blood flow, and pathogenesis are reviewed.
1, Clinical manifestations
BD has a mean age of onset of 60 years and is a chronic progressive vascular dementia. BD-like damage is seen at autopsy in approximately 4% of the general population and 35% of dementia patients. Clinical symptoms include frontal lobe executive dysfunction, mild memory loss, mental abnormalities, slow thought processing, affective disorders, apathy, urinary incontinence, Parkinsonian-like gait disturbance, and pseudobulbar palsy. Brain atrophy, such as enlarged ventricles and widened sulci, may be present. However, most patients with LA are mostly asymptomatic [1]. de Leeuw et al [4] found that middle-aged aortic sclerosis was significantly associated with periventricular LA after 20 years. miyazawa et al [5] studied 135 neurologically normal individuals and found that hemiventricular LA was associated with advanced age, hypertension, and reduced local cerebral blood flow (rCBF).
2, Neuropathology
Typical BD changes are located in the periventricular and deep white matter of the brain. They appear as large, fused lesions with smooth margins that may be continuous with the lateral ventricles; or as patchy or punctate damage. The subcortical arcuate fibers (U-fibers) are often not damaged. Vasculopathic changes include wall thickening and fibrinoid necrosis of small arteries, segmental destruction of large arteries, and atherosclerosis. The degree of wall thickening correlates with the degree of LA. Other pathologic changes include decreased nerve fiber density in deep white matter areas and astrocytic changes. axonal damage, and reduced myelin sheath. Microglia activation may be associated with chronic ischemia or axonal injury. Swelling and disintegration of certain astrocytes and protrusions may be associated with edema. It can be associated with a variety of pathological conditions, such as perivascular gap expansion, small subcortical infarcts, demyelination, and gliosis [1]. Subcortical vasculopathy can result in focal LI, diffuse white matter changes such as neuronal loss, demyelination, and gliosis. Autopsy reveals that severe LA is mostly associated with multiple LI, with small penetrating arteries showing abnormal hyaline degeneration and luminal narrowing [6].
3, Changes in cerebral blood flow (CBF)
3.1 Normal CBF distribution
Catafau et al [7] used radionuclide technetium 99 to study the type of distribution of rCBF in normal young and old people and compared age differences, gender, and asymmetry of rCBF between hemispheres and found that rCBF was highest in the cerebellum, followed by the occipital, temporal, parietal, frontal, and basal ganglia. White matter rCBF was significantly lower than gray matter. Compared with young adults, rCBF was significantly lower in the left frontal and left posterior temporal regions in older adults. rCBF was symmetrically distributed, independent of age.
3,2 CBF in patients with LA
PET studies found that rCBF and cerebral metabolic rate were reduced in cortical and white matter in BD patients compared with normal controls and LA patients without dementia. rCBF and cerebral metabolic rate were not elevated in gray and white matter in BD patients, indicating that the risk of ischemia in these regions was not elevated. In LA patients without dementia, reduced rCBF and increased oxygen extraction fraction were seen in deep white matter regions, suggesting that these regions can maintain normal metabolic rates during reduced blood flow but are at risk for ischemic injury. It is presumed that asymptomatic patients are in the early stages of the disease and develop BD as soon as cortical function is involved.SPECT studies have found reduced perfusion in the frontal lobes and basal ganglia early in patients with BD. As symptoms worsen, more extensive perfusion impairment is seen [1].Markus et al. used quantitative perfusion MRI techniques to find that patients with LA have reduced white matter rCBF, but normal gray matter rCBF. The role of hypoperfusion in the pathogenesis of LA was proposed and the examination method was superior to PET without radioactivity [6]. rCBF and glucose metabolism (rMRGlu) were not found to be altered in patients with severe LA and multiple LI by Sabri et al. Neuropsychological impairment in the aforementioned patients was associated with reduced rCBF and rMRGlu, and LI and LA seen on MRI were not associated with rCBF and rMRGlu [2]. Hatazawa et al [8] used a PET study and found that rCBF was significantly lower in patients with asymptomatic LA compared to controls and that the severity of LA did not correlate with the degree of hypoperfusion.
Mochizuki et al [9] found central motor conduction time (CMCT) and rCBF in patients with LA. CMCT was significantly prolonged in patients with dementia and rCBF was significantly lower in parietal cortex, frontal white matter and thalamus compared to patients without dementia. There was a significant negative correlation between CMCT and CBF in frontal cortex, temporal cortex, frontal white matter and thalamus. prolonged CMCT in LA patients was associated with reduced rCBF. kobari et al [10] used xenon CT to study 17 patients with AD and found reduced rCBF in cortical, subcortical structures such as thalamus, basal ganglia, and bilateral hemispheric white matter in AD patients compared to controls. Siennicki Lantz et al [11] examined rCBF and polysomnography in 24 AD patients and found that white matter rCBF was significantly lower in AD patients compared to controls, significantly in the posterior regions (temporoparietal-occipital). Quantitative EEG correlated with white matter rCBF in the posterior region. LA changes are common in patients with normal cranial pressure hydrocephalus (AHS). Kristensen et al [12] used SPECT study and found that rCBF was reduced in AHS patients, which was evident in the caudate nucleus, temporal lobe gray matter, and subcortical white matter.
4, Pathogenesis
4.1 Anatomy and physiology
The blood supply to the white matter of the cerebral hemispheres mostly originates from the perforating arteries of the soft membrane arteries on the surface of the brain, which emanate from the arachnoid vessels at right angles and enter the white matter region along the myelinated fibers. The length of these vessels varies from 20 to 50 mm, with an average diameter of 100-200 um, and the diameter of the vessels remains constant during their migration. These vessels do not bifurcate but send out short vertical branches to supply the white matter, with each short branch of the perforating artery forming a cylindrical metabolic unit. The blood supply to the adjacent white matter region of the lateral ventricles originates from the choroidal artery of the subventricular artery or from the terminal branches of the striatal artery, which supply the basal ganglia, internal capsule, and part of the thalamus; these vessels are approximately 15 mm long and flow into afferent penetrating arteries originating from the soft meningeal artery, with sparse or absent anastomoses between them. (or watershed) that is particularly vulnerable to systemic or focal CBF reduction. Atherosclerosis underlies the reduced white matter CBF in the elderly and hypertensive patients, and other factors include aging-related vascular tortuosity and lengthening. However, van de Bergh, de Reuck et al. suggested that the above ventricular-derived vessels are venous rather than arterial, suggesting that the periventricular white matter area is a “distal supply zone”, a condition that is more susceptible to moderately reduced blood flow due to the lack of anastomosis. Even though anastomoses exist in the precapillary area, only one metabolic unit is supplied by a single penetrating artery. The white matter immediately adjacent to the cerebral cortex (3-4 mm wide), the so-called U-fibers, is supplied by both long penetrating arteries and short penetrating arteries that span the white matter and adjacent cortex, and this mode of blood supply can result in unimpaired U-fibers [3].
The periventricular white matter is an arterial marginal zone that is already at the edge of perfusion under physiological conditions and is particularly vulnerable to damage from reduced cerebral blood flow. In contrast, the subcortical white matter is not an arterial watershed region. Arteriosclerosis can induce hyaline degeneration, tortuosity and extension of subcortical white matter vessels, which can lead to reduced cerebral blood flow and finally ischemia [4].Hatazawa et al [8] found that hypoperfusion in the white matter and basal ganglia of the brain in patients with asymptomatic LA can be caused by arteriosclerosis of long penetrating medullary arteries and ductus arteriosus, independent of LA. It is hypothesized that the hypoperfusion associated with LA may be related to subclinical sclerosis of the medullary arteries and small arteries.
4, 2 Normal cranial pressure hydrocephalus (AHS) and LA
4, 2, 1 The accumulation of cerebrospinal fluid in the ventricles can lead to diffusion of periventricular cerebrospinal fluid and increased interstitial pressure in the brain parenchyma, resulting in white matter ischemia. After shunt surgery in patients with normal cranial pressure hydrocephalus, normalization of white matter blood flow and significant improvement in symptoms with corresponding improvement in LA severity are seen [3, 12].
4, 2, 2 Alteration of ventricular canal boundaries
Cerebrospinal fluid leakage into the adjacent brain parenchyma may be a result of altered ventricular canalicular membrane cell structure. Aging of the perforating arteries and alterations in the blood-brain barrier (BBB) can prevent the reabsorption of interstitial fluid. Some studies have demonstrated that cerebral edema can precede LA, so transient cerebral edema can exacerbate LA. head CT hypointensity may be due to hypertension or alterations in the BBB. leakage from the BBB can occur, and capillary permeability to proteins may be increased in patients with systemic hypertension. Transient hypertension can lead to fluid infiltration and protein leakage. Impaired venous return can also lead to interstitial white matter edema [3].
4,3 Cerebrovascular reserve capacity
Cupini et al [13] suggested that patients with multiple subcortical infarcts have poor cerebrovascular reserve capacity and that multiple subcortical resting infarcts are associated with lower cerebrovascular reactivity (CR), suggesting that small vessel disease and hypoperfusion may be the pathogenesis of multiple subcortical resting infarcts. The causative factors of subcortical infarction are generally considered to be small vessel disease, thromboembolic occlusion of small arteries, and hemodynamic impairment in the presence of hypoperfusion. cupini et al. found that poor hemodynamic reserve capacity was associated with multiple subcortical ischemic damage, supporting the idea that some ischemic subcortical damage can be associated with hemodynamic ischemic impairment of brain tissue.
4,4 Vascular risk factors
Changes in blood viscosity and coagulation status can contribute to the development of BD. Elevated mediators of several pathways of coagulation fibrinolysis, including fibrinogen (which increases plasma viscosity), thrombin-antithrombin complexes, prothrombin fragment F1+2 (prothrombin fragment Fl+2), and D-dimer levels have been shown to occur 3 months before the onset of dementia in patients with BD, but not in patients without dementia. The activation of this pathway can lead to microembolism. Activation of this pathway can lead to microembolism and microcirculatory disturbances, which can exacerbate these damages [1].
4,5 Animal experiments
Ouchi et al [14] used PET to study the activity of rCBF and postsynaptic cholinergic receptors in Wistar rats with bilateral common carotid arteries (CCAs) ligated for 7 days and 1 month, and found that frontal cortical rCBF was significantly lower in the ligated group than in the cerebellar and control groups. and control groups. Common carotid artery ligation resulted in prolonged cerebral hypoperfusion and delayed reduction in postsynaptic cholinergic receptor activity, but no degeneration of cortical neurons. Uehara et al [15] ligated the common carotid arteries bilaterally in rats at 5 days postnatally, and the brains were removed by execution 7 days later. White matter changes such as cystic and coagulative necrosis were seen. The subcortical white matter CBF decreased to 25% of the control group. Immunohistochemistry confirmed that amyloid precursor protein (APP) immunoreactive axonal structures were seen in the internal capsule and subcortical white matter, indicating that the white matter was more susceptible to damage from reduced CBF. shi et al [16] used MRI to assess the effect of 17p estradiol (17p-estradiol, E2) on focal cerebral ischemia in rats and found no change in MRI signal in ovariectomized rats, while ovarie resected, estradiol-treated rats showed a significant reduction in MRI signal, indicating that estrogen can provide selective protection against ischemic brain injury without involving CBF alterations.
5. Treatment and outlook
The clinical significance of LA is still debated, and most scholars believe that LA can gradually lead to cognitive impairment and eventually vascular dementia. de Leeuw et al [4] suggested that the pathological process of periventricular LA begins in middle age or before middle age, and interventional treatment should be given before clinical detection of LA and cognitive impairment. Further in-depth studies are needed.