1.Clinical manifestations
With the widespread use of CT and MRI of the head, subcortical white matter damage can be detected. The lack of diagnostic value of CT and MRI fused white matter changes (WMCs) is generally referred to as leukoaraiosis (LA). Binswanger’s case was mentioned and later the term Binswanger’s encephalopathy (BD) was introduced [1].Marie first referred to fused WMCs in the periventricular and coronal regions of the brain as a cavernous state. This cavernous state is strongly associated with hypertension and is associated with dementia, Parkinson’s syndrome (PD)-like gait disturbances, and pseudobulbar palsy, but not necessarily with stroke-like manifestations. BD is now mostly used as a nomenclature to distinguish non-stroke periventricular leukoencephalopathy from lacunar status stroke [1-3].
LA is common in elderly and dementia patients, and imaging reveals poorly delineated, patchy, diffuse white matter damage. Head CT detects WMCs in up to 30% of patients with Alzheimer’s disease (AD), up to 70% of patients with vascular dementia (VD), and up to 15% of normal older adults. Symptoms of WMCs include slowed thinking, cognitive decline and dementia, bilateral pyramidal fasciculus signs such as tonicity, active reflexes, positive Babinski’s sign, light paralytic gait, bilateral extrapyramidal signs such as slow movements, tonicity, cogwheel phenomenon, tremor, pseudobulbar palsy signs such as positive occlusal reflexes, strong crying, dysarthria, dysphagia, depression , and elevated stroke risk [4, 5].DeGroot et al [6] studied 1077 randomized older adults and found that both periventricular and subcortical WMCs were associated with neuropsychological testing, and that people with severe periventricular WMCs had severely impaired psychomotor speed, and whole-brain cognitive function. Compared to memory operations, operations involving the speed of cognitive processes were more severely impaired in people with WMCs.
2. Neuropathology
BD pathology reveals fibrinoid and hyaline-like degeneration of small arteries in brain tissue, subintimal thickening of small arteries, and white matter damage. Sclerosis and demyelination of the involved subcortical vessels and small infarcted arteries, activation of microglia in brain tissue, and clusters of macrophages visible in sparse white matter areas. It is often accompanied by lacunar infarcts. Subcortical U-fibers are not involved [1, 2, 7].
Rosenberg et al [7] studied the relationship between matrix metalloproteinases (MMPs) and BD and found that microglia/macrophage marker (PG-MI)-positive cells in BD patients were evident near the injured small arteries and diffusely distributed in the white matter. Stromelysin-1 (stromelysin-1), or matrix metalloproteinase 3 (MMP3), was seen in macrophages but not in white matter gliosis.Vinters et al [8] studied autopsy material from 20 patients (68-92 years) with ischemic vascular dementia (IVD) and found that multiple ischemic brain damage can cause progressive cognitive function and memory impairment and also exacerbate Cystic infarcts were seen in 5 patients with CNS, with lacunar infarcts and microinfarcts being the most common. hippocampal damage in the distal septum was seen in 11 cases. Multiple lacunar infarcts were often associated with severe atherosclerosis and small arteriosclerosis. one patient had significant amyloid cerebrovascular disease and also severe AD changes. the IVD was associated with extensive ischemic microdamage within the CNS, with a rate of hippocampal damage exceeding 50%.
Certain scholars have found that additional vascular disease exacerbates the accumulation of hyperphosphorylated tau protein in the CA1 region of the hippocampus in patients with mild AD, but attenuates the extent of double helix microfilament (PHF) formation in patients with severe AD (CA2/3, CA4 regions).Esiri et al. studied 24 elderly patients with cerebrovascular disease dementia, 19 patients with non-demented cerebrovascular disease, and 18 patients without dementia and cerebrovascular disease Patients with brain tissue specimens found that microangiopathy was associated with a history of dementia, mainly in the form of subcortical WMCs and microinfarcts. Snowdon et al. studied 61 patients with AD and found that patients with luminal cerebral infarcts located in the basal ganglia, thalamus, and deep white matter had poorer cognitive function and higher incidence of dementia compared to patients without luminal infarcts, and patients with luminal cerebral infarcts had less neuropathological damage in AD. Many familial microangiopathies are associated with stroke and dementia, such as autosomal dominant cerebral hemorrhage combined with amyloid cerebrovascular disease-Dutch type (HCHWA-D), autosomal dominant cerebral arteriopathy with subcortical infarction and white matter encephalopathy (CADASIL) in patients with microangiopathy severity associated with brain parenchymal damage [8].
3, Neuroimaging
Imaging changes in LA are seen as poorly delineated, patchy, diffuse white matter hypodensity on head CT. The rate of head MRI detection is much higher, with corresponding long T1 and T2 signals or iso-T1 and long T2 signals visible [4, 5].Sultzer et al [9] used PET to study the metabolic rate of each brain lobe in 11 patients with VD and found that reduced cortical metabolic rate correlated with the severity of subcortical WMCs, but there was heterogeneity between subcortical WMCs and cortical metabolic rate. Mean whole-brain cortical metabolism was significantly lower in patients with periventricular WMCs in the anterior subcortical region compared with those without damage. Patients with basal ganglia or thalamic cavernous infarcts had significantly lower metabolic rates in the frontal cortex compared to patients without damage. Neurobehavioral scores, verbal output scores, and anxiety/depression scores correlated with the severity of WMCs.Sultzer et al. suggested that cortical metabolic dysfunction in patients with VD is associated with subcortical ischemic WMCs and that frontal cortical metabolism is particularly susceptible to pathological changes in the subcortical nuclei.The effect of perirhinal WMCs is most pronounced in patients with VD, and whole-brain cortical metabolism in patients with such damage Total WMCs are associated with temporal lobe hypometabolism, but the relationship between frontal WMCs and reduced brain metabolism is most pronounced in patients with VD. When examined alone, patients with lacunar infarcts in the basal ganglia/thalamic region showed a significant decrease in ipsilateral frontal cortical metabolism. Sub-striatal anterior PVH was associated with reduced ipsilateral frontal cortical metabolism [9].Tzourio et al [5] studied 834 (63-75 years) elderly people and found that WMCs were strongly associated with cerebral blood flow velocity (CBF-V). It is possible that hypertension-related small vessel disease leads to reduced CBF-V and cerebral blood flow and finally WMCs.
4. Pathogenesis
The mechanism of white matter damage is not known, and it is generally believed that there may be ischemic injury in the pathogenesis of LA.
4,1 Anatomy and physiology
Subcortical white matter ischemia is mainly oligodendrocyte and myelin destruction. The white matter is mainly composed of nerve fibers, axons and glial cells and does not contain neuronal cytosol or synapses [10]. The blood supply to the white matter mostly originates from the perforating arteries of the soft membrane arteries on the brain surface, starting at right angles from the arachnoid vessels and crossing the vertical areas of the brain surface to enter the white matter region along the myelinated fibers. These vessels send out short vertical branches to supply the white matter, with each short branch of a single perforating artery forming a cylindrical metabolic unit. The blood supply to the white matter region adjacent to the lateral ventricular wall originates from the choroidal artery of the subventricular artery or from the terminal branches of the striatal artery. These vessels, which partially supply the basal ganglia, internal capsule, and part of the thalamus, are approximately 15 mm long and flow into afferent penetrating arteries originating from the soft meningeal arteries, with sparse or absent anastomoses between them. deReuck et al. suggested that this type of vascular formation results in the white matter region surrounding the vessels as an arterial border region (or watershed) that is particularly vulnerable to systemic or focal reduction in CBF. Atherosclerosis underlies the reduced white matter blood flow in the elderly and hypertensive patients, and other factors include aging-related vascular tortuosity and lengthening. However, van de Bergh, de Reuck et al. suggest that the ventricular-derived vessels described above are venous rather than arterial, suggesting that the periventricular white matter area is a “distal blood supply zone,” a condition that is more susceptible to moderately reduced blood flow because of the lack of anastomosis. Even if an anastomosis exists in the precapillary, a penetrating artery supplies blood to only one metabolic unit. The white matter immediately adjacent to the cerebral cortex (3-4 mm wide), the so-called U-fibers, is supplied by both long perforating arteries and short perforating arteries crossing the white matter and adjacent to the cortex, a mode of blood supply that can result in unimpaired U-fibers [1, 3].
Subcortical structures are generally considered to be associated with the speed of cognitive processes and memory functions. The white matter of the subcortical structures can be divided into subcortical and periventricular regions. The subcortical region consists of dense short circuit U fibers, whereas the periventricular region consists of many long joint fibers that link subcortical structures such as the striatum to the cortex. Subcortical WMLs mainly disrupt short cortico-cortical connections consisting of bowed U fibers that are dense; periventricular WMLs disrupt long association bundles that connect more distant cortical areas. Cognitive function is most heavily involved in psychomotor speed, while subcortical dementia is dominated by slowing of cognitive processes [1, 6].
4, 2 Normal cranial pressure hydrocephalus and LA
Roman proposed a mechanism for LA in normal cranial pressure hydrocephalus. 1st, the accumulation of cerebrospinal fluid in the ventricles can cause an increase in interstitial pressure in the brain parenchyma around the ventricles, leading to white matter ischemia. After shunt surgery in patients with normal cranial pressure hydrocephalus, white matter blood flow is normalized, symptoms improve significantly, and the severity of LA improves accordingly. No. 2, alteration of the ventricular canal boundary. Leakage of cerebrospinal fluid into the adjacent brain parenchyma may be the result of structural changes in the ventricular canalicular membrane cells. Aging-related changes in the perforating arteries and alterations in the blood-brain barrier (BBB) can prevent reabsorption of excess interstitial fluid. Cerebral edema can precede LA, so transient cerebral edema can exacerbate LA changes. Hypointense changes seen on CT of the head may be the result of hypertension or changes in the BBB, which can leak, as in patients with systemic hypertension where capillary permeability to proteins may be increased. Transient hypertension can also lead to fluid infiltration and protein leakage. Interstitial white matter edema can also result from impaired venous return [3].
4, 3 Matrix metalloproteinases and LA
Rosenberg et al [7] proposed that MMPs can be involved in VD-related white matter injury.MMPs are a gene family of more than 20 extracellular matrix-degrading neutral proteases that can be secreted by astrocytes, endothelial cells, microglia and neurons. Cerebral ischemia can result in elevated MMP9 24-48 hours after stroke, and MMP2 is elevated during the trauma repair and cyst formation phases 7 days after onset. Leukoglutinase disrupts macromolecules at the basal level, leading to proteolytic disruption of the blood-brain barrier. another member of the MMP gene family, MMP3, is seen in macrophages of multiple sclerosis patients and neurons of AD patients, is highly destructive of the extracellular matrix, and is associated with arthritis and breast tissue degeneration. Thus MMPs can be involved in the disintegration of myelin sheaths, leading to white matter damage.
4,4 Animal experiments
Kurumatani et al [11] clamped the bilateral carotid arteries of adult Mongolian gerbils to establish a chronic brain tissue hypoperfusion model, a model in which LA and lateral ventricle enlargement were seen. The changes in myelin basic protein (MBP), neuromicrofilament H (NFH), and glial protofibrillary acidic protein (GFAP) levels were detected after 2 months of brain tissue hypoperfusion, and it was found that MBP and NFH decreased, while GFAP increased. the changes in MBP appeared before NFH. This indicates that the white matter changes in chronic hypoperfusion state are mainly myelin changes.
Isolated studies have shown that ischemic damage to cerebral white matter is mediated by nonsynaptic cellular mechanisms, such as reversal of sodium-calcium exchange, leading to the entry of calcium ions into axons.Kumura et al [12] studied calcium ion concentrations associated with depolarization of cortical gray matter and subcortical white matter after 120 minutes of whole brain ischemia in cats and found that the direct current potential in gray matter decreased rapidly within minutes after induction of ischemia. Similar changes were seen in the white matter a little later. The extracellular calcium ion concentration in the gray matter decreased rapidly, whereas the extracellular calcium ion concentration in the white matter increased over 20-30 minutes and then decreased slowly, reaching a minimum only 60 minutes after vascular occlusion. It is proposed that small, delayed transmembrane changes in calcium ions are associated with delayed ischemic membrane dysfunction in the central white matter conduction bundle.
5. Treatment and outlook
Vinters reported that amyloid cerebrovascular disease (CAA) changes are common in patients with BD, so antiplatelet therapy is not recommended in older adults with significant periventricular WMCs to avoid an increased risk of hemorrhagic stroke development [13]. the application of anticoagulants in patients with LA leads to a significantly higher risk of cerebral hemorrhage [1].