This review of age-related brain microvascular pathologies focuses on topics studied by this laboratory, including anatomy of the blood supply, tortuous vessels, venous collagenosis, capillary remnants, vascular density and microembolic brain injury. Our studies feature thick sections, large blocks embedded in celloidin, and vascular staining by alkaline phosphatase. This permits study of the vascular network in three dimensions, and the differentiation of afferent from efferent vessels. Current evidence suggests that there is decreased vascular density in ageing, Alzheimer's disease and leukoaraiosis, and cerebrovascular dysfunction precedes and accompanies cognitive dysfunction and neurodegeneration. A decline in cerebrovascular angiogenesis may inhibit recovery from hypoxia-induced capillary loss. Cerebral blood flow is inhibited by tortuous arterioles and deposition of excessive collagen in veins and venules. Misery perfusion due to capillary loss appears to occur before cell loss in leukoaraiosis, and cerebral blood flow is also reduced in the normal-appearing white matter. Hypoperfusion occurs early in Alzheimer's disease, inducing white matter lesions and correlating with dementia. In vascular dementia, cholinergic reductions are correlated with cognitive impairment, and cholinesterase inhibitors have some benefit. Most lipid microemboli from cardiac surgery pass through the brain in a few days, but some remain for weeks. They can cause what appears to be a type of vascular dementia years after surgery. Donepezil has shown some benefit. Emboli, such as clots, cholesterol crystals and microspheres can be extruded through the walls of cerebral vessels, but there is no evidence yet that lipid emboli undergo such extravasation.

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Review: cerebral microvascular pathology in ageing and neurodegeneration.

Interplay between Cytosolic Dopamine, Calcium, and α-Synuclein Causes Selective Death of Substantia Nigra Neurons

Objective: To evaluate the efficacy and tolerability of donepezil in patients with vascular dementia (VaD). Methods: Patients (n = 616; mean age, 75.0 years) with probable or possible VaD, according to National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche en l’Enseignement en Neurosciences criteria, were randomized to receive donepezil 5 mg/day (n = 208), donepezil 10 mg/day (after 5 mg/day for the first 28 days) (n = 215), or placebo (n = 193) for 24 weeks. Results: Seventy-six percent of the patients enrolled had probable VaD. A total of 75.3% of the 10 mg donepezil group and 80.8% of the 5 mg group completed the study compared with 83.4% of the placebo group. Both donepezil-treated groups showed improvements in cognitive function on the Alzheimer’s Disease Assessment Scale–cognitive subscale compared with placebo, with a mean endpoint treatment difference, as measured by the change from baseline score, of approximately 2 points (donepezil 5 mg, −1.65 [ p = 0.003]; 10 mg, −2.09 [ p = 0.0002]). Greater improvements on the Clinician’s Interview-Based Impression of Change–plus version were observed with both donepezil groups than with the placebo group (overall donepezil treatment vs placebo p = 0.008); 25% of the placebo group showed improvement compared with 39% ( p = 0.004) of the 5 mg group and 32% ( p = 0.047) of the 10 mg group. Withdrawal rates due to adverse events were low (placebo, 8.8%; donepezil 5 mg, 10.1%; 10 mg, 16.3%). Conclusions: Donepezil-treated patients demonstrated significant improvements in cognition and global function compared with placebo-treated patients, and donepezil was well tolerated.

Donepezil in vascular dementia: A randomized, placebo-controlled study

Background and Purpose—Clinical observations suggest that patients with vascular dementia (VaD) may benefit from treatment with cholinesterase inhibitors. This study evaluated the efficacy and safety of donepezil for relieving symptoms of dementia in VaD. Methods—Patients (n603; mean age, 73.9 years; 55.2% men) with probable (70.5%) or possible (29.5%) VaD, according to criteria of the National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et l’Enseignement en Neurosciences(AIREN), were randomized to 24 weeks of treatment with donepezil 5 mg/d (n198), donepezil 10 mg/d (5 mg/d for first 28 days; n206), or placebo (n199). Analyses were based on the intent-to-treat population.

Efficacy and Tolerability of Donepezil in Vascular Dementia Positive Results of a 24-Week, Multicenter, International, Randomized, Placebo-Controlled Clinical Trial

Breakdown of cellular membranes is a characteristic feature of neuronal degeneration in acute (stroke) and chronic (senile dementia) neurological disorders. The present review summarizes recent experimental and clinical work which concentrated on changes of choline-containing phospholipids as indicators of neuronal membrane breakdown. Experimental studies identified glutamate release, calcium influx, and activation of cellular phospholipase A2 (PLA2) as important steps initiating membrane breakdown in cultured neurons or brain slices under hypoxic or ischemic conditions. Proton NMR studies have shown an elevation of choline-containing compounds in the brain of Alzheimer patients while neurochemical studies in post mortem-brain demonstrated increases of the catabolic metabolite, glycerophosphocholine, an indicator of PLA2 activation. In contrast, studies of cerebrospinal fluid, phosphorus NMR studies, and measurements of phospholipases in post mortem Alzheimer brain gave ambiguous results which may be explained by methodical limitations. The finding that, in experimental studies, choline was a rate-limiting factor for phospholipid biosynthesis has stimulated clinical studies aimed at counteracting phospholipid breakdown, e.g. by combinations of choline and cytidine. Future experimental approaches should clarify whether loss of membrane phospholipids is cause or consequence of the neurodegenerative disease process.

Membrane breakdown in acute and chronic neurodegeneration: focus on choline-containing phospholipids.

The acetylcholine (ACh) and choline (Ch) concentrations in the cerebrospinal fluid were investigated in patients with vascular dementia of the Binswanger type (VDBT) or multiple small infarct type (MSID) as compared with patients with Alzheimer-type dementia (ATD). The ACh concentration in patients with ATD was found to be significantly lower than in controls (73%, p < 0.0001), and showed a significant positive correlation with dementia scale scores (rs=0.63, p < 0.03). The Ch concentration in the CSF of ATD patients was approximately the same as in controls. In VDBT/MSID patients, the ACh concentration was significantly lower than in controls (p < 0.001), also showing a significant positive correlation with dementia scale scores (rs=0.62, p < 0.02), but was significantly higher than in ATD patients (p < 0.001). Moreover, the Ch concentration in VDBT/MSID patients was significantly higher than in controls (p < 0.001) or ATD patients (p < 0.001). These results suggest that simultaneous determination of ACh and Ch concentrations in CSF may be useful for differentiating VDBT/MSID from ATD and that increasing the ACh level using cholinergic agents may be a beneficial therapeutic strategy for the treatment of ATD as well as VDBT/MSIT, and is worthy of further investigation.

Cerebrospinal fluid acetylcholine and choline in vascular dementia of Binswanger and multiple small infarct types as compared with Alzheimer-type dementia

The concentration of catecholamines and indoleamines in the cerebrospinal fluid of patients with vascular parkinsonism (VP) was compared to that in patients with Parkinson's disease (PD) and controls. Compared to the controls, the concentration of tyrosine was significantly higher, and the concentration of L-dopa and 3-O-methyldopa (3-OMD) was significantly lower in both VP and PD patients. The balance between the 3-OMD/L-dopa and dopamine (DA)/L-dopa ratios was changed in favor of 3-OMD/L-dopa in both VP patients and PD patients suggesting the preservation of a compensatory mechanism. All these changes were less marked in VP patients than in PD patients. A remarkable finding was that in contrast to PD patients the concentration of DA and norepinephrine (NE) was significantly higher in VP patients than in the controls. The decrease in the concentration of 5-hydroxytryptamine (5-HT) was significantly greater in VP patients than in PD patients. In PD patients, the concentration of DA, NE, and 5-HT showed significant correlation with the severity of motor symptoms. In VP patients, the concentration of 5-HT alone showed significant correlation with the severity of motor symptoms and cognitive dysfunction. These findings suggest that VP patients may have similar disturbances in the DA synthesis pathway as PD patients, but differ from PD patients in that the concentrations of DA and NE are elevated and the decrease in the 5-HT concentration is greater in VP patients.

Concentration of catecholamines and indoleamines in the cerebrospinal fluid of patients with vascular parkinsonism compared to Parkinson's disease patients

M. Saheki

Papers

Cerebrospinal fluid acetylcholine and choline in vascular dementia of Binswanger and multiple small infarct types as compared with Alzheimer-type dementia

Concentration of catecholamines and indoleamines in the cerebrospinal fluid of patients with vascular parkinsonism compared to Parkinson's disease patients