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Advanced Neurology Anticoagulants as neuroprotective therapeutics

and small-molecular inhibitors of FXI, all aimed at detected. 64,88,119 As a result, CBF decline and hypoperfusion
preventing fibrin-Aβ deposition and its vascular and have been proposed as bona fide in vivo predictors of future
neuronal sequelae. One advantage of these agents is that cognitive disorders. Clinical studies have demonstrated
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119
they are expected to pose a relatively low risk of bleeding that circulation-promoting physical exercise can slow
due to minimal interference with hemostasis. In addition, cognitive impairment in AD patients. 120
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fibrin-targeting immunotherapies are being clinically Advanced brain imaging has revealed a spatial-
evaluated for their potential to reduce neuroinflammation, temporal pattern of CBF reduction in individuals ranging
neurodegenerative changes, and cognitive impairment in from healthy subjects to those with mild cognitive
patients with dementia. 106 impairment and AD. The decline of CBF begins in regions,

4.4. Pathophysiological consequences such as the precuneus, posterior cingulate, and temporal-
parietal areas before spreading to broader regions. This
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In early AD, Aβ-induced vasculopathies, such as Aβ-CAA, reduction in CBF, along with the consequent deficits in
vasoconstriction, and procoagulant and proinflammatory oxygen (hypoxia) and glucose supply, correlates with the
states, are key drivers for occlusive, cellular, and severity of vascular Aβ load and the associated dysfunction
hemorrhagic lesions, leading to vascular and BBB in the AD brain. 16,64,66,88,89,119
dysfunction (Figure 1). 6,15,16,25 Key pathological contributors
in this vascular environment include Aβ, fibrin(ogen), The hypometabolic tissue milieu contributes to
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fibrin-Aβ clots, aggregates from activated platelets, and inflammatory, neurodegenerative, and cognitive sequelae.
occlusive neutrophil extracellular traps. 6,7,15,16,25,49,64 The This situation is further intensified by the increased
brain’s pathophysiological consequences to these factors metabolic demands from elevated Aβ production and
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include a decline in CBF, hypoperfusion, and a subsequent amyloidosis development. In fact, ischemia and hypoxia
decrease in nutrient supply and metabolism. 6,7,15,16,25,49,64 In in the brain have been shown to stimulate the synthesis of
addition, BBB dysfunction enables thrombin, fibrin(ogen), Aβ from APP cleavage, driven by both the upregulation of
and other harmful agents to infiltrate parenchymal tissue. BACE1 gene expression and the activation of γ-secretase.
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On the other hand, the release of parenchymal Aβ and Likewise, tau pathology has been found to worsen in
other toxic products into the bloodstream for dilution response to declining CBF and the accumulation of
and degradation becomes impaired. This creates a self- parenchymal Aβ. 7,64,74
7
reinforcing cycle of increased vascular and parenchymal Moreover, in AD individuals carrying the APOE4 risk
Aβ accumulation, further exacerbating the spread of allele, the loss of capillary pericytes and BBB dysfunction
Aβ and associated pathology in the brain. 6,7,16,25,49,64 The have been associated with reduced CBF and are predictors
resulting sequelae include chronic neuroinflammation, of cognitive decline. Pericytes are highly sensitive to
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largely driven by an excessive glial response and ischemic conditions, and the severity of pericyte loss and
neurodegeneration characterized by synaptic and neuronal BBB breakdown correlates with the vascular Aβ load. 64
loss. These processes contribute to the progressive decline
in memory and cognitive function. 6,7,49,64 4.4.2. BBB breakdown and dysfunction
Aβ-induced vascular pathologies have a particularly
4.4.1. CBF reduction, brain hypoperfusion, and damaging effect on the endothelium of blood vessels,
cognitive decline
a layer consisting of endothelial cells connected by tight
Chronic hypoperfusion, defined as persistent insufficient junctions. The endothelium forms the primary barrier
7,86
blood flow to the brain (ischemia), results from sustained lining the interior surface of all blood vessels and regulates
reduction in CBF. 7,15,66,88,89,92,117 This condition significantly substance exchange between the blood, parenchymal
impairs cerebral metabolism and the overall functioning tissue, and ISF of the brain. This vascular endothelium
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of the nervous system. The supply of essential blood is a crucial component of the BBB, along with the outer
components – such as oxygen, glucose (the brain’s primary basement membrane, mural cells (pericytes in capillaries,
energy source), proteins, and cellular elements – becomes VSMCs in arterioles, and arteries), and surrounding
increasingly restricted. Chronic reductions in CBF have astrocyte endfeet. 7
been documented in both AD patients 7,88,117 and mouse Capillaries, the smallest and most widely distributed
models. 64,66 The typical decline in CBF is in the range of 25% blood vessels in the brain, are particularly important for
of normal levels, but in certain brain regions, reductions the selective transport of nutrients, ions, and signaling
can exceed 50%. 118 molecules. This selective transport involves the
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Notably, even in the early, asymptomatic stages of AD, exchange of substances across the BBB from the blood into
reductions in CBF and increased vascular resistance can be the brain’s parenchymal tissue and vice versa. Through
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Volume 3 Issue 4 (2024) 16 doi: 10.36922/an.3799