Alzheimer Disease: de la Torre JC

de la Torre JC. · No affiliation provided · Ann Neurol. · Pubmed #15929049 No free full text.

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de la Torre JC. · Center for Alzheimer's Research, Sun Health Research Institute, Sun City, AR 85351, USA. · J Alzheimers Dis. · Pubmed #18599962 No free full text.

Abstract: Cardiovascular and cerebrovascular disease are reported to be major risk factors to Alzheimer's disease (AD). These risk factors mainly affect the elderly (over age 60) and previously were believed to only promote vascular dementia (VaD). Cardiovascular and cerebrovascular pathology involving structural lesions of the heart and carotid or vertebral artery stenosis stemming from intima media thickening or vessel plaque formation can insidiously reduce blood flow to the brain. Since heart and carotid artery disease are common findings in elderly patients and can provoke chronic cerebral hypoperfusion, we submit that individuals with even very mild memory complaints should undergo screening using echocardiography and carotid Doppler ultrasound. These non-invasive, safe, cost-effective ultrasound techniques can often detect correctable or treatable early lesions involving the carotid arteries and the heart that contribute to cerebral hypoperfusion. Inasmuch as cerebral hypoperfusion can be a pathophysiologic trigger of AD, its prevention or attenuation should tangibly reverse or at least delay the onset and impact of severe cognitive meltdown. This clinical approach may have an important impact in reducing the number of new AD and VaD cases and lessen the catastrophic socio-economic burden these dementias are expected to have on the US healthcare system in the near future.

de la Torre JC. · Institute of Pathology, Case Western Reserve School of Medicine, Cleveland, Ohio, USA. · Neurodegener Dis. · Pubmed #18322369 No free full text.

Abstract: A large body of evidence indicates that sporadic Alzheimer's disease (AD) is a vascular disorder with neurodegenerative consequences and needs to be treated and managed as such. Epidemiologic studies of vascular risk factors, together with preclinical detection tools for AD are proof of concept that cerebral hypoperfusion is one of the earliest pathological signs in the development of cognitive failure. Vascular risk factors involving heart disease and stroke in the elderly individual who already possesses a dwindling cerebrovascular reserve due to advancing age contribute to further decline in cerebral blood flow (CBF) resulting in unrelenting brain hypoperfusion. Brain hypoperfusion, in turn, can reach a critically attained threshold of cerebral hypoperfusion (CATCH) giving rise to a neuronal energy crisis via reduced ATP synthesis. The ensuing metabolic energy crisis initially carves up ischemic-sensitive neurons in the hippocampus and posterior parietal cortex setting up cognitive meltdown and progressive neurodegenerative and atrophic changes in the brain. Neuronal energy compromise accelerates oxidative stress, excess production of reactive oxygen species, aberrant protein synthesis, ionic membrane pump dysfunction, signal transduction impairment, neurotransmitter failure, abnormal processing of amyloid precursor protein resulting in beta-amyloid deposition and axonal microtubule disruption from tau hyperphosphorylation. The high energy metabolic changes leading to oxidative stress and cellular hypometabolism precede clinical expression of AD. Regional CBF measurements using neuroimaging techniques can predict AD preclinically at the mild cognitive impairment stage or even before any clinical manifestation of dementia is expressed. Clinical diagnostic assessment of elderly persons who could develop or already present with memory complaints can prevent, reverse or slow down AD development. Although pathologic aging is the subject of thousands of studies, the question of why the elderly (and not younger people) succumb to AD has not been adequately addressed. The explanation(s) as to why vascular risk factors, for example, can trigger AD or vascular dementia usually in the elderly and not the young should provide vital clues in the search for a strategically effective dementia treatment. This review offers inductive hypothetical darts relative to that critical question.

de la Torre JC. · Institute of Pathology, Case Western Reserve School of Medicine, Gig Harbor, WA, USA. · Neurol Res. · Pubmed #16945216 No free full text.

Abstract: BACKGROUND: Heart disease and stroke are two of the major leading causes of death and disability in the world. Mainly affecting the elderly population, heart disease and stroke are important risk factors for Alzheimer's disease (AD). METHODS: This review examines the evidence linking chronic brain hypoperfusion (CBH) produced by several types of heart disease and stroke on the development of AD. RESULTS: The evidence indicates a strong association between such risk factors as coronary artery bypass surgery (CABG), atrial fibrillation, aortic/mitral valve damage, hypertension, hypotension, congestive heart failure, cerebrovascular-carotid atherosclerosis, and transient ischemic attacks in producing CBH. In people whose cerebral perfusion is already diminished by their advanced age, further cerebral blood flow reductions from heart-brain vascular-related risk factors, seemingly increases the probability of AD. The evidence also suggests that a neuronal energy crisis brought on by a relentless CBH is responsible for protein synthesis defects that later result in the classic AD neurodegenerative lesions such as the formation of excess beta-amyloid plaques and neurofibrillary tangles. CONCLUSIONS: Knowledge of how heart disease and stroke can progress to AD should provide a better understanding of the physiopathology characteristic of AD and also target more precise therapy in preventing, controlling or reversing this dementia.

de la Torre JC. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA. · Trends Mol Med. · Pubmed #16288900 No free full text.

Abstract: There is already considerable evidence from epidemiological, pathological and clinical reports that vascular factors are crucial in the pathogenesis of Alzheimer's disease (AD). Cerebral hypoperfusion has been shown to be a preclinical condition and a most accurate indicator for predicting whether people will develop AD. Now, a new study by Zlokovic and colleagues reveals that the vascular gene MEOX2 has a low expression in cultured brain endothelial cells from AD patients. This, together with evidence linking a dysfunctional cerebrovasculature to the pathogenesis of AD, suggests that the homeobox gene MEOX2 downregulation provides a therapeutic target to AD and a better understanding of this disorder.

Seyidova D, Aliyev A, Rzayev N, Obrenovich M, Lamb BT, Smith MA, de la Torre JC, Perry G, Aliev G. · Microscopy Research Center, Institute of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA. · In Vivo. · Pubmed #15341188 No free full text.

Abstract: Nitric oxide (NO) is a key bioregulatory active molecule in the cardiovascular, immune and nervous systems, synthesized through converting L-arginine to L-citrulline by NO synthase (NOS). Research exploration supports the theory that this molecule appears to be one of the key factors for the disruption of normal brain homeostasis, which causes the development of brain lesions and pathology such as in Alzheimer's disease (AD). Especially the vascular content of NO activity appears to be a major contributor to this pathology before the overexpression of NOS activity in other brain cellullar compartments develop. We theorize that pharmacological intervention using NO donors and/or NO suppressors should delay or minimize brain lesion development and further progression of brain pathology and dementia.

Aliyev A, Seyidova D, Rzayev N, Obrenovich ME, Lamb BT, Chen SG, Smith MA, Perry G, de la Torre JC, Aliev G. · Microscopy Research Center, Case Western Reserve University, Cleveland, OH 44106, USA. · Neurol Res. · Pubmed #15265272 No free full text.

Abstract: Nitric oxide (NO) is a short-life key bioregulatory active molecule in the cardiovascular, immune and nervous systems. NO is synthesized by converting L-arginine to L-citrulline by enzymes called NO synthase (NOS). The growing body of evidence strongly supports the theory that this molecule appears to be one of the key targets for the disruption of normal brain homeostasis, which causes the development of brain lesions and pathology such as in Alzheimer's disease (AD) or other related dementia. The vascular content of NO activity appears especially to be a main contributor to this pathology before the over-expression of other NOS isoforms activity in a different brain cellular compartment. We speculate that pharmacological intervention using NO donors and/or NO suppressors will be able to delay or minimize the development of brain pathology and further progression of mental retardation.

de la Torre JC. · Institute of Pathology, Case Western Reserve University, Cleveland, OH, USA. · Neurol Res. · Pubmed #15265269 No free full text.

Abstract: Considerable evidence now indicates that Alzheimer's disease (AD) is a vascular disorder with neurodegenerative consequences. As a result, AD and vascular dementia (VaD) can each be described as a 'vasocognopathy'. The term better describes the origin of the disease (vaso: vessel/blood flow), its primary effect on a system (-cogno: relating to cognition) and its clinical course (-pathy: disorder). Evidence that AD is a vasocognopathy is partly supported by the following multidisciplinary findings: (1) epidemiologic studies linking AD and vascular risk factors to cerebral hypoperfusion; (2) evidence that AD and vascular dementia (VaD) share practically all reported risk factors; (3) evidence that pharmacotherapy which increases or improves cerebral perfusion lowers AD symptoms; (4) evidence of preclinical detection of AD candidates using regional cerebral perfusion and glucose uptake studies; (5) evidence of overlapping clinical symptoms in AD and VaD; (6) evidence of parallel cerebrovascular and neurodegenerative pathologic markers (including plaques and tangles) in AD and VaD; (7) evidence that cerebral infarction increases AD incidence by 50%; (8) evidence that chronic brain hypoperfusion can trigger hypometabolic, cognitive and neurodegenerative changes typical of AD; (9) evidence that most autopsied AD brains contain cerebrovascular pathology; (10) evidence that mild cognitive impairment (a transition stage for AD) converts to AD or VaD in 48% and 56% of cases, respectively, within several years. The collective evidence presented here poses a powerful argument for the re-classification of AD as a vascular disorder. Re-classification would allow a new strategy that could result in the tactical development and application of genuinely effective treatments, provide earlier diagnosis and reduce AD prevalence by focusing on the root of the problem.

de la Torre JC. · Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · Lancet Neurol. · Pubmed #14980533 No free full text.

Abstract: The cause of Alzheimer's disease (AD) is unknown. This gap in knowledge has created a stumbling block in the search for a genuinely effective treatment or cure for this dementia. This article summarises the arguments for a causal role for either amyloid deposition or cerebrovascular pathology as the primary trigger in the development of non-genetic AD. A bare-bones survey of the published research reveals no compelling evidence that amyloid deposition is neurotoxic in human beings or that it results in neurodegenerative changes involving synaptic, metabolic, or neuronal loss in human or transgenic-mouse brains. By contrast, the data supporting AD as a primary vascular disorder are more convincing. Findings suggesting a vascular cause of AD come from epidemiological, neuroimaging, pathological, pharmacotherapeutic, and clinical studies. The consensus of these studies indicates that chronic brain hypoperfusion is linked to AD risk factors, AD preclinical detection and pharmacotherapeutic action of AD symptoms.

Aliev G, Smith MA, Obrenovich ME, de la Torre JC, Perry G. · The Microscopy Research Center and Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland OH 44106, USA. · Neurotox Res. · Pubmed #14715433 No free full text.

Abstract: Chronic vascular hypoperfusion induces oxidative stress and brain energy failure, and leads to neuronal death, which manifests as cognitive impairment and the development of brain pathology as in Alzheimer disease (AD). It is becoming more widely accepted that AD is characterized by impairments in energy metabolism. We hypothesize that hypoperfusion-induced mitochondrial failure plays a central role in the generation of reactive oxygen species, resulting in oxidative damage to brain cellular compartments, especially in the vascular endothelium and neuronal cell bodies in AD. All of these changes have been found to occur before pathology and coexist during the progression of AD. In this review we have summarized recent evidence and our own knowledge regarding the relationship between the hypoperfusion-induced vascular damage that initiates oxidative stress and mitochondrial abnormalities that appear to be a key target for the development of AD pathology. Future investigations into both the mechanisms behind amyloid beta (Abeta) deposition and the possible accelerating effects of environmental factors, such as chronic hypoxia/reperfusion may open the door for effective pharmacological treatments of AD. We hypothesize that an imbalance between endothelium derived vasoconstrictors and vasodilators, along with an antioxidant system deficiency and mitochondria lesions are prominent in AD. Future studies examining the importance of mitochondrial pathophysiology in different brain cellular compartments may provide insight not only into neurodegenerative and/or cerebrovascular disease pathobiology but may also provide targets for treating these conditions.

de la Torre JC. · UCSD-Neuropathology Division, 1363 Shinly, Suite 100, Escondido, CA 92026, USA. · J Alzheimers Dis. · Pubmed #12515901 No free full text.

Abstract: Presently, non-genetic Alzheimer's disease (AD) is wrongly classified as a neurodegenerative disorder. When vascular lesions are present, AD is considered to be a vascular dementia. However, compelling evidence indicates that (AD) is a vascular disorder with neurodegenerative consequences. There is an urgent clinical need to ascertain the true cause of this dementia. In this review, evidence indicating that AD is a vascular disorder comes from a number of different disciplines including studies in epidemiology, pharmacology, neuroimaging, clinical medicine, pathology, physiology and experimental research. This collective evidence also addresses many previously puzzling questions regarding: i) past and present treatment failures in AD, ii) strange association of AD risk factors with many vascular-related disorders, iii) parallel lesions, clinical symptoms risk factors and potentially interchangeable treatments present in AD and vascular dementia, iv) historical difficulty in finding neurodegenerative markers to detect AD pre-clinically, and, v) paradoxical pathophysiologic events preceding AD neurodegenerative changes. Re-classifying AD as a vascular disorder would very likely improve the chances of finding a useful treatment for this disorder because clinical study designs could focus on more realistic and relevant pathologic targets than is presently practiced. A short summary of potential new research lines that may provide novel therapy in the treatment and management of AD is discussed.

de la Torre JC. · Division of Neuropathology, University of California-San Diego, 1363 Shinly, Suite 100, Escondido, CA 92026, USA. · Ann N Y Acad Sci. · Pubmed #12480752 No free full text.

Abstract: Considerable evidence now indicates that Alzheimer's disease (AD) is primarily a vascular disorder. This conclusion is supported by the following evidence: (1) epidemiologic studies linking vascular risk factors to cerebrovascular pathology that can set in motion metabolic, neurodegenerative, and cognitive changes in Alzheimer brains; (2) evidence that AD and vascular dementia (VaD) share many similar risk factors; (3) evidence that pharmacotherapy that improves cerebrovascular insufficiency also improves AD symptoms; (4) evidence that preclinical detection of potential AD is possible from direct or indirect regional cerebral perfusion measurements; (5) evidence of overlapping clinical symptoms in AD and VaD; (6) evidence of parallel cerebrovascular and neurodegenerative pathology in AD and VaD; (7) evidence that cerebral hypoperfusion can trigger hypometabolic, cognitive, and degenerative changes; and (8) evidence that AD clinical symptoms arise from cerebromicrovascular pathology. The collective data presented in this review strongly indicate that the present classification of AD is incorrect and should be changed to that of a vascular disorder. Such a change in classification would accelerate the development of better treatment targets, patient management, diagnosis, and prevention of this disorder by focusing on the root of the problem. In addition, a theoretical capsule summary is presented detailing how AD may develop from chronic cerebral hypoperfusion and the role of critically attained threshold of cerebral hypoperfusion (CATCH) and of vascular nitric oxide derived from endothelial nitric oxide synthase in triggering the cataclysmic cerebromicrovascular pathology.

de la Torre JC. · Department of Neuropathology, University of California at San Diego, CA 92026, USA. · Stroke. · Pubmed #11935076 links to  free full text

Abstract: BACKGROUND: The main stumbling block in the clinical management and in the search for a cure of Alzheimer disease (AD) is that the cause of this disorder has remained uncertain until now. SUMMARY OF REVIEW: Evidence that sporadic (nongenetic) AD is primarily a vascular rather than a neurodegenerative disorder is reviewed. This conclusion is based on the following evidence: (1) epidemiological studies showing that practically all risk factors for AD reported thus far have a vascular component that reduces cerebral perfusion; (2) risk factor association between AD and vascular dementia (VaD); (3) improvement of cerebral perfusion obtained from most pharmacotherapy used to reduce the symptoms or progression of AD; (4) detection of regional cerebral hypoperfusion with the use of neuroimaging techniques to preclinically identify AD candidates; (5) presence of regional brain microvascular abnormalities before cognitive and neurodegenerative changes; (6) common overlap of clinical AD and VaD cognitive symptoms; (7) similarity of cerebrovascular lesions present in most AD and VaD patients; (8) presence of cerebral hypoperfusion preceding hypometabolism, cognitive decline, and neurodegeneration in AD; and (9) confirmation of the heterogeneous and multifactorial nature of AD, likely resulting from the diverse presence of vascular risk factors or indicators of vascular disease. CONCLUSIONS: Since the value of scientific evidence generally revolves around probability and chance, it is concluded that the data presented here pose a powerful argument in support of the proposal that AD should be classified as a vascular disorder. According to elementary statistics, the probability or chance that all these findings are due to an indirect pathological effect or to coincidental circumstances related to the disease process of AD seems highly unlikely. The collective data presented in this review strongly support the concept that sporadic AD is a vascular disorder. It is recommended that current clinical management of patients, treatment targets, research designs, and disease prevention efforts need to be critically reassessed and placed in perspective in light of these important findings.

de la Torre JC. · Department of Neuroscience, University of California, San Diego, La Jolla, California 92093, USA. · Ann N Y Acad Sci. · Pubmed #11193790 No free full text.

Abstract: After nearly a century of inquiry, the cause of Alzheimer's disease (AD) remains to be found. In this review, basic and clinical evidence is presented that assembles and hypothetically explains most of the key pathologic events associated with the development of AD. These pathologic events are triggered in AD by impaired cerebral perfusion originating in the microvasculature that affects the optimal delivery of glucose and oxygen and results in an energy metabolic breakdown of brain cell biosynthetic and synaptic pathways. We propose that two factors must be present before cognitive dysfunction and neurodegeneration is expressed in the AD brain: (1) advanced aging, (2) presence of a condition that lowers cerebral perfusion, such as a vascular risk factor. The first factor introduces a normal but potentially menacing process that lowers cerebral blood flow in proportion to increased aging, while the second factor adds a crucial burden that further lowers brain perfusion and places vulnerable neurons in a state of metabolic compromise leading to a death pathway. These two factors will lead to a critically attained threshold of cerebral hypoperfusion (CATCH). CATCH is a self-sustaining and progressive circulatory insufficiency that will destabilize neurons, synapses, neurotransmission, and cognitive function, creating in its wake a neurodegenerative process characterized by the formation of senile plaques, neurofibrillary tangles, amyloid angiopathy, and, in some cases, Lewy bodies. Since any of a considerable number of vessel-related conditions must be present in the aging individual for cognition to be affected, CATCH supports the heterogeneic disease profile assumed to be characteristic of the AD syndrome. A brief discussion of target therapy based on the proposed pathogenesis of AD is also reviewed.

de la Torre JC, Stefano GB. · Department of Pathology, University of California, San Diego, 1363 Shinly, Suite 100, Escondido, CA 92026, USA. · Brain Res Brain Res Rev. · Pubmed #11113503 No free full text.

Abstract: Evidence is fast accumulating which indicates that Alzheimer's disease is a vascular disorder with neurodegenerative consequences rather than a neurodegenerative disorder with vascular consequences. It is proposed that two factors need to be present for AD to develop: (1) advanced ageing, (2) presence of a condition that lowers cerebral perfusion, such as a vascular-risk factor. The first factor introduces a normal but potentially insidious process that lowers cerebral blood flow in inverse relation to increased ageing; the second factor adds a crucial burden which further lowers brain perfusion and places vulnerable neurons in a state of high energy compromise leading to a cascade of neuronal metabolic turmoil. Convergence of the two factors above will culminate in a critically attained threshold of cerebral hypoperfusion (CATCH). CATCH is a hemodynamic microcirculatory insufficiency that will destabilize neurons, synapses, neurotransmission and cognitive function, creating in its wake a neurodegenerative state characterized by the formation of senile plaques, neurofibrillary tangles, amyloid angiopathy and in some cases, Lewy bodies. Since any of a considerable number of vascular-related conditions must be present in the ageing individual for cognition to be disturbed, CATCH identifies an important aspect of the heterogeneic disease profile assumed to be present in the AD syndrome. It is proposed that CATCH initiates AD by distorting regional brain capillary structure involving endothelial cell shape changes and impairment of nitric oxide (NO) release which affect signaling between the immune, cardiovascular and nervous systems. Evidence is presented that in many tissues there is a basal level of NO being produced and that the actions of several signaling molecules may initiate increases in basal NO levels. Moreover, these temporary increases in basal NO levels exert inhibitory cellular actions, via cellular conformational changes. Findings indicate that (a) constitutive NO is responsible for a basal or 'tonal' level of NO; (b) this NO keeps particular types of cells in a state of inhibition and (c) activation of these cells occurs through disinhibition. Consequently, tissues not maintaining a basal NO level are more prone to excitatory, immune, vascular and neural influences. Under such circumstances, these tissues cannot be down-regulated to normal basal levels, thus prolonging their excitatory state. Thus, the clinical convergence of advanced ageing in the presence of a chronic, pre-morbid vascular risk factor, can, in time, contribute to an endotheliopathy involving basal NO deficit, to the degree where regional metabolic dysfunction leads to cognitive meltdown and to progressive neurodegeneration characteristic of Alzheimer's disease.

de la Torre JC. · Department of Neurosciences (MTF-0624), University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0624, USA. · Neurobiol Aging. · Pubmed #10867218 No free full text.

Abstract: This review discusses the experimental and clinical data which indicate that chronic cerebral hypoperfusion can affect metabolic, anatomic, and cognitive function adversely. In aged but not young animals, chronic brain hypoperfusion results in regional pre- and post-synaptic changes, protein synthesis abnormalities, energy metabolic dysregulation, reduced glucose utilization, cholinergic receptor loss, and visuo-spatial memory deficits. Additionally, aging animals that are kept for prolonged periods of time after chronic brain hypoperfusion, also develop brain capillary degeneration in CA1 hippocampus and neuronal damage extending from the hippocampal region to the temporo-parietal cortex where neurodegenerative tissue atrophy eventually forms. All these pathologic events occur in rodents in the absence of senile plaques and neurofibrillary tangles. Alzheimer brains reveal similar biochemical and structural changes as those experimentally induced in aging animals. Moreover, regional cerebral hypoperfusion is one of the earlier (if not the earliest) clinical manifestations in both the sporadic and familial forms of Alzheimer's disease. In addition, therapy that improves or increases cerebral perfusion is generally of some benefit to Alzheimer patients. Conversely, a variety of disorders with different etiologies that impair or diminish cerebral perfusion are reported to be risk factors for this dementia. These findings have prompted us to propose the concept that advanced aging in the presence of a vascular risk factor can converge to create a critically attained threshold of cerebral hypoperfusion (CATCH) that triggers regional brain microcirculatory disturbances and impairs optimal delivery of energy substrates needed for normal brain cell function. The outcome of this defect generates a chain of events leading to the progressive evolution of brain metabolic, cognitive and tissue pathology that characterize Alzheimer's disease. The possible role of CATCH in familial and early onset Alzheimer's disease is briefly discussed from a theoretical vantagepoint. The growing and most recent evidence in support of the CATCH concept is the focus of this review.

de la Torre JC. · Department of Neuroscience, University of California, San Diego, La Jolla 92093, USA. · Alzheimer Dis Assoc Disord. · Pubmed #10850734 No free full text.

Abstract: Considerable clinical and experimental data have shown that cerebral perfusion is progressively decreased during increased aging and that this decrease in brain blood flow is significantly greater in Alzheimer disease (AD). The authors propose that advanced aging with a comorbid condition, such as a vascular risk factor, which further decreases cerebral perfusion, promotes a critically attained threshold of cerebral hypoperfusion (CATCH). With time, CATCH induces brain capillary degeneration and suboptimal delivery of energy substrates to neuronal tissue. Because glucose is the main fuel of brain cells, its impaired delivery, with the deficient delivery of oxygen, compromises neuronal stability because the supply for aerobic glycolysis fails to meet brain tissue demand. The outcome of CATCH is a metabolic cascade that involves, among other things, mitochondrial dysfunction, oxidative stress, decreased adenosine triphosphate production, abnormal protein synthesis, cell ionic pump deficiency, signal transduction defects, and neurotransmission failure. These events contribute to the progressive cognitive decline characteristic of patients with AD, as well as regional anatomic pathology, consisting of synaptic loss, senile plaques, neurofibrillary tangles, tissue atrophy, and neurodegeneration. CATCH identifies the clinical heterogeneic pattern that characterizes AD because it provides compelling evidence that any of a multitude of different etiopathophysiologic vascular risk factors, in the presence of advanced aging, can lead to AD. The evidence in support of CATCH as the pathogenic trigger of AD is crystallized in this review.

de la Torre JC. · Department of Neurosciences, University of California, San Diego, La Jolla 92093, USA. · Ann N Y Acad Sci. · Pubmed #10818533 No free full text.

Abstract: After nearly a century of inquiry, the cause of sporadic Alzheimer's disease (AD) remains to be found. On the subject of AD pathogenesis, recent basic and clinical evidence strongly argues in favor of the concept that AD is linked to brain circulatory pathology. This concept, when viewed from many different medical disciplines and from close pre-morbid similarities to vascular dementia, assembles and hypothetically explains most of the key pathologic events associated with the development of AD. These pathologic events are triggered in AD by impaired cerebral perfusion originating in the microvasculature which affects the optimal delivery of glucose and oxygen and results in an energy metabolic breakdown of brain cell biosynthetic and synaptic pathways. We propose that two factors converge to initiate cognitive dysfunction and neurodegeneration as expressed in AD brain: (1) advanced aging, and (2) the presence of a condition that lowers cerebral perfusion. The first factor introduces a normal but potentially deconstructing process that lowers cerebral blood flow in proportion to increased aging, whereas the second factor adds a crucial burden that further lowers brain perfusion to a critical threshold that triggers neuronal metabolic compromise. When age and a condition that lowers cerebral perfusion converge, critically attained threshold of cerebral hypoperfusion (CATCH) results. CATCH is a cyclical and progressive cerebrovascular insufficiency that will destabilize neurons, synapses, neurotransmission, and cognitive ability, eventually evolving into a neurodegenerative process characterized by the formation of senile plaques, neurofibrillary tangles, and amyloid angiopathy. The concept of impaired cerebral perfusion as the cause of this dementia also explains the heterogeneic profile observed in AD patients, because an extensive list of risk factors for AD are also reported to significantly diminish blood flow to the aging brain.

de la Torre JC. · Department of Neurosciences, UCSD School of Medicine, La Jolla, CA 92093, USA. · Acta Neuropathol. · Pubmed #10412794 No free full text.

Abstract: After nearly a century of inquiry, the cause of Alzheimer's disease (AD) remains to be found. In this review, basic and clinical evidence is presented that assembles and hypothetically explains most of the key pathologic events associated with the development of AD. These pathologic events are triggered in AD by an impaired cerebral perfusion originating in the microvasculature which affects the optimal delivery of glucose and oxygen and results in a breakdown of metabolic energy pathways in brain cells such as in the biosynthetic and synaptic pathways. We propose that two factors need to be present before cognitive dysfunction and neurodegeneration is expressed in AD brain: advanced aging, and the presence of a condition that lowers cerebral perfusion. The first factor introduces a normal but potentially menacing process that lowers cerebral blood flow in correlation to increased aging, while the second factor adds a crucial element which further lowers brain perfusion and establishes the heterogeneic disease profile observed in AD patients. These two factors will lead to a critical threshold cerebral hypoperfusion. Critical threshold cerebral hypoperfusion is a self-perpetuating, contained and progressive circulatory insufficiency that will destabilize neurons, synapses, neurotransmission and cognitive function, creating in its wake a neurodegenerative process characterized by the formation of senile plaques, neurofibrillary tangles, and amyloid angiopathy. A discussion of target therapy based on the proposed pathogenesis of AD is also briefly reviewed.

Obrenovich ME, Smith MA, Siedlak SL, Chen SG, de la Torre JC, Perry G, Aliev G. · Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. · Neurotox Res. · Pubmed #17000469 No free full text.

Abstract: Heterotrimeric guanine nucleotide-binding (G) protein-coupled receptor kinases (GRKs) are cytosolic proteins that are known to contribute to the adaptation of the heptahelical G protein-coupled receptors (GPCRs) and to regulate downstream signals through these receptors. GPCRs mediate the action of messengers that are key modulators of cardiac and vascular cell function, such as growth and differentiation. GRKs are members of a multigene family, which are classified into three subfamilies and are found in cardiac, vascular and cerebral tissues. Increasing evidence strongly supports the hypothesis that vascular damage is an early contributor to the development of Alzheimer disease (AD) and/or other pathology that can mimic human AD. Based on this hypothesis, and since kinases of this family are known to regulate numerous receptor functions both in the brain, myocardium and elsewhere, we explored cellular and subcellular localization by immunoreactivity of G protein-coupled receptor kinase 2 (GRK2), also known as beta-adrenergic receptor kinase-1(betaARK1), in the early pathogenesis of AD and in ischemia reperfusion injury models of brain hypoperfusion. In the present study, we used the two-vessel carotid artery occlusion model, namely the 2-VO system that results in chronic brain hypoperfusion (CBH) and mimics mild cognitive impairment (MCI) and vascular changes in AD pathology. Our findings demonstrate the early overexpression of GRK2 member kinase in the cerebrovasculature, especially endothelial cells (EC) following CBH, as well as in select cells from human AD tissue. We found a significant increase in GRK2 immunoreactivity in the EC of AD patients and after CBH, which preceded any amyloid deposition. Since GRK2 activity is associated with certain compensatory changes in brain cellular compartments and in ischemic cardiac tissue, our findings suggest that chronic hypoperfusion initiates oxidative stress in these conditions and appears to be the main initiating injury stimulus for disruption of brain and cerebrovascular homeostasis and metabolism.

de la Torre JC, Aliev G. · 1Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · J Cereb Blood Flow Metab. · Pubmed #15703700 No free full text.

Abstract: An aging rat model of chronic brain hypoperfusion (CBH) that mimics human mild cognitive impairment (MCI) was used to examine the role of nitric oxide synthase (NOS) isoforms on spatial memory function. Rats with CBH underwent bilateral common carotid artery occlusion (2-vessel occlusion (2-VO)) for either 26 or 8 weeks and were compared with nonoccluded sham controls (S-VO). The neuronal and endothelial (nNOS/eNOS) constitutive inhibitor nitro-L-arginine methyl ester (L-NAME) 20 mg/kg was administered after 26 weeks for 3 days to 2-VO and S-VO groups and spatial memory was assessed with a modified Morris watermaze test. Only 2-VO rats worsened their spatial memory ability after L-NAME. Electron microscopic immunocytochemical examination using an antibody against eNOS showed 2-VO rats had significant loss or absence of eNOS-containing positive gold particles in hippocampal endothelium and these changes were associated with endothelial cell compression, mitochondrial damage and heavy amyloid deposition in hippocampal capillaries and perivascular region. In the 8-week study, three groups of 2-VO rats were administered an acute dose of 7-NI, aminoguanidine or L-NIO, the relatively selective inhibitors of nNOS, inducible NOS and eNOS. Only rats administered the eNOS inhibitor L-NIO worsened markedly their watermaze performance (P = 0.009) when compared with S-VO nonoccluded controls. We conclude from these findings that vascular nitric oxide derived from eNOS may play a critical role in spatial memory function during CBH possibly by keeping cerebral perfusion optimal through its regulation of microvessel tone and cerebral blood flow and that disruption of this mechanism can result in spatial memory impairment. These findings may identify therapeutic targets for preventing MCI and treating Alzheimer's disease.

de la Torre JC, Pappas BA, Prevot V, Emmerling MR, Mantione K, Fortin T, Watson MD, Stefano GB. · Department of Pathology, University of California, San Diego, CA. · Neurol Res. · Pubmed #14503018 No free full text.

Abstract: Chronic brain hypoperfusion (CBH) using permanent occlusion of both common carotid arteries in an aging rat model, has been shown to mimic human mild cognitive impairment (MCI), an acknowledged high risk condition that often converts to Alzheimer's disease. An aging rat model was used to determine whether hippocampal nitric oxide (NO) is abnormally expressed following CBH for two or eight weeks. At each time point, spatial memory was measured with the Morris water maze and hippocampal A beta 1-40/1-42 concentrations were obtained using sandwich ELISA. Real-time amperometric measures of NO representing the constitutive isoforms of neuronal nitric oxide synthase (nNOS) and endothelial (e)NOS were also taken at each time point to ascertain whether NO levels changed as a result of CBH, and if so, whether such NO changes preceded or followed any memory or amyloid-beta pathology. We found that two weeks after CBH, NO hippocampal levels were upregulated nearly four-fold when compared to nonoccluded rats but no alteration in spatial memory of A beta products were observed at this time point. By contrast, NO concentration had declined to control levels by eight weeks but spatial memory was found significantly impaired and A beta 1-40 (but not A beta 1-42) had increased in the CBH group when compared to control rats. Since changes in shear stress are known to upregulate eNOS but generally not nNOS, these results suggest that shear stress induced by CBH hyperactivated vascular NO derived from eNOS in the first two weeks as a reaction by the capillary endothelium to maintain homeostasis of local cerebral blood flow. The return of vascular NO to basal levels after eight weeks of CBH may have triggered metabolic changes within hippocampal cells resulting in hippocampal dysfunction as reflected by spatial memory impairment and by accumulation of A beta 1-40 peptide. In conclusion, our study shows that CBH initiates spatial memory loss in aging rats thus mimicking human MCI and also increases A beta 1-40 in the hippocampus. The memory and amyloid changes are preceded by NO upregulation in the hippocampus. These preliminary findings may be important in understanding, at least in part, the molecular mechanisms that precede memory impairment during chronic brain ischemia and as such, the pre-clinical stage leading to Alzheimer's disease.