Alzheimer's disease

Intracranial MR dynamics in clinically diagnosed Alzheimer's disease: the emerging concept of "pulse wave encephalopathy"

Authors: Henry-Feugeas MC.

As increasingly shown in neuropathological and predementia clinical studies, cognitive decline with altered intracranial dynamics can fulfill current clinical criteria of dementia of the Alzheimer's type (DAT) and there is a marked pathogenic complexity of this epidemic syndrome. Whereas structural studies only suggest the unexpected frequency of cerebrovascular changes in late life DAT, flow quantification MR sequences now offer a great opportunity of in vivo accurate analysis of cerebrovascular function. Their first applications have allowed development of a modern concept of the intracranial dynamics; a complex windkessel system allows two processes that are crucial to insure brain oxygenation and nutrition, a periodic systolic marked expansion of the intracranial blood compartment within the rigid cranial cavity on the one hand, a marked dampening of the arterial pulse wave before it reaches capillary level on the other hand. This modern concept has allowed better understanding of two archetypes of windkessel failure or so-called pulse wave encephalopathy, normal pressure hydrocephalus and subcortical arteriosclerotic encephalopathy. Dynamic MRI may now help to detect and classify distinct patterns of cerebrovascular dysfunction in DAT. This dynamic approach helps to understand the major association between aging and DAT as well as the increasingly recognized overlap between Alzheimer's pathology, normal pressure hydrocephalus and arteriosclerotic neurodegeneration. Evidence of such a great variety of disturbances in intracranial dynamics behind a single clinical syndrome of DAT can greatly impact therapeutic research on this devastating disorder.

Cerebrospinal fluid dynamics in the human cranial subarachnoid space: an overlooked mediator of cerebral disease. I. Computational model

Authors: Gupta S, Soellinger M, Grzybowski DM, Boesiger P, Biddiscombe J, Poulikakos D, Kurtcuoglu V.

Abnormal cerebrospinal fluid (CSF) flow is suspected to be a contributor to the pathogenesis of neurodegenerative diseases such as Alzheimer's through the accumulation of toxic metabolites, and to the malfunction of intracranial pressure regulation, possibly through disruption of neuroendocrine communication. For the understanding of transport processes involved in either, knowledge of in vivo CSF dynamics is important. We present a three-dimensional, transient, subject-specific computational analysis of CSF flow in the human cranial subarachnoid space (SAS) based on in vivo magnetic resonance imaging. We observed large variations in the spatial distribution of flow velocities with a temporal peak of 5 cm s(-1) in the anterior SAS and less than 4 mm s(-1) in the superior part. This could reflect dissimilar flushing requirements of brain areas that may show differences in susceptibility to pathological CSF flow. Our methods can be used to compare the transport of metabolites and neuroendocrine substances in healthy and diseased brains.

The effects of MyD88 deficiency on exploratory activity, anxiety, motor coordination and spatial learning in C57BL/6 and APPswe/PS1dE9 mice.

Authors: Lim JE, Song M, Jin J, Kou J, Pattanayak A, Lalonde R, Fukuchi KI.

Toll-like receptors (TLRs) are a family of pattern-recognition receptors in innate immunity and provide a first line defense against pathogens and tissue injuries. In addition to important roles in infection, inflammation, and immune diseases, recent studies show that TLR signaling is involved in modulation of learning, memory, mood, and neurogenesis. Because MyD88 is essential for the downstream signaling of all TLRs, except TLR3, we investigated the effects of MyD88 deficiency (MyD88-/-) on behavioral functions in mice. Additionally, we recently demonstrated that a mouse model of Alzheimer's disease (AD) deficient for MyD88 had decreases in Aβ deposits and soluble Aβ in the brain as compared with MyD88 sufficient AD mouse models. Because accumulation of Aβ in the brain is postulated to be a causal event leading to cognitive deficits in AD, we investigated the effects of MyD88 deficiency on behavioral functions in the AD mouse model at 10 months of age. MyD88 deficient mice showed more anxiety in the elevated plus-maze. In the motor coordination tests, MyD88 deficient mice remained on a beam and a bar for a longer time, but with slower initial movement on the bar. In the Morris water maze test, MyD88 deficiency appeared to improve spatial learning irrespective of the transgene. Our findings suggest that the MyD88-dependent pathway contributes to behavioral functions in an AD mouse model and its control group.

The projected effect of risk factor reduction on Alzheimer's disease prevalence

Authors: Barnes DE, Yaffe K.

At present, about 33·9 million people worldwide have Alzheimer's disease (AD), and prevalence is expected to triple over the next 40 years. The aim of this Review was to summarise the evidence regarding seven potentially modifiable risk factors for AD: diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity or low educational attainment, and physical inactivity. Additionally, we projected the effect of risk factor reduction on AD prevalence by calculating population attributable risks (the percent of cases attributable to a given factor) and the number of AD cases that might be prevented by risk factor reductions of 10% and 25% worldwide and in the USA. Together, up to half of AD cases worldwide (17·2 million) and in the USA (2·9 million) are potentially attributable to these factors. A 10-25% reduction in all seven risk factors could potentially prevent as many as 1·1-3·0 million AD cases worldwide and 184 000-492 000 cases in the USA.

Alzheimer's disease: cerebral glaucoma?

Authors: Wostyn P, Audenaert K, De Deyn PP.

In a 1994 Medical Hypotheses paper, it was speculated that high intracranial pressure (ICP) might increase the probability of developing Alzheimer's disease (AD). A study of cerebrospinal fluid pressure (CSFP) in normal volunteers showed interindividual variations in CSFP. Some normals had what would normally be considered elevated CSFP. The hypothesis postulated that this subgroup with a high characteristic individual ICP level might be more susceptible to developing AD. The Medical Hypotheses paper further speculated that in more advanced stages of AD, such pressure factor could already be missing due to the disease process. The present article discusses recent research findings regarding CSFP distribution in AD patients that could be interpreted as support for this hypothesis. Exposure of central nervous system tissue to high pressure stress is not unique to the ICP space. Indeed, a similar situation occurs in the intraocular pressure (IOP) space in eyes with glaucoma. Interestingly, recent research has revealed similarities in the process leading to retinal ganglion cell death in glaucoma and neuronal cell death in AD. In the present paper, we raise the question of whether AD could be a cerebral form of glaucoma. Indeed, the linking of glaucoma to mechanisms of AD could reflect the anatomical and functional similarities between the IOP space and the ICP space. Further studies are warranted, however, especially to determine the possible role of high ICP in at least some cases of AD.

Alzheimer's disease-related changes in diseases characterized by elevation of intracranial or intraocular pressure

Authors: Peter Wostyn a, Kurt Audenaert b and Peter Paul De Deyn c, d

In this review, we focus on the coexistence of Alzheimer's disease-related changes in brain diseases, such as normal pressure hydrocephalus and traumatic brain injury, and in glaucoma at the level of the retinal ganglion cells. This is a group of diseases that affect central nervous system tissue and are characterized by elevation of intracranial or intraocular pressure and/or local shear stress and strain. In considering possible mechanisms underlying Alzheimer-type changes in these diseases, we briefly summarize recent evidence indicating that caspase activation and abnormal processing of β-amyloid precursor protein, which are important events in Alzheimer's disease, may play a role both in glaucoma and following traumatic brain injury. With regard to normal pressure hydrocephalus, evidence suggests that changes in cerebrospinal fluid circulatory dynamics ultimately may result in reduced clearance of neurotoxins, such as β-amyloid peptides and tau protein, that play a role in the pathogenesis of Alzheimer's disease. Data presented in this review could be interpreted to suggest that Alzheimer-type changes in these diseases may result at least in part from exposure of central nervous system tissue to increased levels of mechanical stress. Evidence for such a relationship is of major importance because it may support an association between elevated mechanical load and the development of Alzheimer-type lesions. Further studies are warranted, however, especially to elucidate the role of elevated mechanical forces in Alzheimer's disease neuropathogenesis.

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