The retina as a window to the brain-from eye research to CNS disorders.
TL;DR: Data is summarized that support examination of the eyes as a noninvasive approach to the diagnosis of select CNS diseases, and the use of the eye as a valuable model to study the CNS.
Abstract: Philosophers defined the eye as a window to the soul long before scientists addressed this cliche to determine its scientific basis and clinical relevance. Anatomically and developmentally, the retina is known as an extension of the CNS; it consists of retinal ganglion cells, the axons of which form the optic nerve, whose fibres are, in effect, CNS axons. The eye has unique physical structures and a local array of surface molecules and cytokines, and is host to specialized immune responses similar to those in the brain and spinal cord. Several well-defined neurodegenerative conditions that affect the brain and spinal cord have manifestations in the eye, and ocular symptoms often precede conventional diagnosis of such CNS disorders. Furthermore, various eye-specific pathologies share characteristics of other CNS pathologies. In this Review, we summarize data that support examination of the eye as a noninvasive approach to the diagnosis of select CNS diseases, and the use of the eye as a valuable model to study the CNS. Translation of eye research to CNS disease, and deciphering the role of immune cells in these two systems, could improve our understanding and, potentially, the treatment of neurodegenerative disorders.
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TL;DR: The current state of knowledge of physiological role and function of microglia during brain development and in the mature brain is summarized and microglial contribution to brain pathologies such as Alzheimer's and Parkinson’s disease, brain ischemia, traumatic brain injury, brain tumor as well as neuropsychiatric diseases are highlighted.
Abstract: Microglia are ramified cells that exhibit highly motile processes, which continuously survey the brain parenchyma and react to any insult to the CNS homeostasis. Although microglia have long been recognized as a crucial player in generating and maintaining inflammatory responses in the CNS, now it has become clear, that their function are much more diverse, particularly in the healthy brain. The innate immune response and phagocytosis represent only a little segment of microglia functional repertoire that also includes maintenance of biochemical homeostasis, neuronal circuit maturation during development and experience-dependent remodeling of neuronal circuits in the adult brain. Being equipped by numerous receptors and cell surface molecules microglia can perform bidirectional interactions with other cell types in the CNS. There is accumulating evidence showing that neurons inform microglia about their status and thus are capable of controlling microglial activation and motility while microglia also modulate neuronal activities. This review addresses the topic: how microglia communicate with other cell types in the brain, including fractalkine signaling, secreted soluble factors and extracellular vesicles. We summarize the current state of knowledge of physiological role and function of microglia during brain development and in the mature brain and further highlight microglial contribution to brain pathologies such as Alzheimer’s and Parkinson’s disease, brain ischemia, traumatic brain injury, brain tumor as well as neuropsychiatric diseases (depression, bipolar disorder, and schizophrenia).
295 citations
Cites background from "The retina as a window to the brain..."
...Neuroinflammation occurs not only in the brain, but also in the retina and optic nerve – which are outgrowths from the diencephalon and thus considered parts of the CNS (London et al., 2013)....
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...The retina and the brain are affected in several neurodegenerative diseases and because they are similar, they respond similarly to any disturbances of tissue homeostasis and share common pathogenic mechanisms (London et al., 2013)....
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20 Mar 2008
225 citations
TL;DR: The data strengthens the link between retinal ganglion cell neuronal and optic nerve axonal loss with AD, and suggests that assessment of macular GC-IPL can be a test to detect neuronal injury in early AD and MCI.
Abstract: BACKGROUND Alzheimer's disease (AD) is a neurodegenerative disorder with emerging evidence that it is associated with retinal ganglion cell loss; however, few data exist to establish this association. OBJECTIVE To determine whether macular ganglion cell-inner plexiform layer (GC-IPL) and retinal nerve fiber layer (RNFL), as quantitatively measured by non-invasive in vivo spectral-domain optical coherence tomography (SD-OCT), are altered in patients with AD and mild cognitive impairment (MCI). METHODS Patients with AD and MCI were recruited from dementia/memory clinics, and cognitively normal controls were selected from the Singapore Epidemiology of Eye Disease program. SD-OCT (Cirrus HD-OCT, software version 6.0.2, Carl Zeiss Meditec Inc, Dublin, CA) was used to measure the GC-IPL and RNFL thicknesses. RESULTS Compared with cognitively normal controls (n = 123), patients with AD (n = 100) had significantly reduced GC-IPL thicknesses in all six (superior, superonasal, inferonasal, inferior, inferotemporal, and superotemporal) sectors (mean differences from -3.42 to -4.99 μm, all p < 0.05) and reduced RNFL thickness in superior quadrant (-6.04 μm, p = 0.039). Patients with MCI (n = 41) also had significantly reduced GC-IPL thicknesses compared with controls (mean differences from -3.62 to -5.83 μm, all p < 0.05). Area under receiver operating characteristic curves of GC-IPL were generally higher than that of RNFL to discriminate AD and MCI from the controls. CONCLUSIONS Our data strengthens the link between retinal ganglion cell neuronal and optic nerve axonal loss with AD, and suggest that assessment of macular GC-IPL can be a test to detect neuronal injury in early AD and MCI.
212 citations
TL;DR: The results confirmed the associations between retinal measurements of SD OCT and AD, highlighting the potential usefulness ofSD OCT measurements as biomarkers of AD.
208 citations
TL;DR: The emerging field of ocular AD warrants further investigation of how the retina may faithfully reflect the neurological disease, particularly the early presenting amyloid biomarkers, using advanced high-resolution imaging techniques may allow large-scale screening and monitoring of at-risk populations.
Abstract: Although historically perceived as a disorder confined to the brain, our understanding of Alzheimer's disease (AD) has expanded to include extra-cerebral manifestation, with mounting evidence of abnormalities in the eye. Among ocular tissues, the retina, a developmental outgrowth of the brain, is marked by an array of pathologies in patients suffering from AD, including nerve fiber layer thinning, degeneration of retinal ganglion cells, and changes to vascular parameters. While the hallmark pathological signs of AD, amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFT) comprising hyperphosphorylated tau (pTau) protein, have long been described in the brain, identification of these characteristic biomarkers in the retina has only recently been reported. In particular, Aβ deposits were discovered in post-mortem retinas of advanced and early stage cases of AD, in stark contrast to non-AD controls. Subsequent studies have reported elevated Aβ42/40 peptides, morphologically diverse Aβ plaques, and pTau in the retina. In line with the above findings, animal model studies have reported retinal Aβ deposits and tauopathy, often correlated with local inflammation, retinal ganglion cell degeneration, and functional deficits. This review highlights the converging evidence that AD manifests in the eye, especially in the retina, which can be imaged directly and non-invasively. Visual dysfunction in AD patients, traditionally attributed to well-documented cerebral pathology, can now be reexamined as a direct outcome of retinal abnormalities. As we continue to study the disease in the brain, the emerging field of ocular AD warrants further investigation of how the retina may faithfully reflect the neurological disease. Indeed, detection of retinal AD pathology, particularly the early presenting amyloid biomarkers, using advanced high-resolution imaging techniques may allow large-scale screening and monitoring of at-risk populations.
182 citations
Cites background from "The retina as a window to the brain..."
...Although many of these changes are common to other neurodegenerative diseases [120], the ability to monitor increasingly detailed changes in the AD eye can illuminate those processes specific to the disease, such as deposition of Aβ....
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..., NFL and GCL) might distinguish ocular pathology specific to AD from that observed in other neurodegenerative diseases, such as AMD and glaucoma [92, 93, 116, 120]....
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References
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TL;DR: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide in plaques in brain tissue and the rest of the disease process is proposed to result from an imbalance between Aβ production and Aβ clearance.
Abstract: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer9s disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance.
12,652 citations
TL;DR: Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.
Abstract: In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.
3,941 citations
TL;DR: It is reported that immunization of the young animals essentially prevented the development of β-amyloid-plaque formation, neuritic dystrophy and astrogliosis, and treatment of the older animals markedly reduced the extent and progression of these AD-like neuropathologies.
Abstract: Amyloid-beta peptide (Abeta) seems to have a central role in the neuropathology of Alzheimer's disease (AD). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes. Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Abeta42), which is the predominant form found in the amyloid plaques of Alzheimer's disease. The PDAPP transgenic mouse, which overexpresses mutant human APP (in which the amino acid at position 717 is phenylalanine instead of the normal valine), progressively develops many of the neuropathological hallmarks of Alzheimer's disease in an age- and brain-region-dependent manner. In the present study, transgenic animals were immunized with Abeta42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-beta deposition and several of the subsequent neuropathological changes were well established. We report that immunization of the young animals essentially prevented the development of beta-amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the older animals also markedly reduced the extent and progression of these AD-like neuropathologies. Our results raise the possibility that immunization with amyloid-beta may be effective in preventing and treating Alzheimer's disease.
3,362 citations
TL;DR: Chondroitin and keratan sulphate proteoglycans are among the main inhibitory extracellular matrix molecules that are produced by reactive astrocytes in the glial scar, and they are believed to play a crucial part in regeneration failure.
Abstract: After injury to the adult central nervous system (CNS), injured axons cannot regenerate past the lesion. In this review, we present evidence that this is due to the formation of a glial scar. Chondroitin and keratan sulphate proteoglycans are among the main inhibitory extracellular matrix molecules that are produced by reactive astrocytes in the glial scar, and they are believed to play a crucial part in regeneration failure. We will focus on this role, as well as considering the behaviour of regenerating neurons in the environment of CNS injury.
2,838 citations
TL;DR: NMO-IgG is a specific marker autoantibody of neuromyelitis optica and binds at or near the blood-brain barrier that distinguishes neuromyleitis opticas from multiple sclerosis.
2,793 citations