Outgrowth Development Research Articles

Recent advancements toward non-invasive imaging of retinal amyloid-beta for early detection of Alzheimer's disease.

Recent advancements toward non-invasive imaging of retinal amyloid-beta for early detection of Alzheimer's disease.

Exploring retinal imaging as a novel biomarker of Alzheimer’s disease

AbstractBackgroundAlzheimer disease (AD) and frontotemporal dementias (FTD) exhibit distinct pathologies but are difficult to reliably differentiate on clinical grounds. Detailed neuropsychiatric evaluations, cerebrospinal fluid analysis, and anatomic or molecular imaging may improve diagnostic accuracy. Even so, these modalities are expensive, time‐consuming, and often inaccessible. The retina is a developmental outgrowth of the brain, and visual dysfunction is well documented in dementia subjects. As such, the retina may be a useful surrogate for diagnosing and monitoring the progression of dementias. We explored the potential role of multimodal retinal imaging for identifying ocular biomarkers of dementia and correlated our findings with cerebral amyloid burden.MethodWe recruited 5 participants with mid‐to‐late stage AD, 2 participants with mid‐to‐late stage FTD, as well as 9 age‐matched healthy controls. Each participant underwent comprehensive ophthalmologic examination and ocular imaging (Optical Coherence Tomography (OCT), OCT‐angiography (OCTA), wide‐field fundus photography, near‐infrared imaging, and fundus autofluorescence). Ocular findings were then correlated with cerebral amyloid burden, as detected by [11C]PiB PET.ResultWe did not observe significant differences in retinal layer thicknesses, retinal perfusion, or sizes of the superficial avascular zones between PET‐confirmed AD, clinically diagnosed FTD, and control subjects. AD subjects consistently demonstrated higher autofluorescence signal intensity (18.5 au), as detected by fundus autofluorescence imaging compared to FTD (16.0 au) and age‐matched control subjects (16.3 au). Near‐infrared ocular imaging also revealed a 1.95 fold increase in retinal reflectance in AD subjects compared to FTD and control subjects.ConclusionIdentification of novel dementia biomarkers is essential for accurate diagnosis and monitoring of dementia progression. Recent studies highlighted the potential use of OCT and OCT‐A to identify retinal layer thickness changes in AD and FTD. Our pilot study suggests that autofluorescence and near‐infrared reflectance, but not OCT or OCT‐A, detect retinal imaging changes that correlate with cerebral amyloid burden. These modalities may thus serve as accurate dementia biomarkers to aid in diagnosis, assessing pathologic severity, and gauging response to therapy in AD and FTD.

Retinal involvement in Alzheimer's disease (AD): evidence and current progress on the non-invasive diagnosis and monitoring of AD-related pathology using the eye.

Alzheimer's disease (AD) is a common form of age-related dementia that mostly affects the aging population. Clinically, it is a disease characterized by impaired memory and progressive cognitive decline. Although the pathological hallmarks of AD have been traditionally described with a general confinement in the brain, recent studies have shown similar pathological changes in the retina, which is a developmental outgrowth of the forebrain. These AD-related neurodegenerative changes in the retina have been implicated to cause early visual problems in AD even before cognitive impairment becomes apparent. With recent advances in research, the commonly held view that AD-related cerebral pathology causes visual dysfunction through disruption of central visual pathways has been re-examined. Currently, several studies have already explored how AD manifests in the retina and the possibility of using the same retina as a window to non-invasively examine AD-related pathology in the brain. Non-invasive screening of AD through the retina has the potential to improve on early detection and management of the disease since the majority of AD cases are usually diagnosed very late. The purpose of this review is to provide evidence on the involvement of the retina in AD and to suggest a possible direction for future research into the non-invasive screening, diagnosis, and monitoring of AD using the retina.

Optical Coherence Tomography in Alzheimer's Disease and Other Neurodegenerative Diseases.

Over the past decade, a surge of evidence has documented various pathological processes in the retina of patients suffering from mild cognitive impairment, Alzheimer’s disease (AD), Parkinson’s disease (PD), and other neurodegenerative diseases. Numerous studies have shown that the retina, a central nervous system tissue formed as a developmental outgrowth of the brain, is profoundly affected by AD. Harboring the earliest detectable disease-specific signs, amyloid β-protein (Aβ) plaques, the retina of AD patients undergoes substantial ganglion cell degeneration, thinning of the retinal nerve fiber layer, and loss of axonal projections in the optic nerve, among other abnormalities. More recent investigations described Aβ plaques in the retina located within sites of neuronal degeneration and occurring in clusters in the mid- and far-periphery of the superior and inferior quadrants, regions that had been previously overlooked. Diverse structural and/or disease-specific changes were also identified in the retina of PD, Huntington’s disease, and multiple sclerosis patients. The pathological relationship between the retina and brain prompted the development of imaging tools designed to noninvasively detect and monitor these signs in living patients. One such tool is optical coherence tomography (OCT), uniquely providing high-resolution two-dimensional cross-sectional imaging and three-dimensional volumetric measurements. As such, OCT emerged as a prominent approach for assessing retinal abnormalities in vivo, and indeed provided multiple parameters that allowed for the distinction between normal aged individuals and patients with neurodegenerative diseases. Beyond the use of retinal optical fundus imaging, which recently allowed for the detection and quantification of amyloid plaques in living AD patients via a wide-field view of the peripheral retina, a major advantage of OCT has been the ability to measure the volumetric changes in specified retinal layers. OCT has proven to be particularly useful in analyzing retinal structural abnormalities consistent with disease pathogenesis. In this review, we provide a summary of OCT findings in the retina of patients with AD and other neurodegenerative diseases. Future studies should explore the combination of imaging early hallmark signs together with structural–functional biomarkers in the accessible retina as a practical means of assessing risk, disease progression, and therapeutic efficacy in these patients.

Ocular indicators of Alzheimer's: exploring disease in the retina.

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.

Transcallosal Projections Require Glycoprotein M6-Dependent Neurite Growth and Guidance.

The function of mature neurons critically relies on the developmental outgrowth and projection of their cellular processes. It has long been postulated that the neuronal glycoproteins M6a and M6b are involved in axon growth because these four-transmembrane domain-proteins of the proteolipid protein family are highly enriched on growth cones, but in vivo evidence has been lacking. Here, we report that the function of M6 proteins is required for normal axonal extension and guidance in vivo. In mice lacking both M6a and M6b, a severe hypoplasia of axon tracts was manifested. Most strikingly, the corpus callosum was reduced in thickness despite normal densities of cortical projection neurons. In single neuron tracing, many axons appeared shorter and disorganized in the double-mutant cortex, and some of them were even misdirected laterally toward the subcortex. Probst bundles were not observed. Upon culturing, double-mutant cortical and cerebellar neurons displayed impaired neurite outgrowth, indicating a cell-intrinsic function of M6 proteins. A rescue experiment showed that the intracellular loop of M6a is essential for the support of neurite extension. We propose that M6 proteins are required for proper extension and guidance of callosal axons that follow one of the most complex trajectories in the mammalian nervous system.

Modes of developmental outgrowth and shaping of a craniofacial bone in zebrafish.

The morphologies of individual bones are crucial for their functions within the skeleton, and vary markedly during evolution. Recent studies have begun to reveal the detailed molecular genetic pathways that underlie skeletal morphogenesis. On the other hand, understanding of the process of morphogenesis itself has not kept pace with the molecular work. We examined, through an extended period of development in zebrafish, how a prominent craniofacial bone, the opercle (Op), attains its adult morphology. Using high-resolution confocal imaging of the vitally stained Op in live larvae, we show that the bone initially appears as a simple linear spicule, or spur, with a characteristic position and orientation, and lined by osteoblasts that we visualize by transgenic labeling. The Op then undergoes a stereotyped sequence of shape transitions, most notably during the larval period occurring through three weeks postfertilization. New shapes arise, and the bone grows in size, as a consequence of anisotropic addition of new mineralized bone matrix along specific regions of the pre-existing bone surfaces. We find that two modes of matrix addition, spurs and veils, are primarily associated with change in shape, whereas a third mode, incremental banding, largely accounts for growth in size. Furthermore, morphometric analyses show that shape development and growth follow different trajectories, suggesting separate control of bone shape and size. New osteoblast arrangements are associated with new patterns of matrix outgrowth, and we propose that fine developmental regulation of osteoblast position is a critical determinant of the spatiotemporal pattern of morphogenesis.

Children's coding of human action: cognitive factors influencing imitation in 3-year-olds.

We used imitation as a tool for investigating how young children code action. The study was designed to examine the errors children make in re-enacting manual gestures they see. Thirty-two 3-year-old children served as subjects. Each child was shown 24 gestures, generated by systematically crossing four factors: visual monitoring, spatial endpoint, movement path, and number of hands. The results showed no difference as a function of whether the children could visually monitor their own responses. Interestingly, children made significantly more errors when the adult's action terminated on a body part than they did when the same movement terminated near the body part. There were also significantly more errors when the demonstrated act involved crossing midline than when it did not, and more errors when it involved one hand rather than two hands. Our hypothesis is that human acts are coded in terms of goals. The goals are hierarchically organized, and because young children have difficulty simultaneously integrating multiple goals into one act they often re-enact the goals that are ranked higher, which leads to the errors observed. We argue that imitation is an active reconstruction of perceived events and taps cognitive processing. We suggest that the goal-based imitation in 3-year-olds is a natural developmental outgrowth of the perceptual-motor mapping and goal-directed coding of human acts found in infancy.

Developmental changes in GAP-43 expression in primary cultures of rat cerebellar granule cells

GAP-43 is a growth-associated protein that has been implicated in the developmental outgrowth of axons. We have examined the profile of GAP-43 levels in rat cerebellar granule cells during their development in vitro. During the first 1–2 days after plating, the majority of cells expressed neurites and after 8 days a complex neuronal network had developed. In situ hybridization studies showed that GAP-43 mRNA levels rapidly increased to peak at 1–2 days and gradually returned to initial values after 7–8 days. Analysis of GAP-43 protein levels followed a similar transient profile. Initially, granule cell perikarya and structures associated with neuritogenesis all displayed GAP-43 immunoreactivity. In older cultures, perikaryal labelling was lost after 10 days whilst process staining decreased more gradually. During the first 48 hours detailed analysis of GAP-43 mRNA revealed two populations of granule cells. It was suggested that cells with significant label originated from the external germinal layer which displays much GAP-43 mRNA in cerebellar sections. Cells with little or no GAP-43, however, probably originated from the internal granular layer since this region displayed no specific labelling. Granule cells within clumps expressed more GAP-43 mRNA compared to isolated cells perhaps indicating cell-cell regulation of expression. These results describe the transient rise in GAP-43 protein and mRNA levels expressed by developing cerebellar granule cell neurons in vitro and provide further evidence for the role GAP-43 plays during neuritogenesis.

Primary structure and transcriptional regulation of GAP-43, a protein associated with nerve growth

Nerve regeneration and developmental outgrowth of axons are both correlated with increased synthesis of an axonal membrane protein designated GAP-43. Phosphorylation of an apparently identical protein, present at lower abundance in adult brains, has been correlated with long-term potentiation, a form of synaptic plasticity. We have now isolated a cDNA clone encoding GAP-43 from neonatal rat brain. The amino acid sequence is extremely hydrophilic, with no potential membrane-spanning domains and no sites for N-linked glycosylation, but with a short hydrophobic segment at the protein's amino terminus, consistent with a model in which GAP-43 extends from the cytoplasmic surface of growth cone and synaptic plasma membranes. Among several tissues and cells examined, GAP-43 mRNA is expressed only in neurons. Developmental and regeneration-associated changes in GAP-43 synthesis appear to be mediated largely at the level of transcription of a single gene.