Dr. Priyal Taribagil
Academic Foundation Doctor Year 2
Royal Free London Foundation Trust
Alzheimer’s Disease is a debilitating neurodegenerative disease and a leading cause of dementia. Its clinical manifestations compose of progressive cognitive impairment with an insidious loss of memory, executive function, social and language impairment (1). The greatest risk factor is age, with incidence of sporadic cases doubling every 5-10 years after 65 (2). On the contrary, genetically driven familial Alzheimer’s disease has a significantly earlier onset and is uncommon. The gold standard means for confirmation of diagnosis is postmortem histological analysis. The presence of extracellular beta amyloid (Aβ) accumulation and intraneuronal deposits of hyperphosphorylated tau are defining features of the disease. These pathological hallmarks help to differentiate Alzheimer’s disease from other forms of dementia, which present with similar clinical symptoms. The fundamental problem with diagnosing the condition is that the pre-clinical stage remains unnoticed as characteristic indicators that allow early diagnosis are yet to be discovered (3). The emergence of the retina as a “window to the brain” has prompted a new means for detecting the disease. As the retina is anatomically and developmentally an extension of the central nervous system, changes in its structure could reflect brain pathology. The remainder of this paper focuses on discussing beta amyloid deposition in the retina as a means for potential early detection of Alzheimer’s disease.
What is Beta Amyloid (Aβ)
Aβ peptide is derived from complex enzymatic breakdown of its precursor protein Amyloid Precursor Protein (APP) (4). The peptide once cleaved, aggregates resulting in the formation of oligomers and fibrils (5). The fibrils subsequently are arranged into beta-pleated sheet structures which accumulate in a variety of different regions in the brain. It is thought that this imbalance contributes to the pathology seen in Alzheimer’s disease. The exact mechanism for damage is unclear, however many studies suggest that amyloid disrupts neural connections, synaptic mechanisms and ultimately contributes to neuronal death (5). The traditional neuropathological phases of the beta amyloid deposition are subdivided into pre-clinical and clinical stages. Phase 1 is thought to demonstrate changes and deposition in the cortical regions of the brain. This continues to spread to the allocortical areas and midbrain. The cerebellum and brain stem can also show evidence of deposition in the later stages of the disease (6).
Beta Amyloid & the Retina
One of the least explored areas in the pathology of Alzheimer’s disease is the extent of visual processing difficulties commonly reported by the patients. Visual symptoms include worsening of visual acuity, contrast sensitivity, deterioration of colour vision, stereopsis, ocular motility dysfunctions and visual field defects (7,8,9). Previously these symptoms were thought to be due to degeneration of the visual pathways in the brain but recent evidence suggests that the retina itself undergoes significant changes.
Some studies conducted on different mice models have identified Aβ immunoreactivity across multiple retinal layers. Post mortem analysis has identified increased retinal Aβ in individuals who had Alzheimer’s disease when compared to age matched controls. More Aβ deposits were identified in the peripheral areas of the superior temporal quadrant, particularly in the primary visual cortex. This may correlate with generalised thinning and Aβ deposition within the retinal layers including specifically the nerve fibre layer, ganglion cell layer and inner plexiform layer (10). To further support these findings, there is evidence that patients with Alzheimer’s disease have more inferior visual field defects which may correlate with this anatomical tendency for deposition (11).
These findings were similarly replicated in a number of mice models. Ning et al. identified age dependent deposition of beta amyloid in double transgenic mice model, notably in the nerve fiber layer (NFL). There was also concomitant activation of microglia and evidence of apoptosis (12). Similar findings were observed by Dutescue et al. although the level of Aβ in the retina was considered to be 75 times less than that in a transgenic brain of a mouse model (13).
On the contrary, there are still a minority of studies that reject the hypothesis of Aβ in retina (9,14,15). Therefore, there is disparity and uncertainty as to whether changes in Alzheimer’s disease do indeed appear in the retina – but it is certainly a promising and exciting prospect. More research is needed to ascertain which areas of the retina are affected first and the appropriate time frames where such changes can be first seen.
Does Beta Amyloid Deposition in the Eye Precede the Brain?
Some studies have reported that retinal Aβ deposition may precede brain Aβ deposition. Koronyo et al. identified presence of Aβ plaques in post mortem eyes from patients with known Alzheimer’s disease and in those with suspected early disease. The amyloid plaques were thought to be identified even before any noticeable changes in the brain (16). With this in mind, there may be a potential role for using this as an ocular biomarker in identifying patients with Alzheimer’s disease or predicting progression of those with early neurodegenerative signs (17).
Problems With Relying on Aβ as a Marker
The exact role of beta amyloid in the eye is still not fully known but some studies suggest that it may have a positive anti-microbial effect in the brain which can be extended to the retina. Processing through the non-amyloidogenic pathway can results in products that have the potential to provide some neuroprotective function. The problem arises when the body is in a pathological state whereby the amyloid is thought to play a more destructive and damaging role. Low levels of Aβ are also considered to be actively involved in synaptic plasticity, memory formation and metabolic homeostasis. Hence, deposition of Aβ may not always be considered pathological.
Furthermore, Aβ has been found in the retina of mice models with other conditions such as age related macular degeneration (AMD), diabetic retinopathy and glaucoma. Nagai et al. observed that Aβ production can be raised in cases of severe hyperglycaemia, particularly in the lens (18). In AMD, the accumulation of drusen contains compounds of amyloid deposits (19). Hence, differentiating between physiological versus pathological deposition may be challenging clinically.
In Vivo Methods
Recent development of the use of curcumin as a “fluoroprobe” to bind to the Aβ, has opened doors for a potential in vivo method of diagnosis and assessment. Curcumin is a non-toxic fluorochrome which binds to Aβ plaques directly (20). Many studies have attempted to use fluorescence scanning laser ophthalmoscopy, after injecting curcumin, to measure the degree of retinal fluorescence and hence assessing Aβ immunoreactivity (20). These studies have demonstrated higher Aβ immunoreactivity in transgenic mice models compared to non-Alzheimer’s disease controls, with levels increasing with age of the specimen. The levels are thought to correlate with the ex vivo Aβ fluorescence and immunoreactivity (21). Age related autofluorescence however may make this challenging.
The characteristic pathological hallmark of Alzheimer’s disease is the abnormal accumulation of beta amyloid plaques. Identification of this in retinal layers prior to brain deposition and neurodegenerative changes may provide an opportunity for early diagnosis and disease management. Non-invasive analysis techniques may then provide an in vivo method of assessment of this potential ocular biomarker. This exciting prospect uses the retina as the “window to the brain”, opening doors to new methods of assessment. Although many smaller studies have supported this theory, larger scaled human trials are needed to fully assess the reliability and sensitivity of this retinal biomarker.
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