Ocular Manifestations of Alzheimer Disease

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Article summary goes here.

Disease Entity

Alzheimer disease (AD) is a primary progressive neurodegenerative disease affecting approximately 4.7% of individuals age 60 years. AD is typically characterized by deterioration of memory and other neurocognitive functions that ultimately interferes with daily life and is can be fatal. AD is the most common form of dementia, accounting for over 50% of cases. In the United States, 5.5 million people are affected and and up to 35 million worldwide have the disease1,2. There is currently no cure for AD but there are treatments with variable and modest efficacy 3.


Pathophysiology

AD is believed to arise from the accumulation of misfolded proteins that induces oxidative and secondary inflammatory damage on the aging brain leading to cognitive decline. Specific pathological features of AD include β-amyloid (Aβ) peptide plaques and tau protein neurofibrillary tangles (NFT). According to the predominant ‘amyloid hypothesis,’ Aβ precipitates secondary to an imbalance between production and clearance such that there is an accumulation and aggregation of Aβ2. NFT are formed from the intracellular aggregation of abnormal tau proteins. Then number of NFT correlates with disease severity. Secondary inflammation and oxidative stress may interfere with synaptic and neuronal activity, leading to neuronal loss and brain atrophy2–4

Diagnosis

As visualization of Aβ and NFT via brain imaging is of limited specificity and resolution, AD diagnosis is primarily clinical with reliance on a range of testing modalities ranging from cognitive assessments and physical exam to brain imaging (MRI, CT, PET). Definitive diagnosis is only through postmortem histological exam with visualization of NFT and Aβ3,5.


Physical examination

Neuro-ophthalmic Manifestations

The ophthalmic findings reported in AD patients are summarized below in Table 1 (from Colligris et al. and Javaid et al).6,7. Of note, the visual variant of AD (VVAD), also known as posterior cortical atrophy (PCA), is characterized by prominent visual symptoms due to localized atrophy of the parieto-occipital lobe. VVAD is For more information, please see corresponding EyeWiki article. Patients with PCA typically present with difficulty reading or problems with visuospatial and visual processing. A homonymous hemianopsia or cortical visual loss with a negative structural imaging study (e.g., MRI) or neuroimaging showing only posterior cortical atrophy may suggest the diagnosis of AD.

Diagnostic procedures

Detection Modalities

Imaging Previously, retinal OCT imaging in AD patients noted NFL layer atrophy and ganglion cell death53,54. However, these findings were not specific to AD and were also reported in other neurodegenerative disorders (e.g., Parkinson disease). Rreduced RNFL thickness on OCT has been associated with memory deficits55. Recent studies have reported detection of hallmark Aβ plaques in the retina in AD patients via scanning laser ophthalmoscope using the natural fluorochrome curcumin that binds to the plaques9,56,57. Fluorescence is quantified via an automated calculation of the retinal amyloid index (RAI). Compared to healthy controls, AD patients had a 2.1-fold increase in fluorescent intensity over baseline. Furthermore, the fluorescence pattern is consistent with histological data showing Aβ deposits clustered in the peripheral superior quadrant, often along blood vessels9. Retinal vascular parameters (RVPs) may also serve as a tool for early AD diagnosis as a study by n tortuosity58. The decreased retinal microvascular network density noted in AD patients suggests retinal vessel reaction to flicker stimulation, delayed in AD patients, could be another potential non-invasive biomarker59,60.

Optical coherence tomography angiography (OCTA) has also been  used on AD patients to detect decreased retinal vasculature density as well as reduced retinal and choroidal flow rates61,62. The metabolic hyperspectral retinal camera is another device currently being studied for its biomarker potential via measurement of regional retinal vessel oxygen saturation. This device utilizes 225 contiguous spectral bands collected at high speeds to localize biomolecules and structures based on their respective spectral signatures63,64. Another study evaluating the association between type 2 diabetes and AD employs microperimetry to measure retinal neurodegeneration. Microperimetry assesses retinal sensitivity by measuring the minimum light intensity which the patients can perceive by stimulating specific areas of retina with spots of light65. 

Another target for AD detection is the pathologic hyperphosphorylated Tau protein (NFT), which has been detected in postmortem human retinas and AD human models in the absence of tau aggregation, suggesting a pre-symptomatic disease stage11,66,67.

Lens Studies have detected β-amyloid in the lens of human AD patients as well as correlation between cortical cataracts and AD degeneration32,34. A clinical trial is currently evaluating the use of aftobetin hydrochloride, a topical amyloid-binding compound to detect β-amyloid in patients with mild cognitive impairment and mild AD (ClinicalTrials.gov Identifier: NCT02928211).

Tear Fluid AD patients have been reported to have increased tear flow rate and protein levels. The presence of lipocalin-1, dermicidin, lysozyme C and lactritin had an 81% sensitivity and 77% specificity for AD35. Pupillary Light Response and Eye Movement Pupillary light reflex amplitude has been noted to be decreased in AD37,68. There is also an ongoing study to track eye movements as an AD diagnostic tool, with previous studies showing delayed saccadic eye movement and smooth ocular pursuit69,70 (ClinicalTrials.gov Identifier: NCT01434940).


Implications

While still in development, this wide range of AD detection modalities are promising as a specific, early and noninvasive method of objective AD diagnosis, with potential for prognostication as well.


References

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