Ocular Manifestations of Alzheimer Disease

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Article initiated by:
Andrew Go Lee, MD, Nita Bhat, MBBS, MS, Shruthi Harish Bindiganavile, MBBS, MS, Hongan Chen
All contributors:
Andrew Go Lee, MD, Caitlin Makenzie Hackl, Nita Bhat, MBBS, MS, Hongan Chen, Calvin W Wong, Osama Al Deyabat, MBBS, Nagham Al-Zubidi, MD, Shruthi Harish Bindiganavile, MBBS, MS, Farida Al Belushi MD, Osama Al Deyabat, MBBS, Sanjana Jaiswal
Assigned editor:
Osama Al Deyabat, MBBS
Review:
Assigned status Up to Date
 by Osama Al Deyabat, MBBS on October 08, 2024.


Disease Entity

Alzheimer disease (AD) is a primary progressive neurodegenerative disease affecting approximately 4.7% of individuals age 60 years. AD is characterized by progressive deterioration in memory, executive function, and other neurocognitive abilities, ultimately interfering with activities of daily living . Furthermore, AD 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 up to 35 million worldwide have the disease[1][2]. Incidence has been estimated to be 11 per 1,000 person-years. There is currently no cure for AD but there are treatments aimed at slowing progression of cognitive decline 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. The number of NFT correlates with disease severity. The number of NFT correlates with disease severity. However, postmortem studies have described individuals with significant NFT and Aβ burden that retain cognitive and executive function, implying genetic susceptibility as a risk modifier. Secondary inflammation and oxidative stress may interfere with synaptic and neuronal activity, leading to neuronal loss and brain atrophy[2][3][4].

A third of AD cases worldwide are attributable to modifiable risk factors, the most common of them being type 2 diabetes, dyslipidemia, obesity, cardiovascular disease, smoking, and use of anticholinergic medications. Protective factors include high education, bilingualism, social engagement, marriage, and physical activity[5].

Diagnosis

The presence of a significant degree of Aβ and NFT in brain is not diagnostic of AD because individuals with significant Aβ or NFT burden may retain cognitive function. As visualization of Aβ and NFT via brain imaging is therefore of limited specificity and resolution, AD diagnosis is made on a primarily clinical basis with support from testing modalities ranging from cognitive assessments and physical exam to brain imaging (MRI, CT, PET). In patients with suspected AD, clinical evaluation for treatable and reversible causes of dementia is performed with a thorough medical history, physical exam, and mental status exam. Importantly, diagnosis of AD should only be made after history of alcohol use, trauma, and vasculopathic risk factors suggesting an alternate pathology have been ruled noncontributory. Definitive diagnosis can be made only through clinical symptoms and signs and a supportive postmortem histological exam with visualization of NFT and Aβ[3][6].

Physical examination

The ophthalmic findings reported in AD patients are summarized below (from Colligris et al. and Javaid et al).[7][8].

Ocular Structures Pathological Changes in AD
Retina
Retinal and choroidal vasculature
  • Retinal and choroidal vascular β-amyloid deposits in transgenic mouse model of AD lead to retinal degeneration[27]
  • Impaired vascularization[28]
Retinal vascular blood flow
  • Blood flow disturbances can lead to neurodegeneration[29]
Optic nerve
  • Axonal degeneration in the axonal segments[14][16]
  • Loss of optic nerve thickness[30][31]
  • Papillary paleness due to axonal loss and perfusion alterations[32]
Lens
  • Correlation between AD and supranuclear cataract[33][34]
  • Presence of abnormal protein deposits[34][35]
Tears
  • Changes in the chemical barrier composition of tears[36]
Cornea
  • Reduced corneal sensitivity[37]
Pupil
  • Pupillary response, possible biomarker[38]
Choroid
  • Attenuation of choroidal thickness[39]
Visual Function Pathological Changes in AD
Visual fields
Visual acuity
Sensory perception
  • Clinically important symptoms of visuospatial disorientation[44][45]
Visual processing
  • Deficits of visual motion perception[46]
Contrast sensitivity
  • Contrast sensitivity disturbances and motion perception[47][48]
Color vision
  • Color discrimination error inversely proportional with mini-mental state examination (MMSE) score[49]
Stereopsis
  • Reduced stereoscopic depth perception[50]
Circadian rhythm
  • Alterations in the circadian rhythm and β-amyloid deposits inside and surrounding degenerating melanopsin retinal ganglion cells (mRGCs)[51][52][53]

Of note, the visual variant of AD (VVAD), also known as posterior cortical atrophy (PCA), is characterized by early onset of visual symptoms due to localized atrophy of the parieto-occipital lobe. Clinicians should be aware that the presenting symptom of VVAD may be vision loss, as early diagnosis is important in referral to rehabilitation and counseling as necessary. 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. For more information on VVAD, please see the corresponding EyeWiki article.

Diagnostic procedures

Retinal Amyloid Plaque Imaging

RNFL layer atrophy and ganglion cell death have been previously described in AD patients[54][55] . However, these findings were not specific to AD and were also reported in other neurodegenerative disorders (e.g., Parkinson disease). Reduced RNFL thickness on OCT has been associated with memory deficits, which is also nonspecific to AD[56]. Recent studies have reported detection of hallmark retinal Aβ plaques in AD patients via scanning laser ophthalmoscope with the natural fluorochrome curcumin that binds to the Aβ amyloid plaques[10][57][58] . 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 in the distribution of blood vessels[10]. Retinal vascular parameters (RVPs) may also serve as a tool for early AD diagnosis [59]. The decreased retinal microvascular network density noted in AD patients suggests that retinal vessel reaction to flicker stimulation, delayed in AD patients, may be another potential non-invasive diagnostic approach[60][61].

Optical coherence tomography angiography (OCTA)

OCTA has also been used on AD patients to detect decreased retinal vasculature density as well as reduced retinal and choroidal flow rates[62][63] . 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 signatures[64][65]. 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 light[66].

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 stage[12][67][68].

Lens

Studies have detected β-amyloid in the lens of human AD patients as well as correlation between cortical cataracts and AD degeneration[33][35]. Furthermore, Aβ lens pathology has been shown to precede MRI manifestations of AD in the brain and clinical manifestations by as much as a decade[69]. Of note, distinctive supranuclear cataracts are associated with early onset AD in Down syndrome patients[70]. A clinical trial is currently evaluating the use of aftobetin hydrochloride, a amyloid-binding compound to detect β-amyloid in patients with mild cognitive impairment and mild AD (ClinicalTrials.gov Identifier: NCT02928211). Thus, detection of Aβ lens pathology may be helpful early diagnosis of AD prior to cognitive decline.

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 AD[36]. Additionally, lacrimal gland dysfunction has been described in relation to AD. However, logistical challenges exist due to the small tear volume that is collected in laboratory diagnostics.

Recent study has also revealed distinct changes in the micro RNA (miRNA) composition of the tear film in AD patients compared to normal populations withs higher concentrations of miRNA detected in AD patients’ tear film. Thus far, miRNA-220b-5p has been identified as a potential marker in patients with dementia, although this is not specific for AD. However, the role of miRNA-220b-5p has not been described in the pathogenesis of AD[71]

Pupillary Light Response and Eye Movement

The locus coeruleus is responsible for pupillary dilatation responses and is also a site of early tau deposition[72]. Thus, when presented with tasks with significant cognitive load, patients with mild cognitive impairment show increased pupillary dilation compared to others[73]. However, this is not specific to AD. Pupillary light reflex amplitude has been noted to be decreased in AD[38][74]. 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 pursuit[75][76] (ClinicalTrials.gov Identifier: NCT01434940).

Implications

While many of these modalities are still in development, ocular approaches to early diagnosis of AD are promising because of their noninvasive method and their potential for prognostication. However, limited specificity of modalities such as pupillary light response and OCT remain significant barriers to clinical application.

Additional Resources

References

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  8. ↑ Colligris, P., Perez de Lara, M. J., Colligris, B. & Pintor, J. Ocular Manifestations of Alzheimer’s and Other Neurodegenerative Diseases: The Prospect of the Eye as a Tool for the Early Diagnosis of Alzheimer’s Disease. J. Ophthalmol. 2018, (2018).
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