Open access peer-reviewed chapter

# Retinal Nerve Fibre Layer Thinning in Alzheimer Disease

By Panitha Jindahra and Gordon T Plant

Submitted: October 15th 2010Reviewed: April 5th 2011Published: September 6th 2011

DOI: 10.5772/16891

## 1. Introduction

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterised by impaired memory and cognitive function. A proportion of patients present with visual symptoms which could result from either anterior or posterior visual pathway dysfunction. Retinal and optic nerve abnormalities have in recent years been studied intensively in Alzheimer disease (AD) and are reviewed in this chapter.

## 2. Evidence of retinal nerve fibre layer thinning in AD

### 2.3. Electrodiagnostic evidence

The results of electrodiagnostic testing are conflicting. ERG studies have failed to demonstrate changes in AD patients (Justino et al., 2001; Kergoat et al., 2001, 2002; Davies et al., 1995). Scotopic and photopic electroretinograms and oscillatory potentials in patients with mild Alzheimer disease were compared with normal individuals in one study (Justino et al., 2001). The amplitude and latency of a and b waves in mild AD patients were normal, reflecting intact function of the outer retina. The oscillatory potentials were also unremarkable in this study. Pattern electroretinogram (PERG) recordings have shown a significant delay in P50 and N95 implicit times and reduction in both P50 and N95 amplitudes in mild to severe AD when compared with the results obtained in control eyes (Parisi et al, 2001, 2003). This might indicate that the dysfunction lies in both ganglionic and preganglionic elements (Parisi et al, 2001, 2003). The delayed P50 and N95 implicit times and the reduced P50 and N95 amplitudes are significantly correlated with the reduced overall mean of the RNFL thickness measured by OCT (Parisi et al., 2001, 2003). No significant difference was found in the latency of the pattern visually evoked potential (PVEP) P100 of AD patients and control subjects (Iseri et al., 2006). The normal PVEP responses revealed no evidence for any abnormality of primary visual cortex or of optic nerve function despite considerable RNFL loss (Iseri et al., 2006). However, some earlier studies did find abnormalities of the flash VEP (Wright et al., 1986; Norman et al., 1995) but probably not useful clinically (Coburn et al., 2003). However using PERG and PVEP, another study revealed a reduction in amplitude of N95 and increased latency of P100 wave in most AD eyes (Krasodomska et al., 2010).

### 2.4. Optic disc morphology in AD eyes

A large cup-to-disc ratio, thin rim area and volume are identified in AD eyes compared to age-matched normal eyes (Tsai et al., 1991; Danesh-Meyer et al., 2006). In one of these studies, the patients had a MMSE result of 21±4 taking an upper limit of the vertical cup-to-disc ratio as 0.42 gives a sensitivity of 0.45 and specificity of 0.84 (Danesh-Meyer et al., 2006). Pallor area to disc area ratio did not significantly differ between AD patients and normal subjects in one study (Tsai et al., 1991). However patients with a higher ratio had a higher Alzheimer disease assessment scale and longer duration of illness (Tsai et al., 1991). The changes are not in a uniform pattern for all AD patients (Berisha et al., 2007).

### 2.5. Information from Down syndrome

It has been shown that all adults with Down syndrome (DS) over 35-40 years old who had autopsies performed have AD pathology in their brains i.e., beta amyloid plaques and neurofibrillary tangles (Malamud, 1972). Amyloid precursor protein gene on the locus of the proximal part of the long arm of chromosome 21 is over-expressed in DS patients (Goldgaber et al., 1987), leading to AD development (Prasher et al., 1998). The DS brain pathology is comparable to AD brain and may be useful in further AD studies (Hof et al., 1995). Regarding visual functions, DS patients have impaired colour discrimination, stereoacuity, and contrast sensitivity, similarly to AD patients (Rocco et al., 1997). Moreover abnormal spatial vision in DS children has been detected without other ophthalmologic abnormalities (Suttle & Turner, 2004). A literature review of children with Down syndrome age 0-16 years revealed that refractive error, strabismus, poor acuity, nystagmus, and blepharitis were common ophthalmologic findings whereas cataract and glaucoma were less common (Creavin & Brown, 2009). A pattern reversal VEP study demonstrated significantly longer P100 latency and smaller amplitude in DS patients (16/36 cases) as compared to age-matched controls (Kakigi et al., 1993). By employing achromatic transient VEP, children with DS had small or undetectable N75 but normal latency as compared to normal developing children (Suttle & Turner, 2004). Patients with DS also responded abnormally to chromatic transient VEP (Suttle & Lloyd, 2005). As far as we are aware, there has been no current report about RNFL measurement in DS eyes.

## 3. Hypotheses to explain RNFL thinning in AD

Three hypotheses to explain retinal ganglion cell fibre damage in AD have been proposed.

### 3.1. Is the retina affected by AD pathology directly?

AD pathology might develop not only in the cortex but also in the retina, perhaps in the ganglion cell layer (Lu et al., 2010). Beta amyloid, amyloid associated proteins, tau and amyloid precursor protein are expressed in the human retina at the level of ganglion cells and fibres in older eyes and in the retinal pigment epithelium in retinitis pigmentosa and age-related macular degeneration (Löffler et al., 1995). However neurofibrillary tangles, senile plaques, and amyloid angiopathy have not been identified in the retina even in association with extensive neuronal loss (Leuba & Kraftsik, 1994; Blanks et al., 1989, 1996b). A further study identified neither neurofibrillary degeneration nor amyloid angiopathy in AD patients’ retinas (Hinton et al., 1986). Glial fibrillary acidic protein (GFAP) localized to Muller cells and astrocytes in the GCL is increased in AD eyes; as is found in retinal injuries and in the AD brain (Blanks et al., 1996b). It indicates that the retinal degeneration is accompanied by a glial response as GFAP is a major cytoskeletal component of astrocytes (Blanks et al., 1996b). Amyloid beta or Abeta deposition was found mainly in the outer and inner plexiform layer in the retina of the APPswe/PS1DeltaE9 transgenic (tg) mouse model of Alzheimer disease (Perez et al., 2009). Likewise, Abeta plaques with increased retinal microvascular deposition of Abeta and neuroinflammation in Tg2576 mouse retinas were detected chiefly from the GCL to the inner plexiform layer and some plaques were also identified in the outer nuclear layer, the photoreceptor layer, and the optic nerve (Liu et al., 2009). Abeta deposits reduced with abeta vaccinations (Liu et al., 2009). Hyperphosphorylated tau was demonstrated in areas adjacent to the plaques (Liu et al., 2009). Furthermore, abeta deposition was observed in the cytosol of lens fibre cells along with equatorial supranuclear cataracts in AD patients as compared to age-matched controls (Goldstein et al., 2003). No supranuclear cataracts were identified in any normal individual in this study (Goldstein et al., 2003). Like AD, an evaluation of lens in patients with Down syndrome revealed supranuclear opacification with accelerated supranuclear abeta accumulation (Moncaster et al., 2010).

Wostyn has proposed a link between glaucoma and AD suggesting that an abnormal high trans-lamina cribrosa pressure difference in AD eyes has led to glaucomatous optic neuropathy (Wostyn et al., 2009). Glaucoma is characterized by a progressive loss of RNFL and a resulting visual field defect. Elevated IOP is a strong risk factor but not all patients with glaucoma have high IOP (Johanson et al., 2008; Berdahl et al., 2008b). The subgroup is classified as normal tension glaucoma (NTG) (Johanson et al., 2008). The retinal ganglion cell fibres in NTG eyes might be vulnerable to normal IOP as it is relatively high in the NTG eyes. The cause of NTG is still unknown. Recent studies have revealed that AD patients may have a higher risk of developing glaucoma than normal subjects (Bayer et al., 2002a; Tamura, 2006) and that glaucoma in AD patients tends to be more progressive than glaucoma in non-AD cases (Bayer & Ferrari, 2002b). A case control study (Chandra et al., 1986), investigating all death certificates (1,930,627) for the United States in 1978, compared 7195 cases who had senile and presenile dementia as the cause of death with other patients who died from other conditions. Gluacoma was associated with these demented patients with odd ratio of 2.6. Early RNFL loss in glaucoma occurs in the temporal inferior and temporal superior regions (Hoyt et al., 1973; Pederson & Anderson, 1980; Tuulonen & Airaksinen, 1991; Jonas et al., 1993) as found in some of the AD studies described above. Trans-lamina cribrosa pressure differences may have resulted in the glaucomatous like RNFL changes. A study (Jonas et al., 2003) revealed that lamina cribrosa forms a barrier between the intraocular space and retrobulbar space. The lamina cribrosa has been found to be thinner in glaucomatous eyes than in control eyes (Fig. 2). The outer part of the cribrosa that is directly in contact with pia mater or indirectly with cerebrospinal fluid (CSF) was significantly thinner in the glaucomatous eyes as compared to the controls, and the shortest distance between the intraocular space and the CSF space was significantly less in the glaucoma patients. The optic disc is situated close to this area. Trans-lamina cribrosa pressure (the pressure gradient across the lamina cribrosa) is derived from the intraocular pressure minus the retrobulbar CSF pressure (Jonas et al., 2003). Normally the intraocular pressure is higher than that in the CSF. Abnormal pressure from either side of the lamina cribrosa may be involved in the pathogenesis of several ocular and neurological conditions. In vivo, high IOP glaucoma can damage the optic nerve head and very low IOP can cause swollen discs.

Reduced ICP in patients with normal tension glaucoma (NTG) could cause abnormal trans-lamina cribrosa pressure (Berdahl et al., 2008a). Trans-lamina cribrosa pressure was significantly greater in patients with primary open angle glaucoma (POAG) and NTG than in normal individuals (Ren et al., 2010). CSF pressure in severe AD patients tends to be disproportionately low (Silverberg et al., 2006) and therefore may create a situation where there is relatively high IOP in their eyes (still within a normal reference range). Glaucomatous-like RNFL changes may then be expected to occur. There is evidence of choroid plexus (CP) degeneration in AD brains and their CSF production is affected (Serot et al., 2003). The choroid plexus consists of villi covered by a single layer of ciliated cuboidal epithelium and extends through the lateral, 3rd, and 4th ventricles, acting as a blood-CSF barrier (Serot et al., 2003). It is contiguous with ependyma; produces CSF; synthesizes several molecules; and carries nutrients from blood to the CSF (Serot et al., 2003; Silverberg, et al., 2001). Two-thirds of the CSF secretion is derived from the CPs, the remainder coming from brain interstitial fluid drainage, which is produced by the capillary-astrocyte complex found in the blood brain barrier (Johanson et al., 2008). The production rate of the blood-CSF barrier is substantially greater than that of the blood brain barrier (Johanson et al., 2008). Another source of CSF production is likely to be ependyma lining the ventricles (Pollay & Curl, 1967). CSF reabsorption (Johanson et al., 2008) occurs along sleeves of subarachnoid spaces surrounding cranial nerves that enter the nose and eyes; through the cribriform plate, nasal mucosa, and cervical lymphatic system eventually. CSF is also drained along spinal nerve arachnoid pathways. Arachnoid villi in the dural sinuses absorb the CSF when ICP is elevated. CSF pressure (Johanson et al., 2008) is normally higher than venous pressure in the dural sinuses. It is steady when CSF formation and reabsorption are balanced. CSF pressure measured by lumbar puncture in a lateral recumbent position is directly proportional to CSF production rate and outflow resistance. CSF pressure is determined by hydrodynamic and haemodynamic parameters. Regarding hydrodynamic factors, reduced CSF production or increased outflow resistance will decrease CSF pressure. In ageing the CP epithelium becomes atrophic; its basement membrane thickens; and CSF secretion decreases by 50% (Serot et al., 2003). These changes in AD choroid plexuses appear more pronounced than in

normal ageing and additionally stroma fibrosis has also been demonstrated in AD (Serot et al., 2003). Abeta proteins have been detected in the choroid plexus in AD brain (Kalaria et al., 1996). Ig and C1q depositions are frequently found along the basement membrane of the plexus in AD brains, suggestive of immunological processes in this location (Serot et al., 2003). As a consequence the choroid plexus cannot function normally (Serot et al., 2003). In young adults, the CSF production rate is 0.4 ml/min or 500 – 600 ml per day, the CSF volume is 150 ml, and the CSF turnover rate is 4 volumes per day (Johanson et al., 2008). In AD patients, on the contrary, the CSF production rate is 0.2 ml/min, the CSF volume is 250 ml due to brain atrophy, and the CSF turnover rate is 1.2 volumes per day (Johanson et al., 2008). In addition to the affected CSF production, the resistance of CSF outflow in AD is becoming greater for there is evidence of abeta depositions in the meninges (Silverberg et al., 2003; Hamano et al., 1997; Kalaria et al., 1996). Further studies are needed to confirm low CSF pressure in AD patients; to establish a relationship between the severity of cognitive impairment, brain atrophy, ventricular volume, CP morphology with CSF pressure; and to establish whether the trans-laminar cribrosa pressure difference plays an important role in the pathogenesis of RNFL thinning in AD.

### 3.3. Retrograde trans-synaptic degeneration secondary to cortical pathology

A study (Arnold et al., 1991) revealed the distribution of NFT and NP among 39 cortical regions in 11 AD patients, having mean age 80.2 years (range 63-88 years) and mean duration of disease 7.5 years (range 3-15 years). It had been shown that NFT in the limbic and temporal lobes were substantially higher than the frontal, parietal, and occipital lobes. NPs were evenly distributed throughout the cortex with the highest density in the temporal and occipital lobes. When comparing NFT among visual cortices namely area 17, 18, and 20 (inferior temporal gyrus) in 8 AD patients aged 48-82 years, the number of NFT was low in area 17 but progressively increased in area 18 and 20 respectively, which paralleled to the hierarchical visual organization (Lewis et al., 1987). NFTs were found predominantly in layer 3 and 5, which contained cortico-cortical and cortico-fugal projecting fibres (Lewis et al., 1987). A substantial number of NPs was identified equally in all three regions. They were present across all cortical layers (Lewis et al., 1987). A study (Kiyosawa et al., 1989) of AD patients with and without impaired visual functions i.e., figure copying, colour vision tested by isochromatic plates, and steropsis showed no change in their primary visual cortices in 18F-fluoro-2-deoxyglucose positron emission tomography (PET) as compared to the results in age-matched controls. Additionally AD cases with impaired visual functions showed significantly decreased glucose metabolism in visual association and inferior parietal areas compared with the controls. AD patients with good vision showed no significant change in these areas. No neuronal loss in area 17 of AD brains was demonstrated in another study (Mountjoy et al., 1983).

## 4. Conclusion

There is increasing evidence of RNFL thinning or RGC loss in patients with AD but the relationship between the degree of cognitive impairment and the degree of RNFL loss has not been established yet. There are a few possibilities that could explain the findings. These include AD change in the retina, abnormal trans-lamina cribrosa pressure, and retrograde trans-synaptic degeneration. The degenerative changes in the brain and retina vary among AD patients because of different AD subtype, severity, and duration. It seems that the RNFL measurement has a good potential to be a monitoring tool in AD patients in the near future. Further investigations are required to understand more about AD pathology in these areas.

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Panitha Jindahra and Gordon T Plant (September 6th 2011). Retinal Nerve Fibre Layer Thinning in Alzheimer Disease, The Clinical Spectrum of Alzheimer's Disease -The Charge Toward Comprehensive Diagnostic and Therapeutic Strategies, Suzanne De La Monte, IntechOpen, DOI: 10.5772/16891. Available from:

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