Screening for Patients with Mild Alzheimer Disease Using Frequency Doubling Technology Perimetry

Abstract

We compared the visual field performances of patients with mild Alzheimer disease (AD) with normal subjects and detected visual field impairment attributable to the magnocellular pathway using frequency doubling technology—Matrix (FDT-Matrix). We recruited 43 patients with mild AD (mean age: 68.0 ± 7.2 years) and 33 controls who are visually and cognitively normal (mean age: 64.1 ± 6.4 years). All participants had at least two reliable FDT-Matrix 30-2 tests. Reliability indices, global indices (mean deviation and pattern standard deviation), and glaucoma hemifield test results were measured with FDT-Matrix. The mean test duration was significantly longer in patient group compared with controls (p = 0.002). Among the reliability indices, false negatives were higher in patient group than controls (p = 0.003). There were statistically significant differences in mean deviation and pattern standard deviation values (p < 0.0001 and p < 0.0001, respectively) and glaucoma hemifield test results (p < 0.001) between the patient and the control group. Our results imply that the pathogenesis of cognitive deterioration may not only be confined to the cortical area but also to the magnocellular pathway. We underline that FDT testing can be useful for the identification of early impairment and the follow-up of patients with AD.

Introduction

Alzheimer disease (AD) is the most common form of dementia and also involves the degeneration of a neuronal subpopulation in the central nervous system.1 The exact cause of AD is unknown, but it is likely to be multifactorial, including age, genetic, and environmental factors.2,3

AD is associated with deficits in visual function, including stereopsis, contrast sensitivity, and motion detection, in almost half of patients.4,5 Visual disturbances are most pronounced in patients with severe dementia.6,7 There is a general agreement that AD affects visual association cortices with relative sparing of the primary visual cortex; however, involvement of the pregeniculate visual pathways remains controversial.8–13

The magnocellular (MGC) pathway has primary receptors in the retina, but the pathway itself extends to the primary visual cortex with lateral and retrograde connections, which relay visual information related to achromatic functions such as motion and contrast.14 Deficits specific to the MGC pathway have also been identified in individuals with AD, even in brain areas devoid of plaques and neurofibrillary tangles. In the lateral geniculate nucleus, the magnocellular layers have been shown to have plaques associated with AD.15 There is histological and clinical evidence that retina ganglion cells (RGCs) and their axons are selectively damaged in patients with AD.1,16–19

The frequency doubling technology—Matrix (FDT-Matrix) perimetry is based on an illusion occurring when a sinusoidal grating of low spatial frequency undergoes counter-phase flickering at a high temporal frequency and measures contrast sensitivity. Recent evidence suggests that the MGC pathway in a human retina is isolated as a whole by the FDT-Matrix stimulus.20 FDT-Matrix perimetry selectively tests the function of the MGC pathway, which accounts for only 5–10% of all ganglion cells and this may account for less redundancy.21 Testing the response of MGC pathway by FDT-Matrix perimetry may be a sensitive method to detect a field defect.22 There are also controversial reports indicating that the FDT effect is not only mediated by the MGC pathway but also by many different ganglion cell mechanisms and is probably organized cortically.20,23 There are several studies demonstrating the value of FDT-Matrix in neurological deficit testing.24–28

Visual function in AD is an essential subject that has been previously studied by objective methodology, including pattern electroretinography (pERG).29–31 This study uses FDT perimetry to investigate possible impairment of the MGC pathway in patients with mild AD. Patients with mild AD can produce reliable visual field (VF) results, exhibiting significant reductions in global sensitivity. Also AD can affect glaucoma hemifield test (GHT) results, which could be related to a dysfunction of the MGC pathway.

Materials and Methods

Patients were selected from the Dementia Section of Neurology Department of Haydarpasa Numune Education and Research Hospital after written informed consent was obtained from all participants. Study was carried out in accordance with the tenets of the Declaration of Helsinki. The patients were diagnosed as clinically probable AD according to the definition of the National Institute of Neurological Communicative Disorders and Stroke/Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) clinical diagnostic criteria and Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV). Neurological and systemic examinations, brain magnetic resonance imaging (MRI), complete hematological and biochemical evaluations were all fulfilled. Complete blood cell count, serum electrolytes, blood urea and creatinine, serum B12 and folate levels, and thyroid and liver function, syphilis, and human immunodeficiency virus (HIV) tests were all performed to exclude other forms of dementia. Subjects were assessed using a Mini-Mental Status Examination (MMSE), right-left orientation and praxis test, basic written calculation, clock drawing test, cube copy, proverbs, go-no-go, Luria sequences, digit span (forward and backward), and other attention tests. Behavioural symptoms were evaluated using the Neuropsychiatric Inventory (NPI). For exclusion of depression, the Geriatric Depression Scale was used. Clinical Dementia Rating (CDR) and Global Deterioration Scale (GDS) were used for clinical staging of the patients.

In this study, mild AD group was designated as MMSE scores ranging from 19 to 23, GDS 4, and a CDR of 1.32–34 The following exclusion criteria were applied: neurological/psychiatric conditions other than mild AD, antidepressant-antipsychotic medication, history of malignancy, head trauma or stroke, drug abuse or addiction, metabolic or endocrine anomalies, diabetes even in the absence of retinopathy, intraocular pressure (IOP) >21 mm Hg even in the absence of glaucoma, presence of glaucoma, congenital colour vision disorders, congenital optic nerve head anomalies, best corrected visual acuity (BCVA) <0.6, high ametropia (sphere dioptre >4 and cylinder dioptre >2), optic media opacities such as cataract (nuclear sclerosis >Grade 2), and central corneal opacities that could bias functional or structural retinal testing and FDT tests performed unreliably.

The control group consisted of volunteers who are age- and gender-matched healthy subjects having no complaints of dementia by the participant or told by their family. The control subjects underwent neurological examination and MMSE. Eleven control subjects did not attend the second or third VF examination and were excluded from the study.

The Humphrey strategies started testing at a single location in each quadrant of the VF. If a stimulus was seen, subsequent stimuli at that location are dimmed one step at a time—usually by 3 or 4 decibels—until they were no longer seen.35 A 3-dB or greater decrease in retinal sensitivity at a single point tested is defined as a VF defect in this area. Thus, a 3-dB decrease in retinal sensitivity of the patient group was compared with the control group and was accepted as clinically significant. Based on power analysis, an estimated sample size was calculated. Forty-four patients for each group resulted in a maximum 5% chance of type I error and 80% power.

Both groups underwent full ophthalmological examination by two ophthalmologists (U.A., M.O.A.). This examination consisted of BCVA (Snellen chart), slit lamp examination, IOP measurement (Goldmann applanation tonometer), angle and fundus examination (Goldman three-mirror lens), and colour vision testing (Ishihara colour test).

The FDT-Matrix threshold program 30-2 was performed (Welch Allyn, Skaneateless Falls, NY, USA; and HFA, Carl Zeiss Meditec, Dublin, CA, USA.). FDT tests were performed by a same investigator for the entire study (U.A.). All enrolled subjects performed at least two Matrix VF tests within 2 weeks. They used the 30-2 threshold program in order to assess the test-retest variability and to rule out a relevant learning curve. In all cases, the first test was not considered in data analysis.36 Mean deviation (MD), pattern standard deviation (PSD), and GHT results were analysed. After excluding the patients with unreliable VFs (defined as greater than 33% fixation losses, false positives, and false negatives), 28 of 43 mild AD patients and 30 of 33 control subjects were included in this cross-sectional study.

In statistical analysis, data from both the right and left eyes of all subjects were evaluated. FDT was considered abnormal if they had repeated (2 consecutive) abnormal VF test results, defined as a MD and PSD outside the 95% normal confidence limits, or a GHT result outside the normal limits.

Statistical Methods

The Student’s t test was used to compare the means of the patient and the control group accounting for age. The generalised estimating equation (GEE) model was used to compare the two groups and age was used a covariable. In this model, subjects were used as independent variables where each subject has correlated measurements (the within-subject effect).37 For the scaled responses, the identity link function was used in this model. This function can be used with any distribution. BCVA, IOP, cup/disc ratio, test duration, MD, PSD values, and reliability indices (RIs) (fixation loss, false positive, false negative) were used as dependent variables. In the summary tables, descriptive statistics were given as a mean ± standard deviation. The Pearson correlation, chi-square, and z proportion tests were used to determine the relation between GHT results and the patient group for both eyes.38 Pearson correlation test was calculated using the MMSE, MD, and PSD values to test for a linear relationship. SPSS Statistics for Windows (version 17.0; SPSS Inc., Chicago, IL, USA) was used for statistical analysis. The results were considered statistically significant if the p values were less than 0.05/k (k = number of comparisons in each hypothesis according to Bonferroni correction).

Results

Reliable VFs, as defined in Materials and Methods, were obtained in 65.1% (28/43) of the patient group (Figure 1) and 90.9% (30/33) of the control subjects. There was a statistically significant difference between two groups in the proportion of reliable VF test performance (p = 0.0188). The final patient group consisted of 13 males and 15 females, with a mean of 68.0 ± 7.2 years. The control group included 15 males and 15 female subjects and the mean age was 64.1 ± 6.4 years (Table 1). Since a statistically significant difference in the mean age between two groups (p = 0.036) existed, age was then used as a covariant variable in GEE analysis. After excluding the patients with unreliable VFs, there were no statistically significant differences for the fixation loss and false-positive responses between the two groups (p = 0.066 and p = 0.039, respectively), whereas there was a statistical significance in the false negatives (p = 0.003) (Table 2).

FIGURE 1.

A sample of reliable test result belonging to a mild Alzheimer patient.

TABLE 1.

Characteristics of groups.

Group	Number of subjects	Unreliable VF	Reliable VF	Male	Female	Age
Patient group	43	15	28 (65.1%)	13	15	68.0 ± 7.2
Control group	33	3	30 (90.9%)	15	15	64.1 ± 6.4
p			0.0188			0.036*

*Age was taken in to consideration as covariant variable in GEE analysis.

TABLE 2.

Descriptive statistics of reliability indices for the patient and the control groups.

Measures	Patient group (n = 28)	Control group (n = 30)	Wald chi-square (df = 1)	p*
Fixation loss	6.21 ± 8.95	3.45 ± 6.64	3.390	0.066
False negative	4.84 ± 9.36	0.59 ± 3.13	8.639	0.003†
False positive	4.66 ± 7.99	1.55 ± 4.89	4.259	0.039

*Generalised estimating equation (GEE) model; df = degrees of freedom.

†If p < 0.05/3, the result is statistically significant according to Bonferroni correction.

The descriptive statistics and p values for the BCVA, IOP, cup/disc ratio, test duration, and MD and PSD parameters for the patient and the control group are summarized in Table 3. There was no significant differences between two groups in terms of BCVA (0.95 ± 0.14 versus 0.99 ± 0.03; p = 0.018), IOP (15.29 ± 2.45 versus 15.05 ± 2.23 mm Hg; p = 0.655), and cup/disc ratio (0.34 ± 0.08 versus 0.31 ± 0.07; p = 0.161).The mean test durations of the patient and the control group were 6.61 ± 0.50 and 6.31 ± 0.42 minutes, respectively. There was a statistically significant difference in test duration between two groups (p = 0.002) (Table 3). Because of the difference in test duration between two groups was look like too small in practice, Cohen's d and effect size were calculated (Cohen’s d = 0.649, effect size r = 0.309). Cohen's d value was between 0.5 and 0.8 and this showed that the time difference between test duration was intermediate.

TABLE 3.

Ocular characteristics and global indices of the patient and the control groups.

Parameter	Patient group (n = 28)	Control group (n = 30)	Wald chi-square (df = 1)	p*
Best corrected visual acuity	0.95 ± 0.14	0.99 ± 0.03	5.588	0.018
Intraocular pressure (mm Hg)	15.29 ± 2.45	15.05 ± 2.23	0.20	0.655
Cup/disc ratio	0.34 ± 0.08	0.31 ± 0.07	1.962	0.161
Test duration (minute)	6.61 ± 0.50	6.31 ± 0.42	9.322	0.002†
Mean deviation (db)	−5.63 ± 5.66	−0.80 ± 2.53	20.182	<0.0001†
Pattern standard deviation (db)	4.42 ± 1.71	3.01 ± 1.08	19.331	<0.0001†

*Generalised estimating equation (GEE) model; df = degrees of freedom.

†If p < 0.05/6, the result is statistically significant according to Bonferroni correction.

The mean MD and PSD values were −5.63 dB (SD: ±5.66) and 4.42 dB (SD: ±1.71) in the patient group and −0.80 dB (SD: ±2.53) and 3.01 dB (SD: ±1.08) in the control group, respectively. The mean MD value in the patient group was significantly (p < 0.0001) lower (Figure 2), and the mean PSD value was significantly (p < 0.0001) higher when compared with the control group (Figure 3).

FIGURE 2.

Means and confidence intervals 95% (error bars) of mean deviation for the patient and the control groups.

FIGURE 3.

Means and confidence intervals 95% (error bars) of pattern standard deviation for patient and the control groups.

The mean MMSE score of the patient group was 21.35 ± 1.39 (range: 19–23), while the mean score of the control group was 28.76 ± 1.85 (range: 27–30). There were no statistically significant correlations between the mean MMSE score of the patient group and both the MD and PSD values for each eye (left eye: p = 0.898 and p = 0.81; right eye: p = 0.893 and p = 0.904, respectively).

The GHT differences between the two groups for both the right and left eyes were analysed and statistically significant differences for both eyes were found (p = 0.003 and p < 0.0001, respectively). Table 4 summarizes the comparison of VFs based on the GHT results between the patient and the control group. There were no statistically significant differences in the abnormally high sensitivity (AHS), borderline sensitivity, and generalised reduction of sensitivity (GRS) results between the eyes of the same subject. Patients with mild AD were usually outside normal limits (ONL), whereas the control subjects were within the normal limits (WNL). The comparison of VFs based on the GHT results showed statistically significant differences in ONL and WNL between the two groups for both eyes (p < 0.001 for all comparisons).

TABLE 4.

The comparison of visual field results based on GHT results in two groups for each eye.

	OD		OS
Measures	Patient group n (%)	Control group n (%)	Patient group n (%)	Control group n (%)
AHS	0 (0.0)	1 (3.3)	0 (0.0)	0 (0.0)
Borderline	5 (17.9)	5 (16.7)	8 (28.6)	4 (13.3)
GRS	1 (3.6)	0 (0.0)	1 (3.6)	0 (0.0)
Outside normal limits	15 (53.6)	4 (13.3)	12 (42.9)	2 (6.7)
Within normal limits	7 (25.0)	20 (66.7)	7 (25.0)	24 (80.0)
p*	0.003		<0.0001

*According to chi-square test results.

AHS = abnormally high sensitivity; GRS = generalised reduction of sensitivity; OD = right eye; OS = left eye.

Discussion

Visual system disturbances are well documented, and can precede other findings of dementia in AD.6,39,40 Visual function testing in patients with AD has revealed abnormalities in contrast sensitivity, depth, and motion perception.9,41–44 In this study, FDT-Matrix data obtained in the patient group showed a marked reduction of the MD and an increase in PSD values when compared with controls.

In a recent study, Risacher et al. evaluated the FDT results of mild cognitive impairment (MCI) and AD patients.45 They found that patients with AD and MCI showed marked deficits in FDT testing, such as increased test duration, reduced general sensitivity (lower MD), and abnormal variability (higher PSD). These results are compatible with our results. They concluded that FDT testing can be used as a biomarker for AD.45 Automated perimetry requires considerable patient cooperation and many patients with mild AD can still produce reliable VF results despite their cognitive deterioration. Our experience with FDT testing in AD taught us that it was difficult to obtain reliable results in patients with moderate to severe cognitive impairment. For this reason, patients with more than mild AD according to MMSE scores were excluded. Although 34.9% of patients with mild AD have unreliable visual field test results, 65.1% of the patient group can still perform the test reliably, which was 90.9% in control group (p = 0.0188). The only statistically significant difference was found in false negatives between the RIs, which was higher in the patient group compared with controls (p = 0.003). Cognitive deterioration or difficulty with concentration may be an influential factor affecting this result. The mean test duration for FDT was just over 6 minutes for both groups. The mean test duration was significantly longer in the patient group than controls (p = 0.002), which also may be the characteristics of deterioration in cognitive function. Despite the longer test durations and high false-negative rates of 65.1%, mild AD patients can still produce reliable VF results and FDT can be used as a screening test in these patients.

The patient group differs significantly in MD and PSD values. A significant amount of decrease in the sensitivities of these patients can be concluded as a marked depression of VF sensitivity compared with the control subjects. A different mechanism may play a role for these abnormalities in the VFs of AD patients. It is not clear that the cortical disease alone is responsible for the VF loss. Field deficits in this patient group may also be related to neuronal degeneration in the retina. The difference between the patient and the control group may be primarily due to cognitive impairment rather than to specific visual disability related to MGC pathway.

The difference between the two groups is also present on GHT testing. The abnormal GHT may result from a regional nerve fibre layer defect. Alternatively, it may be a function of the MD being reduced. It has been hypothesized that testing for the frequency doubling effect is a sensitive method to identify VF loss originated from the MGC pathway.22 Dysfunction of the MGC pathway in AD was suspected after obtaining the temporal frequency deficits in at least one study.46 Abnormalities in pERG parameters consistent with RGC dysfunction have been measured in patients with AD.29–31 In patients with AD, the amplitude of the pERG, which reflects RGC function, is reduced and this is most pronounced for high frequency temporal patterns.29,30 These results may imply the selective loss of the large RGCs that underline the MGC pathway and that such cells are most sensitive to high temporal frequencies.29 Other reports indicate that the FDT effect is mediated by many different ganglion cell mechanisms and is probably organized in cortex.20,23 Our results imply that multiple ganglion cell damages are present in the patient group probed with FDT testing.

Danesh-Meyer et al. reported the results of confocal scanning laser ophthalmoscopy (CSLO) of the optic discs in patients with AD and in a control group.47 They found changes in the morphology of the optic discs in patients with AD, suggesting that patients with AD have a loss of retinal axons compared with healthy individuals.47 Using optic coherence tomography (OCT) in patients with AD, Iseri et al. showed a decrease in the peri-papillary retinal nerve fibre layer thickness.48 In previous histological studies, a reduction in the number of RGCs and axons in patients with AD have been shown.1,16,49 These structural changes confined to the optic nerve and retinal nerve fibre layer may be related to the functional abnormalities obtained by FDT testing. One alternative way to address this conclusion may be to examine the association of the FDT test with structural glaucomatous change by CSLO/OCT. The VF changes should be accompanied by structural changes.

Our results imply that the pathogenesis of cognitive deterioration may not only be confined to the cortical area but also to the MGC pathway. The degradation of lower-order visual function due to MGC pathway damage may contribute to impaired performance on tasks requiring higher-order cognitive function. FDT testing may be useful for the identification of early impairment and for the follow-up of patients with AD. Future studies including structural imaging combined with VF testing may yield stronger and more convincing information regarding the source of visual loss in AD. Moreover, investigating the specificity and sensitivity of FDT testing in Alzheimer disease may provide more strong evidence for the rationale if the following FDT over time will be useful in this group of patients. Identification of early impairment of Alzheimer disease with the help of FDT testing may provide better patient care, which is so important for this group of patients.

Acknowledgements

Statistical analyses of the data were performed by MeStACon (Medical Statistics and Analysis Consultancy System), SBB Consulting GmbH, Vienna.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.