- Email: [email protected]
The ‘eye test’ in recognition of late-onset Alzheimer’s disease
Archives of Gerontology and Geriatrics 27 (1998) 171 – 177
The ‘eye test’ in recognition of late-onset Alzheimer’s disease Ludovica Caputo a, Margherita Casartelli a, Chiara Perrone a, Marisa Santori b, Giorgio Annoni a,*, Carlo Vergani a a
Dipartimento di Medicina Interna, Cattedra di Gerontologia e Geriatria, Uni6ersita` di Milano, and Ospedale Maggiore, IRCCS-6ia Pace 9 -20122 Milano, Italy b Istituto di Clinica Oculistica, Uni6ersita` di Milano, and Ospedale Maggiore, IRCCS-Milano, Italy Received 26 January 1998; received in revised form 12 May 1998; accepted 13 May 1998
Abstract A rapid and specific diagnostic test for Alzheimer’s disease (AD), the prevalent cause of dementia in the elderly, is currently unavailable. The aim of this study was to verify the validity of the recently proposed ‘Eye Test’ in the identification of AD patients, based on their supposed greater mydriatic response to cholinergic antagonists. We tested the pupillary response to the instillation of 0.01% tropicamide in 48 subjects: 15 patients with probable or possible Alzheimer’s disease, five patients with vascular dementia (VD), 16 elderly controls (EC) and 12 young controls (YC). Mean pupil dilation in the treated eye at 30 and 40 min after drops instillation was not significantly different among the four groups. The mean change in anisocoria at 30 min was significantly greater in the AD group (0.90 mm, S.D. 0.83) than in the YC group (0.21 mm, S.D. 0.46), but no significant difference was found among the AD group, the EC group and the VD group. Our results, therefore, do not support the potential usefulness of the pupillary response to dilute tropicamide for identifying individuals with AD. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: ‘Eye test’; Alzheimer’s disease; Diagnosis; Elderly
* Corresponding author. [email protected]
Tel.:
+39
2
55035357;
fax:
+39
2
55017492;
e-mail:
0167-4943/98/$ - see front matter © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0167-4943(98)00112-5
gior-
172
L. Caputo et al. / Arch. Gerontol. Geriatr. 27 (1998) 171–177
1. Introduction Alzheimer’s disease (AD), the prevalent cause of dementia in the elderly, afflicts about 5% of people over 65 years, 19% of individuals aged 75–85 and 45% of those above 85 (Evans et al., 1989). The disease, clinically characterized by a progressive decline of memory and other cognitive functions, is associated with a reduced activity of several neurotransmitters, namely acetylcholine (Perry et al., 1977; Whitehouse et al., 1981; Sims et al., 1983). Main histologic hallmarks of AD are the accumulation of neurofibrillary tangles and senile plaques, particularly in the neocortex and hippocampus; the identification of these markers at post-mortem examination is essential for the definite diagnosis. According to the criteria proposed by the NINCDS-ADRDA Work Group, a diagnosis of ‘probable’ or ‘possible’ AD can be reached with an accurate clinical and instrumental evaluation (McKahn et al., 1984). Therefore, a rapid and specific diagnostic test for AD, especially in the early phases of the disease, although expected, is currently not available. With this aim in view, Scinto et al. (1994) proposed that the pupillary response to a cholinergic antagonist, tropicamide, may be such a test. Basis for their work was the evidence of certain similarities between subjects with AD and those with Down’s syndrome (DS): the latter, in fact, develop, after the age of 30 years, the characteristic brain lesions of AD, and, in some cases, the clinical features of dementia. People with DS also show supersensitivity to anticholinergic agents, both at cardiac (Harris and Goodman, 1968) and ocular level: indeed, the mydriatic response following instillation of tropicamide 0.01% has been shown to be about 3-fold that of healthy subjects, independently of age (Sacks and Smith, 1989). In detail, Scinto et al. (1994) reported in 19 patients with clinically diagnosed or suspected AD a greater mydriatic response to a very dilute solution of tropicamide (0.01%) as compared to 32 normal elderly controls, with a concordance of 95% between the pupillary response and the clinical diagnosis. However, in more recent articles, Litvan and Fitzgibbon (1996) and Loupe et al. (1996) deny the validity of the test, since the pupillary response to dilute tropicamide, in their studies, did not significantly differ among AD patients, young and elderly controls. Given these few and contradictory reports in literature, purpose of this study was to verify the validity of the ‘eye test’ for identifying patients with AD.
2. Subjects and methods
2.1. Subjects From May through November 1995, 36 aged outpatients were consecutively enrolled by the geriatric ward of the Ospedale Maggiore IRCCS of Milano (Italy). Twenty mild demented subjects were assigned to two groups, the first of which included 15 patients with probable or possible AD, according to NINCDS-
L. Caputo et al. / Arch. Gerontol. Geriatr. 27 (1998) 171–177
173
ADRDA criteria (McKahn et al., 1984) and the second five patients with vascular dementia (VD), according to NINDS-AIREN criteria (Roman, 1993). Sixteen elderly subjects (EC) without cognitive deficits, affected by different internal diseases, were enrolled as controls. A fourth group (young control group, YC) included 12 young healthy subjects. The main characteristics of the study population are shown in (Table 1). The demented patients and the elderly controls were assessed by means of a complete geriatric examination, including ADL (Katz et al., 1963), IADL (Lawton and Brody, 1969), MMSE (Folstein et al., 1975), CDR (Morris, 1993) and the GDS (Yesavage et al., 1982), routine laboratory tests (including TSH, FT4, B12 vitamin, folates), chest X-ray and ECG. Brain imaging (CT or NMR) was performed in all the demented patients, together with a conventional neuropsychological evaluation, including tasks of attention, memory, language, visual-perception and intelligence (Spinnler and Tognoni, 1987). All subjects underwent a complete ophthalmologic evaluation before the beginning of the study. Exclusion criteria comprehended: eye diseases, history of eye surgery, use of medications that could influence pupillary motility, diabetes mellitus.
2.2. Procedure Pupillary measurements were obtained with a computerized videopupillography system (C2514 IRISCORDER, Hamamatsu, Japan), supplied with an infrared light source, a video camera, which transfers the image to a screen, and a printer. For each measurement, the device gives the value of the initial pupil diameter and of its variation in response to a light stimulus. The test was performed according to the following procedure, which is very close to the one proposed by Scinto et al. (1994): 1. Baseline measurement of pupil diameter in both eyes, with the patients seated in a comfortable semi-darkened room, listening to a tape of classical music; to reduce anxiety, the baseline measurement was obtained only after the subjects had been in the room for 15 min; 2. Instillation of one drop of 0.01% tropicamide in the inferior fornix of one eye (randomly chosen) and of one drop of distilled water in the other eye; Table 1 Clinical features of the study population (mean 9S.D.)
Age (years) Sex (M/F) MMSE CDR Duration of disease (years)
EC (n = 16)
YC (n = 12)
AD (n = 15)
VD (n =5)
72.99 4.7 4/12 28.1 91.7
27.3 93.1 5/7
7497.5 7/8 19.2 95.0 1.28 90.47 2.3 91.4
73.2 9 6.1 5/0 20.4 9 2.9 1.25 9 0.5 3.0 9 1.6
Abbreviations are explained in the text.
174
L. Caputo et al. / Arch. Gerontol. Geriatr. 27 (1998) 171–177
Table 2 Baseline pupil diameter and change in pupil diameter (mean 9 S.D.) of the treated eye from baseline at 30 and 40 min after instillation of 0.01% tropicamide
Baseline pupil diameter (mm) Dilation at 30 min (mm) Dilation at 40 min (mm)
EC (n =16)
YC (n = 12)
AD (n = 15)
VD (n = 5)
4.389 0.56 0.529 0.48 0.579 0.59
5.81 90.61* 0.12 90.38 0.13 90.45
4.30 9 0.57 0.76 9 0.51 0.82 9 0.59
3.94 90.99 0.64 90.36 0.74 90.38
*PB0.001 vs. EC, AD and VD groups.
3. Measurement of pupil diameter of both eyes 30 and 40 min after the administration of the drops. We estimated the repeatability of the test in relation to the possible influence of the light stimulus on subsequent measurements, making eight consecutive evaluations of pupil diameter, one every 10 s, in both eyes of eight young controls. A mean coefficient of variation of 2.54% was obtained, showing a high degree of repeatability of the test.
2.3. Statistical analysis The analysis of variance for repeated measures was utilized, testing the variability due to the factors: group, sex, anisocoria, time of measurement (30 vs. 40 min) and their interaction, using as a dependent variable the change of pupil diameter from baseline in the eye treated with tropicamide. In a second analysis, we considered the change in anisocoria (difference between the change of pupil diameter in the treated eye and that in the contralateral eye) as a dependent variable, using the factorial analysis of variance and multiple comparisons method according to Bonferroni. The one-way analysis of variance was adopted for comparing the baseline values of pupil diameter in the four groups.
3. Results The results are summarized in (Table 2) and presented as mean9 S.D. The baseline value of pupil diameter (estimated in the treated eye) was significantly greater in the YC group as compared to the three groups of AD subjects, VD subjects and EC. Although the mean dilation at 30 min. after drops instillation was greater in the AD group than in the VD group and in the EC group, and least in the YC group, these differences were statistically not significant (P= 0.124). Mean dilation in the treated eye was not significantly different between sexes (P=0.69). There was no significant difference between the change of pupil diameter from baseline in the treated eye at 30 and at 40 min after instillation of tropicamide (P=0.90). Mean change in pupil diameter was significantly different between the
L. Caputo et al. / Arch. Gerontol. Geriatr. 27 (1998) 171–177
175
two eyes (P B 0.01); this difference, due simply to the mydriatic effect of tropicamide, was not the same in the four groups (PB 0.05). On the basis of this latter result, we carried out a further analysis, using the non-treated eye as a control, that is, considering the change in anisocoria as a variable. This change was slightly greater within each of the four groups than the mere change in pupil diameter of the treated eye (Table 3): the pupil diameter of the control eye, in fact, showed a tendency to decrease with time. The change in anisocoria at 30 min was significantly different between the YC group and the AD group (P B0.05), but not among the AD group, the EC group and the VD group. Moreover, this significance was lost at 40 min after drops administration (P= 0.07).
4. Discussion It is known that the pupillary response to topical administration of cholinergic or anticholinergic agents can be influenced by several factors, like the extent of corneal penetration, aqueous fluid turnover and iris colour (Pomara and Sitaram, 1995). Marx et al. (1995) reported an extremely variable pupillary response to dilating agents also in young, healthy adults. Metabolic disorders affecting nerve conduction, above all diabetes mellitus, can alter pupillary motility (Smith and Dewhirst, 1986). The work by Loupe et al. (1996), in which the pupillary response after administration of dilute tropicamide was evaluated both in light and in darkness, introduces a further source of variability in the response, i.e. the level of environmental illumination. At present, the report of Scinto et al. (1994) of pupillary hypersensitivity to anticholinergic agents in AD patients has not been confirmed by other investigators. Loupe et al. (1996) and Litvan and FitzGibbon (1996) studied the pupillary responses to diluted tropicamide in patients with AD, older and young controls. In these studies, mean change in pupil diameter and area in the treated eye, as well as mean change in anisocoria, were not significantly different among the groups; only the mean percent change in pupil diameter of the treated eye showed a trend toward faster maximum dilation in the AD groups, but no cut-off value that effectively distinguished AD subjects from controls could be established.
Table 3 Change in anisocoria (difference between the change of pupil diameter in the treated eye and that in the contralateral eye) (mean 9 S.D.) from baseline at 30 and 40 min after instillation of 0.01% tropicamide
Change at 30 min (mm) Change at 40 min (mm) *PB0.05 vs. YC group.
EC (n= 16)
YC (n = 12)
AD (n =15)
VD (n =5)
0.67 90.55 0.779 0.60
0.21 90.46 0.38 90.28
0.90 9 0.83* 1.23 91.20
0.82 90.21 0.90 90.63
176
L. Caputo et al. / Arch. Gerontol. Geriatr. 27 (1998) 171–177
Our study, performed in a sample of subjects comparable with that of Scinto and colleagues, does not demonstrate a mydriatic response after instillation of 0.01% tropicamide significantly greater in AD patients in comparison with elderly patients without cognitive deficits. A significant difference was recorded exclusively between AD patients and young control subjects and only considering the change in anisocoria as a variable: this analysis, using the non-treated eye as a control, takes into account elements such as fatigue or anxiety that can possibly influence pupil diameter during the test. In particular, the mean decrease of pupil size in the control eye in all the four groups could be a consequence of the reduction in the level of anxiety during the test. The finding of a greater baseline value of the pupil diameter in our YC group confirms the well-known tendency of the pupil to become smaller with age (Pruett, 1994). Moreover, we found a trend toward a lesser pupillary dilation in the YC group, which reaches statistical significance only in comparison with the AD patients, and only when the change in pupil diameter of the contralateral eye is taken into account. This could be ascribed to age-related changes of the central and/or autonomic nervous system, since functional deficits of both parasympathetic and sympathetic inputs in the iris have been reported in older patients (Pfeifer, 1983). The small size of the VD group does not allow us to draw any definite conclusion in their regard. Nonetheless, the data agree with the findings of Treloar et al. (1995), whose study did not show any difference in the pupillary response to tropicamide between patients with AD and with multi-infarct dementia. On the contrary, Scinto et al. (1994) suggested that the pupil dilation assay may help to distinguish between AD and non-Alzheimer’s-type dementias. In conclusion, our findings do not support the potential usefulness of the pupillary response to dilute tropicamide for identifying individuals with AD, as previously proposed. The search for genetic or biochemical markers of the disease seems, at the moment, a more promising direction for the efforts of the researchers.
Acknowledgements We thank Aldo Poli, M.D. for advice on data analysis. Chiara Perrone is a recipient of an AGER (Association for Geriatric Research and the Study of Longevity, Milano) fellowship. The videopupillography system (C2514 IRISCORDER, Hamamatsu, Japan) was provided by Mediolanum Farmaceutici.
References Evans, D.A., Funkenstein, H.H., Albert, M.S., et al., 1989. Prevalence of Alzheimer’s disease in a community population of older persons; higher than previously reported. J. Am. Med. Assoc. 262, 2551–2556.
L. Caputo et al. / Arch. Gerontol. Geriatr. 27 (1998) 171–177
177
Folstein, M.F., Folstein, S.E., McHugh, D.R., 1975. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12, 189 – 198. Harris, W.S., Goodman, R.M., 1968. Hyper-reactivity to atropine in Down’s syndrome. New Engl. J. Med. 279, 407–410. Katz, S., Ford, A.B., Moskowits, R.W., Jacson, B.A., Jaffee, M.W., 1963. Studies of illness in the aged: the index of ADL: a standardized measure of biological and psychosocial function. J. Am. Med. Assoc. 185, 914–919. Lawton, M.P., Brody, E.M., 1969. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9, 179 – 186. Litvan, I., FitzGibbon, E.J., 1996. Can tropicamide eye drop response differentiate patients with progressive supranuclear palsy and Alzheimer’s disease from healthy control subjects? Neurology 47, 1324–1326. Loupe, D.N., Newman, N.J., Green, R.C., et al., 1996. Pupillary response to tropicamide in patients with Alzheimer’s disease. Ophthalmology 103, 495 – 503. Marx, J.L., Kumar, S.R., Thach, A.B., Kiat – Winarko, T., Frambach, D.A., 1995. Detecting Alzheimer’s disease (letter). Science 267, 1577 – 1581. McKahn, G., Drachman, D., Folstein, M., Katzman, R., Price, D., Stadlan, E.M., 1984. Clinical diagnosis of Alzheimer’s disease; Report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services task force on Alzheimer’s disease. Neurology 34, 939–944. Morris, J.C., 1993. The clinical dementia rating (CDR): current version and scoring rules. Neurology 43, 2412–2414. Perry, E.K., Perry, R.H., Blessed, G., Tomlinson, B.E., 1977. Necropsy evidence of central cholinergic deficits in senile dementia. Lancet 1 (8004), 189. Pfeifer, M.A., 1983. Differential changes of autonomic nervous system function with age in men. Am. J. Med. 75, 249. Pomara, N., Sitaram, N., 1995. Detecting Alzheimer’s disease (letter). Science 267, 1577 – 1581. Pruett, R.C., 1994. Aging changes. In: Albert, D.M., Jakobiec, F.A. (Eds.), Principles and Practice of Ophthalmology. Saunders, Philadelphia, PA. Roman, G.C., 1993. Vascular dementia: diagnostic criteria for research studies; report of the NINDSAIREN International Workshop. Neurology 43, 250 – 260. Sacks, B., Smith, S., 1989. People with Down’s syndrome can be distinguished on the basis of cholinergic dysfunction. J. Neurol. Neurosurg. Psychiatry 52, 1294 – 1295. Scinto, L.F.M., Daffner, K.R., Dressler, D., et al., 1994. A potential non invasive neurobiological test for Alzheimer’s disease. Science 266, 1051 – 1054. Sims, N.R., Bowen, D.M., Allen, S.J., et al., 1983. Presynaptic cholinergic dysfunction in patients with dementia. J. Neurochem. 40, 503–509. Smith, S.A., Dewhirst, R.R., 1986. A simple diagnostic test for pupillary abnormality in diabetic autonomic neuropathy. Diabet. Med. 3, 38 – 41. Spinnler, H., Tognoni, G., 1987. Standardizzazione e taratura italiana di test neuropsicologici. Ital. J. Neurol. Sci. (Suppl. 8), Ed. Masson, pp. 23 – 99. Treloar, A., Assin, M., Macdonald, A., 1995. Detecting Alzheimer’s disease (letter). Science 267, 1577–1581. Whitehouse, P.J., Price, D.L., Clark, A.W., Coyle, J.T., DeLong, M.R., 1981. Alzheimer’s disease: evidence for selective loss of cholinergic neurons in nucleus basalis. Ann. Neurol. 10, 122 – 126. Yesavage, J.A., Brink, T.L., Rose, T.L., et al., 1982. Development and validation of a geriatric depression screening scale: a preliminary report. J. Psychiatr. Res. 17, 37 – 49.
.
The ‘eye test’ in recognition of late-onset Alzheimer’s disease Ludovica Caputo a, Margherita Casartelli a, Chiara Perrone a, Marisa Santori b, Giorgio Annoni a,*, Carlo Vergani a a
Dipartimento di Medicina Interna, Cattedra di Gerontologia e Geriatria, Uni6ersita` di Milano, and Ospedale Maggiore, IRCCS-6ia Pace 9 -20122 Milano, Italy b Istituto di Clinica Oculistica, Uni6ersita` di Milano, and Ospedale Maggiore, IRCCS-Milano, Italy Received 26 January 1998; received in revised form 12 May 1998; accepted 13 May 1998
Abstract A rapid and specific diagnostic test for Alzheimer’s disease (AD), the prevalent cause of dementia in the elderly, is currently unavailable. The aim of this study was to verify the validity of the recently proposed ‘Eye Test’ in the identification of AD patients, based on their supposed greater mydriatic response to cholinergic antagonists. We tested the pupillary response to the instillation of 0.01% tropicamide in 48 subjects: 15 patients with probable or possible Alzheimer’s disease, five patients with vascular dementia (VD), 16 elderly controls (EC) and 12 young controls (YC). Mean pupil dilation in the treated eye at 30 and 40 min after drops instillation was not significantly different among the four groups. The mean change in anisocoria at 30 min was significantly greater in the AD group (0.90 mm, S.D. 0.83) than in the YC group (0.21 mm, S.D. 0.46), but no significant difference was found among the AD group, the EC group and the VD group. Our results, therefore, do not support the potential usefulness of the pupillary response to dilute tropicamide for identifying individuals with AD. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: ‘Eye test’; Alzheimer’s disease; Diagnosis; Elderly
* Corresponding author. [email protected]
Tel.:
+39
2
55035357;
fax:
+39
2
55017492;
e-mail:
0167-4943/98/$ - see front matter © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0167-4943(98)00112-5
gior-
172
L. Caputo et al. / Arch. Gerontol. Geriatr. 27 (1998) 171–177
1. Introduction Alzheimer’s disease (AD), the prevalent cause of dementia in the elderly, afflicts about 5% of people over 65 years, 19% of individuals aged 75–85 and 45% of those above 85 (Evans et al., 1989). The disease, clinically characterized by a progressive decline of memory and other cognitive functions, is associated with a reduced activity of several neurotransmitters, namely acetylcholine (Perry et al., 1977; Whitehouse et al., 1981; Sims et al., 1983). Main histologic hallmarks of AD are the accumulation of neurofibrillary tangles and senile plaques, particularly in the neocortex and hippocampus; the identification of these markers at post-mortem examination is essential for the definite diagnosis. According to the criteria proposed by the NINCDS-ADRDA Work Group, a diagnosis of ‘probable’ or ‘possible’ AD can be reached with an accurate clinical and instrumental evaluation (McKahn et al., 1984). Therefore, a rapid and specific diagnostic test for AD, especially in the early phases of the disease, although expected, is currently not available. With this aim in view, Scinto et al. (1994) proposed that the pupillary response to a cholinergic antagonist, tropicamide, may be such a test. Basis for their work was the evidence of certain similarities between subjects with AD and those with Down’s syndrome (DS): the latter, in fact, develop, after the age of 30 years, the characteristic brain lesions of AD, and, in some cases, the clinical features of dementia. People with DS also show supersensitivity to anticholinergic agents, both at cardiac (Harris and Goodman, 1968) and ocular level: indeed, the mydriatic response following instillation of tropicamide 0.01% has been shown to be about 3-fold that of healthy subjects, independently of age (Sacks and Smith, 1989). In detail, Scinto et al. (1994) reported in 19 patients with clinically diagnosed or suspected AD a greater mydriatic response to a very dilute solution of tropicamide (0.01%) as compared to 32 normal elderly controls, with a concordance of 95% between the pupillary response and the clinical diagnosis. However, in more recent articles, Litvan and Fitzgibbon (1996) and Loupe et al. (1996) deny the validity of the test, since the pupillary response to dilute tropicamide, in their studies, did not significantly differ among AD patients, young and elderly controls. Given these few and contradictory reports in literature, purpose of this study was to verify the validity of the ‘eye test’ for identifying patients with AD.
2. Subjects and methods
2.1. Subjects From May through November 1995, 36 aged outpatients were consecutively enrolled by the geriatric ward of the Ospedale Maggiore IRCCS of Milano (Italy). Twenty mild demented subjects were assigned to two groups, the first of which included 15 patients with probable or possible AD, according to NINCDS-
L. Caputo et al. / Arch. Gerontol. Geriatr. 27 (1998) 171–177
173
ADRDA criteria (McKahn et al., 1984) and the second five patients with vascular dementia (VD), according to NINDS-AIREN criteria (Roman, 1993). Sixteen elderly subjects (EC) without cognitive deficits, affected by different internal diseases, were enrolled as controls. A fourth group (young control group, YC) included 12 young healthy subjects. The main characteristics of the study population are shown in (Table 1). The demented patients and the elderly controls were assessed by means of a complete geriatric examination, including ADL (Katz et al., 1963), IADL (Lawton and Brody, 1969), MMSE (Folstein et al., 1975), CDR (Morris, 1993) and the GDS (Yesavage et al., 1982), routine laboratory tests (including TSH, FT4, B12 vitamin, folates), chest X-ray and ECG. Brain imaging (CT or NMR) was performed in all the demented patients, together with a conventional neuropsychological evaluation, including tasks of attention, memory, language, visual-perception and intelligence (Spinnler and Tognoni, 1987). All subjects underwent a complete ophthalmologic evaluation before the beginning of the study. Exclusion criteria comprehended: eye diseases, history of eye surgery, use of medications that could influence pupillary motility, diabetes mellitus.
2.2. Procedure Pupillary measurements were obtained with a computerized videopupillography system (C2514 IRISCORDER, Hamamatsu, Japan), supplied with an infrared light source, a video camera, which transfers the image to a screen, and a printer. For each measurement, the device gives the value of the initial pupil diameter and of its variation in response to a light stimulus. The test was performed according to the following procedure, which is very close to the one proposed by Scinto et al. (1994): 1. Baseline measurement of pupil diameter in both eyes, with the patients seated in a comfortable semi-darkened room, listening to a tape of classical music; to reduce anxiety, the baseline measurement was obtained only after the subjects had been in the room for 15 min; 2. Instillation of one drop of 0.01% tropicamide in the inferior fornix of one eye (randomly chosen) and of one drop of distilled water in the other eye; Table 1 Clinical features of the study population (mean 9S.D.)
Age (years) Sex (M/F) MMSE CDR Duration of disease (years)
EC (n = 16)
YC (n = 12)
AD (n = 15)
VD (n =5)
72.99 4.7 4/12 28.1 91.7
27.3 93.1 5/7
7497.5 7/8 19.2 95.0 1.28 90.47 2.3 91.4
73.2 9 6.1 5/0 20.4 9 2.9 1.25 9 0.5 3.0 9 1.6
Abbreviations are explained in the text.
174
L. Caputo et al. / Arch. Gerontol. Geriatr. 27 (1998) 171–177
Table 2 Baseline pupil diameter and change in pupil diameter (mean 9 S.D.) of the treated eye from baseline at 30 and 40 min after instillation of 0.01% tropicamide
Baseline pupil diameter (mm) Dilation at 30 min (mm) Dilation at 40 min (mm)
EC (n =16)
YC (n = 12)
AD (n = 15)
VD (n = 5)
4.389 0.56 0.529 0.48 0.579 0.59
5.81 90.61* 0.12 90.38 0.13 90.45
4.30 9 0.57 0.76 9 0.51 0.82 9 0.59
3.94 90.99 0.64 90.36 0.74 90.38
*PB0.001 vs. EC, AD and VD groups.
3. Measurement of pupil diameter of both eyes 30 and 40 min after the administration of the drops. We estimated the repeatability of the test in relation to the possible influence of the light stimulus on subsequent measurements, making eight consecutive evaluations of pupil diameter, one every 10 s, in both eyes of eight young controls. A mean coefficient of variation of 2.54% was obtained, showing a high degree of repeatability of the test.
2.3. Statistical analysis The analysis of variance for repeated measures was utilized, testing the variability due to the factors: group, sex, anisocoria, time of measurement (30 vs. 40 min) and their interaction, using as a dependent variable the change of pupil diameter from baseline in the eye treated with tropicamide. In a second analysis, we considered the change in anisocoria (difference between the change of pupil diameter in the treated eye and that in the contralateral eye) as a dependent variable, using the factorial analysis of variance and multiple comparisons method according to Bonferroni. The one-way analysis of variance was adopted for comparing the baseline values of pupil diameter in the four groups.
3. Results The results are summarized in (Table 2) and presented as mean9 S.D. The baseline value of pupil diameter (estimated in the treated eye) was significantly greater in the YC group as compared to the three groups of AD subjects, VD subjects and EC. Although the mean dilation at 30 min. after drops instillation was greater in the AD group than in the VD group and in the EC group, and least in the YC group, these differences were statistically not significant (P= 0.124). Mean dilation in the treated eye was not significantly different between sexes (P=0.69). There was no significant difference between the change of pupil diameter from baseline in the treated eye at 30 and at 40 min after instillation of tropicamide (P=0.90). Mean change in pupil diameter was significantly different between the
L. Caputo et al. / Arch. Gerontol. Geriatr. 27 (1998) 171–177
175
two eyes (P B 0.01); this difference, due simply to the mydriatic effect of tropicamide, was not the same in the four groups (PB 0.05). On the basis of this latter result, we carried out a further analysis, using the non-treated eye as a control, that is, considering the change in anisocoria as a variable. This change was slightly greater within each of the four groups than the mere change in pupil diameter of the treated eye (Table 3): the pupil diameter of the control eye, in fact, showed a tendency to decrease with time. The change in anisocoria at 30 min was significantly different between the YC group and the AD group (P B0.05), but not among the AD group, the EC group and the VD group. Moreover, this significance was lost at 40 min after drops administration (P= 0.07).
4. Discussion It is known that the pupillary response to topical administration of cholinergic or anticholinergic agents can be influenced by several factors, like the extent of corneal penetration, aqueous fluid turnover and iris colour (Pomara and Sitaram, 1995). Marx et al. (1995) reported an extremely variable pupillary response to dilating agents also in young, healthy adults. Metabolic disorders affecting nerve conduction, above all diabetes mellitus, can alter pupillary motility (Smith and Dewhirst, 1986). The work by Loupe et al. (1996), in which the pupillary response after administration of dilute tropicamide was evaluated both in light and in darkness, introduces a further source of variability in the response, i.e. the level of environmental illumination. At present, the report of Scinto et al. (1994) of pupillary hypersensitivity to anticholinergic agents in AD patients has not been confirmed by other investigators. Loupe et al. (1996) and Litvan and FitzGibbon (1996) studied the pupillary responses to diluted tropicamide in patients with AD, older and young controls. In these studies, mean change in pupil diameter and area in the treated eye, as well as mean change in anisocoria, were not significantly different among the groups; only the mean percent change in pupil diameter of the treated eye showed a trend toward faster maximum dilation in the AD groups, but no cut-off value that effectively distinguished AD subjects from controls could be established.
Table 3 Change in anisocoria (difference between the change of pupil diameter in the treated eye and that in the contralateral eye) (mean 9 S.D.) from baseline at 30 and 40 min after instillation of 0.01% tropicamide
Change at 30 min (mm) Change at 40 min (mm) *PB0.05 vs. YC group.
EC (n= 16)
YC (n = 12)
AD (n =15)
VD (n =5)
0.67 90.55 0.779 0.60
0.21 90.46 0.38 90.28
0.90 9 0.83* 1.23 91.20
0.82 90.21 0.90 90.63
176
L. Caputo et al. / Arch. Gerontol. Geriatr. 27 (1998) 171–177
Our study, performed in a sample of subjects comparable with that of Scinto and colleagues, does not demonstrate a mydriatic response after instillation of 0.01% tropicamide significantly greater in AD patients in comparison with elderly patients without cognitive deficits. A significant difference was recorded exclusively between AD patients and young control subjects and only considering the change in anisocoria as a variable: this analysis, using the non-treated eye as a control, takes into account elements such as fatigue or anxiety that can possibly influence pupil diameter during the test. In particular, the mean decrease of pupil size in the control eye in all the four groups could be a consequence of the reduction in the level of anxiety during the test. The finding of a greater baseline value of the pupil diameter in our YC group confirms the well-known tendency of the pupil to become smaller with age (Pruett, 1994). Moreover, we found a trend toward a lesser pupillary dilation in the YC group, which reaches statistical significance only in comparison with the AD patients, and only when the change in pupil diameter of the contralateral eye is taken into account. This could be ascribed to age-related changes of the central and/or autonomic nervous system, since functional deficits of both parasympathetic and sympathetic inputs in the iris have been reported in older patients (Pfeifer, 1983). The small size of the VD group does not allow us to draw any definite conclusion in their regard. Nonetheless, the data agree with the findings of Treloar et al. (1995), whose study did not show any difference in the pupillary response to tropicamide between patients with AD and with multi-infarct dementia. On the contrary, Scinto et al. (1994) suggested that the pupil dilation assay may help to distinguish between AD and non-Alzheimer’s-type dementias. In conclusion, our findings do not support the potential usefulness of the pupillary response to dilute tropicamide for identifying individuals with AD, as previously proposed. The search for genetic or biochemical markers of the disease seems, at the moment, a more promising direction for the efforts of the researchers.
Acknowledgements We thank Aldo Poli, M.D. for advice on data analysis. Chiara Perrone is a recipient of an AGER (Association for Geriatric Research and the Study of Longevity, Milano) fellowship. The videopupillography system (C2514 IRISCORDER, Hamamatsu, Japan) was provided by Mediolanum Farmaceutici.
References Evans, D.A., Funkenstein, H.H., Albert, M.S., et al., 1989. Prevalence of Alzheimer’s disease in a community population of older persons; higher than previously reported. J. Am. Med. Assoc. 262, 2551–2556.
L. Caputo et al. / Arch. Gerontol. Geriatr. 27 (1998) 171–177
177
Folstein, M.F., Folstein, S.E., McHugh, D.R., 1975. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12, 189 – 198. Harris, W.S., Goodman, R.M., 1968. Hyper-reactivity to atropine in Down’s syndrome. New Engl. J. Med. 279, 407–410. Katz, S., Ford, A.B., Moskowits, R.W., Jacson, B.A., Jaffee, M.W., 1963. Studies of illness in the aged: the index of ADL: a standardized measure of biological and psychosocial function. J. Am. Med. Assoc. 185, 914–919. Lawton, M.P., Brody, E.M., 1969. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9, 179 – 186. Litvan, I., FitzGibbon, E.J., 1996. Can tropicamide eye drop response differentiate patients with progressive supranuclear palsy and Alzheimer’s disease from healthy control subjects? Neurology 47, 1324–1326. Loupe, D.N., Newman, N.J., Green, R.C., et al., 1996. Pupillary response to tropicamide in patients with Alzheimer’s disease. Ophthalmology 103, 495 – 503. Marx, J.L., Kumar, S.R., Thach, A.B., Kiat – Winarko, T., Frambach, D.A., 1995. Detecting Alzheimer’s disease (letter). Science 267, 1577 – 1581. McKahn, G., Drachman, D., Folstein, M., Katzman, R., Price, D., Stadlan, E.M., 1984. Clinical diagnosis of Alzheimer’s disease; Report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services task force on Alzheimer’s disease. Neurology 34, 939–944. Morris, J.C., 1993. The clinical dementia rating (CDR): current version and scoring rules. Neurology 43, 2412–2414. Perry, E.K., Perry, R.H., Blessed, G., Tomlinson, B.E., 1977. Necropsy evidence of central cholinergic deficits in senile dementia. Lancet 1 (8004), 189. Pfeifer, M.A., 1983. Differential changes of autonomic nervous system function with age in men. Am. J. Med. 75, 249. Pomara, N., Sitaram, N., 1995. Detecting Alzheimer’s disease (letter). Science 267, 1577 – 1581. Pruett, R.C., 1994. Aging changes. In: Albert, D.M., Jakobiec, F.A. (Eds.), Principles and Practice of Ophthalmology. Saunders, Philadelphia, PA. Roman, G.C., 1993. Vascular dementia: diagnostic criteria for research studies; report of the NINDSAIREN International Workshop. Neurology 43, 250 – 260. Sacks, B., Smith, S., 1989. People with Down’s syndrome can be distinguished on the basis of cholinergic dysfunction. J. Neurol. Neurosurg. Psychiatry 52, 1294 – 1295. Scinto, L.F.M., Daffner, K.R., Dressler, D., et al., 1994. A potential non invasive neurobiological test for Alzheimer’s disease. Science 266, 1051 – 1054. Sims, N.R., Bowen, D.M., Allen, S.J., et al., 1983. Presynaptic cholinergic dysfunction in patients with dementia. J. Neurochem. 40, 503–509. Smith, S.A., Dewhirst, R.R., 1986. A simple diagnostic test for pupillary abnormality in diabetic autonomic neuropathy. Diabet. Med. 3, 38 – 41. Spinnler, H., Tognoni, G., 1987. Standardizzazione e taratura italiana di test neuropsicologici. Ital. J. Neurol. Sci. (Suppl. 8), Ed. Masson, pp. 23 – 99. Treloar, A., Assin, M., Macdonald, A., 1995. Detecting Alzheimer’s disease (letter). Science 267, 1577–1581. Whitehouse, P.J., Price, D.L., Clark, A.W., Coyle, J.T., DeLong, M.R., 1981. Alzheimer’s disease: evidence for selective loss of cholinergic neurons in nucleus basalis. Ann. Neurol. 10, 122 – 126. Yesavage, J.A., Brink, T.L., Rose, T.L., et al., 1982. Development and validation of a geriatric depression screening scale: a preliminary report. J. Psychiatr. Res. 17, 37 – 49.
.