Reverse Fox Test for Detecting Visuospatial Dysfunction Corresponding to Parietal Hypoperfusion in Mild Alzheimer’s Disease

Abstract

Background/Aim:

We developed a novel visuospatial clinical task to detect parietal dysfunction in mild Alzheimer’s disease (AD).

Methods:

A total of 65 outpatients, including 47 with mild AD and 18 cognitively and neuroradiologically normal individuals with subjective memory impairment (NL), performed the “Reverse Fox” test and underwent brain single photon emission tomography. Patients with AD were divided into subgroups according to the results of the Reverse Fox test (successful vs unsuccessful).

Results:

Success in the Reverse Fox test was achieved by 31.9% of patients with AD and 94.4% of NL. The unsuccessful AD subgroup had reduced perfusion of the medial parietal and bilateral temporoparietal regions compared with the successful AD subgroup.

Conclusions:

Failure in the Reverse Fox test was related to parietal hypoperfusion in patients with mild AD. Our findings suggest that the Reverse Fox test may be one of the useful supporting tools for detecting mild AD at outpatient clinic.

Keywords

Alzheimer’s disease single photon emission computed tomography gesture imitation screening test visuospatial abilities

Introduction

Although memory impairment is known to be the most prominent feature of Alzheimer’s disease (AD), visuospatial deficits have also been well documented in the literature on AD and could be one of the key symptoms of mild AD.^1
–3 Patients with AD often get lost, have difficulty in understanding where they are, and have difficulty in finding objects for which they are searching.

Among various neuropsychological tests for the assessment of visuospatial function, visuoconstructional tasks based on finger (hand) positions have been employed clinically to detect cognitive decline in patients with AD. Because of visuospatial and visuomotor dysfunction, individuals with AD have difficulty in correctly positioning their hands to perform such tasks. The method of imitating the examiner’s hand positions may provide a simple and effective tool for detecting AD and has already been adopted as an easy screening test for visuospatial dysfunction.⁴ Some authors have suggested that the ability to imitate hand positions is related to the severity of AD.^5,6

The parietal lobe is thought to play a crucial role in visuospatial function, including the assessment of hand positions. Since bilateral parietal hypoperfusion on single photon emission computed tomography (SPECT) is a characteristic feature in patients with AD,^7
–9 we hypothesized that impaired imitation of hand positions would be associated with parietal hypoperfusion in early stage AD.

In the present study, we devised the new method of hand imitation test and validated the clinical usefulness of the new method, which is called the “Reverse Fox test,” as a simple tool for detecting parietal hypoperfusion in patients with mild AD. The objectives of this study were to obtain data on the performance of patients with AD in the Reverse Fox test and to investigate the relationship between performance in this test and other neuropsychological tests as well as with regional cerebral blood flow (rCBF) measured by SPECT.

Methods

Patients

We examined 225 consecutive outpatients aged 65 to 89 years who visited the memory clinic of Keio University Hospital, between June 2009 and March 2012. Persons with mild AD and cognitively and neuroradiologically normal individuals with subjective memory impairment (NL) were included, while those with moderate or severe AD, those with other types of dementia (e.g., vascular dementia, dementia with Lewy bodies, or frontotemporal lobar degeneration), those with mild cognitive impairment, those with other types of brain damage, and those with psychiatric disorders (including delusional disorder, mood disorder, convulsive disorder, and substance abuse) were excluded from the study. As a result, 47 patients with mild AD (30 women) and 18 NL (14 women) were enrolled in the study (total N = 65). The mean age (± standard deviation) was 77.9 ± 5.2 and 75.1 ± 5.2 years in the AD and NL groups, respectively.

Patients were diagnosed as having probable AD based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria.¹⁰ The severity of dementia was classified according to the Clinical Dementia Rating (CDR) scale,¹¹ and only patients with AD with a score of 0.5 or 1 were included. The NL patients presented to our memory clinic with the complaint of memory impairment, but they all maintained their activities of daily living (ADLs) and had well-preserved cognitive function based on the results of detailed neuropsychological testing. Their CDR score was 0. Although the NL group had no significant magnetic resonance image (MRI) or SPECT findings, we cannot state that they are “normal” in the strict sense because they complained of subjective cognitive impairment.¹² Thus, the individuals in this group could have had preclinical AD.¹³ However, we regard them as normal for the purpose of the present study based on the preservation of ADL and cognitive function. In the AD group, 10 (23%) of 47 patients were taking donepezil and 2 patients (4%) were taking memantine. This study was approved by the ethics committee of Keio University School of Medicine.

Reverse Fox Test

All participants were asked to imitate the shape called a Reverse Fox by using both hands. The test was done as follows.

First, the examiner instructed a participant to carefully watch the examiner’s hands and then make the same shape. Subsequently, the examiner placed both hands as shown in Figure 1A. Instructions were given in a nonverbal manner without referring to a “fox.” If a participant failed to copy the hand positions at this step, the test was stopped.

Figure 1.

Demonstration of the hand positions. The examiner demonstrates (A) 2 foxes position and (B) the “Reverse Fox” position.

Next, the examiner twisted 1 hand so that the right index finger was touching the left little finger and the right little finger was touching the left index finger (Figure 1B). The examiner was careful not to give verbal instructions (such as “please make a reversed fox”) that could assist the participant to compensate for visuospatial deficits.

The AD group was divided into subgroups based on their performance in the Reverse Fox test (“successful” subgroup who completed imitating the Reverse Fox hands gesture vs “unsuccessful” subgroup who failed). Then analyses were conducted using demographic data, neuropsychological test performance, and neuroimaging data comparing the successful with the unsuccessful subgroup.

Clinical Evaluation

To evaluate cognitive function, detailed neuropsychological testing was performed in all patients by experienced clinical neuropsychologists [M.K. (Mika Konishi) and N.S. (Nao Sait)]. Global cognitive function was measured with the Mini-Mental State Examination and Raven’s colored progressive matrices. The Rey auditory verbal learning test and the logical memory subtest of the Wechsler memory scale–revised were used to assess verbal memory, while the Rey-Osterrieth complex figure test (ROCFT) was used for assessment of visual memory.¹⁴ Executive function was evaluated by using the modified Stroop test, the trail-making test, and the verbal fluency test.¹⁴ A shorter version of the geriatric depression scale was used to evaluate the subjective mood of each participant.¹⁵

Statistical analyses were performed using SPSS for Macintosh (version 18.0; SPSS Inc. Chicago, Illinois). Student t tests were used to compare demographic data and indices of neuropsychological performance between the AD and NL group and the successful and unsuccessful AD subgroup. All statistical tests were 2 tailed, and P < .05 was considered to indicate statistical significance.

Magnetic Resonance Imaging and SPECT

All participants underwent brain MRI and N-isopropyl-p-(123I) iodoamphetamine (IMP) SPECT. The MRI studies were performed using a 1.5T GE scanner (General Electric 1.5-Tesla scanner). Axial and sagittal T1-weighted, axial T2-weighted, and axial fluid-attenuated inversion recovery images were acquired for all participants. To assess the extent of hippocampal atrophy, we used voxel-based specific regional analysis system for AD software (VSRAD).¹⁶ This software automatically evaluates the severity of gray matter loss in the entorhinal cortex by comparing a patient’s gray matter volume with the original normal database template, and the extent of atrophy is expressed as a Z score relative to the normal range.

All the SPECT studies were performed using triple-head rotating gamma camera (Toshiba GXA-9300A/DI; Toshiba Corporation, Tokyo, Japan) mounted with ultra high-resolution fan-beam collimators. The imaging was started 30 minutes after intravenous injection of 222 MBq of N-isopropyl-p-(123I) iodoamphetamine (IMP). Comparison of brain perfusion on SPECT was performed using the 3-dimensional stereotactic surface projection (3D-SSP) technique.¹⁷ Three-dimensional stereotactic surface projection images were created with the NEUROSTAT image analysis program, which is suitable for an anatomical standardization of atrophic brains.¹⁸

Results

Table 1 shows the demographic data and the results of neuropsychological testing for the AD and NL groups. Alzheimer’s disease performed significantly worse on almost all the neuropsychological tests than NL. Regarding the relation between the outcome of the Reverse Fox test and the results of neuropsychological testing, no significant differences were observed between the successful and unsuccessful AD subgroups. The mean Z score of VSRAD was significantly higher in the AD group than in the NL group, while no significant difference was observed between the successful and unsuccessful AD subgroups.

Table 1.

Demographic Data of the Participants and Neuropsychological Test Results.^a

	NL Group	AD Group	P Value	Successful AD Subgroup	Unsuccessful AD Subgroup	P Value
Number	18	47		15	32
Age (65-89)	75.1 ± 5.2	77.9 ± 5.2	.054	78.7 ± 5.1	77.6 ± 5.2	.474
Education	13.4 ± 2.5	13.5 ± 2.8	.975	13.2 ± 2.6	13.6 ± 2.9	.654
GDS (0-15)	5.7 ± 4.2	4.8 ± 3.6	.390	5.1 ± 4.4	4.6 ± 3.3	.693
MMSE (0-30)	28.6 ± 1.1	22.0 ± 3.5	<.001	22.7 ± 3.2	21.7 ± 3.7	.335
RCPM (0-36)	31.6 ± 3.5	25.5 ± 5.0	<.001	27.1 ± 4.4	24.7 ± 5.2	.121
RAVLT (0-15)	11.1 ± 2.4	2.7 ± 2.6	<.001	3.3 ± 3.0	2.4 ± 2.4	.306
ROCFT copy (0-36)	35.0 ± 0.9	33.2 ± 4.1	.124	33.8 ± 1.7	32.9 ± 4.9	.509
ROCFT recall (0-36)	17.8 ± 5.3	5.5 ± 4.7	<.001	6.1 ± 4.8	5.2 ± 4.8	.579
LM II (0-25)	9.6 ± 2.4	1.6 ± 1.6	<.001	1.8 ± 1.3	1.5 ± 1.8	.644
TMT-B	173 ± 54	336 ± 137	<.001	357 ± 145	326 ± 135	.496
mST	27.9 ± 10.2	52.8 ± 32.4	.009	40.5 ± 14.1	58.9 ± 37.1	.082
VFT initial	25.0 ± 5.9	17.2 ± 7.6	.001	19.1 ± 6.8	16.3 ± 8.0	.265
VFT category	42.6 ± 7.2	24.1 ± 7.2	<.001	26.5 ± 3.8	23.0 ± 8.1	.129
Z score of VSRAD	0.89 ± 0.52	1.72 ± 1.11	.001	1.64 ± 1.39	1.75 ± 0.99	.766

Abbreviations: AD, Alzheimer’s disease; NL, cognitively and neuroradiologically normal individuals with subjective memory impairment; GDS, shorter version of geriatric depression scale; MMSE, Mini-Mental State Examination; RCPM, Raven’s colored progressive matrices; RAVLT, Rey auditory verbal learning test; ROCFT, Rey-Osterrieth complex figure test; LM II, delayed recall in logical memory subtest of the Wechsler memory scale-revised; TMT-B, trail making test B; mST, modified Stroop test; VFT, verbal fluency test; VSRAD, voxel-based specific regional analysis system for Alzheimer's disease; SD, standard deviation.

^a Values are mean ± SD.

The success rate in the Reverse Fox test was 31.9% (15 of 47) for the AD group and 94.4% (17 of 18) for the NL group. The positive predictive value of the test for AD was 97.0%, while the negative predictive values were 53.1% (Table 2). The most frequent error pattern was touching both index fingers together and both little fingers together without twisting either hand. In the AD group, 3 (30%) of 10 patients taking donepezil and 12 (32.4%) of 37 patients not taking donepezil succeeded in the Reverse Fox test. Pearson’s chi-square test indicated that donepezil did not affect the performance on the Reverse Fox test (chi-square = .021, P = .884). In all, 2 patients were given memantine in the AD group, only 1 patient succeeded the test and another did not, suggesting no effect of memantine on the results of this test.

Table 2.

Results of the “Reverse Fox” Test in the AD Group.

	Sensitivity (Success Rate)	Specificity	Positive Predictive Value	Negative Predictive Value
AD	68.1% (31.9%)	94.4%	97.0%	53.1%

Abbreviations: AD, Alzheimer’s disease; Specificity, success rate in the NL group.

As compared with the NL group, the AD group demonstrated decreased perfusion over a wide range of brain regions, including the temporoparietal region, parahippocampal gyrus, precuneus, and posterior cingulate cortex (PCC; Figure 2A). Moreover, 3D-SSP SPECT analyses demonstrated that the unsuccessful AD subgroup had lower perfusion of the medial parietal region (including the precuneus and PCC) than the successful AD subgroup. The unsuccessful AD subgroup also had lower perfusion of the bilateral temporoparietal regions especially on the left side (Figure 2B).

Figure 2.

Images reconstructed by the 3D-SSP technique. After global normalization to the mean blood flow of the entire brain, rCBF was compared using the Z test. Color coding indicates the statistical significance (Z score) of the decrease in rCBF with red representing a more significant rCBF reduction. Anatomic reference maps for the right lateral, left lateral, superior, Foxinferior, anterior, posterior, right medial, and left medial views (from left to right). A, Reduction in rCBF in the AD group compared with the NL group. B, Reduction in rCBF in the unsuccessful AD subgroup compared with the successful AD subgroup. AD indicates Alzheimer’s disease; 3D-SSP, 3-dimensional stereotactic surface projection; rCBF, regional cerebral blood flow.

Discussion

The present study investigated the usefulness of the Reverse Fox test for detecting parietal hypofunction in early stage AD at the outpatient clinic. Although the sensitivity (error rate) of 68.1% for mild AD was not sufficient, the high specificity (94.4%) combined with high-positive predictive values (97.0%) indicated that this test might be a clinically useful supporting tool for detecting mild AD. Persons who fail in this test are very unlikely to be “normal.”

The unsuccessful AD subgroup showed lower perfusion of the bilateral temporoparietal regions and medial parietal region (including the precuneus and PCC) compared with the successful AD subgroup. These findings are compatible with the well-known concept that the temporoparietal region has a crucial role in visuoconstructive ability.^19,20 Some researchers have proposed that visuospatial deficits can precede typical memory impairment in the very prodromal phase of AD,^21,22 and recent studies have suggested that deficits of visuospatial function might be an early predictor of AD.^23,24 Accordingly, impaired performance in the Reverse Fox test might be a very early predictor of pathological cognitive decline in patients with AD.

In addition, a longitudinal SPECT study has shown that reduction of rCBF in the temporoparietal region and PCC is significantly associated with subsequent rapid cognitive deterioration.²⁵ Thus, the Reverse Fox test may be available for predicting a potential risk of progression in patients with AD, which is an intriguing topic for future study.

The Reverse Fox test is very simple and rapid to perform, allowing it to be done in the daily memory clinic. Moreover, this test does not tax the memory of the patient, which is advantageous in the clinical setting since persons with mild AD are often unwilling to receive memory tests. When diagnosing early dementia at the outpatient clinic, it is desirable to evaluate cognitive function with simple and rapid tasks that assess particular cognitive domains.²⁶ The deficits of gesture imitation in AD have often been documented in relation to apraxia.^27,28 Our Reverse Fox test is a test for imitation of meaningless gesture, which is considered a form of praxis and also evaluates visuospatial and visuomotor ability based on the copying of hand positions.

In the present study, there were no significant differences in the performances in neuropsychological testing between the successful and unsuccessful AD subgroups. Visuospatial manipulation often be examined using the task of coping figures,^29,30 whereas no significant differences were observed in scores of copying ROCFT between the successful and unsuccessful AD subgroups. The fact that the mean score of AD of copying ROCFT was as high as the mean score of NL (33.2 ± 4.1 in AD and 35.0 ± 0.9 in NL, P = .124) and clustered toward the top of score of copying ROCFT (ceiling effect) might be accountable for the present result.

The present study had a number of limitations. First, the total number of participants included in the study was relatively small. Moreover, the NL group was actually composed of “CDR 0” individuals, that is, “cognitively” preserved and “neuroradiologically” normal persons. We thought that it was useful to compare performance in the Reverse Fox test between mild AD and the NL groups in the present study, but it would be better to investigate a larger number of “healthy” individuals. Second, the Reverse Fox test should also be performed in patients with other types of dementia (eg, dementia with Lewy bodies, vascular dementia, and/or frontotemporal lobar degeneration). Third, the present study only examined the participants at 1 time point. Accordingly, we need the longitudinal data to determine whether the Reverse Fox test is useful for predicting cognitive decline.

In conclusion, our present findings suggest that the Reverse Fox test is a clinically useful and simple tool for the rapid detection of parietal hypofunction in patients with mild AD. Individuals with early AD who failed this simple test had lower rCBF in the bilateral temporoparietal and medial parietal regions (including the precuneus and PCC) than those who passed it. Furthermore, our findings suggest that the Reverse Fox test may be one of the useful supporting tools for detecting mild AD at outpatient clinic.

Footnotes

Acknowledgments

We thank all participants in the study for their contribution and are grateful for the help and support of Keio University Hospital.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Almkvist

. Neuropsychological features of early Alzheimer's disease: preclinical and clinical stages. Acta Neurol Scand Suppl. 1996;165:63–71.

Hodges

. Alzheimer’s centennial legacy: origins, landmarks and the current status of knowledge concerning cognitive aspects. Brain. 2006;129(11):2811–2822.

Tippett

Sergio

. Visuomotor integration is impaired in early stage Alzheimer’s disease. Brain Res. 2006;1102(1):92–102.

Rousseaux

Rénier

Anicet

Pasquier

Mackowiak-Cordoliani

. Gesture comprehension, knowledge and production in Alzheimer's disease. Eur J Neurol. 2012;19(7):1037–1044.

Yamaguchi

Maki

Yamagami

. Yamaguchi fox-pigeon imitation test: a rapid test for dementia. Dement Geriatr Cogn Disord. 2010;29(3):254–258.

Bakchine

Lacomblez

Palisson

Laurent

Derouesne

. Relationship between primitive reflexes, extra-pyramidal signs, reflective apraxia and severity of cognitive impairment in dementia of the Alzheimer type. Acta Neurol Scand. 1989;79(1):38–46.

Austin

Nair

Meier

. Effects of hypoperfusion in Alzheimer's disease. J Alzheimers Dis. 2011;26(S3):123–133.

Alegret

Vinyes-Junqué

Boada

. Brain perfusion correlates of visuoperceptual deficits in mild cognitive impairment and mild Alzheimer's disease. J Alzheimers Dis. 2010;21(2):557–567.

Matsuda

. Role of neuroimaging in Alzheimer’s disease, with emphasis on brain perfusion SPECT. J Nucl Med. 2007;48(8):1289–1300.

10.

McKhann

Drachman

Folstein

Katzman

Price

Stadlan

. 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. 1984;34(7):939–944.

11.

Morris

. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43(11):2412–2414.

12.

Reisberg

Gauthier

. Current evidence for subjective cognitive impairment (SCI) as the pre-mild cognitive impairment (MCI) stage of subsequently manifest Alzheimer’s disease. Int Psychogeriatrics. 2008;20(1):1–16.

13.

Sperling

Aisen

Beckett

. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on aging-Alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):280–292.

14.

Lezak

. Nuropsychological assessment. 3rd ed. New York: Oxford UP; 1996.

15.

Sheik

Yesavage

. Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. Clin Gerontol. 1986;5(1-2):165–172.

16.

Hirata

Matsuda

Nemoto

. Voxel-based morphometry to discriminate early Alzheimer’s disease from controls. Neurosci Lett. 2005;382(3):269–274.

17.

Minoshima

Berger

Lee

Mintun

. An automated method for rotational correction and centering of three-dimensional functional brain images. J Nucl Med. 1992;33(8):1579–1585.

18.

Ishii

Willoch

Minoshima

. Statistical brain mapping of 18F-FDG PET in Alzheimer's disease: Validation of anatomic standardization for atrophied brains. J Nucl Med. 2001;42(4):548–557.

19.

Kravitz

Saleem

Baker

Mishkin

. A new neural framework for visuospatial processing. Nat Rev Neurosci. 2011;12(4):217–230.

20.

Melrose

Ettenhofer

Harwood

. Cerebral metabolism, cognition, and functional abilities in Alzheimer’s disease. J Geriatr Psychiatry Neurol. 2011;24(3):127–134.

21.

Alescio-Lautier

Michel

Herrera

. Visual and visuospatial short-term memory in mild cognitive impairment and Alzheimer disease: role of attention. Neuropsychologia. 2007;45(8):1948–1960.

22.

Hort

Laczò

Vyhnàlek

Bojar

Bure

Vlek

. Spatial navigation deficit in amnestic mild cognitive impairment. Proc Natl Acad Sci U S A. 2007;104(10):4042–4047.

23.

Chapman

Mapstone

McCrary

, et al. Predicting conversion from mild cognitive impairment to Alzheimer's disease using neuropsychological tests and multivariate methods. J Clin Exp Neuropsychol. 2011;33(2):187–199.

24.

Iachini

Iavarone

Senese

Ruotolo

Ruggiero

Visuospatial memory in healthy elderly, AD and MCI: a review. Curr Aging Sci. 2009;2(1):43–59.

25.

Hanyu

Sato

Hirao

Kanetaka

Iwamoto

Koizumi

. The progression of cognitive deterioration and regional cerebral blood flow patterns in Alzheimer's disease: a longitudinal SPECT study. J Neurol Sci. 2010;290(1-2):96–101.

26.

Kashima

. Small test for dementia of Alzheimer’s type. Psychogeriatics. 2007;7(1):1–3.

27.

Crutch

Rossor

Warrington

. The quantitative assessment of apraxic deficits in Alzheimer's disease. Cortex. 2007;43(7):976–986.

28.

Parakh

Roy

Koo

Black

. Pantomime and imitation of limb gestures in relation to the severity of Alzheimer's disease. Brain Cogn. 2004;55(2):272–274.

29.

Binetti

Cappa

Magni

Padovani

Bianchetti

Trabucchi

. Visual and spatial perception in the early phase of Alzheimer's disease. Neuropsychology. 1998;12(1):29–33.

30.

Kramer

Wells

. The role of perceptual bias in complex figure recall. J Clin Exp Neuropsychol. 2004;26(6):838–845.