RESEARCH ARTICLEOpen Access
Prospective memory tasks: a more sensitive
method for screening cognitive impairment
Ying Ji1, Ling Wei2, Dehua Chui1,3, Kai Wang2*and Dongsheng Fan1*
Background: Cognitive change is prevalent in patients with amyotrophic lateral sclerosis (ALS), but still lack a
widely accepted and sensitive screening method. In this study, we try to find a sensitive screening battery for
detecting subtle cognitive deficits in patients with ALS.
Methods: Eighty consecutive ALS patients and 57 matched normal controls underwent the Mini-Mental Status
Examination (MMSE), the verbal fluency test (VFT), the Stroop Color Word Interference Test (CWT), and the
prospective memory (PM) tests, including event-based (EBPM) and time-based (TBPM).
Results: The patients did not differ from the controls in the MMSE, the VFT and the CWT. By contrast, statistically
significant differences were found in the PM tests (EBPM: P=0.043; TBPM: P<0.001). More interestingly, TBPM was
more sensitive than EBPM in the early-phase patients.
Conclusions: Prefrontal lobar dysfunction does exist among ALS patients and may spread from the medial to the
lateral region. The PM tests seem more sensitive in ALS patients with frontotemporal dysfunction than are the
classical cognitive measures.
Amyotrophic lateral sclerosis (ALS) is now considered a
multisystem disease that co-occurs with frontotemporal
dysfunction. A majority of studies on cognitive function
have suggested that ALS patients suffer from varying
degrees of impairment in different fields of cognitive
functioning. The prefrontal cortex (PFC) is the area
most involved in early-stage ALS patients with fronto-
temporal dysfunction [1,2]. There are three principal cir-
dorsolateral, ventromedial and orbitofrontal . Among
them the dorsolateral-caudate nucleus circuit related to
the executive functions has been the most investigated
in ALS patients [4,5]. However, no widely accepted and
sensitive screening tool is available for early detection
because traditional neuropsychological examinations can
have normal results in early-stage ALS patients. Memory
abnormalities have been less well characterized, and pre-
vious studies have mostly focused on retrospective mem-
ory (RM), although prospective memory (PM) is now
gaining attention. PM is the ability to carry out intended
actions in the future, it requires subjects to execute
some activities at an appropriate time point, either
upon the occurrence of a specified stimulus in the en-
vironment (event-based PM, EBPM) or at a special
point in time (time-based PM, TBPM), while the sub-
ject is engaged in an ongoing, attention demanding ac-
tivity. It contains two components: a prospective and a
retrospective component. The prospective component
involves remembering that one needs to do something
in the future whereas retrospective component is to re-
member the content of the action that is supposed to
be performed. [6,7] Converging evidence from a num-
ber of neuropsychological, electrophysiological and
neuroimaging studies has indicated that the PFC is the
core area for PM, but varies with different subtypes [8,9].
A meta-analysis of Brodmann area 10 coritco-function
also showed that specific part of rostral PFC associated
with different cognitive processes (i.e. working memory,
* Correspondence: firstname.lastname@example.org; email@example.com
2Department of Neurology, Anhui Medical University First Hospital, Hefei,
1Department of Neurology, Peking University Third Hospital, Beijing, China
Full list of author information is available at the end of the article
© 2012 Ji et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Ji et al. BMC Neurology 2012, 12:142
episodic memory retrieval, mentalizing ) is all required by
PM task [10,11]. For this reason, our study attempted to
determine if assessing PM can lead to a sensitive ALS
Eighty-nine consecutive patients diagnosed with ALS
according to the EI Escorial criteria  were recruited
from the neurology department of Peking University
Third Hospital. Exclusion criteria included those with
severe depression or anxiety [Hamilton Depression Rat-
ing Scale (HAMD) > 20 or Hamilton Anxiety Rating
Scale (HAMA) > 8], or with abnormal respiratory func-
tion [forced vital capacity (FVC) < 50%], or with upper
limb involvement that cannot complete PM tasks. The
study ultimately included an 80-patient cohort. The dis-
ease severity was evaluated by the ALS Functional Rat-
ing Scale (ALSFRS).
symptoms, 23.8% of the patients were bulbar onset, and
76.3% were spinal onset. The patients in our study were
also classified according to various diagnostic levels. The
patients diagnosed with clinically definite or clinically
probable ALS were classified as advanced-phase ALS
(ap-ALS), while clinically probable-laboratory supported
and clinically possible ALS were classified as early-phase
education-matched healthy adults were also recruited
for this study. The ethical committee of Peking Univer-
sity Third Hospital approved the present study. The
study design was thoroughly explained and written in-
formation was provided to each subject, and if they
agreed to participate, an informed consent form accord-
ing to the Declaration of Helsinki was signed.
Basedon the clinical
PM was assessed using a standard Chinese version of
the PM test designed by Einstein and McDaniel [7,15].
The test was divided into 2 parts.
1) In the EBPM, 32 pictures (the first 2 pictures were
practice items) were presented to the participants.
Twelve frequently used Chinese nouns were on each pic-
ture. Ten of the nouns belonged to a certain category,
and the other 2 belonged to another group (e.g., fruit,
city, color). The participants were asked to pick the 2
distinctive nouns and read them. The accuracy rate was
recorded. If the 2 nouns were animals (target words),
the participants were instructed to perform the EBPM
task (patting their legs). There were 7 pairs of target
words, and they appeared on the 2nd (for practice), 6th,
11th, 16th, 21st, 25th and 31st slides. One point was
scored for each correct selection. After the 32nd slide,
the participants were asked to say their telephone num-
bers immediately (2 points). The maximum total score
on the EBPM test was 8. Next, the participants were
asked to recall all of the animals they had just picked as
a simple RM index called RM1.
2) In the TBPM, the participants were asked to select
the largest and the smallest numbers from a series of
pictures. Twelve numbers were on each picture. They
were instructed to pat their legs every 5 minutes (at 5,
10, and 15 minutes from the beginning of the test). Two
points were scored for patting their legs for less than
10 seconds after or before the exact time and 1 point
for patting them longer than 10 seconds but less than
30 seconds. A table clock was placed beside the screen.
A maximum of 6 points were possible in this part. Also
the participants were asked to repeat the three time
points, and the results were used as their RM2.
After finishing each part, the participants were asked
to recall the instruction as accurately as possible.
The ALS patients and controls completed a series of
(MMSE) was administered for global assessment of cog-
nitive function. Executive functioning was estimated by
a verbal fluency test (VFT) for categories (animals and
fruits) and by the Stroop Color Word Interference Test
(CWT). In addition, the PM task was completed by the
The data that followed a normal distribution were char-
acterized by the mean (SD) and compared using an inde-
pendent T test; otherwise, the median (interquartile
range (IQR)) and the Mann–Whitney U test were used.
Significance was defined as a p value < 0.05. Spearman’s
rank-order correlations were also computed for the
patients. The statistical analyses were performed using
SPSS 15.0 software.
No significant demographic differences were found be-
tween the ALS patients and controls, including age, sex
and educational background. Due to dysarthria and mild
color-blindness, 74 patients completed the VFT, while 69
patients and 55 controls finished the CWT. Table 1
summarizes the results of executive functioning tests.
The ALS patients performed equivalently on MMSE,
VFT and CWT compared to the controls. Due to
illiteracy, only 74 patients and 52 controls completed the
PM task. The results indicate that the ALS patients
performed significantly more poorly on both the EBPM
(z=−2.027, p=0.043) and TBPM (z=−3.782, p<0.001)
tests (Table 2). Further comparisons showed that the
ap-ALS patients (n=27) demonstrated deficits in both
Ji et al. BMC Neurology 2012, 12:142
Page 2 of 5
p=0.011), but the ep-ALS patients (n=47) had TBPM
deficits only (z=−3.937, p<0.001). We did not find differ-
ence on PM task between bulbar onset and spinal onset
participants or groups of bulbar involved and not.
Meanwhile ALS patients had lower score on RM2 than
controls, but all the participants can recall the instruc-
In the correlation analysis, the TBPM did not correlate
significantly with the ALSFRS or executive functioning
test scores within the patient group, but the association
between the EBPM and VFT scores was significant (ani-
mals: r = 0.382, p = 0.001; fruits: r = 0.417, p<0.001).
Frontal lobe dysfunction is the most central part of ALS
patients with cognitive change, though area beyond the
frontal lobe may also be involved . This point of
view has been widely accepted and confirmed by a num-
ber of various types of studies. A structural imaging
study found most of the frontal regions, including left
middle and inferior frontal gyrus and the medial pre-
motor cortex, were significantly more atrophy in ALS/
FTD group than pure ALS patients . Another PET
study showed that hypometabolism only confined in
frontal lobe in FTD/MND compared to FTD . Thus
examinations related to frontal lobe are being a relative
topic in this area. Consistent with prior studies, the
MMSE was not a sensitive screening index for fronto-
temporal dysfunction . There are some screen
batteries focused on executive function appear to be
more effective such as Frontal Assessment Battery (FAB)
, but still lack consistent evidence. Nevertheless, at
least one global cognitive screening instrument should
be used with ALS patients to rule out other causes of cog-
nitive impairment , and the patients’ physical disabilities
must also be noted. More detailed neuropsychological
assessments should subsequently be performed. Unexpect-
edly, we found that the Chinese ALS patients performed as
well as the controls in the VFT and CWT. Executive func-
tion, particularly as assessed by the VFT, is considered to be
a sensitive indicator for detecting ALS cognitive impair-
ment in most studies performed in Western countries
. Our study implies that, due to cultural differences
or other reasons, the VFT might not be appropriate for
ALS patients in China. However, the ALS patients had
greater deficits in the PM task without traditional ex-
ecutive functioning impairment.
RM impairment has not been consistently observed in
ALS patients with cognitive deficits. To the best of our
knowledge, this is the first study to examine PM impair-
ment in ALS patients. PM has recently been used in a
wide range of research studies and in clinical practice
for many kinds of diseases, especially those associated
with the PFC, such as schizophrenia and Alzheimer dis-
ease, both of which had impaired PM performance
[21,22]. The link between rostral PFC and PM was ini-
tially noted from brain lesion studies that some
researchers found patients who suffered frontal lobe le-
sion had impaired PM . The first neuroimaging
study which carried out in 1998 confirmed the relation
between rostral PFC and PM, and then was evidenced
by a series of researches [8,24]. Besides, ERP study on
normal aging has also suggested that declining PM is the
product of diminished frontal function . Combined
with behavior researches , it seems to be a secure
finding that performance of PM is typically accompanied
by activations within rostral PFC so far . Therefore,
the present study confirms that ALS patients do have
PFC impairment. More importantly, it provides evidence
for our prediction that compared to traditional neuro-
psychological examinations, PM tests might serve as a
more sensitive screening battery for detecting subtle
cognitive changes earlier.
More interestingly, the ap-ALS patients demonstrated
deficits on both the EBPM and TBPM, but the ep-ALS
patients performed significantly more poorly on the
TBPM only. It seems likely that the EBPM and TBPM
do not always decline in parallel. This dissociation in
PM impairment has been suggested by a number of
studies, such as one that applied PM tasks to patients
with Parkinson disease and found that the patients
had impaired EBPM, but not TBPM [15,27]. These find-
ings suggest that the two PM subtypes are mediated by
Table 1 The demographic data and neuropsychological
test results for the ALS patients and controls
Age, y 53.1 (12.1) 50.9 (10.0)0.247
Education, y 12 (9–15)12 (9–14)0.118
Male (%)51 (63.8)28 (49.1) 0.088
MMSE 29 (27–30)29 (28–30)0.139
VF (animal)16.0 (12.8-19.3)17.0 (14.0-20.5) 0.192
VF (fruit)11.0 (9.0-13.3)11.0 (10.0-14.5)0.131
CWT8.0 (5.0-12.5)10.0 (7.0-15.0) 0.126
Table 2 The PM task results for the ALS patients and
EBPM6 (4–8)7 (5.25-8)0.043
RM13 (2–4)3 (2–4.75)0.931
Accuracy rate of EBPM (%)100 (96.7-100)100 (100–100)0.364
TBPM6 (4–6)6 (6–6)<0.001
RM26 (6–6)6 (6–6)0.016
Accuracy rate of TBPM (%)91.3 (87.5-94.1)91.3 (89.4-93.9)0.582
Ji et al. BMC Neurology 2012, 12:142
Page 3 of 5
different neural networks. This phenomenon may be
explained by the gateway theory of Burgess et al .
This hypothesis states that the rostral PFC plays a role
in switching between stimulus-independent thought
(SIT) and stimulus-oriented thought (SOT). The lateral
PFC is crucial for maintaining attention toward intern-
ally generated thoughts, including attention state switch-
ing between SIT and SOT, while the medial PFC plays a
role in attention tasks directed toward external stimuli.
The research of Okuda et al. suggests that frequent at-
tention switching between performing ongoing activities
and focusing on EBPM tasks is more closely related to
the lateral area of the rostral PFC. By contrast, ongoing
activities and watching the clock to check the time are
both exhibited externally in the TBPM task, implying a
correlation between the medial PFC cortex and TBPM
tasks . Based on this view, our observation that the
EBPM test scores showed greater distinction between
the ep-ALS and ap-ALS patients than did the TBPM test
scores could be interpreted as indicating that the PFC
dysfunction in ALS patients may have spread from the
medial to the lateral PFC. Moreover, the correlation ana-
lysis found that only the EBPM was correlated with the
VFT, which relies more on dorsolateral PFC; this result
also supports our interpretation.
There was also a larger difference between the two
groups in RM2 than in RM1. This result may not indi-
cate that the ALS patients had poor RM compared to
the controls because the RM2 task was easier than the
RM1 task on which the ALS patients performed com-
parably to the controls. Meanwhile the instruction recall
was fairly well in patients group also revealed the relative
preserved retrospective component. It is not clear
whether this difference can be attributed to difficulties
in time perception, and it requires further study.
Our study did not find difference on PM task between
bulbar and spinal onset or bulbar involved and not. The
association between cognitive changes and bulbar onset
has been suggested by some studies [29,30], but still
under controversial . The relative small sample size
of bulbar onset group maybe one of the reason of our
negative result. Therefore it is cautious to make final
conclusion and needs more research to clarification.
This study has certain limitations. First, our ALS
patients exhibited equivalent performances on trad-
itional executive examinations, but the finite tests
chosen and the patients with severe depression and anx-
iety or severe dysarthria were excluded may have influ-
enced the results. Second, this study using a simple PM
task not based on any imaging examination is very pre-
liminary, but we are inspired by the result. It is a hope
that this study may draw attention on this field, and
more complex PM task combined with imaging or elec-
trophysiological method could be carried in the future.
Third, this study was a cross-sectional study and found
that the ALS stage may be a predictor of cognitive func-
tioning. Long-term follow-up studies should be con-
ducted. Therefore, we urge caution when drawing strong
conclusions until further research clarifies or verifies the
findings in this study.
In summary, using comparatively systemic neuropsycho-
logical tests, our study confirms that Chinese ALS
patients have cognitive impairments. PFC dysfunction
does exist and may have spread from the medial to the
lateral part. The PM tasks seem more sensitive than the
traditional neuropsychological measures for detecting
cognitive dysfunction in patients with ALS.
We declare that we have no conflict of interest.
YJ carried out the neuropsychological measures and drafted the manuscript.
LW carried out the neuropsychological measures. DC participated in the
design of the study and performed the statistical analysis. KW conceived of
the study, and participated in the design of the study. DF conceived of the
study, participated in its design and coordination and helped to draft the
manuscript. All authors read and approved the final manuscript.
This study was supported by grants from the National Natural Sciences
Foundation of China (81030019, 30871359), the Beijing Natural Science
Foundation (7082099, 7102161), Doctoral Fund of Chinese Ministry of
Education (20100001110084), and the Capital Medical Technology
Development Foundation (SF-2009-III-34).
1Department of Neurology, Peking University Third Hospital, Beijing, China.
2Department of Neurology, Anhui Medical University First Hospital, Hefei,
China.3Neuroscience Research Institute, Peking University, Beijing, China.
Received: 3 April 2012 Accepted: 10 October 2012
Published: 21 November 2012
1. Jeong Y, Park KC, Cho SS, Kim EJ, Kang SJ, Kim SE, Kang E, Na DL: Pattern of
glucose hypometabolism in frontotemporal dementia with motor
neuron disease. Neurology 2005, 64:734–736.
2. Chang JL, Lomen-Hoerth C, Murphy J, Henry RG, Kramer JH, Miller BL,
Gorno-Tempini ML: A voxel-based morphometry study of patterns of
brain atrophy in ALS and ALS/FTLD. Neurology 2005, 65:75–80.
3.Alvarez JA, Emory E: Executive function and the frontal lobes: a meta-
analytic review. Neuropsychol Rev 2006, 16:17–42.
4.Abrahams S, Leigh PN, Goldstein LH: Cognitive change in ALS: a
prospective study. Neurology 2005, 64:1222–1226.
5.Flaherty-Craig C, Eslinger P, Stephens B, Simmons Z: A rapid screening
battery to identify frontal dysfunction in patients with ALS. Neurology
6.Costa A, Caltagirone C, Carlesimo GA: Prospective memory impairment in
mild cognitive impairment: an analytical review. Neuropsychol Rev 2011,
7.Einstein GO, McDaniel MA, Richardson SL, Guynn MJ, Cunfer AR: Aging and
prospective memory: examining the influences of self-initiated retrieval
processes. J Exp Psychol Learn Mem Cogn 1995, 21:996–1007.
8.Simons JS, Scholvinck ML, Gilbert SJ, Frith CD, Burgess PW: Differential
components of prospective memory? Evidence from fMRI.
Neuropsychologia 2006, 44:1388–1397.
9.West R, Covell E: Effects of aging on event-related neural activity related
to prospective memory. NeuroReport 2001, 12:2855–2858.
Ji et al. BMC Neurology 2012, 12:142
Page 4 of 5
10. Gilbert SJ, Spengler S, Simons JS, Steele JD, Lawrie SM, Frith CD, Burgess
PW: Functional specialization within rostral prefrontal cortex (area 10): a
meta-analysis. J Cogn Neurosci 2006, 18:932–948.
Okuda J, Fujii T, Ohtake H, Tsukiura T, Yamadori A, Frith CD, Burgess PW:
Differential involvement of regions of rostral prefrontal cortex
(Brodmann area 10) in time- and event-based prospective memory. Int J
Psychophysiol 2007, 64:233–246.
Brooks BR, Miller RG, Swash M, Munsat TL: El Escorial revisited: revised
criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph
Lateral Scler 2000, 1:293–299.
The Amyotrophic Lateral Sclerosis Functional Rating Scale: Assessment of
activities of daily living in patients with amyotrophic lateral sclerosis.
The ALS CNTF treatment study (ACTS) phase I-II Study Group. Arch Neurol
Charil A, Corbo M, Filippi M, Kesavadas C, Agosta F, Munerati E, Gambini A,
Comi G, Scotti G, Falini A: Structural and metabolic changes in the brain
of patients with upper motor neuron disorders: a multiparametric MRI
study. Amyotroph Lateral Scler 2009, 10:269–279.
Cheng HD, Wang K, Xi CH, Niu CS, Fu XM: Prefrontal cortex
involvement in the event-based prospective memory: evidence from
patients with lesions in the prefrontal cortex. Brain Inj 2008,
Abrahams S, Goldstein LH, Suckling J, Ng V, Simmons A, Chitnis X, Atkins L:
Frontotemporal white matter changes in amyotrophic lateral sclerosis.
J Neurol 2005, 252:321–331.
Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B: Are
amyotrophic lateral sclerosis patients cognitively normal? Neurology 2003,
Floris G, Borghero G, Chio A, Secchi L, Cannas A, Sardu C, Calvo A, Moglia
C, Marrosu MG: Cognitive screening in patients with amyotrophic
lateral sclerosis in early stages. Amyotroph Lateral Scler 2012,
Strong MJ, Grace GM, Freedman M, Lomen-Hoerth C, Woolley S, Goldstein
LH, Murphy J, Shoesmith C, Rosenfeld J, Leigh PN, Bruijn L, Ince P, Figlewicz
D: Consensus criteria for the diagnosis of frontotemporal cognitive and
behavioural syndromes in amyotrophic lateral sclerosis. Amyotroph
Lateral Scler 2009, 10(3):131–146.
Abrahams S, Leigh PN, Harvey A, Vythelingum GN, Grise D, Goldstein LH:
Verbal fluency and executive dysfunction in amyotrophic lateral sclerosis
(ALS). Neuropsychologia 2000, 38:734–747.
Twamley EW, Woods SP, Zurhellen CH, Vertinski M, Narvaez JM, Mausbach
BT, Patterson TL, Jeste DV: Neuropsychological substrates and everyday
functioning implications of prospective memory impairment in
schizophrenia. Schizophr Res 2008, 106:42–49.
Martins S, Damasceno B: Prospective and retrospective memory in mild
Alzheimer's disease. Arq Neuropsiquiatr 2008, 66:318–322.
Shallice T, Burgess PW: Deficits in strategy application following frontal
lobe damage in man. Brain 1991, 114:727–741.
Okuda J, Fujii T, Yamadori A, Kawashima R, Tsukiura T, Fukatsu R, Suzuki K,
Ito M, Fukuda H: Participation of the prefrontal cortices in prospective
memory: evidence from a PET study in humans. Neurosci Lett 1998,
McFarland CP, Glisky EL: Frontal lobe involvement in a task of time-based
prospective memory. Neuropsychologia 2009, 47:1660–1669.
Burgess P, Gonen-Yaacovi G, Volle E: Functional neuroimaging studies of
prospective memory: What have we learnt so far? Neuropsychologia 2011,
Katai S, Maruyama T, Hashimoto T, Ikeda S: Event based and time based
prospective memory in Parkinson's disease. J Neurol Neurosurg Psychiatry
Burgess PW, Dumontheil I, Gilbert SJ: The gateway hypothesis of
rostral prefrontal cortex (area 10) function. Trends Cogn Sci 2007,
Schreiber H, Gaigalat T, Wiedemuth-Catrinescu U, Graf M, Uttner I, Muche R,
Ludolph AC: Cognitive function in bulbar- and spinal-onset amyotrophic
lateral sclerosis. A longitudinal study in 52 patients. J Neurol 2005,
30.Sterling LE, Jawaid A, Salamone AR, Murthy SB, Mosnik DM, McDowell E,
Wheaton M, Strutt AM, Simpson E, Appel S, Schulz PE: Association between
dysarthria and cognitive impairment in ALS: A prospective study.
Amyotroph Lateral Scler 2010, 11:46–51.
Raaphorst J, de Visser M, Linssen WH, de Haan RJ, Schmand B: The
cognitive profile of amyotrophic lateral sclerosis: A meta-analysis.
Amyotroph Lateral Scler 2010, 11:27–37.
Cite this article as: Ji et al.: Prospective memory tasks: a more sensitive
method for screening cognitive impairment in ALS?. BMC Neurology 2012
Submit your next manuscript to BioMed Central
and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at
Ji et al. BMC Neurology 2012, 12:142
Page 5 of 5