Brain, Vol. 124, No. 2, 389-398,
February 2001
© 2001 Oxford University Press
Memory and executive function in sporadic and familial Parkinson's disease
1 Neurologie A, Clinique Neurologique, CHU de Lille, 2 Psychology Department, Charles de Gaulle University, Lille, France
Correspondence to:
Kathy Dujardin, Neurologie A, Hôpital Salengro, CHU de Lille, 59037 Lille Cedex France E-mail: kdujardin{at}nordnet.fr
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Abstract |
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Some studies have demonstrated that the motor symptomatology in sporadic and familial Parkinson's disease was identical. From a physiopathological point of view, and perhaps in the future from a therapeutic point of view, it seems important to determine whether sporadic and familial Parkinson's disease are also similar with regard to cognitive impairment. The aim of the present study was to assess cognitive functions in patients suffering from sporadic and familial Parkinson's disease. Executive functions and memory were investigated in particular. Two groups of 12 patients with Parkinson's disease (sporadic and familial) and 12 healthy controls performed a set of tasks known to evaluate different aspects of executive function and memory. One-way analysis of variance tested for significant group effects, and when justified, post hoc analysis was performed. Cognitive impairment was different in sporadic and familial forms of Parkinson's disease. Indeed, although executive function was impaired in both groups of patients, deficits in tests of explicit memory recall were only observed in patients with sporadic Parkinson's disease. Although the impairment observed in both groups of patients suggests a disruption of the striatoprefrontal circuits, this disruption seems to be quantitatively more important and more widespread in the sporadic patients than in the familial ones. In both patient groups, the deficits probably result from dopaminergic and nondopaminergic deprivation and a greater participation of nondopaminergic factors in patients with sporadic Parkinson's disease could be suggested. In this group, a xenobiotic could be responsible for an acquired metabolic defect involving more widespread structures of the striatoprefrontal circuits, leading to disruption of nondopaminergic loops. Cholinergic deprivation is considered in particular.
familial Parkinson's disease; dysexecutive syndrome; frontostriatal circuit
MDRS = Mattis Dementia Rating Scale; UKPDBB = United Kingdom Parkinson's Disease Brain Bank; UPDRS = Unified Parkinson's Disease Rating Scale; VIQ = verbal intelligence quotient; WAIS-R = Wechsler Adult Intelligence Scale—revised; WCST = Wisconsin Card Sorting Test
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Introduction |
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Parkinson's disease is a neurodegenerative disorder whose main clinical manifestations include rest tremor, rigidity, akinesia and postural instability (Parkinson, 1817
). Other features are dysautonomia, dystonic cramps and cognitive dysfunction of subcorticofrontal type sometimes leading to dementia (Cummings, 1988). Pathologically, Parkinson's disease is characterized by selective degeneration of the pigmented nuclei of the brainstem, mainly the substantia nigra, and of some other subcortical structures such as the pedunculopontine nucleus and the substantia innominata. In these areas, there is neuronal loss and gliosis and Lewy bodies, which are intracytoplasmic eosinophilic inclusions with a pale halo surrounding the core, are observed in the surviving neurons after haematoxylin–eosin staining (Forno, 1990). From a biochemical point of view, the characteristic of Parkinson's disease is impairment of the dopaminergic systems but some other neurotransmitters are also concerned (Agid et al., 1990).
The primary cause of Parkinson's disease is still unknown. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism (Langston et al., 1983) suggested that Parkinson's disease could be due to some toxic environmental exposures. However, until now, no environmental toxin or protoxin responsible for Parkinson's disease has been identified. If it exists, it would only be effective in some subjects characterized by some metabolic abnormality(ies). These latter could sometimes be genetically determined. Indeed, a higher risk of developing the disease has been demonstrated among first-degree relatives and sometimes second-degree relatives of patients with Parkinson's disease compared with relatives of controls (Payami et al., 1994). Moreover, some large kindreds with autopsy-proven Lewy body Parkinson's disease have also been published recently (Golbe et al., 1990, 1996; Waters and Miller, 1994). Genetic markers on chromosome 4q21-q23 were found to be linked to the Parkinson's disease phenotype in a large kindred with autosomal dominant Parkinson's disease where a mutation of the 
-synucleine gene was then discovered (Polymeropoulos et al., 1996, 1997). More recently, a susceptibility locus for Parkinson's disease was mapped on chromosome 2p13 (Gasser et al., 1998).
Some studies have demonstrated that sporadic Parkinson's disease and familial Parkinson's disease are clinically identical (Plante-Bordeneuve et al., 1995) or only differ in age of onset (Bonifati et al., 1995). From a physiopathological point of view, and perhaps in the future from a therapeutic point of view, it seems important to determine whether sporadic Parkinson's disease and familial Parkinson's disease are also similar with regard to cognitive impairment.
As neuropsychological studies have provided evidence that memory and executive function are usually affected in nondemented patients with Parkinson's disease (Lees and Smith, 1983; Pillon and Dubois, 1996), the aim of the present study was to extensively assess these functions in patients suffering from sporadic and familial Parkinson's disease.
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Methods |
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Subjects
Parkinson's disease diagnosis was considered to be definite when a parkinsonian patient satisfied the criteria of the United Kingdom Parkinson's Disease Brain Bank (UKPDBB) (Gibb and Lees, 1988
) except for the presence of more than one affected relative. Since 1993, each patient with definite Parkinson's disease and accompanying family members were interviewed concerning any occurrence of Parkinson's disease, Parkinson's disease-like symptoms and any other CNS disorder in relatives. When a secondary case of Parkinson's disease was found in a family, this affected person was examined, when possible, by one of ourselves (L.D. or A.D.) or by a senior neurologist of our group who used UKPDBB criteria to retain Parkinson's disease diagnosis. When this examination was impossible (because of death, for example), Parkinson's disease was considered as definite when UKPDBB criteria could be retrospectively applied to the data obtained from a neurological report or neurologist interview. Parkinson's disease diagnosis was considered as probable when based on an incomplete medical report and/or general practitioner interview and/or convincing data obtained from relatives. The diagnosis of Parkinson's disease was considered as possible when at least two (three when there was tremor) parkinsonian symptoms from a checklist were present. Such criteria were used previously (Lazzarini et al., 1994), especially in the family where the mutation of the -synucleine gene was discovered (Golbe et al., 1996; Polymeropoulos et al., 1996, 1997).
When, after thorough investigation, no other occurrence of Parkinson's disease could be identified in the family which was otherwise well known by the patient and accompanying family members [indeed, the proportion of secondary cases of Parkinson's disease is a function of pedigree completeness (Lazzarini et al., 1994)], Parkinson's disease was considered as sporadic. Relatives who were reported to be unaffected by Parkinson's disease or any other CNS disorder were not examined as Maraganore and colleagues found no false negatives among relatives reported as normal (Maraganore et al., 1991).
Patients performing below the lowest quintile of the reference population (Schmidt et al., 1994) at the Mattis Dementia Rating Scale (MDRS, Mattis, 1976) were excluded, as well as those obtaining a verbal intelligence quotient (VIQ) below 85, as assessed by the verbal scale of the Wechsler Adult Intelligence Scale—revised (WAIS-R; Wechsler, 1981) and a score higher than 18 at the Montgomery and Asberg Depression Rating Scale (Montgomery and Asberg, 1979).
Twenty-four nondemented patients with Parkinson's disease (12 men, 12 women; mean age 64.83; SD 9.05; range 44–77) participated in the study. Among them, 12 were considered to present familial Parkinson's disease because at least one relative of the first or the second degree was identified as also presenting Parkinson's disease, according to the criteria previously described.
As indicated in Table 1, seven among the 12 patients with familial Parkinson's disease had between two and nine relatives with definite or probable Parkinson's disease. They were matched as closely as possible with respect to severity of the disease, presence or not of fluctuations and/or dyskinesias and VIQ to 12 patients considered to present sporadic Parkinson's disease. In each group, 11 patients were on treatment when examined.
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A group of 12 healthy control subjects chosen to match the groups of Parkinson's disease patients as closely as possible with respect to age and VIQ also participated in the study. They had no parkinsonian symptoms and had never received neuroleptic treatment. Their family history was negative for Parkinson's disease or Parkinson's disease-like symptoms. Ten of these control subjects were spouses of patients with familial Parkinson's disease. The two others were spouses of sporadic Parkinson's disease patients.
The characteristics of the patients and control subjects are shown in Tables 2 and 3.
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The procedure was approved by the ethical committee of the Lille University Hospital and informed consent was obtained from all participants.
The groups did not differ with respect to age [F(2,33) = 1.82, P = 0.18], years of education [F(2,33) = 0.18, P = 0.83], WAIS-R VIQ [F(2,33) = 1, P = 0.38] and depression [F(2,33) = 0.35, P = 0.71]. In addition, both groups of patients did not differ with respect to disease duration [t(22) = 0.11, P = 0.11], age at onset of the disease [t(22) = 0.019, P = 0.49], severity of the motor symptoms as evaluated off medication by the score on part III of the UPDRS (Fahn et al., 1987) [t(22) = 0.13, P = 0.10] and by the Hoehn and Yahr stage [t(22) = 0.67, P = 0.26], dementia score on the MDRS [t(22) = 1.37, P = 0.09] and L-dopa dosage [t(22) = 0.94, P = 0.18] (Hoehn and Yahr, 1967). In addition to their dopaminergic medication, some patients were also receiving other medication at the time of testing. Details of the treatments are shown in Table 4.
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Neuropsychological assessment
Memory
Immediate memory.
Three span tests were administered. The WAIS-R digit span test gave forward and backward digit spans. Spatial span was measured by the Corsi Spatial Span Test (Corsi, 1972
). Word span was measured by the Belleville et al. (1998) Word Span Test (Belleville et al., 1998).
Working memory.
Working memory was evaluated by the performance in the alphabetic span test of Belleville et al. (1998). Subjects were orally presented with word lists whose length was equal to their word span. In a first stage, they were instructed to recall them in exactly the same order as they were presented. There were five trials. In a second stage, they were instructed to recall the words in alphabetical order according to the first letter. There were 10 trials. In the third stage, they again had to recall the words in the same order as they were presented. Two indices were computed: SR, number of lists correctly recalled in direct order (= stages 1 + 3) and AR, number of lists correctly recalled in alphabetic order (= stage 2). Performance was evaluated by the decline of storage abilities related to the processing in working memory: 
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Declarative memory.
For verbal material, declarative memory was evaluated by the French version of the Grober and Buschke word list learning and recall test (Grober and Buschke, 1987).
For visuospatial material, the test developed by Pillon and colleagues (Pillon et al., 1996, 1997) to evaluate memory for spatial location, with a procedure close to that of Grober and Buschke, was used.
Executive function
A range of tests evaluated different aspects of executive function.
Planning abilities.
Planning abilities were evaluated by a word fluency task and a spatial sequences generation task.
In the word fluency task, the subjects were first instructed to name, in 1 min, as many words as they could beginning with the letter `P'. People's names and proper nouns were not permitted as well as words from the same root. Thereafter, they were instructed to name, in 1 min, as many animal nouns as they could. Scores for each part of the task were analysed separately. Performance was assessed by the number of different words named in 1 min.
The spatial sequences generation task was derived from those developed by Owen and co-workers (Owen et al., 1995). The patients were presented with a board with four keys disposed as a cross. They were instructed to produce as many sequences as possible without repetition by touching each of the four keys in turn. A given sequence could start and end with any of the four keys. Every sequence had to include each of the keys. The subjects were allowed 24 trials. They were not informed that there were 24 possible four-keys combinations. There was no time limit. The keyboard was connected to a computer which recorded the responses. Performance was assessed by the total number of different sequences generated within 24 trials, the number of novel sequences before producing the first repetition and the percentage of perseverative errors [an error (repetition of a sequence already produced) was considered as perseverative if the sequence realized on a trial was the same as those produced on the preceding trial].
Resistance to interference.
Resistance to interference was evaluated by a dual-task paradigm close to those developed by Brown and Peterson (Brown, 1958; Peterson, 1959). The primary task was a short-term memory retention task: the subject was visually presented a trigram of consonants for three seconds and, after a delay of retention, he was required to recall the three consonants in exactly the same order as they were presented. In order to avoid anticipation and habituation effects the delay was variable. In the present study, two delays were used—6 and 15 s. They were randomly variable among the 15 trials of the task. The task was realized in three conditions: control, mild interference and high interference, which varied depending on the secondary task.
In the control condition, the delay of retention was free. In the mild interference condition, it was occupied by the realization of a secondary task. In this condition, the secondary task consisted of one by one forward counting from a number given by the examiner. In the high interference condition, the secondary task consisted of a three by three backwards counting task from a number given by the examiner. In each condition, performance was assessed by the number of trigrams correctly restituted in the correct order.
Set shifting abilities.
Set shifting abilities were evaluated by Nelson's version of the Wisconsin Card Sorting test (WCST), an alternating word fluency task and motor sequences (Nelson, 1976). Performance in the WCST was evaluated by the number of categories achieved, the total number of errors and the percentage of perseverative errors (using Nelson's version, an error was scored as perseverative if it followed the same category concept as the immediately preceding response).
In the alternating word fluency task, the patients were instructed to alternately name a word beginning with the letter `L' and a word beginning with the letter `R'. People's names and proper nouns were not permitted as well as words from the same root. Performance was assessed by the number of different words named in 1 min.
The motor sequences were based on Luria's neuro- psychological investigation (Luria, 1966). After the description and realization by the examiner of a movement, the subject was instructed to realize it with no time limit.
The task comprised three parts.
- (i) Simple movements: (a) touch the fingers in turn with the thumb while counting them (this movement was realized with both hands together and repeated five times); (b) bring together, then separate the fingers of both hands and repeat five times; (c) bring together, then separate the fingers of both hands and clench the hands (this movement was repeated five times). Each movement correctly achieved was scored 1 and each sequence was scored on 5.
- (ii) Alternate movements: (a) both hands palm down, alternately clench and extend opposite hands (this movement was realized five times); (b) open hands, right hand palm up, left hand palm down and alternate five times; (c) right hand open palm up, left hand closed palm down and alternate five times. Each movement correctly achieved was scored 1 and each sequence was scored on 5.
- (iii) Rhythms: the subject was instructed to put his index fingers on the table: (a) tap twice with right hand, once with left hand and alternate five times. (b) tap twice with right hand, once with left hand, three times with right hand, twice with left hand and repeat five times; (c) tap twice with left hand, once with right hand, once with left hand, twice with right hand and repeat five times. Each movement correctly achieved was scored 1 and each sequence was scored on 5. Each part of the task was then scored on 15.
- (ii) Alternate movements: (a) both hands palm down, alternately clench and extend opposite hands (this movement was realized five times); (b) open hands, right hand palm up, left hand palm down and alternate five times; (c) right hand open palm up, left hand closed palm down and alternate five times. Each movement correctly achieved was scored 1 and each sequence was scored on 5.
Data analysis
For all tasks except the Brown–Peterson paradigm, nonparametric Kruskal–Wallis analyses of variance were performed in order to test for significant effects of group on performance parameters. A 5% level of significance was adopted. When appropriate, nonparametric Mann–Whitney tests were carried out for post hoc analyses. The Bonferroni correction was adopted to avoid multiple post hoc tests effect. The value was thus 0.017.
For the Brown–Peterson paradigm, a two factors analysis of variance (group x task condition) with repeated measures on the task condition factor was performed. A 5% level of significance was adopted.
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Results |
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Mean values and corresponding standard deviation for each parameter of the different tasks are shown in Table 5
for the three groups.
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Memory
Immediate memory
Whatever the span test, there was no group effect.
Working memory
The decline of storage abilities related to the processing in working memory was not different in the three groups of subjects.
Declarative memory
Grober and Buschke word list learning and recall test.
The Kruskal–Wallis H test revealed a significant group effect for the number of words recalled during free recall (P = 0.047). Post hoc comparisons revealed that the sporadic Parkinson's disease patients recalled significantly fewer words than the two other groups. The other comparisons were not significant. There was no group effect on the number of words recalled during cued recall nor on the number of words correctly identified during the recognition phase.
Pillon et al. memory for spatial location test.
The Kruskal–Wallis H test revealed a significant group effect on the number of pictures correctly located during the encoding phase (P = 0.013), during free recall (P = 0.009), cued recall (P = 0.002) and on the number of false alarms during the recognition phase (P = 0.006). Post hoc comparisons revealed that during the encoding phase, sporadic Parkinson's disease patients correctly located significantly fewer pictures than the familial Parkinson's disease patients (P = 0.004) and the control subjects (P = 0.0005). There was no difference between these latter two groups. During free recall, sporadic Parkinson's disease patients correctly located significantly fewer pictures than the familial Parkinson's disease patients (P = 0.004) and the control subjects (P = 0.005). There was no difference between these latter two groups. During cued recall, sporadic Parkinson's disease patients correctly located significantly fewer pictures than the familial Parkinson's disease patients (P = 0.01) and the control subjects (P = 0.001). There was no difference between these latter two groups. During the recognition phase, sporadic Parkinson's disease patients made significantly more false alarms than control subjects (P = 0.004). There was a tendency for the familial Parkinson's disease patients to make more false alarms than control subjects (P = 0.03). There was no difference between both patient groups.
Executive function
Planning abilities
There was no significant group effect in the word fluency task.
In the spatial sequences generation task, the Kruskal–Wallis H test revealed a significant group effect for the total number of different sequences generated (P = 0.02) and the percentage of perseverative errors (P = 0.03). There was no group effect on the number of novel sequences before producing the first repetition. Post hoc comparisons revealed that both groups of patients generated significantly fewer different sequences than the control subjects (sporadic Parkinson's disease/controls, P = 0.012; familial Parkinson's disease/controls, P = 0.013). There was no difference between both groups of patients. Both groups of patients also made more perseverative errors than control subjects (sporadic Parkinson's disease/controls, P = 0.017; familial Parkinson's disease/controls, P = 0.017) but there was no difference between them.
Resistance to interference
The two-factor ANOVA revealed a significant main effect of group [F(2,66) = 11.26, P = 0.0001] and task condition [F(2,66) = 94.90, P = 0.0001]. The group x task interaction was not significant [F(4,66) = 1.57, P = 0.19]. However, examination of the raw data seemed to indicate a task effect which varied depending on the group of subjects. For examination of these raw data, it appeared that the absence of significant interaction was related to the presence of partial interactions which cancelled themselves. Another ANOVA considering only two modalities of the group factor (familial Parkinson's disease versus controls and sporadic Parkinson's disease versus controls) was then conducted. The first ANOVA revealed a significant main effect of group (familial Parkinson's disease versus controls) [F(1,44) = 50.58, P = 0.0007] and task [F(1,44) = 12.56, P = 0.0001] but no significant group x task interaction [F(2,44) = 1.31, P = 0.27]. The second ANOVA revealed significant main effects of groups (sporadic Parkinson's disease versus controls) [F(1,44) = 99.54, P = 0.0001] and task [F(1,44) = 30.12, P = 0.0001] and a significant group x task interaction [F(2,44)= 3.42, P = 0.038]. Post hoc analysis revealed that sporadic Parkinson's disease performed similarly to controls in control condition but recalled significantly fewer trigrams with the mild interference [t(22) = 4.37, P = 0.0001] and high interference task conditions [t(22) = 3.26, P = 0.002].
Set shifting abilities
WCST.
Whatever the parameter, there was no significant group effect.
Alternating word fluency task.
The Kruskal–Wallis H test revealed a significant group effect (P = 0.03). Post hoc comparisons revealed that the sporadic Parkinson's disease patients performed significantly worse than control subjects (P = 0.008). The other comparisons were not significant.
Motor sequences.
The Kruskal–Wallis H test revealed a significant group effect in the three conditions of the task: simple movements (P = 0.006), alternate movements (P = 0.03) and rhythms (P = 0.005). Post hoc analysis revealed that for the simple movements, familial Parkinson's disease patients performed significantly worse than controls (P = 0.003) and the other comparisons were not significant. For the alternate movements, familial Parkinson's disease patients performed significantly worse than controls (P = 0.013) and the other comparisons were not significant. For the rhythms, both groups of patients performed significantly worse than control subjects (sporadic Parkinson's disease/controls: P = 0.017, familial Parkinson's disease/controls: P = 0.002) but there was no difference between them.
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Discussion |
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An extensive battery of tests was used here to assess executive function and memory in 12 patients with sporadic and 12 patients with familial Parkinson's disease. In contrast with the motor disability which has been demonstrated to be similar in both forms of Parkinson's disease (Bonifati et al., 1995
; Plante-Bordeneuve et al., 1995), the present results suggest that cognitive impairment is different in sporadic Parkinson's disease and familial Parkinson's disease. Indeed, although executive function was impaired in both groups of patients, deficits in tests of explicit memory recall were only observed in sporadic Parkinson's disease.
For executive function, significant group effects were observed for the spatial sequences generation task, the dual-task paradigm, the alternating word fluency test and the motor sequences. Post hoc analyses revealed that for most parameters both groups of patients were significantly impaired compared with the healthy controls and there was no significant difference between the patient groups. This is thus in agreement with the results of many other studies which gave evidence for impairment in executive function in Parkinson's disease (Cools et al., 1984; Taylor and Saint-Cyr, 1986; Gotham et al., 1988; Cooper et al., 1991) and suggests that this impairment is not dependent on the aetiology of the disease. However, in the dual-task paradigm, although both groups performed significantly worse than the control subjects, the sporadic Parkinson's disease patients had more difficulty in resisting interference from the secondary tasks than the familial Parkinson's disease patients. Moreover, although there was no significant difference, examination of the raw data showed clear evidence of a general tendency for the sporadic Parkinson's disease patients to perform worse than familial Parkinson's disease patients. As the number of patients was small, it cannot be excluded that significant differences could emerge with larger samples.
Memory deficits were restricted to explicit recall of verbal information and memory for spatial locations. As observed in previous studies (Pillon et al., 1994; Buytenhuis et al., 1994; Van Spaendonck et al., 1996), there was a significant group effect in the free recall of the Grober and Buschke Word Learning Test, with no difference for the other parameters. Post hoc analysis revealed that only sporadic Parkinson's disease patients were impaired and recalled significantly fewer words than the control subjects and also than the familial Parkinson's disease patients whose performance was very close to that of the healthy controls. This deficit has usually been reported as an impairment in the spontaneous use of implicit strategies for retrieval of information in episodic memory and is considered to reflect frontostriatal dysfunction (Pillon et al. 1994; Patenaude and Baillargeon, 1996). A significant group effect was observed for all task parameters of the spatial location memory task, except for the number of hits during the recognition phase. This is in agreement with the results of Pillon et al. (1996). Post hoc analysis, however, revealed that only sporadic Parkinson's disease patients were impaired and performed significantly worse than the control subjects and the familial Parkinson's disease patients. The only parameter for which the familial Parkinson's disease patients were impaired was the number of false alarms: like the sporadic Parkinson's disease patients, they made significantly more false alarms than control subjects. Pillon and colleagues clearly demonstrated that the PD impairment in this task was related to a difficulty in using strategic processes for spontaneous establishment of arbitrary associative links between two stimuli, in the present case a picture and its location on a matrix (Pillon et al., 1998). They suggested that this impairment also reflected frontostriatal dysfunction. Their hypothesis is, moreover, supported by recent work by Tomita and co-workers using single-unit recording in monkeys and showing that the prefrontal cortex exerts executive control on the posterior association cortex during voluntary recall of visual items (Tomita et al., 1999).
Thus, the memory deficits observed here were not related to genuine memory dysfunction, but resulted from executive dysfunction. Patients with Parkinson's disease have difficulties in self-elaboration of internal strategies for organizing material when its organization is not explicit, and for retrieving it from long term memory. Such deficits were only observed in sporadic Parkinson's disease patients.
Although the impairment observed in both groups of patients suggests a disruption of the striatoprefrontal circuits, this disruption seems to be quantitatively more important and more widespread in the sporadic Parkinson's disease than in the familial Parkinson's disease patients. How can such differences be explained?
Several factors could be evoked: cognitive impairment in patients with Parkinson's disease has been shown to be related to age at onset of the disease, age at examination and disease duration (Portin and Rinne, 1984; Dubois et al., 1990). However, since both patient groups were matched as strictly as possible for these characteristics and as there was no significant group effect on these variables, it is unlikely that age or disease duration differences could account for differences in cognitive function in sporadic Parkinson's disease and familial Parkinson's disease.
The rate of disease progression could also be involved. Indeed, although the differences were not significant, the motor symptoms were slightly less severe in familial than sporadic Parkinson's disease and the disease duration also slightly differed. According to previous studies (Diamond et al., 1989; Illiaroshkin et al., 1994; Röhl et al., 1994), the rate of progression of a degenerative disease can be calculated as the ratio of the severity of symptoms to the duration of the disease. In our study, the ratio of motor score (UPDRS, part III, off state) to disease duration in months revealed no significant difference in the mean rate of disease progression in both groups [familial Parkinson's disease: mean = 0.51 (range 0.12–1.88 and sporadic Parkinson's disease mean = 0.46 (range 0.03–1.04), t = 0.29, P = 0.39]. Such a hypothesis thus appears to be unlikely.
Dementia or differences in intellectual function must also be discarded. Indeed, patients suspected of dementia or with a too low VIQ were excluded. Moreover, the groups were strictly matched on these variables.
It also seems unlikely that the observed differences could be related to differences in treatment. Firstly, when assessed, all patients were on stable L-dopa dosage. Secondly, there is no consensus with regard to L-dopa effects on cognition in Parkinson's disease. Some results suggested performance improvement when Parkinson's disease patients were on L-dopa treatment (Halgin et al., 1977; Rogers et al., 1987). Other studies did not show any improvement of cognitive function in Parkinson's disease patients receiving L-dopa treatment (Pillon et al., 1989). As the L-dopa dosages were on average equivalent in both patient groups, this is probably not an appropriate explanation for the differences observed in the present study between sporadic Parkinson's disease and familial Parkinson's disease. These differences could thus be related to the sporadic or familial character of the disease.
In Parkinson's disease, cognitive impairment, in particular executive dysfunction, has been related to the dysfunction of the dorsolateral striatoprefrontal loop consecutive to loss of dopaminergic nigral neurones (Alexander et al., 1986; Taylor and Saint-Cyr, 1992; Mega and Cummings, 1994). However, disruption of nondopaminergic subcorticofrontal systems has also been considered as a cause of cognitive disturbance in Parkinson's disease. The cholinergic system, in particular, has been implicated in frontal lobe dysfunction (Dubois et al., 1987), but many other transmitter systems, such as noradrenergic and serotoninergic pathways, display heavy projections to the prefrontal cortex and could also be involved (Cooper et al., 1992). It can be suggested that, in familial Parkinson's disease, a genetically determined metabolic defect could be responsible for lesions involving specifically some of the dopaminergic structures of the striatoprefrontal circuits, leading to a moderate cognitive impairment; the participation of nondopaminergic pathology being relatively limited. Conversely, in sporadic Parkinson's disease, a xenobiotic could be responsible for an acquired metabolic defect involving more widespread structures of the striatoprefrontal circuits, leading then to larger disruption of the dopaminergic and nondopaminergic loops. Cholinergic deprivation must be considered in particular. Recently, Bédard and colleagues investigated the consequences of anticholinergic drug administration to Parkinson's disease patients and demonstrated that long-term cholinergic blockade in Parkinson's disease led to an exacerbation of the subcorticofrontal syndrome (Bédard et al., 1999). Only tests depending on executive function were affected, other abilities were not. Their results were thus in agreement with those of previous studies showing an enhancement of set-shifting difficulties and working memory deficits in patients with Parkinson's disease treated with anticholinergic drugs (Cooper et al., 1992; Van Spaendonck et al., 1993). This suggests that the cholinergic mechanisms underlying cognitive impairment in Parkinson's disease are probably not related to the reduction of the innominatocortical and septohippocampal cholinergic fibres involved in the amnesic deficit of the patients with Alzheimer-type dementia. They are more probably related to other cholinergic systems arising from tegmental nuclei (pedunculopontine and laterodorsal) and projecting to the thalamus, the basal ganglia and the prefrontal cortex and which are lesioned in parkinsonian syndromes (Jellinger, 1988). It can be suggested that in familial Parkinson's disease, these cholinergic systems could be partially preserved leading to a less severe dysexecutive syndrome than in sporadic Parkinson's disease. Moreover, the fact that some aspects of executive function, like the self-elaboration of learning and memory strategies, were preserved in the familial Parkinson's disease patients while other aspects were impaired, suggests that they could depend on different neurotransmitter systems. This reinforces the hypothesis that executive function is not a unitary process.
In conclusion, although the present results need to be confirmed with a larger number of patients, the differences in cognitive function between the familial Parkinson's disease and sporadic Parkinson's disease patients suggest quantitatively different dopaminergic and nondopaminergic system impairments in each group. This hypothesis could be confirmed by accurate neuropathological and biochemical post-mortem examination of the brain in both familial Parkinson's disease and in sporadic Parkinson's disease. Dopaminergic and cholinergic structures in particular should be examined in such studies.
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Acknowledgments |
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We gratefully acknowledge the help of Bernard Pillon (INSERM EPI 0007, Hôpital de la Salpêtrière, Paris) who permitted use of the spatial location memory test. P. Rogelet, I. Delalande, S. Brique, B. Delisse and P. Houdart participated in clinical examination of the patients. This work was supported by a grant of the Lille CHU (PARKFANORD project)
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Received July 24, 2000. Revised October 3, 2000. Accepted October 9, 2000.
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