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Mean indicative values adapted from refs. 6, 22, 29, 32, 52.

-, absent; ±, mild or discussed; +, moderate or present in a proportion of patients; ++, severe and present in a majority of patients.

Mean indicative values adapted from refs. 6, 22, 29, 32, 52.

-, absent; ±, mild or discussed; +, moderate or present in a proportion of patients; ++, severe and present in a majority of patients.

Parkinson's Disease

Cognitive changes in the majority of patients with PD are subtle and mainly restricted to attentional and retrieval deficits. It is only by using appropriate neuropsychological tests that these cognitive changes can be detected. They mainly concern (a) the visuospatial domain, observed in visuospatial paradigms that require self-elaboration of the response or forward-planning capacity; (b) memory, that is, working memory and long-term memory, especially in tasks that involve self-organization of the to-be-remembered material, temporal ordering and conditional associative learning, and procedural learning; and (c) executive functions, namely concept formation and problem solving, set-maintenance and set-shifting (for a review, see ref. 46).

Mood and behavioral changes are also described in PD. Depression is encountered in about 30% of patients and has been the focus of a large number of studies (47). It is important to diagnose it because depression induces attention and memory disorders and, if sufficiently severe, impairs cognitive functions especially those of the executive system in relation to a significant decrease in frontal metabolism evidenced on positron emission tomography (PET) scan studies. More recently, attention has been drawn to apathy and its relation to basal ganglia disorders. Apathy is not infrequent in PD and has repercussions on cognitive functions, affect, and behavior (48,49).

Unlike depression, anxiety symptoms almost always begin after the onset of the motor symptoms and are related to medication-induced on-off fluctuations and wearing-off condition in most of the cases. Drug-induced psychiatric disorders are frequently found in PD and mainly consist of hallucinations and delusions. These disorders are, however, much more frequent in PDD or DLB (44).

To conclude, the clinical diagnosis of PD relies on the evidence of a parkinsonian syndrome responsive to levodopa in the absence of severe intellectual or memory dysfunction. This is the rule, at least, in the young-onset form of the disease. In the late-onset one, however, a subcorticofrontal dementia may occur after several years of evolution, which may result from the compounding effect of disease-related neuronal lesions and age-related neuronal changes (50). PDD is characterized by a marked dysexecutive syndrome, accompanied by a severe amnesic syndrome with a persistent response to cuing, in the absence of true aphasia, apraxia, or agnosia, and may be difficult to diagnose. DSM-IV criteria of dementia (18) are well suited to AD, but less appropriate for PD because the severe motor deficits may themselves affect patient's autonomy. Moreover, an overestimation of the severity of cognitive impairment may result from nonspecific factors (akinesia, hypophonia, depression, anxiety, marked cognitive slowing with delay in responses, uncontrolled dyskinesias) that interfere with the evaluation of cognitive functions.

Multiple System Atrophy

Cognitive changes are mild in the parkinsonian variant of MSA (MSA-P, previously called striatonigral degeneration), at least in the early stage of the disease, before patients reach a severe akinetic state with dysarthria, which may affect the cognitive evaluation. The few studies of cognition in MSA, including the MSA-P variant, display few differences from the neuropsychological pattern of PD: some more severe deficits in the Stroop test (51) or in verbal fluency (52). In our experience, neuropsychological testing does not help to distinguish between the two disorders. In contrast, when faced to an axial parkinsonian syndrome poorly responsive to levodopa, the absence of a severe subcorticofrontal syndrome strongly favors the diagnosis of MSA-P and decreases the probability for PSP (22,53).

Psychiatric disorders have been poorly studied in MSA-P. Depression, anxiety, and emotional lability have been described, but not psychosis (54).

Progressive Supranuclear Palsy

Cognitive and behavioral changes are consistent even in the early stages of the disease. Cognitive slowing and inertia occur in the first year in 52% of cases. As the disease progresses, these changes progressively worsen. From 24 patients who underwent two or more neuropsychological evaluations over time, 38% showed a global impairment at their first examination, and 70% 15 mo later. The changes may become severe enough to warrant the diagnosis of dementia, but the deficits still conform to the pattern of subcorticofrontal dementia. The dysexecutive syndrome of PSP is much more severe than that observed in any other subcortical disorders, and the memory deficit is dramatically improved in conditions that facilitate retrieval processing such as cueing and recognition.

Cognitive slowing appears evident in patients with PSP, who answer questions and solve even the simplest problems with delay. It is a genuine slowing of central-processing time unrelated to motor or affective disorders, as demonstrated experimentally using reaction time tasks (55) and event-related brain potentials (56).

Cognitive slowing may contribute to decreased lexical fluency that is more severely impaired in patients with PSP than in patients with PD or AD, although naming is more affected in the latter (25). The deficit is observed in different types of fluency, including semantic fluency, where patients have to list animal names or objects that can be found in a supermarket, phonemic fluency, where patients are required to produce words beginning with a given letter, and design fluency, where patients must produce abstract designs (57).

A tendency to perseverate may also account for some of the deficits, particularly in tasks involving concept formation and shifting ability. In the Wisconsin Card Sorting Test, PSP patients complete a smaller number of categories than patients with PD or MSA-P. This lack of flexibility affects both categorical and motor sequencing, as shown by the poor performance of patients with PSP in the Trail Making Test and in the motor series of Luria. Patients with PSP also experience difficulty in conceptualization and problem-solving ability, which may account for their poor performance in similarities, interpretation of proverbs, comprehension of abstract concepts, arithmetic and lineage problems, tower tasks, and picture arrangement.

This severe dysexecutive syndrome contributes to the memory deficits and instrumental disorders observed in PSP. Short-term memory was found to be impaired using the Brown-Peterson paradigm, a working memory task in which the patients were more sensitive than controls to interference. Long-term memory is also disturbed in PSP, as shown by immediate and delayed recall of the subtests of the Wechsler Memory Scale, the Rey Auditory Verbal Learning Test, and the California Verbal Learning Test. However, when encoding is controlled by using semantic category cues and when recall is performed with the same cues, as in the Grober and Buschke procedure, recall performance of the patients dramatically improves, confirming that there is no genuine amnesia in the disease (29).

Various speech disorders have been described in PSP. A severe reduction of spontaneous speech resembling dynamic aphasia is usually observed (58), but abnormal loquacity has also been reported. Word-finding difficulty may occur, but it is generally less severe than in AD patients. Semantic or syntactic comprehension disorders are absent or mild. Dynamic apraxia may be found (32). Bilateral apraxic errors for transitive and intransitive movements have been reported, but they are much less severe than in CBD (59). Visual and auditory perception may be disturbed, but there is no evidence of object agnosia or alexia. Therefore, instrumental disorders of patients with PSP, when present, are rather considered to be a consequence of impaired executive and perceptual-motor functions or attentional disorders.

Besides cognitive impairment, patients with PSP exhibit behavioral disorders. They show severe difficulty in self-guided behavior and are abnormally dependent on stimuli from the environment. They involuntarily grasp all the objects presented in front of them; they imitate the examiner's gestures passively and use objects in the absence of any explicit verbal orders (25). Such uncontrolled behaviors are never observed in normal control subjects in the absence of explicit demands and are considered to result from a lack of the inhibitory control normally exerted by the frontal lobes (12). PSP patients also have difficulty in inhibiting an automatic motor program once it is initiated. This can easily be evaluated with the "signe de l'applaudissement" ["clapping sign"] (60): when asked to clap their hands three times consecutively, as quickly as possible, these patients have a tendency to clap more (four or five times), sometimes initiating an automatic program of clapping that they are unable to stop, as if they had difficulty in programming voluntary acts that compete with overlearned motor skills. This sign seems to be specific to striatal dysfunction occurring in PSP (61). Changes in mood, emotion, and personality have also been described: most frequently bluntness of affective expression and lack of concern about personal behavior or the behavior of others, but sometimes obsessive disorders or disinhibition with bulimia, inappropriate sexual behavior, or aggressiveness. These changes are difficult to investigate, given the lack of insight and the transient nature of the emotions expressed. The testimony of caregivers is therefore required. Administering the Neuropsychiatry Inventory (NPI) to patients' informants showed that patients with PSP exhibited apathy almost as a rule, since it was observed in 91% of the cases (43). Apathy was more frequent in PSP than in any other parkinsonian syndrome.

Corticobasal Degeneration

The cognitive profile of this disease is distinct from that of PSP, because of the presence of signs suggestive of cortical involvement. Many patients present only limb clumsiness and gesture disorders at the first examination, without any—or with few—cognitive or behavioral symptoms (26). In contrast, the disease may begin by other signs of cortical involvement, particularly nonfluent progressive aphasia (62). Finally, a severe frontal cognitive and behavioral syndrome may initiate the disease in some patients (63).

CBD is typically defined by unilateral rigidity of one arm with apraxic features, accounting for the proposition of the new term "progressive asymmetric rigidity and apraxia syndrome" (64). Gesture disorders are so characteristic of the disease that the diagnosis can be suspected on the simple analysis of the motor disturbances. They consist, at first, of the patient experiencing difficulty or showing perplexity in the performance of delicate and fine movements of the fingers of one hand. At this stage, patients complain of clumsiness and loss of manual dexterity, reminiscent of "limb apraxia," variously described as "kinesthetic" in patients with lesions of the parietal cortex, or "kinetic" in patients with lesions of the premotor cortex. Systematic evaluation shows disorders of dynamic motor execution (impaired bimanual coordination, temporal organization, control, and inhibition) (32). Asymmetric praxis disorders (difficulty in posture imitation, symbolic gesture execution, and object utilization) are also regularly observed, even at this stage. Ideomotor apraxia is frequent, especially in patients who have initial symptoms in the right limb, in agreement with the hypothesis of a predominant storage of "movement formulae" in the left hemisphere (65). In addition, central deficits in action knowledge and mechanical problem solving have been linked to parietal lobe pathology (66). "Alien limb phenomenon," in which a limb behaves in an uncooperative or foreign way, has been attributed to lesions affecting the supplementary motor area. Its occurrence, in the absence of a known callosal lesion, would be highly suggestive of the diagnosis of CBD.

Other signs of cortical involvement have been observed in CBD. Linguistic disturbances are found, consisting of word-finding difficulties, decreased lexical fluency, transcortical motor aphasia, or progressive phonetic disintegration (67). These deficits resembling primary progressive nonfluent aphasia can even be an initial symptom of CBD. Neglect and visuospatial deficits have also been reported. Constructive apraxia is observed in patients with predominant right-hemisphere lesions, in relation with the well-known influence of this hemisphere on visuospatial function.

Other cognitive changes resemble the subcorticofrontal dysfunction of PSP: a dysexecutive syndrome and a learning deficit that can be alleviated by semantic cuing (32). The environmental dependency syndrome, thought to be related to a release of the inhibition normally exerted by the frontal lobes on the activity of the parietal lobes (12), is less frequent, however, in CBD than in PSP, probably because of the parietal lobe dysfunction in this disease. Early subcorticofrontal syndrome in CBD would predict a shorter survival.

In most of the clinical studies performed on CBD patients, the level of intellectual deterioration was mild or moderate until an advanced stage of the disease. In some cases, however, patients with a severe dysexecutive syndrome associated with memory disorders and impaired instrumental activities may reach the threshold of dementia in which both cortical and subcorticofrontal components play a role. Thus, dementia is not infrequent in CBD and may even be observed from the onset in unusual clinical presentation. In 10 out of 13 cases with pathologically proven CBD, dementia was noticed within 3 yr of onset of symptoms (68).

Besides frontal lobe-type behavioral alterations, patients with CBD may present neuropsychiatry disorders. In a series of CBD patients, the NPI showed that depression, apathy, irritability, and agitation were the symptoms most commonly exhibited (45). The depression and irritability of patients with CBD were more frequent and severe than those of patients with PSP, whereas patients with PSP exhibited more apathy.

Dementia With Lewy Bodies

The diagnosis of DLB can be suspected clinically on the basis of the early occurrence of a cognitive decline resembling a chronic confusional state with fluctuating cognitive signs and visual and/or auditive hallucinations in a patient with mild parkinsonism (69). The rapidly progressive dementia is accompanied by aphasia, dyspraxia, or spatial disorientation, suggestive of temporoparietal dysfunction. The neuropsychological profile differs from that of patients with AD: cognitive deficits are more acute, attentional fluctuations more intense, and psychotic features appear earlier. Moreover, patients with DLB present a more severe dysexecutive impairment but less severe memory deficits than patients with AD (34). The neuropsychological pattern of DLB can also be distinguished from the subcortical dementia of PD on the basis of the early occurrence of cognitive deficits and psychotic features, and the presence of linguistic and visuospatial disorders (44,70). It is, however, controversial whether DLB constitutes a disorder different from or overlapping with PDD. By convention, DLB is only considered when the cognitive changes appear before, with or within 1 yr after the occurrence of parkinsonism and cannot be proposed when they appear several years later (69). At a

Table 3

Diagnostic Contribution of Motor and Cognitive Deficits

Table 3

Diagnostic Contribution of Motor and Cognitive Deficits

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