Stereotypic behaviors in degenerative dementias.

Stereotypies are simple or complex involuntary/unvoluntary behaviors, common in fronto-temporal dementia (FTD), but not studied in other types of degenerative dementias. The aim was to investigate stereotypy frequency and type in patients with FTD, Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and Parkinson's disease with dementia (PDD) in a multicenter observational study; and to investigate the relation of stereotypies to cognitive, behavioral and motor impairment. One hundred fifty-five consecutive outpatients (45 AD, 40 FTD, 35 PSP and 35 PDD) were studied in four hospitals in northern Italy. Stereotypies were examined by the five-domain Stereotypy Rating Inventory. Cognition was examined by the Mini Mental State and Frontal Assessment Battery, neuropsychiatric symptoms by the Neuropsychiatric Inventory, and motor impairment and invalidity by the Unified Parkinson's Disease Rating Scale part III, and activities of daily living. Stereotypies were present in all groups. FTD and PDD had the greatest frequency of one-domain stereotypies; FTD also had the greatest frequency of two-or-more domain stereotypies; movement stereotypies were the most common stereotypies in all groups. AD patients had fewer stereotypies than the other groups. Stereotypies are not exclusive to FTD, but are also fairly common in PSP and PDD, though less so in AD. Stereotypies may be underpinned by dysfunctional striato-frontal circuits, known to be damaged in PSP and PDD, as well as FTD.

Motor features and response to oral levodopa in patients with Parkinson's disease under continuous dopaminergic infusion or deep brain stimulation.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN DBS) and continuous dopaminergic infusions (jejunal levodopa or subcutaneous apomorphine) are indicated in complicated Parkinson's disease (PD), although it remains unsettled how they compare to each other. METHODS: We investigated the daytime motor condition in patients with advanced PD under monotherapy with jejunal levodopa, subcutaneous apomorphine, or STN DBS and also measured the motor changes produced by an additional standard morning dose of levodopa. Motor performance was assessed with the UPDRS-III, hand taps, the AIMS dyskinesia score and patients' diaries. Outcome measures were time to best motor 'on' after start of morning treatment, daytime variability of motor condition, motor scores. RESULTS: The time to 'on' was longest in the jejunal levodopa group. DBS and jejunal levodopa treatments produced stable motor conditions without appreciable 'off' episodes. Continuous apomorphine infusion was associated with the worst motor scores (UPDRS-III and taps) and the most frequent off-states. Jejunal levodopa infusion was associated with the highest AIMS scores. Addition of a levodopa dose produced shortening of time to 'on' and a transient motor improvement in the jejunal levodopa group without increase in dyskinesias; in the DBS and apomorphine groups, there was an increase in dyskinesias without changes in UPDRS-III or taps. CONCLUSIONS: STN DBS provided adequate trade-off between motor improvement and dyskinesia control, although dyskinesias could be elicited by adding oral levodopa. Jejunal levodopa infusion produced adequate motor improvement with slow time to 'on' and moderate dyskinesias. Apomorphine infusion produced insufficient motor control and negligible dyskinesias.

Diffusion tensor imaging shows different topographic involvement of the thalamus in progressive supranuclear palsy and corticobasal degeneration.

BACKGROUND AND PURPOSE: In progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), postmortem studies show different topographic involvement of the thalamus, basal ganglia, and their cortical connections. Diffusion tensor imaging (DTI) is an MR imaging technique sensitive to gray and white matter microstructure integrity. This study was performed to determine whether DTI may demonstrate microstructural differences between PSP and CBD, particularly within the thalamus and its cortical connections. MATERIALS AND METHODS: Nine patients with probable PSP, 11 with probable CBD, and 7 controls formed the study group. Apparent diffusion coefficient average (ADC(ave)) and fractional anisotropy (FA) values were measured in regions of interest positioned in the ventrolateral (motor), medial, anterior, and posterior regions of the thalami, basal ganglia, fronto-orbital white matter, cingulum, supplementary motor area (SMA), and precentral and postcentral gyri in patients and controls. RESULTS: In PSP, ADC(ave) values were increased in several areas: the thalamus, particularly in its anterior and medial nuclei; cingulum; motor area; and SMA. FA values were particularly decreased in the fronto-orbital white matter, anterior cingulum, and motor area. In CBD, ADC(ave) was increased in the motor thalamus, in the precentral and postcentral gyri, ipsilateral to the affected frontoparietal cortex, and in the bilateral SMA. FA was mainly decreased in the precentral gyrus and SMA, followed by the postcentral gyrus and cingulum. CONCLUSIONS: In patients with PSP, thalamic involvement was diffuse and prevalent in its anterior part, whereas in CBD involvement was asymmetric and confined to the motor thalamus. DTI may be useful in the differential diagnosis of these 2 parkinsonian disorders.

Impaired body movement representation in DYT1 mutation carriers.

OBJECTIVE: The only known genetic cause of early-onset primary torsion dystonia is the GAG deletion in the DYT1 gene. Due to the reduced penetrance, many mutation carriers remain clinically asymptomatic, despite the presence of subclinical abnormalities, mainly in the motor control circuitry. Our aim was to investigate whether the DYT1 mutation impairs the inner simulation of movements, a fundamental function for motor planning and execution, which relies upon cortical and subcortical systems, dysfunctional in dystonia. METHODS: DYT1 manifesting patients, DYT1 non-manifesting carriers and control subjects were asked to fixate body (hand, foot, face) or non-body (car) stimuli on a computer screen. Stimuli were presented at different degrees of orientations and subjects had to mentally rotate them, in order to give a laterality judgement. Reaction times and accuracy were collected. RESULTS: DYT1 carriers, manifesting and non-manifesting dystonic symptoms, were slower in mentally rotating body parts (but not cars) than control subjects. CONCLUSIONS: The DYT1 gene mutation is associated with a slowness in mental simulation of movements, independently from the presence of motor symptoms. SIGNIFICANCE: These findings suggest that the cognitive representation of body movements may be altered subclinically in dystonia, thus contributing to the endophenotypic trait of disease.

Progressive myoclonic ataxia with intrathecal immune activation in six patients.

In six patients with slowly progressive sporadic cerebellar ataxia and cortical multifocal action myoclonus, cerebrospinal fluid (CSF) IgG index was persistently very high (1.2-6.7) and numerous oligoclonal bands were detected. Progressive cognitive impairment and MRI cerebellar and cerebral atrophy were observed. No serum antibodies were found. Various degenerative, metabolic, inflammatory and systemic diseases were excluded. The cerebellum may be the main target of a degenerative or immune process and releases antigens that, enhancing a compartmentalised (auto)immune response, as suggested by the persistent intrathecal activation, could lead to further cerebellar damage. As the frequency of CSF oligoclonal banding in myoclonic ataxia is unknown, our patients' disease might represent a hitherto unreported entity or a subset of progressive myoclonic ataxia.

Progressive dysarthria: definition and clinical follow-up.

Progressive dysarthria is a common sign of several degenerative disorders of the central nervous system; it may also be a distinct nosographic entity. We identified nine patients in which progressive dysarthria remained the sole neurological sign for at least 2 years after onset. At least a year after hospital admission, the following diagnoses were made: two cases of corticobasal degeneration, one of frontotemporal dementia, one of primary progressive aphasia, one of motor neuron disease (MND)-dementia, one of ALS, and one of ALS-aphasia. In the remaining two patients progressive dysarthria remained the only neurological sign at latest examination. We conclude that in most cases progressive dysarthria is the presenting sign of an established neurodegenerative disease (generally degenerative dementia or motor neuron disease), although the possibility that progressive dysarthria is a distinct entity cannot be excluded. To clarify this issue, studies (probably multicenter) on more patients with longer clinical follow-up and pathological confirmation are required.

Distal-proximal differences in limb apraxia in corticobasal degeneration but not progressive supranuclear palsy.

Limb apraxia is an important diagnostic sign of cortico-basal degeneration (CBD), although it is also found in progressive supranuclear palsy (PSP). We investigated whether the severity of apraxia differed between proximal and distal arm movements in the two diseases, as suggested by their differing patterns of motor impairment. We studied 24 CBD patients, 25 PSP patients, and 19 healthy controls using a battery of cognitive tests and an ideomotor apraxia test that examined imitation of hand and of whole arm gestures separately. CBD and PSP patients did not differ in general characteristics or disability and were similarly impaired in cognitive performance. Within-group differences between distal and proximal gesture scores were significant only for CBD patients ( p=0.007), in whom distal movements were more compromised. This finding suggests the presence of limb kinetic apraxia in CBD, perhaps in association with ideomotor apraxia.

Cognitive and behavioral disturbances in Parkinson's disease.

The dysfunction of the striato frontal circuits that occurs in Parkinson's disease results in cognitive and behavioural problems as well as motor impairment. Depression is frequent and cognitive deficits also occur that progress with advancing illness, sometimes to subcortical dementia. Spread of Lewy bodies to the cortex, cholinergic and monoaminergic neurotransmission deficiency, or concurrent Alzheimer pathology may be the anatomical bases of dementia.

Neurophysiological features in relation to clinical signs in clinically diagnosed corticobasal degeneration.

We investigated the association between clinical and neurophysiological characteristics in patients with a clinical diagnosis of probable corticobasal degeneration (CBD), and searched for neurophysiological features supporting the diagnosis in life. Ten patients with clinically probable CBD underwent comprehensive neurological evaluation and brain MRI. Long latency reflexes (LLR), upper limb somatosensory (SEP) and motor evoked (MEP) potentials were recorded. The mini-mental state examination (MMSE), the phonemic verbal fluency test (PVFT) and the De Renzi ideomotor apraxia test were also performed. Polygraphic EEG was performed in the six patients with myoclonus. The SEP N30 frontal component was absent bilaterally in four patients, was absent on the left side in one, and had increased latency in other three. MEPs were abnormal in four patients (three had prolonged central motor conduction time, one of whom also had increased MEP threshold, and one had increased MEP threshold). All six patients with myoclonus had enhanced LLRs at rest, which were also of abnormally increased amplitude during motor activation; latencies were generally shorter than in classic cortical reflex myoclonus. On back-averaging, no EEG spikes time-locked to EMG activity were found in any myoclonus patient. Five patients were demented by MMSE, eight had ideomotor apraxia scores in the ideomotor apraxia range and five had defective verbal fluency. Brain MRI revealed asymmetric cortical atrophy in all patients, particularly evident frontoparietally. Neurophysiological techniques, particularly LLR, can assist CBD diagnosis especially in patients with myoclonus. Patients with evident parkinsonism had greater SEP N30 (frontal) abnormalities, while most patients with marked paresis had slower MEP times.

A study of arm movements in Huntington's disease under visually controlled and blindfolded conditions.

The so-called bradykinesia of Huntington's disease (HD) seems not due to reduced movement speed alone but may also be task-dependent. We therefore investigated the influence of visual control on the ability of HD patients to perform a motor task. Ten HD patients, never treated with neuroleptic drugs and with mild functional impairment in activities of daily living, performed the task blindfolded and not blindfolded, as did 10 age- and education-matched healthy controls. The task was to use the dominant hand to trace out the contours of a 20 x 20 cm square in a clockwise direction, pausing at each corner. The square was marked on the table at which the subject sat. Accuracy was stressed rather than speed. A videocamerabased system recorded movement trajectories, from which kinematic and error parameters were derived. Patients and controls moved at comparable speeds but patients took longer to complete the task due to more curvilinear and hence longer trajectories. Patients spent more time in the deceleration phase of the movement, and in the blindfold condition had more variable movements as indicated by greater error variability scores. Correlation analysis showed that kinematic parameters in patients did not correlate with involuntary movement scores. These findings indicate that abnormalities of motor control are present in HD when movement accuracy (and not velocity) is required. HD patients are more dependent on visual control than normal subjects.

Cognitive and psychiatric characterization of patients with Huntington's disease and their at-risk relatives.

We examined cognitive and psychiatric disturbances in patients with Huntington's disease (HD) in comparison to at-risk asymptomatic subjects. Cognitive and psychiatric scales and an HD motor scale were administered to 40 HD patients, 17 pre-symptomatic HD gene carriers (AR+) and 28 non gene carriers (AR-). HD patients did worse than AR+ and AR- in all motor, cognitive and psychiatric measures, while AR+ and AR-subjects did not differ between each other. HD patients had high scores for negative psychiatric symptoms, but there was no correlation between illness duration and psychiatric or cognitive performance. In HD, disease course and symptomatology are heterogeneous and negative psychiatric symptoms are common.

Comparison of natural histories of progressive supranuclear palsy and multiple system atrophy.

In order to identify early clinical features and survival predictors of supranuclear palsy (PSP) and multiple system atrophy (MSA), we compared the disease course of patients consecutively referred between 1987 and 1999 and followed to December 1999. Thirty-nine PSP and 74 MSA patients were diagnosed according to commonly accepted clinical criteria. Length of survival was ascertained from death certificates or by contacting relatives. Ten-year survival after disease onset was 29% for both disorders. Median survival was 7.0 years (PSP) and 7.5 (MSA). Neither age, symptoms at onset, or disability at diagnosis predicted survival. At diagnosis, all PSP patients had oculomotor palsy, whereas 89% of MSA patients had dysautonomia; bradykinesia and falls were the most frequent common signs. Distinctive early signs were palilalia, cognitive impairment and hyperreflexia in PSP; hypophonia, anterocollis and dysautonomia in MSA. MSA patients responded better to levodopa. Attention to early distinctive features can improve differential diagnosis and inform subsequent management.

Effect of bilateral subthalamic electrical stimulation in Parkinson's disease.

BACKGROUND: Bilateral high frequency subthalamic stimulation has been reported to be effective in the treatment of Parkinson's disease and levodopa-induced dyskinesias. To analyze the results of this surgical procedure we critically reviewed 17 parkinsonian patients with advanced disease complicated by motor fluctuations and dyskinesias. METHODS: Between January 1998 and June 1999 these 17 consecutive patients (age 48-68 years; illness duration 8-27 years) underwent bilateral stereotactically guided implantation of electrodes into the subthalamic nucleus in the Department of Neurosurgery of the Istituto Nazionale Neurologico "C. Besta." Parameters used for continuous high-frequency stimulation were: frequency 160 Hz, pulse width 90 microsec, mean amplitude 2.05 +/- 0.45 V. Parts II and III of the UPDRS were used to assess motor performance before and after operation by the neurologic team. The follow-up ranged between 6 and 18 months. RESULTS: At latest examination, mean UPDRS II and III scores had improved by 30% (on stimulation, off therapy) with mean 50% reduction in daily off time. Peak dyskinesias and early morning dystonias also improved in relation to therapy reduction. Side effects were persistent postoperative supranuclear oculomotor palsy and postural instability in one case, worsened off-medication hypophonia in three, and temporary nocturnal confusion episodes in three. Postoperative MRI revealed a clinically silent intracerebral haematoma in one case. One electrode required repositioning. CONCLUSIONS: Continuous high frequency STN stimulation is an effective treatment for advanced PD. A functionally useful and safe electrode placement can be performed without microrecording.

Non-motor effects of deep brain stimulation of the subthalamic nucleus in Parkinson's disease: preliminary physiological results.

Although deep brain stimulation (DBS) is a clinically effective therapy for patients with advanced Parkinson's disease (PD), its physiological effects on the brain and possible actions on non-motor functional systems remain largely unknown. This study evaluated the effects of DBS of the subthalamic nucleus (STN) on neurophysiological variables and on cardiovascular physiology. Nine patients affected by PD undergoing chronic DBS of the STN have been studied. We performed electroencephalography (EEG), somatosensory (SEPs) and visual evoked potentials (VEPs), exteroceptive masseteric silent period and sympathetic skin response (SSR) studies with DBS ON and OFF. To assess the effects of stimulation on the cardiovascular system the tilt test and plasma renin activity were studied. When we turned the DBS OFF, both SEP N20 and the VEP P100 component increased significantly in amplitude whereas the SSR decreased in amplitude and increased in latency. Although plasma renin activity tended to increase with DBS OFF, its modification induced by postural changes and blood pressure values did not significantly differ with DBS ON and OFF. We conclude that DBS of the STN in PD, besides inducing a clinical improvement, induces several non-motor effects.

Acute effects of bilateral subthalamic nucleus stimulation on clinical and kinematic parameters in Parkinson's disease.

After implantation with subthalamic stimulators, nine patients with advanced Parkinson's disease were studied on the task of tracing out, as accurately as possible, the four corners of a square with the dominant hand. The task was performed in four treatment conditions: on stimulation-off medication, off stimulation-off medication, off stimulation-on medication, and on stimulation-on medication. Movement times and peak velocities improved significantly only in the on stimulation-on medication condition compared to off stimulation-off medication. The improvement in clinical parameters with stimulation only (relative to off stimulation off medication) was of borderline significance, while consistent and significant clinical improvement was only obtained with addition of medication (on medication-on stimulation). This study provides quantitative evidence of the effect of subthalamic stimulation on kinematic measures in Parkinson's disease (PD) and suggests that combined treatment (medication and stimulation) is superior to either treatment alone.

Neuropsychological follow up in patients with Parkinson's disease, striatonigral degeneration-type multisystem atrophy, and progressive supranuclear palsy.

OBJECTIVES: Impairment of executive function is frequent in Parkinson's disease (PD), striatonigral degeneration-type multisystem atrophy (SND), and progressive supranuclear palsy (PSP); sometimes frank dementia is also present. However, the progression of cognitive decline has not been adequately studied. The objectives were to delineate the progression of cognitive impairment in these parkinsonisms and to elucidate interdisease differences. METHODS: Twenty three patients with SND and 21 with PSP, referred consecutively, and 18 patients with PD matched for severity of parkinsonism were compared on a comprehensive battery of cognitive tests and motor invalidity scales. A mean of 21 months later (range 18-24 months) the patients were called for retesting. RESULTS: Only 12 patients with PD (66.6%), 14 with SND (60.8%), and 11 with PSP (52.4%) were retested; those who dropped out refused, had died, or were too disabled. The patients with PSP performed worse than patients with PD or SND in the short tale, verbal fluency, visual search, and Benton tests at first evaluation. Overall cognitive performance was similar in the PD and SND groups except that the SND group did significantly worse on the verbal fluency test. Between group comparison of changes in scores from first to second evaluation showed that patients with PSP deteriorated significantly in the Nelson test compared with patients with PD or SND, and that patients with PSP or SND declined significantly on the visual search test compared with patients with PD. There was no difference between the groups for motor decline. Two patients with PSP were demented (DSM IV criteria) at first evaluation and six at second evaluation; no patients with PD or SND were demented at either evaluation. CONCLUSIONS: The greater decline of patients with PSP in attention, set shifting, and categorisation abilities is probably related to the conspicuous frontal deafferentation associated with direct premotor and prefrontal involvement, and to dysfunction of the midbrain ascending activating system, known to occur in PSP.

Cognitive and magnetic resonance imaging aspects of corticobasal degeneration and progressive supranuclear palsy.

OBJECTIVE: To identify cognitive and MRI features important for the clinical diagnosis of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP); these diseases share several clinical features and are often difficult to distinguish on clinical grounds. METHODS: Cognitive functions and MRI characteristics were examined in 16 patients with CBD and 28 patients with PSP, all diagnosed according to current clinical criteria (none was examined by autopsy). RESULTS: MRI findings differed significantly between the two groups: 87.5% of patients with CBD but none with PSP had asymmetric frontoparietal atrophy, whereas 89.3% of patients with PSP but only 6.3% of those with CBD had midbrain atrophy. Cognitive examination showed that ideomotor apraxia (De Renzi's test) was significantly more frequent in CBD, and executive functions (Nelson's test) were significantly more impaired in patients with PSP. CONCLUSIONS: MRI findings of asymmetric frontoparietal atrophy in CBD and midbrain atrophy in PSP are the most consistent and useful aids to careful clinical evaluation for differentiating between the two diseases.

Affective symptoms in multiple system atrophy and Parkinson's disease: response to levodopa therapy.

The objective was to determine the extent to which psychiatric disturbances (especially mood disorders) generally considered poor prognostic factors, are present in patients with striatonigral (SND) type multiple system atrophy (MSA) compared with patients with idiopathic Parkinson's disease (IPD). The Hamilton depression scale (HAM-D), brief psychiatric rating scale (BPRS), and Unified Parkinson's disease rating scale (UPDRS) were administered to clinically probable non-demented patients with SND-type MSA and patients with IPD matched for age and motor disability, at baseline and after receiving levodopa. At baseline total HAM-D score was greater in patients with IPD. Overall, BPRS score did not differ between the two groups; however, patients with IPD scored higher on anxiety items of the BPRS, and patients with MSA had higher scores on the item indicating blunted affect. After levodopa, both groups improved significantly in UPDRS and HAM-D total scores (just significant for patients with MSA). Patients with IPD improved significantly in total BPRS score but patients with MSA did not. At baseline patients with IPD were more depressed and anxious than patients with MSA who, by contrast, showed blunted affect. After levodopa, depression and anxiety of patients with IPD improved significantly whereas the affective detachment of patients with MSA did not change. Major neuronal loss in the caudate and ventral striatum, which are part of the lateral orbitofrontal and limbic circuits, may be responsible for the blunted affect not responsive to levodopa therapy found in patients with MSA.

Executive processes in Parkinson's disease--random number generation and response suppression.

In producing random numbers, subjects typically deviate systematically from statistical randomness. It is considered that these biases reflect constraints imposed by underlying structures and processes, rather than a deficient concept of randomness. Random number generation (RNG) places considerable demands on executive processes, and provides a possibly useful tool for their investigation. A group of patients with Parkinson's disease (PD) and a group of controls were tested on a RNG task, both alone and with a concurrent attention-demanding task (manual tracking). Both groups showed the biases in RNG described previously, including a strong counting tendency and repetition avoidance. Overall RNG performance did not differ between the groups, although differences were found in the counting biases in the patient and control groups, with the controls showing a bias towards counting in twos, and the patients a bias towards counting in ones. The secondary task reversed the bias shown by controls and exacerbated the bias in the patients. A network modulation model may help explain many of the features of RNG. We suggest that naturally biased output from an associative network must be actively suppressed by an attention-demanding, limited-capacity process. This suppression may be disrupted by the pathophysiology of PD and by concurrent tasks. Convergent evidence from various sources is discussed which supports a role of the dorsolateral prefrontal cortex (DLPFC) in this process.

Cognitive dysfunction and impaired organization of complex motility in degenerative parkinsonian syndromes.

BACKGROUND: A frontostriatal pattern of cognitive decline, consisting of a frontal lobe-like syndrome without genuine cortical defects such as amnesia, apraxia, aphasia, or agnosia, is well established in basal ganglial diseases. Recent pathological investigations, however, have again noted cortical damage in progressive supranuclear palsy (PSP), suggesting that cortical defects could be present. OBJECTIVES: To delineate the pattern of cognitive impairment and to detect higher-order motor impairments (including ideomotor apraxia) in parkinsonian syndromes. PATIENTS AND METHODS: We assessed ideomotor apraxia, and simple and sequential tapping in patients with Parkinson disease, multiple system atrophy, and PSP with similar disease severity, age range, and education. We also administered a comprehensive battery of neuropsychological tests to examine general intelligence, memory, executive functions, attention, and visuospatial orientation. The results were compared between groups and with a matched normal control group. RESULTS: Sequential tapping and the imitation of sequences of gestures were impaired in all patient groups, with patients with PSP performing worse than the other groups. Based on ideomotor apraxia scores and a qualitative analysis of errors, 3 patients with PSP and 2 with multiple system atrophy were considered apraxic. General intelligence and executive functions were compromised in all patient groups. The impairment of patients with PSP was more pervasive than that of the other groups, and included compromise of visuospatial functions, attention, and memory. Discriminant analysis of all cognitive and motor tests showed that the tapping and ideomotor apraxia tests best identified the patients vs control subjects. CONCLUSIONS: The presence of cortical as well as subcortical damage in patients with PSP and those with multiple system atrophy is indicated by the presence of pervasive cognitive and motor disturbances in the former, substantial motor disorganization in the latter, and the finding of ideomotor apraxia in some patients with these diseases. Furthermore, the discovery that tests of motor and gesture best identified all patients vs control subjects is consistent with the existence of a common motor disorganization in these parkinsonian syndromes, in agreement with the known damage to the corticostriatal pathways in these conditions.