Paola Soliveri

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.

Reduced risk factors for vascular disorders in parkinson disease patients : A case-control study

Background and Purpose— Sympathetic hyperactivity is a contributing cause of vascular disorders because it increases blood pressure, blood sugar, and blood lipids. Pervasive compromise of the central and peripheral autonomic nervous systems is common in idiopathic Parkinson disease (IPD) resulting in reduced sympathetic and parasympathetic function. We hypothesized that IPD was associated with reduced prevalence of cardiovascular disease risk factors as a result of reduced sympathetic activity. Methods— We performed a retrospective case-control study on 178 newly diagnosed consecutive IPD patients, and 533 age- (±3 years) and sex-matched controls with other neurological diseases seen over the same period at the same hospital. For each case and control the following were noted on admission: smoking, diabetes, hypertension, body mass index, serum glucose, plasma cholesterol, triglycerides and total lipid levels, and blood pressure. Results— Diabetes, history of smoking, high blood pressure, high blood glucose, high blood cholesterol, and triglycerides were significantly less frequent in IPD than controls. Conclusions— IDP is a natural model of impaired hypothalamic-pituitary-adrenal axis activity and generalized sympathetic denervation. We interpret the association of untreated IPD with reduced vascular diseases risk factors as attributable to reduced autonomic activity, suggesting that autonomic hyperactivity may be involved in the pathogenesis of vascular disorders.

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 Parkinsons 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.

Motor and cognitive performances of parkinsonian patients in the on and off phases of the disease.

Twenty-one Parkinsonian patients were tested in on and off phases during chronic levodopa therapy for cognitive function, affective status, and evaluation of motor performance with reaction and movement times. A worsening of mood was observed from the on to the off phase. No variation in cognitive performance was observed from the on to the off phase in spite of evident motor changes. Mood changes during on-off variations may reflect involvement of mesocortical and mesolimbic dopaminergic systems.

Dementia and cognitive impairment in Parkinson's disease.

The frequency of dementia, the clinical characteristics and the pattern of cognitive impairment were studied in 147 unselected Parkinsonian patients. Twenty-one patients (14.28%) were judged to be demented. They had a more severe and widespread cognitive deficit although they were affected particularly in those tests that already discriminated Parkinsonian patients from controls. A direct comparison of Parkinsonian dementia with other types of dementia is needed to validate the concept of subcortical dementia.

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.

Effect of neuroleptic treatment on involuntary movements and motor performances in Huntington's disease.

Eighteen patients with Huntingtons chorea were examined before and after neuroleptic treatment (haloperidol, pimozide, tiapride) to study the effect of such treatment on hyperkinesia and motor performance. Pimozide and haloperidol improved hyperkinesia; none of the drugs significantly affected motor performance. No correlation was found between the severity of hyperkinesia and motor performance scores, or between hyperkinesia and intelligence score, before and after therapy.

Cause and course in a series of patients with sporadic chorea

Abstract.Objective: To identify correlations between clinical and neuroimaging features in sporadic chorea and to explicate the evolution of choreas of differing aetiologies. Methods: We analysed the clinical and neuroimaging data of 51 consecutive cases (17 males, 34 females; age 16–95 years) of sporadic chorea admitted to the neurology departments of two general hospitals from January 1994 to December 1999, and two neurological institutes from January 1997. Six months later the patients were reassessed clinically and those still with chorea (20 cases) were asked to undergo the genetic tests for Huntingtons disease and dentatorubropallidoluysian atrophy. Results: There were 9 cases of focal dyskinesias, 18 of hemichorea, and 24 of generalised chorea; onset was acute in 17, subacute in 27, and insidious in seven. Analysis permitted classification as follows: vascular-related (21 cases); vasculitis (1 case); hypoxia (2 cases); drug-induced (7 cases); AIDS-related (5 cases), borreliosis (1 case); Sydenhams chorea (1 case); hyperglycaemia (2 cases); hyponatraemia (2 cases); Huntingtons disease (HD) (5 cases) and acanthocytosis (1 case). In 3 patients neither etiological factors nor neuroradiological alterations were found. Conclusions: Although a convincing concordance between choreic signs and neuroradiological findings was possible in 4 patients only, it was possible to assign an aetiology in most cases with vascular related causes the most frequent and metabolic factors often participating. Huntingtons disease is not unusual as a cause of sporadic choreas. HIV infection is an emerging cause of chorea and AIDS-related disease should be considered in young patients presenting without a family history of movement disorders. We emphasize the importance of follow-up to identify persistent chorea for which genetic testing is mandatory.

Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48.

Hereditary spastic paraplegias are a heterogeneous group of neurodegenerative disorders, clinically classified in pure and complex forms. Genetically, more than 70 different forms of spastic paraplegias have been characterized. A subgroup of complicate recessive forms has been distinguished for the presence of thin corpus callosum and white matter lesions at brain imaging. This group includes several genetic entities, but most of the cases are caused by mutations in the KIAA1840 (SPG11) and ZFYVE26 genes (SPG15). We studied a cohort of 61 consecutive patients with complicated spastic paraplegias, presenting at least one of the following features: mental retardation, thin corpus callosum and/or white matter lesions. DNA samples were screened for mutations in the SPG11/KIAA1840, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG48/AP5Z1 and SPG54/DDHD2 genes by direct sequencing. Sequence variants were found in 30 of 61 cases: 16 patients carried SPG11/KIAA1840 gene variants (26.2%), nine patients carried SPG15/ZFYVE26 variants (14.8%), three patients SPG35/FA2H (5%), and two patients carried SPG48/AP5Z1 gene variants (3%). Mean age at onset was similar in patients with SPG11 and with SPG15 (range 11-36), and the phenotype was mostly indistinguishable. Extrapyramidal signs were observed only in patients with SPG15, and epilepsy in three subjects with SPG11. Motor axonal neuropathy was found in 60% of cases with SPG11 and 70% of cases with SPG15. Subjects with SPG35 had intellectual impairment, spastic paraplegia, thin corpus callosum, white matter hyperintensities, and cerebellar atrophy. Two families had a late-onset presentation, and none had signs of brain iron accumulation. The patients with SPG48 were a 5-year-old child, homozygous for a missense SPG48/AP5Z1 variant, and a 51-year-old female, carrying two different nonsense variants. Both patients had intellectual deficits, thin corpus callosum and white matter lesions. None of the cases in our cohort carried mutations in the SPG21/ACP33 and SPG54/DDH2H genes. Our study confirms that the phenotype of patients with SPG11 and with SPG15 is homogeneous, whereas cases with SPG35 and with SPG48 cases present overlapping features, and a broader clinical spectrum. The large group of non-diagnosed subjects (51%) suggests further genetic heterogeneity. The observation of common clinical features in association with defects in different causative genes, suggest a general vulnerability of the corticospinal tract axons to a wide spectrum of cellular alterations.

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

Abstract. 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.