Biomedical subjects
Publications and source records attributed to G Pezzoli.
We report the results of a family-based study of LRRK2 G2019S penetrance in Parkinson disease. We studied 19 families identified through the analysis of unrelated consecutive patients. The cumulative incidence of the disease was 15% at 60 years, 21% at 70 years, and 32% at 80 years. This study provides accurate estimates of G2019S penetrance by minimizing the selection bias.
BACKGROUND: Polymorphisms in the glutathione S-transferase pi gene (GSTP1), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the GenePD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. METHODS: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. RESULTS: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. CONCLUSIONS: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.
In this study a comparative analysis of iron molecules during aging was performed in locus coeruleus (LC) and substantia nigra (SN), known targets of Parkinson's Disease (PD) and related disorders. LC and SN neurons, especially the SN pars compacta, degenerate in PD and other forms of parkinsonism. Iron and its major molecular forms, such as ferritin and neuromelanin (NM), were measured in LC and SN of normal subjects at various ages. Iron levels were lower, H-ferritin/iron ratio was higher and the iron content in NM was lower in LC than in SN. Iron deposits were abundant in SN tissue, very scarse in LC tissue and completely absent in pigmented neurons of both SN and LC. In both regions H- and L-ferritins were present only in glia. This suggests that in LC neurons iron mobilization and toxicity is lower than that in SN and is efficiently buffered by NM. Ferritins accomplish the same buffering function in glial cells.
A decline in verbal fluency is the most consistent neuropsychological sequela of deep brain stimulation (DBS) for Parkinson's disease. We assessed clinical correlates and switching and clustering subcomponents in 26 parkinsonians undergoing subthalamic DBS. Post-surgical motor improvement was accompanied by worsening at both letter and category fluency tasks. Total number of words and switches decreased, while average cluster size was unchanged. Worsening tended to be prominent in patients with baseline poorer cognitive status and more depressed mood. Impairment of shifting suggests prefrontal dysfunction, possibly due to disruption of fronto-striatal circuits along the surgical trajectory and/or to high frequency stimulation itself.
BACKGROUND: The clinical condition of advanced Parkinson's disease (PD) patients is often complicated by motor fluctuations and dyskinesias which are difficult to control with available oral medications. OBJECTIVE: To compare clinical and neuropsychological 12 month outcome following subcutaneous apomorphine infusion (APO) and chronic deep brain stimulation of the subthalamic nucleus (STN-DBS) in advanced PD patients. METHODS: Patients with advanced PD and medically untreatable fluctuations underwent either APO (13 patients) or STN-DBS (12 patients). All patients were clinically (UPDRS-III, AIMS, 12 h on-off daily) and neuropsychologically (MMSE, Hamilton-17 depression, NPI) evaluated at baseline and at 12 months. APO was discontinued at night. RESULTS: At 12 months APO treatment (74.78+/-24.42 mg/day) resulted in significant reduction in off time (-51%) and no change in AIMS. Levodopa equivalent medication doses were reduced from 665.98+/-215 mg/day at baseline to 470+/-229 mg/day. MMSE, NPI, and Hamilton depression scores were unchanged. At 12 months STN-DBS resulted in significant clinical improvement in terms of reduction in daily off time (-76%) and AIMS (-81%) as well as levodopa equivalent medication doses (980+/-835 to 374+/-284 mg/day). Four out of 12 patients had stopped oral medications. MMSE was unchanged (from 28.6+/-0.3 to 28.4+/-0.6). Hamilton depression was also unchanged, but NPI showed significant worsening (from 6.58+/-9.8 to 18.16+/-10.2; p<0.02). Category fluency also declined. CONCLUSIONS: Both APO and STN-DBS resulted in significant clinical improvement in complicated PD. STN-DBS resulted in greater reduction in dopaminergic medications and provided 24 h motor benefit. However, STN-DBS, unlike APO, appears to be associated with significant worsening on NPI resulting from long term behavioral problems in some patients.
Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.
Several patients with Parkinson' s disease (PD) reveal an history of chronic exposure to hydrocarbon-solvents. Chronic exposure to hydrocarbon-solvents has been proposed as a risk factor for more severe forms of PD with earlier onset of symptoms and reduced response to dopaminergic therapy. A direct correlation between disease severity and exposure degree has been previously shown. Seven exposed PD patients (two with low degree exposure and five with high degree exposure), 10 unexposed PD patients matched for sex, age and Hoehn and Yahr scale (=3 in the "on" phase), and 10 unexposed PD patients matched for sex, age and l-dopa daily intake instead of disease severity (Hoehn and Yahr scale=3.5 in the "on" phase) were studied. Twenty normal subjects without previous exposure to hydrocarbon-solvents and matched for age and sex with HPD patients were studied for comparison. The purpose of the study was to assess neuronal degeneration in the striatum of exposed vs unexposed PD patients. The authors investigated whether neuronal damage/loss was detectable in the lentiform nucleus measuring N-acetylaspartate (NAA) levels by 1-H MRS. Multiple single voxel MRS water-suppressed spectra were obtained also from the white matter and the occipital lobe. NAA was normal in the lentiform nucleus of patients with low exposure as well as in patients with no exposure whereas it was decreased in PD patients with high degree exposure. White matter and occipital lobe NAA content was normal both in exposed and unexposed PD patients. Clinical expression is more severe in PD patients with previous high degree solvent exposure because of the associated post-synaptic damage of the nigro-striatal pathway.
Clinical diagnosis of multiple system atrophy (MSA) relays on signs and symptoms that are often difficult to identify particularly at early stage. Indeed neuropathological studies have demonstrated that MSA is the first cause of misdiagnosis in a cohort of patients presenting with parkinsonian features. Dopamine transporter imaging (DAT) shows striatal decrements in both MSA and Parkinson's disease (PD) making it not sensitive for differential diagnosis. Studies of dopamine D2 receptors with IBZM may help revealing striatal degeneration but a large overlap exist particularly if PD patients with advanced disease are included. We have measured brain flow with technetium-99m ethyl cysteinate dimer (ECD-SPECT) in 36 MSA patients and compared it with 43 PD and 39 age-matched controls. Using Statistical Parametric Mapping (SPM99) we found areas of significant reduced perfusion in the striatum, brain stem and cerebellum in MSA compared to the other groups. We believe that ECD-SPECT imaging may offer significant advantages compared to other imaging techniques in the assessment of neuronal degeneration in MSA and may help the clinician in the diagnostic characterization of patients presenting with atypical parkinsonism.
BACKGROUND: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson's disease. OBJECTIVE: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson's disease. RESULTS: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson's disease phenotype and a broad range of onset age (34 to 73 years). CONCLUSIONS: G2019S is the most common genetic determinant of Parkinson's disease identified so far. It is especially frequent among cases with familial Parkinson's disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson's disease.
Recent molecular biology research on neurodegenerative diseases, including parkinsonisms, has identified mutations in the genes that code for the proteins alpha-synuclein and tau, which have been used to classify them into synucleinopathies and tauopathies. The synucleinopathies include, besides the most common and well studied Parkinson's disease (PD), dementia with Lewy bodies, which accounts for approximately 20% of all cases of dementia in the elderly, and multiple system atrophy, whereas the tauopathies include rare and rapidly progressive syndromes, such as progressive supranuclear palsy and corticobasal degeneration. Data we collected at our center in over 2900 parkinsonian patients show that PD accounts for no more than 70% of parkinsonisms. The various syndromes have many features in common that make the differential diagnosis difficult in the early stages of disease. Our data are consistent with the findings reported in the international literature and provide additional information useful for differential diagnosis.
Deep Brain Stimulation (DBS) is an effective treatment for patients with advanced Parkinson's disease (PD) and motor complications whose condition can no longer be improved by adjustment of medical therapy. PD patients often report increased daily somnolence and night sleep abnormalities partially related to dopaminergic treatment. In a survey of 386 consecutive non-demented non-depressed PD patients seen in our clinic over a period of 3 months we found increased daily somnolence to be relatively uncommon in non-demented PD patients, although it may be associated with stable treatment with high dose dopamine agonists. Disease related factors seemed responsible for night sleep abnormalities. Because DBS of the subthalamic nucleus (STN) reduces motor disability, as well as total medication intake, one would expect a similar benefit on sleep abnormalities. Indeed, recent evidence suggests that chronic STN-DBS may improve sleep quality through increased nocturnal mobility and reduction of sleep fragmentation.
Although genomic screening studies have identified several genes associated with Parkinson's disease (PD), there is evidence that environmental factors are also involved in the pathogenesis of the disease and that hydrocarbon-solvents may be one of them. The genetic component is less evident in late-onset PD. To assess whether age and PD may affect the catabolism of the hydrocarbon n-hexane, a two-part study was performed. In the first part the urinary levels of its main metabolites, 2,5-hexanedione and 2,5-dimethylpyrroles, were measured in 108 patients and 108 healthy controls, matched by age and sex. Metabolite urinary excretion was significantly reduced in PD patients as compared with controls and was inversely related to age in both groups. In the second part the same comparison was made between 24 non-smoking and 10 smoking patients, matched to controls, after smoking of a hydrocarbon-rich cigarette. In these subjects also n-hexane and 2,5-hexanedione blood levels were measured. There was no appreciable difference in n-hexane blood levels between patients and controls in non-smokers, whereas there was a significant increase in patients over controls in smokers (p < 0.01). 2,5-hexanedione blood levels were significantly lower in patients than in healthy controls, both in non-smokers and in smokers, but the reduction was more pronounced in smokers (-46.3 % versus -10.7 %). The same was true for 2,5-hexanedione and 2,5-dimethylpyrrole urinary levels. This study suggests that aging and PD may be associated with a reduction in the capacity to eliminate the hydrocarbon n-hexane. This metabolic alteration may play a role in the pathogenesis of PD.
We used SPECT and the tracer (123)I-Ioflupane to measure dopamine transporter (DAT) binding in the caudate nucleus and the putamen of 70 patients with Parkinson's disease (PD), 10 with multiple system atrophy (MSA-P type), and 10 with progressive supranuclear palsy (PSP). Data were compared with 12 age-matched control subjects. We found significant reductions in mean striatal values in all three forms of parkinsonism. However, decrements were significantly greater in PSP (0.51+/-0.39, p<0.01) compared with MSA-P (0.70+/-0.33) and PD (0.95+/-0.38). No differences were found between MSA and PD. Putamen/caudate ratios were greater in PSP (0.83+/-0.12, p<0.01) than in PD (0.51+/-0.11), suggesting a more-uniform involvement of dopamine nerve terminals in both caudate nucleus and putamen. Our results confirm that DAT binding can provide an accurate and highly sensitive measure of dopamine degeneration. PSP patients may show a different pattern of neuronal loss compared with MSA and PD.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) markedly improves motor symptoms and reduces medication needs in Parkinson's disease (PD) patients. However, its effect on brain function has remained unclear. We used SPECT and the tracer ECD to measure regional cerebral blood flow before and 6 months after DBS of the STN in 22 PD patients and 13 healthy controls. PD patients were divided into good and poor responders to DBS, if changes in "off" UPDRS motor scores after surgery were >60% or <40%, respectively. Statistical analysis was performed using the SPM99 software. At baseline, all PD patients showed significant perfusion reductions in cortical areas (premotor frontal, parietal, and occipital). After DBS, changes were normalized only in the good responders, while cortical defects in the poor responders were unchanged. No flow decrements were detected in basal ganglia and thalamus in both groups, suggesting that DBS does not have a "lesion-like" effect. We conclude that good surgery outcome is associated with normalization of cortical flow abnormalities in PD.
deep brain stimulation is a widely accepted surgical therapy for the symptomatic treatment of advanced parkinson's disease; high frequency chronic stimulation of the subthalamic nucleus proved its efficacy to control the major motor symptoms. In the neurosurgical department of Monza we treated 72 parkinsonian patients (November 1998-January 2003). One year follow-up results are: decrease of tremor 90%, hypertonous 56%, bradykinesia 70%, voice impairment amelioration 30%, mean total daily L-dopa intake reduced 58%. Freezing and balance did not ameliorate, some voice impairment and psychic derangement have been observed. Major surgical complications were: haemorrage (1 case - transient hemiparesis), infections (2 cases), pulmonary embolisation (1 case). To optimise the surgical results, careful clinical and instrumental selection of the patients are mandatory before surgery.
OBJECTIVE: To evaluate the current rate of underweightness amongst Parkinson's disease (PD) patients at an Italian referral centre. DESIGN: Epidemiological study on consecutive patients presenting for the first time in a 16-month period. SETTING: Nutritional service of PD referral centre in Milan, Italy. SUBJECTS: Three-hundred and sixty-four PD patients diagnosed according to CAPIT criteria. METHODS: Anthropometric assessments: BMI and waist-to-hip ratio; evaluation of therapeutic physical activity (h/week). RESULTS: Three-hundred and sixty-four patients were included (180 female, 184 male), mean (s.d.) age 65.9 (8.9) y, mean (s.d.) duration of PD 10.6 (5.3) y; 134 patients (37%) were overweight and 92 (25%) were obese; 11 (3%) were underweight; 127 (35%) had normal BMI. No important differences in BMI according to sex and smoking status were observed. There was highly significant inverse correlation between duration of disease and BMI (P<0.001): mean (s.d.) duration of disease was 9.7 (4.7) y in overweight+obese patients, 11.1 (5.5) y in patients with normal BMI and 14.1 (7.2) y in underweight patients (P=0.0059). The waist-to-hip ratio was a cardiovascular risk factor in 47.7% of men and 73.8% of women. Mean (s.d.) therapeutic physical activity was 1.07 (1.59) h/week in overweight and obese patients vs 1.61 (2.04) h/week in patients with normal BMI (50.5% increase; P=0.03). CONCLUSIONS: At present underweightness is uncommon in PD patients in Italy; this may be due to the increase in the prevalence of overweightness in the Italian population and to modern antiparkinsonian therapy.
Deep brain Stimulation (DBS) is an effective treatment for patients with advanced Parkinson's disease (PD) and motor complications who can no longer be improved by adjustment of medical therapy. Selection of surgery candidates and follow-up after surgery are critical for good outcome. Functional neuroimaging can help in the clinical assessment of these patients. We have used single photon emission computed tomography (SPECT) and the tracer ECD to measure regional cerebral blood flow before and 6 months after DBS of the subthalamic nucleus (STN) in 20 patients with advanced PD. We found a significant increase in the anterior cingulate/supplementary motor cortex in the 12 good responders (change in off unified UPDRS >50%). Conversely, patients with poor response (n=8; change in off UPDRS-III <50% following DBS) revealed a significant worsening of cortical hypoperfusion particularly in the prefrontal areas. No flow decrements were detected in the basal ganglia and in the thalamus in both groups during DBS stimulation suggesting that DBS does not have a "lesion like" effect. If DBS stimulates and does not inactivate STN projection neurons, flow reduction in the poor responders may be secondary to increased inhibitory basal ganglia output.
Neuroimaging studies of striatal dopamine transporters (DAT) have shown that this measurement is a specific marker of dopaminergic degeneration in patients with Parkinson's disease. However, little data is available in subjects with early disease onset, particularly in those with autosomal recessive parkinsonism. We measured striatal DAT binding in 10 patients with early onset PD (onset <40 years) and in 10 with late onset PD (onset >50 years) using PET and the tracer [(11)C]FECIT. One early onset subject presented a mutation in the parkin gene consistent with autosomal recessive parkinsonism. Data were compared with those of 15 control subjects. We found a comparable decrement of striatal DAT binding in early and late onset PD. Loss was widespread and bilateral in the patient carrying the Park2 mutation, suggesting a different pattern of denervation in these individuals.