Mariateresa Buongiorno

Combined dementia-risk biomarkers in Parkinson's disease: A prospective longitudinal study

Neuropsychological (mostly posterior-cortical) deficits, quantitative magnetic resonance imaging (MRI) atrophy patterns, and low cerebrospinal fluid (CSF) levels of amyloid-β have been separately related to worsening cognition in Parkinsons disease (PD). However, these biomarkers have not been longitudinally assessed in combination as PD-dementia predictors. In this prospective longitudinal study, 27 non-demented PD patients underwent CSF, neuropsychological and 3-T brain-MRI studies at baseline and were re-assessed 18 months later in terms of progression to dementia (primary outcome) and longitudinal neuropsychological and cortical thickness changes (secondary outcomes). At follow-up 11 patients (41%) had progressed to dementia. Lower CSF amyloid-β, worse verbal learning, semantic fluency and visuoperceptual scores, and thinner superior-frontal/anterior cingulate and precentral regions were significant baseline dementia predictors in binary logistic regressions as quantitative and/or dichotomised traits. All participants without baseline biomarker abnormalities remained non-demented whereas all with abnormalities in each biomarker type progressed to dementia, with intermediate risk for those showing abnormalities in a single to two biomarker types (p = 0.006). Both the dementia-outcome and low baseline CSF amyloid-β were prospectively associated with limbic and posterior-cortical neuropsychological decline and frontal, limbic and posterior-cortical thinning from baseline to follow-up. These findings suggest that the combination of CSF amyloid-β, neuropsychological and cortical thickness biomarkers might provide a basis for dementia-risk stratification and progression monitoring in PD.

Rapidly progressive diffuse Lewy body disease

Lewy body syndromes (mainly Parkinsons disease and dementia with Lewy bodies) share many clinical features and usually have a slowly progressive course. Some patients may show rapid symptoms progression.

Long-term response to continuous duodenal infusion of levodopa/ carbidopa gel in patients with advanced Parkinson disease: The Barcelona registry

INTRODUCTION Continuous infusion of levodopa/carbidopa intestinal gel (LCIG) is an effective treatment for patients with advanced Parkinson Disease (PD) that cannot be further improved by oral therapy. METHODS We conducted an observational, prospective, and multicenter study to collect, in a large sample of PD treated with LCIG, long-term information about the outcome and safety of the treatment. The assessments were performed before LCIG, 1, 3, 6 months after, and ever since, every 6 months. RESULTS We studied 72 patients with a mean observation time of 22 months and a maximum of 48 months. During follow-up 28 patients discontinued the treatment, especially for lack of efficacy or adverse events related to the drug. We obtained a significant improvement of motor and non-motor fluctuations, mean off time and some non-motor symptoms. A significant increase in the percentage of time with dyskinesias was found in patients having less than 50% of the day with dyskinesias before LCIG. However, patients having already many dyskinesias before LCIG experienced a significant decrease of the troublesome dyskinesias, meaning that outcomes might be different depending on specific clinical characteristics. Adverse effects were in general minor but one case of intestinal perforation and one of abdominal cellulite were observed. CONCLUSIONS We confirmed that LCIG is a very effective treatment option for advanced PD; however considering the findings that dyskinesia can increase and the potential for serious side effects, we suggest the necessity for development of guidelines that better define the profile of responders.

Nonmotor Symptoms in LRRK2 G2019S Associated Parkinson’s Disease

Background Idiopathic Parkinson’s disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined. Objective To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients. Methods The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated. Results University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p<0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination. Conclusion Neuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD.

Amyloid-β and τ biomarkers in Parkinson's disease–dementia

Dementia is a frequent and devastating non-motor complication of advanced Parkinsons disease (PD). There is growing evidence of a synergistic role of Alzheimers-type brain lesions containing τ and amyloid-β (Aβ) proteins and cortical Lewy aggregates in PD-related dementia (PDD). Therefore, biomarkers of both τ and Aβ may be seen as diagnostic and predictive markers of PDD. Here, we review the available studies in PD and PDD using cerebrospinal fluid (CSF) total τ, phospho-τ, and/or Aβ levels, and PET probes targeting Alzheimers-type lesions. Overall, high CSF τ and phospho-τ levels and/or low CSF Aβ levels have been found in part of PDD patients, and a longitudinal study has found greater worsening in cognitive performance over time in non-demented PD patients with low baseline CSF Aβ levels. Few studies are available on the use of PET imaging in PD, all of them using the Pittsburgh B compound (PIB), and with figures of about 30% of scans with PIB uptake in the AD-range in PDD. We conclude that these CSF and PET markers deserve further evaluation as candidate biomarkers of dementia in PD. According to this, we are currently undertaking a longitudinal project on the predictive value of dementia of the combined use of CSF τ and Aβ and (18)F-FDDNP PET in PD.

123I-MIBG cardiac uptake, smell identification and 123I-FP-CIT SPECT in the differential diagnosis between vascular parkinsonism and Parkinson's disease.

UNLABELLED Vascular parkinsonism (VP) may occur as a distinct clinicopathological entity but the comorbid presence of vascular damage in Parkinsons disease (PD) is very frequent too. This differential diagnosis has therapeutic and prognostic implications but remains challenging as the usefulness of a number of supporting tools is still controversial. OBJECTIVE To ascertain the clinical value of cardiac (123)I-meta-iodobenzylguanidine ((123)I-MIBG) SPECT, olfactory function and (123)I-FP-CIT SPECT as supporting tools in the differential diagnosis between VP and PD. METHODS Cross-sectional study of 15 consecutive patients with suspected VP, 15 PD patients and 9 healthy subjects. Cardiac (123)I-MIBG SPECT (heart-to-mediastinum ratio) and olfactory testing (University of Pennsylvania Smell Identification Test-UPSIT) were performed in all of them. (123)I-FP-CIT SPECT was performed in VP-suspected patients. RESULTS Heart-to-mediatinum ratio was significant lower in suspected VP (mean 1.45) and PD (mean 1.16) compared to control group (mean 1.69) (p = 0.017 and p < 0.0001). VP patients presented a higher ratio than PD patients (p = 0.001). Control group presented a significant higher UPSIT score (mean 30.71) when compared to both VP (mean 18.33) and PD (mean 15.29) (p = 0.001 for both groups). Those VP with a cardiac (123)I-MIBG non suggestive of PD were more likely to have a higher UPSIT score (p = 0.006). (123)I-FP-CIT SPECT imaging was heterogeneous (7/15 VP normal, 3/15 abnormal suggestive of PD and 5/15 abnormal but atypical for PD). CONCLUSIONS The use of cardiac (123)I-MIBG SPECT and to a lesser extent UPSIT could assist the differential diagnosis between VP and PD in subjects in which the diagnosis remains uncertain despite (123)I-FP-CIT SPECT imaging.

Cross-Sectional and Longitudinal Cognitive Correlates of FDDNP PET and CSF Amyloid-β and Tau in Parkinson’s Disease1

Tau and amyloid-β (Aβ) aggregates have been suggested to play a role in the development of dementia in Parkinsons disease (PD). Positron emission tomography (PET) with [18F]FDDNP and the determination of cerebrospinal fluid (CSF) levels of these proteins constitute a means to visualize in vivo Aβ and tau brain accumulation. Information about longitudinal changes of these CSF and PET biomarkers in PD with regard to progression to dementia is lacking. We assessed the cross-sectional and longitudinal associations of CSF and PET biomarkers of tau and Aβ with PD-related cognitive dysfunction in 6 healthy-controls (HC), 16 patients with PD without dementia (PDND), and 8 PD with dementia (PDD). All subjects underwent comprehensive neuropsychological testing, [18F]FDDNP PET, and CSF Aβ-tau determination. After 18 months, the PDND group was re-assessed clinically and by neuropsychological, PET, and CSF determinations. Cross-sectionally, PDD had higher [18F]FDDNP binding in lateral temporal regions and lower levels of CSF Aβ levels compared to PDND, with a congruent correlation between the [18F]FDDNP binding and CSF Aβ levels. Longitudinally, higher baseline lateral temporal [18F]FDDNP binding was associated to longitudinal worsening in cognitive performances and progression to dementia among subjects classified as PDND at baseline, who additionally disclosed at follow-up an increase in lateral-temporal FDDNP binding, as well as a reduction in CSF Aβ and an increase in CSF tau levels. These results confirm the relevance of these CSF and PET biomarkers to PDD, being specifically the first to show [18F]FDDNP PET as a dementia risk biomarker in PD, along with longitudinal CSF and PET changes over time.

White matter hyperintensities, cerebrospinal amyloid-β and dementia in Parkinson's disease

Abstract White-matter hyperintensities (WMHs) have been related to small-vessel disease, but also to amyloid-β (Αβ) vascular deposition, particularly in parieto-occipital regions. Low cerebrospinal fluid (CSF) Aβ [1-42] levels (biomarker of parenchymal and/or vascular Aβ deposition) and WMHs have been associated with Parkinsons disease (PD) and related dementia (PDD), separately but not in combination. We studied 50 subjects: 38 PD patients (19 non-demented [PDND]+19 PDD) and 12 healthy-controls. Baseline regional WMHs from FLAIR MRI-sequences were dichotomized into none-to-mild vs. moderate-to-severe by an expert radiologist blind to clinical and CSF data using an adaption of the Age-Related White Matter Changes scale. Baseline CSF α-synuclein, τ and Aβ [1-42] levels were determined with ELISA techniques. Progression to dementia in PDND patients was clinically evaluated at 18months. For analyses purposes patients were considered altogether (PDND+PDD) and separately (PDND vs. PDD). At baseline, moderate-to-severe parieto-occipital WMHs were significantly more frequent in PDD than in PDND ( p =0.049) and controls ( p =0.029), without significant differences in other regions. In regression models CSF Aβ was significantly associated in the entire PD cohort with moderate-to-severe parieto-occipital WMHs independently of age, vascular risk factors, APOE-4 and dementia. There were no associations with CSF α-synuclein and τ. Progression to dementia at 18months was more frequent in patients with moderate-to-severe parieto-occipital WMHs and low CSF Aβ vs. those with none-to-mild parieto-occipital WMHs and normal CSF Aβ ( p =0.007). It remains to be seen whether the relationship between CSF Aβ and WMHs in PD and their association with PD-dementia is a reflection of not only parenchymal, but also vascular Αβ deposition.