Mariangela Pierantozzi

Magnetic resonance imaging markers of Parkinson's disease nigrostriatal signature

One objective of modern neuroimaging is to identify markers that can aid in diagnosis, disease progression monitoring and long-term drug impact analysis. In this study, Parkinson-associated physiopathological modifications were characterized in six subcortical structures by simultaneously measuring quantitative magnetic resonance parameters sensitive to complementary tissue characteristics (i.e. volume atrophy, iron deposition and microstructural damage). Thirty patients with Parkinsons disease and 22 control subjects underwent 3-T magnetic resonance imaging with T₂*-weighted, whole-brain T₁-weighted and diffusion tensor imaging scans. The mean R₂* value, mean diffusivity and fractional anisotropy in the pallidum, putamen, caudate nucleus, thalamus, substantia nigra and red nucleus were compared between patients with Parkinsons disease and control subjects. Comparisons were also performed using voxel-based analysis of R₂*, mean diffusivity and fractional anisotropy maps to determine which subregion of the basal ganglia showed the greater difference for each parameter. Averages of each subregion were then used in a logistic regression analysis. Compared with control subjects, patients with Parkinsons disease displayed significantly higher R₂* values in the substantia nigra, lower fractional anisotropy values in the substantia nigra and thalamus, and higher mean diffusivity values in the thalamus. Voxel-based analyses confirmed these results and, in addition, showed a significant difference in the mean diffusivity in the striatum. The combination of three markers was sufficient to obtain a 95% global accuracy (area under the receiver operating characteristic curve) for discriminating patients with Parkinsons disease from controls. The markers comprising discriminating combinations were R₂* in the substantia nigra, fractional anisotropy in the substantia nigra and mean diffusivity in the putamen or caudate nucleus. Remarkably, the predictive markers involved the nigrostriatal structures that characterize Parkinsons physiopathology. Furthermore, highly discriminating combinations included markers from three different magnetic resonance parameters (R₂*, mean diffusivity and fractional anisotropy). These findings demonstrate that multimodal magnetic resonance imaging of subcortical grey matter structures is useful for the evaluation of Parkinsons disease and, possibly, of other subcortical pathologies.

Subthalamic stimulation activates internal pallidus: Evidence from cGMP microdialysis in PD patients

Parkinsons disease patients benefit from deep brain stimulation (DBS) in subthalamic nucleus (STN), but the basis for this effect is still disputed. In this intraoperative microdialysis study, we found elevated cGMP extracellular concentrations in the internal segment of the globus pallidus, despite negligible changes in glutamate levels, during a clinically effective STN‐DBS. This supports the view that a clinically beneficial effect of STN‐DBS is paralleled by an augmentation (and not an inactivation) of the STN output onto the GPi. Ann Neurol 2005;57:448–452

Non-motor functions in parkinsonian patients implanted in the pedunculopontine nucleus: Focus on sleep and cognitive domains

Between 2005 and 2007, six patients affected by idiopathic Parkinsons disease (IPD) were submitted to the bilateral implantation (and subsequent deep brain stimulation - DBS) of the pedunculopontine nucleus (PPN) plus the subthalamic nucleus (STN). This review synthesizes the effects of PPN low-frequency stimulation on non-motor functions, focusing on patient sleep quality and cognitive performance. If not associated to STN-DBS, PPN-DBS promoted a modest amelioration of patient motor performance. However, during PPN-DBS, they experienced on the one hand a significant improvement in executive functions and working memory, on the other hand a beneficial change in sleep architecture. Overall, the limited sample hampers definite conclusions. Yet, although the PPN-DBS induced motor effects are quite disappointing (discouraging extended trials based upon the sole PPN implantation), the neuropsychological profile supports the contention by which in selected PD patients, with subtle cognitive deficits or vanished efficacy of previous implanted STN, PPN-DBS might still represent a reliable and compassionate option.

Different TMS patterns of intracortical inhibition in early onset Alzheimer dementia and frontotemporal dementia.

OBJECTIVE To investigate putative changes in cortical excitability of patients affected by early-onset mild dementia by means of transcranial magnetic stimulation (TMS) and to verify whether a peculiar neurophysiological profile may contribute to characterise Alzheimers disease (AD) vs frontotemporal dementia (FTD). METHODS Motor threshold and intracortical inhibition (ICI) and facilitation (ICF) after paired-pulse TMS (inter-stimulus intervals from 1 to 20 ms) were studied in two groups of early-onset demented patients with a neuropsychological profile suggestive of AD (n = 12) and FTD (n = 8). Twelve age-matched healthy subjects were considered as control group. In both patient groups, recordings were performed before and after a single oral dose of 4 mg galantamine. RESULTS No significant difference in motor threshold was observed among the three studied groups. On the contrary, early-onset AD showed a significant reduction of ICI compared to control group, no changes were detected in FTD patients. No significant changes in ICF were found between both patient groups and healthy subjects. The acute administration of galantamine reversed the modified ICI in AD group. CONCLUSIONS The differential pattern of ICI exhibited by early-onset AD vs FTD in the early stage of disease may represent a non-invasive, reproducible electrophysiological tool, which may contribute to early differential diagnosis and, possibly, to monitor therapeutic effectiveness. SIGNIFICANCE The present results support the possibility that subtle, early modifications in intracortical circuitry features AD, but not FTD patients.

Deep brain stimulation of both subthalamic nucleus and internal globus pallidus restores intracortical inhibition in Parkinson's disease paralleling apomorphine effects: a paired magnetic stimulation study

OBJECTIVE We investigated the effect of bilateral subthalamic nucleus (STN) and internal globus pallidus (GPi) deep brain stimulation (DBS) on intracortical inhibition (ICI) in patients with advanced Parkinsons disease (PD). METHODS The activity of intracortical inhibitory circuits was studied in 4 PD patients implanted with stimulating electrodes both in STN and GPi by means of paired-pulse transcranial magnetic stimulation, delivered in a conditioning-test design at short (1-6 ms) interstimulus intervals (ISI). The effect of apomorphine on the same PD patients was also investigated. RESULTS We observed that implanted PD patients showed a significant increase in ICI during either bilateral STN or GPi DBS at 3 ms ISI, and during bilateral STN DBS at 2 ms ISI in comparison to their off DBS condition. The same statistical improvement was observed during apomorphine infusion at 3 and 2 ms ISI. In each condition, the electrophysiological changes were associated with a significant clinical improvement as measured by the Unified Parkinsons Disease Rating Scale motor examination. CONCLUSIONS These results are consistent with the hypothesis that basal ganglia DBS can mimic the effects of pharmacological dopaminergic therapy on PD patients cortical activity. We propose that in PD patients, the basal ganglia DBS-induced improvement of ICI may be related to a recovery in modulation of thalamo-cortical motor pathway.

Multi-target strategy for Parkinsonian patients : The role of deep brain stimulation in the centromedian-parafascicularis complex

The intra-laminar (IL) thalamic complex, composed of centromedian (CM) and parafascicular (Pf) nucleus, is a strategic crossroad for the activity of the basal ganglia and is recently regaining its position has a putative neurosurgical target for Parkinsonian syndromes. The multi-target approach we have encouraged since the late nineties has allowed the combined implantation of a standard target (the subthalamic nucleus-STN or the internal pallidus-GPi) plus an innovative one (CM/Pf) in well-identified Parkinsons disease (PD) patients; hence, it is possible to study, in the same PD patients, the specific target-mediated effects on different clinical signs. Here, we focus on the potential usefulness of implanting the CM/Pf complex when required in the management of contra-lateral tremor (resistant to standard deep brain stimulation-DBS - in STN - , n=2) and disabling involuntary movements, partially responsive to GPi-DBS (n=6). When considering global UPDRS scores, CM/Pf-DBS ameliorate extra-pyramidal symptoms but not as strongly as STN (or GPi) does. Yet, CM/Pf acts very powerfully on tremor and contributes to the long-term management of l-Dopa-induced involuntary movements. The lack of cognitive deficits and psychic impairment associated with the improvement of their quality of life, in our small cohort of CM/Pf implanted patients, reinforces the notion of CM/Pf as a safe and attractive area for surgical treatment of advanced PD, possibly affecting not only motor but also associative functions.

Increased blood-cerebrospinal fluid transfer of albumin in advanced Parkinson’s disease

BackgroundAlterations in blood–brain barrier permeability have been proposed to represent a relevant factor contributing to Parkinson’s disease progression. However, few studies have addressed this issue in patients at different stages of disease.MethodsAlbumin was measured in cerebrospinal fluid and serum samples obtained from 73 non-demented subjects with idiopathic Parkinson’s disease and 47 age-matched control subjects. The albumin ratio (AR) was calculated to assess blood-cerebrospinal fluid and blood–brain barrier function. The group of patients with Parkinson’s disease included 46 subjects with Hoehn-Yahr staging between 1 and 2 and 27, with a score ranging from 2.5 to 4.ResultsStatistically significant differences in albumin ratio were found between patients with advanced disease, and both early-stage and unaffected groups. Conversely, early-phase patients did not differ from healthy subjects. Additionally, dopaminergic treatment seems to exert a possible effect on AR values.ConclusionsOur study demonstrates that possible dysfunction of the blood-cerebrospinal fluid barrier, blood–brain barrier, or both, characterize Parkinson’s disease progression. The associations between clinical scores, treatments and biochemical findings suggest a progressive impairment of barrier integrity during the course of the disease.

123I-FP-CIT semi-quantitative SPECT detects preclinical bilateral dopaminergic deficit in early Parkinson's disease with unilateral symptoms.

Background and aim123I-FP-CIT SPECT has been successfully used to detect the loss of dopaminergic nigrostriatal neurons in Parkinsons disease at an early stage. In this study we evaluated the capacity of 123I-FP-CIT SPECT to assess bilateral dopamine transporter (DAT) loss in de-novo hemi-Parkinsons disease (PD) patients with one-sided clinical symptoms. Patients and methodsTwenty-nine de-novo hemi-PD patients at an early stage (Hoehn & Yahr stage 1) and 18 gender and age matched healthy subjects were studied. SPECT imaging was always performed at 4 h post-injection. The ratios of striatal (S) to non-specific occipital (O) binding for the entire striatum (S/O), caudate nuclei (C/O), putamina (Pput/O), and the putamen to caudate nucleus index (Pput/C) were calculated in both the basal ganglia. ResultsIn PD patients S/O, C/O and Pput/O ratio values contralateral to the clinically affected side were significantly lower (P<0.001) than in the control group (−38%, −34% and −42%, respectively). A significant reduction (P<0.001) of the striatal binding ratios was also found ipsilaterally (S/O, −31%; C/O, −28%; Pput/O, −33%). The Pput/C index was also bilaterally significantly reduced (P<0.01). DAT loss was significantly greater (P<0.001) in the contralateral than in the ipsilateral S; and putamen bilaterally presented a higher dopaminergic deficit than did caudate. ConclusionOur results indicate that semi-quantitative 123I-FP-CIT SPECT detects a bilateral dopaminergic deficit in early PD with unilateral symptoms and preclinical DAT loss in the ipsilateral striatal binding, corresponding to the side not yet affected by motor signs. Semi-quantitative analysis may thus be used to diagnose PD at an early stage as well as to identify individuals developing bilateral dopaminergic damage.

Pramipexole in comparison to l-dopa: a neuropsychological study

Summary. Twenty right-handed patients affected by early/mild Parkinsons disease were evaluated in a randomised study using neuropsychological and clinical assessements during three treatment modalities: when in the off treatment condition, when on pramipexole, and when on l-dopa. In comparison to the off treatment condition, the DA-agonist pramipexole produced a significant impairment of short term verbal memory, attentional-executive functions and verbal fluency, while l-dopa did not. Moreover, pramipexole opposite to l-dopa, failed to improve FAS and Stroop tests. Present findings indicate that pramipexole may worsen cognitive functions although not exceeding normative values.

CSF markers in Alzheimer disease patients are not related to the different degree of cognitive impairment

Standard markers in cerebrospinal fluid (CSF), as soluble amyloid beta 1-42 (Abeta1-42) and total tau protein (t-tau), may contribute to dementia subtypes diagnostic accuracy. Yet, their sensitivity to assess the different degree of cognitive deficit is not fully clarified. Our study analyses Abeta1-42 and t-tau CSF levels in different cohorts of Alzheimers disease (AD) patients, distinguished as early AD (mild cognitively impaired subjects recently converted to AD), mild AD (MMSE<23; > or =18), and moderately advanced AD (MMSE<18). The control group was represented by age-matched patients affected by depressive pseudo-dementia. Reduced Abeta1-42 and increased t-tau CSF levels were confirmed as hallmarks of AD at any disease stage. In early AD patients, Abeta1-42 levels were already significantly low, if compared to the control group (336 vs 867 ng/L; p<0.0001). On the contrary, Abeta1-42 levels did not differ between AD subgroups, and in particular between mild to moderate AD. A significant progressive increase of t-tau concentration was found when comparing early AD (269 ng/L) to more advanced AD stages (468 ng/L and 495 ng/L for mild and moderate AD, respectively). Our findings confirm that the impairment of amyloidogenic cascade is an early, even pre-clinical process, but suggest that soluble Abeta1-42 concentration has a negligible correlation with the clinical progression. Conversely, t-tau concentration correlates with the transition towards marked cognitive impairment.