Effects of dopaminergic treatment on inhibitory control differ across Hoehn and Yahr stages of Parkinson's disease

: Motor inhibitory control, a core component of cognitive control, is impaired in Parkinson's disease, dramatically impacting patients' abilities to implement goal-oriented adaptive strategies. A progressive loss of the midbrain's dopamine neurons characterizes Parkinson's disease and causes motor features responsive to dopaminergic treatments. Although such treatments restore motor symptoms, their impact on response inhibition is controversial. Most studies failed to show any effect of dopaminergic medicaments, although three studies found that these drugs selectively improved inhibitory control in early-stage patients. Importantly, all previous studies assessed only one domain of motor inhibition, i.e. reactive inhibition (the ability to react to a stop signal). The other domain, i.e. proactive inhibition (the ability to modulate reactive inhibition pre-emptively according to the current context), was utterly neglected. To re-examine this issue, we recruited cognitively unimpaired Parkinson's patients under dopaminergic treatment in the early (Hoehn and Yahr, 1-1.5, n = 20), intermediate (Hoehn and Yahr 2, n = 20), and moderate/advanced (Hoehn and Yahr, 2.5-3, n = 20) stages of the disease. Using a cross-sectional study design, we compared their performance on a simple reaction-time task and a stop-signal task randomly performed twice on dopaminergic medication (ON) and after medication withdrawal (OFF). Normative data were collected on 30 healthy controls. Results suggest that medication effects are stage-dependent. In Hoehn and Yahr 1-1.5 patients, drugs selectively impair reactive inhibition, leaving proactive inhibition unaffected. In the ON state, Hoehn and Yahr two patients experienced impaired proactive inhibition, whereas reactive inhibition is no longer affected, as it deteriorates even during the OFF state. By contrast, Hoehn and Yahr 2.5-3 patients exhibited less efficient reactive and proactive inhibition in the OFF state, and medication slightly improved proactive inhibition. This evidence aligns with the dopamine overdose hypothesis, indicating that drug administration may overdose intact dopamine circuitry in the earliest stages, impairing associated cognitive functions. In later stages, the progressive degeneration of dopaminergic neurons prevents the overdose and can exert some beneficial effects. Thus, our findings suggest that inhibitory control assessment might help tailor pharmacological therapy across the disease stage to enhance Parkinson's disease patients' quality of life by minimizing the hampering of inhibitory control and maximizing the reduction of motor symptoms

Clinical correlates of "pure" essential tremor: the TITAN study

BackgroundTo date, there are no large studies delineating the clinical correlates of "pure" essential tremor (ET) according to its new definition.MethodsFrom the ITAlian tremor Network (TITAN) database, we extracted data from patients with a diagnosis of "pure" ET and excluded those with other tremor classifications, including ET-plus, focal, and task-specific tremor, which were formerly considered parts of the ET spectrum.ResultsOut of 653 subjects recruited in the TITAN study by January 2022, the data of 208 (31.8%) "pure" ET patients (86M/122F) were analyzed. The distribution of age at onset was found to be bimodal. The proportion of familial cases by the age-at-onset class of 20 years showed significant differences, with sporadic cases representing the large majority of the class with an age at onset above 60 years. Patients with a positive family history of tremor had a younger onset and were more likely to have leg involvement than sporadic patients despite a similar disease duration. Early-onset and late-onset cases were different in terms of tremor distribution at onset and tremor severity, likely as a function of longer disease duration, yet without differences in terms of quality of life, which suggests a relatively benign progression. Treatment patterns and outcomes revealed that up to 40% of the sample was unsatisfied with the current pharmacological options.DiscussionThe findings reported in the study provide new insights, especially with regard to a possible inversed sex distribution, and to the genetic backgrounds of "pure" ET, given that familial cases were evenly distributed across age-at-onset classes of 20 years. Deep clinical profiling of "pure" ET, for instance, according to age at onset, might increase the clinical value of this syndrome in identifying pathogenetic hypotheses and therapeutic strategies

Data-driven clustering of combined Functional Motor Disorders based on the Italian registry

Functional Motor Disorders (FMDs) represent nosological entities with no clear phenotypic characterization, especially in patients with multiple (combined FMDs) motor manifestations. A data-driven approach using cluster analysis of clinical data has been proposed as an analytic method to obtain non-hierarchical unbiased classifications. The study aimed to identify clinical subtypes of combined FMDs using a data-driven approach to overcome possible limits related to "a priori" classifications and clinical overlapping

Clinical correlates of “pure” essential tremor: the TITAN study

BackgroundTo date, there are no large studies delineating the clinical correlates of “pure” essential tremor (ET) according to its new definition.MethodsFrom the ITAlian tremor Network (TITAN) database, we extracted data from patients with a diagnosis of “pure” ET and excluded those with other tremor classifications, including ET-plus, focal, and task-specific tremor, which were formerly considered parts of the ET spectrum.ResultsOut of 653 subjects recruited in the TITAN study by January 2022, the data of 208 (31.8%) “pure” ET patients (86M/122F) were analyzed. The distribution of age at onset was found to be bimodal. The proportion of familial cases by the age-at-onset class of 20 years showed significant differences, with sporadic cases representing the large majority of the class with an age at onset above 60 years. Patients with a positive family history of tremor had a younger onset and were more likely to have leg involvement than sporadic patients despite a similar disease duration. Early-onset and late-onset cases were different in terms of tremor distribution at onset and tremor severity, likely as a function of longer disease duration, yet without differences in terms of quality of life, which suggests a relatively benign progression. Treatment patterns and outcomes revealed that up to 40% of the sample was unsatisfied with the current pharmacological options.DiscussionThe findings reported in the study provide new insights, especially with regard to a possible inversed sex distribution, and to the genetic backgrounds of “pure” ET, given that familial cases were evenly distributed across age-at-onset classes of 20 years. Deep clinical profiling of “pure” ET, for instance, according to age at onset, might increase the clinical value of this syndrome in identifying pathogenetic hypotheses and therapeutic strategies

Effects of prismatic lenses on lateral axial dystonia in Parkinson's disease: a pilot study

: OBJECTIVE: In Parkinson's disease (PD), postural abnormalities such as lateral axial dystonia (LAD) are relatively common. Evidence suggests that both peripheral and central mechanisms contribute to these postural abnormalities. We previously reported an improvement in LAD following the use of prisms in two PD patients. Here, we further investigate the effects of prismatic lenses in a case series of nine patients with PD and LAD. METHODS: Nine patients underwent an orthoptic evaluation and were provided with prismatic lenses. Patients were evaluated at baseline and after one and three months of permanent prismatic lens use and again re-evaluated one month after the discontinuation of prismatic lens use. RESULTS: We found a linear relationship between disease duration and LAD severity. Compared to basal measurements, we observed a slight improvement in LAD. Furthermore, we found a significant reduction in self-perceived back pain due to the use of prismatic lenses. There was no significant association between the individual effects of prismatic lenses in patients with PD and their baseline LAD or other clinical and demographic features (all P>0.05). CONCLUSION: The present pilot study provides novel data on the possible effectiveness of prismatic lenses for LAD treatment in PD patients

Cerebrospinal-fluid Alzheimer’s disease biomarkers and blood-brain barrier integrity in a natural population of cognitive intact Parkinson’s disease patients

Background: Cerebrospinal-fluid (CSF) Alzheimer’s Disease (AD) biomarkers have been extensively studied in Parkinson’s Disease (PD). Although reduced CSF beta-amyloid1-42 (Aβ42) levels have been associated with cognitive decline in PD, the alteration of CSF tau proteins remains controversial. In addition, the impairment of the blood-brain barrier (BBB) has been previously demonstrated along the PD progression. Objective: The aim of the present study was to assess CSF AD biomarkers and BBB integrity in a natural cohort of cognitive intact PD patients compared to matched controls. Method: We measured and correlated CSF AD biomarkers and CSF/serum albumin ratio (expression of BBB integrity) in 124 PD patients and 46 controls. We distributed PD patients in three subgroups based on the Hoehn and Yahr (H&Y) staging: mild PD (1-1.5, n=40); moderate PD (2-2.5, n=58); advanced PD (3-5, n=26). PD patients were also distinguished as tremor dominant (TD, n=44) and non-tremor dominant (NTD, n=80). Results: PD patients showed lower CSF Aβ42levels and higher CSF/serum albumin ratio compared to controls. CSF total tau (t-tau) concentrations as well as the CSF/serum albumin ratio gradually increased among H&Y stages. Conversely, we did not find differences between TD and NTD patients. Significantly, we documented the positive correlation between CSF t-tau levels and both CSF/serum albumin ratio and motor impairment in PD patients. Conclusion: This study performed in cognitive intact PD patients confirms the progressive increase of CSF tau proteins levels and BBB impairment along with the evolution of PD pathology. Since the BBB ensures the clearance of tau proteins from brain, we hypothesize that the dysfunction of the BBB throughout the disease progression may possibly cause the concurrent increase of CSF tau proteins levels in PD, which could be irrespective of cognitive decline

An attempt to dissect a peripheral marker based on cell pathology in Parkinson's disease

Peripheral markers in Parkinson's disease (PD) represent a hot issue to provide early diagnosis and assess disease progression. The gold standard marker of PD should feature the same reliability as the pathogenic alteration, which produces the disease itself. PD is foremost a movement disorder produced by a loss of nigrostriatal dopamine innervation, in which striatal dopamine terminals are always markedly reduced in PD patients to an extent, which never overlaps with controls. Similarly, a reliable marker of PD should possess such a non-overlapping feature when compared with controls. In the present study, we provide a novel pathological hallmark, the autophagosome, which in each PD patient was always suppressed compared with each control subject. Autophagosomes were counted as microtubule-associated proteins 1A/1B light chain 3B (LC3)-positive vacuoles at ultrastructural morphometry within peripheral (blood) blood mononuclear cells (PBMC). This also provides the gold standard to assess the autophagy status. Since autophagy may play a role in the pathogenesis of PD, autophagosomes may be a disease marker, while participating in the biology of the disease. Stoichiometric measurement of alpha-synuclein despite significantly increased in PD patients, overlapped between PD and control patients. Although the study need to be validated in large populations, the number of autophagy vacuoles is neither related with therapy (the amount was similarly suppressed in a few de novo patients), nor the age in PD or controls

The histograms report the mean (and SD) CSF concentration for 5-HT (left, blue) and 5-HIAA (right, red) in the three studied populations.

<p>Note the different scaling in the y axes. PD cohort showed significantly lower levels (* p<0.05; ** p<0.005).</p

The graph shows the individual 5-HT concentration levels, comparing PD patients under LD alone (LD, n = 10) and DA plus LD (CT, combined therapy, n = 15).

<p>The difference is not significant. Not included, due to exiguity of the samples, the values of <i>denovo</i> (n = 6) and patients under DA alone (n = 4). To note, any therapy regards the period preceding the 3-days washout implicit to the study.</p

The table shows the lack of significant difference in CSF 5-HT (†) and 5-HIAA (‡) levels, when PD patients are sub-divided by gender, disease phenotype, and selected non-motor features.

<p>BDI  =  Beck Depression Inventory; AES  =  Apathy Evaluation Scale PSQI  =  Pittsburgh Sleep Quality Index.</p