Jacopo Cristini

Introduction: Parkinson’s disease (PD) is a common neurodegenerative movement disorder characterized by motor features and a range of non-motor manifestations that vary substantially across those affected. PD has a complex, multifactorial etiology arising from interactions between environmental exposures and genetic susceptibility. Accumulating evidence from candidate gene studies and genome-wide associations studies suggest that genetic variation not only influences disease risk but also may explain some of the observed clinical variability. Accordingly, this systematic review synthesizes current evidence on genotype-phenotype associations in PD to examine the strength and the consistency of the evidence for genetic contributions to PD clinical manifestations, and also to identify biological pathways underlying this clinical variability. Methods: Following PRISMA guidelines, MEDLINE and Embase were searched for human genetic association studies investigating genotype-phenotype associations in PD. Functional enrichment analyses identified overrepresented biological processes across implicated genes. Results: We identified 5,734 publications, of which 33 met inclusion criteria. Genetic influences on the clinical manifestations of PD have been investigated predominantly through genes implicated in monogenic forms, with GBA and LRRK2 emerging as the most frequently studied. GBA variants consistently correlated with earlier onset, hyposmia, autonomic dysfunction, cognitive decline, and greater non-motor symptom burden. LRRK2 variants were linked to later onset, relatively preserved olfaction, and milder non-motor features. Functional enrichment analyses revealed distinct biological patterns. Genes associated with age at onset were enriched for neuronal maintenance and degeneration, those linked to olfactory function in autonomic and gliotic processes, genes related to non-motor symptoms in dopaminergic and catecholamine signaling, those associated with motor signs in synaptic transmission, oxidative stress, and clinical features of PD, and genes linked to disease severity in cellular stress and protein stability. Conclusions: Distinct genetic variants appear to contribute to specific clinical manifestations of PD, and pathway-level enrichment analyses generate hypotheses about the partially distinct biological processes that may be involved. These findings highlight the need for integrative genomic and longitudinal research to refine patient stratification and guide personalized therapeutic strategies.

A single bout of cardiovascular exercise (CVE) can promote neuroplasticity in an intensity-dependent manner. Consequently, performing CVE immediately after encoding may enhance motor memory consolidation, with stronger effects reported for high intensities. However, most evidence comes from fine-motor tasks, and data on complex whole-body skills are still scarce. In this pre-registered experiment, 41 neurotypical young adults practiced a balance task used to study gross-motor learning. Immediately after encoding, we randomized participants into three groups: a high-intensity interval CVE group (90/60% W_max), a moderate-intensity interval CVE group (45/25% W_max), or a resting group. These CVE protocols have previously been shown to enhance consolidation in fine-motor tasks. To evaluate consolidation, we conducted retention tests 24 h and 7 days later and calculated relative offline changes from the end of encoding to the retention tests. Contrary to our hypothesis, both CVE groups showed reduced offline learning at the 24-hour retention test compared to rest (weighted mean CVE: 2.9%; REST: 12.5%), indicating a large effect. This negative effect was unaffected by biological sex, cardiorespiratory fitness, subjective sleep quality, and post-exercise lactate levels, but was no longer present at the 7-day retention test. Our findings suggest that post-encoding CVE may attenuate early consolidation of complex whole-body motor skills, regardless of intensity. This challenges assumptions derived from fine-motor paradigms and holds relevance for applied sport and rehabilitation contexts, warranting further investigation. We discuss possible mechanisms, including catecholamine-driven reduction of frontal brain processes and interference between overlapping neural circuits engaged by the motor task and CVE.

Cardiovascular exercise (CE) shows promise for stroke recovery, partly by inducing neuroplasticity through excitatory neural signaling. While mechanisms are well-documented in animal models, the neurophysiological effects of CE in humans post-stroke—especially in the early subacute phase when the brain may be more responsive—remain unclear. In this study, 76 individuals within 3 months of their first-ever ischemic stroke were randomized to eight weeks of progressive CE using recumbent steppers plus standard care, or standard care alone. Corticospinal excitability (CSE) was assessed bilaterally using single and paired-pulse transcranial magnetic stimulation (TMS) at baseline, four weeks, and eight weeks. TMS was delivered at rest (chronic effect) and following a single high-intensity interval training (HIIT) session (acute effect). A single HIIT session at baseline significantly increased acute CSE in the contralesional hemisphere. However, despite significant improvements in cardiorespiratory fitness—indicating the effectiveness of the CE intervention—CE training did not lead to significant chronic or acute changes in CSE compared to standard care. This is the first study to investigate the effects of CE on CSE in early subacute stroke. Our findings indicate that while CE improves fitness levels during this critical period of recovery, it may have limited effects on CSE. Trial Registration: https://clinicaltrials.gov/study/NCT05076747 .

The capacity to reacquire motor skills lost after a stroke is crucial to promote upper-limb motor recovery, but the impact of lesion location on motor skill acquisition and the underlying neurophysiological mechanisms remain uncertain. Cortico-spinal excitability, measured with transcranial magnetic stimulation, provides information about the functional integrity of the cortico-spinal tract, a structure essential for upper-limb motor function and recovery post-stroke. Cortico-spinal excitability is a biomarker that has been used to predict upper-limb motor recovery and guide interventions post-stroke. We investigated associations between different cortico-spinal excitability measures of facilitation and inhibition and the capacity to improve the performance of a short-term visuomotor adaptation task that required accurate force modulation with the most affected hand in 103 individuals with either cortical (n = 34) or subcortical (n = 69) lesions. Cortico-spinal excitability measures included resting motor threshold, resting and active excitability derived from the amplitude of motor evoked potentials, cortical silent period, as well as intracortical facilitation and short intracortical inhibition. Both lesion groups showed similar rates of motor skill performance but individuals with subcortical lesions exhibited more impairment in the most affected hand and lower excitability in the ipsilesional hemisphere inferred from a reduced amplitude of motor evoked potentials elicited during an active muscle contraction. Exploratory analyses revealed that upper-limb impairments and reductions in active and resting excitability in the ipsilesional hemisphere were exacerbated in individuals with subcortical lesions affecting the cortico-spinal tract. In individuals with cortical lesions, better motor skill performance was associated with lower motor thresholds (β = −0.25, 95% CI [−0.47, −0.03]; P = 0.024) and higher intracortical inhibition (β = −3.93, 95% CI [−6.89, −0.98]; P = 0.011) in the ipsilesional hemisphere. In contrast, in individuals with subcortical lesions motor skill performance was associated with smaller motor evoked potentials (β = −4.46, 95% CI [−8.54, −0.38]; P = 0.033), less intracortical inhibition (β = 3.45, 95% CI [0.34,6.56]; P = 0.030) and higher facilitation (β = 1.34, 95% CI [0.15,2.54]; P = 0.028) in the ipsilesional hemisphere. Associations with intracortical inhibition and facilitation in the subcortical group were driven primarily by observations from individuals with lesions affecting the cortico-spinal tract. Importantly, no associations were found in the contralesional hemisphere. Reinforcing the existence of lesion-specific neurophysiological reorganization patterns, individuals with cortical and subcortical lesions show divergent associations between cortico-spinal excitability and the capacity to improve the performance of a short-term visuomotor adaptation task. The use of cortico-spinal excitability as a biomarker to guide motor recovery interventions such as non-invasive brain stimulation or to predict upper-limb recovery post-stroke should consider lesion location.

Importance: Corticobasal syndrome (CBS) is a rare tauopathy, with a complex pathophysiology that usually includes neuroinflammation. Parkinsonism, cognitive impairments, and sleep disturbances are common in CBS, although alterations in sleep architecture remain poorly characterized. Regular exercise has been recommended in CBS to manage gait dysfunction, balance issues, and cognitive decline. However, the effects of regular exercise on sleep quality, sleep architecture, and systemic inflammation in CBS remain unclear. Objective: The purpose of this study was to describe the effects of regular exercise in CBS. Design: The design of this study was a case report. Settings: This study was conducted in an academic laboratory. Participants: An individual with CBS participated in this case study. Intervention: The participant completed a 12-week multimodal training program. Main Outcome(s) and Measure(s): Cardiorespiratory fitness level was assessed with a symptom-limited cardiopulmonary exercise test and strength with a submaximal 1-repetition maximum test. Subjective and objective sleep quality were assessed using the Parkinson Disease (PD) Sleep Scale-2 and actigraphy, respectively. Sleep architecture was evaluated with polysomnography. Cognition and motor function were assessed with the Scale for Outcomes in PD-Cognition and Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS-III), respectively, functional mobility with the Time Up and Go (TUG), and fatigue with the PD Fatigue Scale. Concentrations of inflammatory markers, including interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor, and C-reactive protein, were measured from serum collected after a 12-hour fasting period. Results: Following the training program (34 sessions; 25.35 hours), improvements in fitness, objective sleep quality and architecture, cognition, TUG, and a reduction in systemic inflammation were observed. Conversely, MDS-UPDRS-III scores deteriorated, and the participant reported diminished subjective sleep quality and increased fatigue. Conclusions: These results, which should be interpreted with caution, suggest that various clinical outcomes improved following multimodal training. Controlled studies are warranted to confirm these observations. Relevance: This is the first case report describing the effects of a training program on sleep architecture and systemic inflammation in CBS.

Regular exercise is a safe adjunct to standard pharmacological treatment and may improve common sleep architecture alterations observed in Parkinson’s disease (PD). However, research in this area is limited, and it is unclear which potential underlying mechanisms are involved. We conducted a proof-of-concept study to investigate whether 12 weeks (3 days/week) of moderate-to-vigorous cardiovascular training (CT) improves sleep architecture and non-rapid-eye-movement (NREM) sleep oscillations in PD. Additionally, we explored potential underlying mechanisms, focusing on measures of intracortical inhibition mediated by gamma-aminobutyric acid (GABA), given its critical role in sleep physiology and dysfunction in PD. We recruited 15 participants at early-to-moderate disease stages (66.0 ± 9.0 years; Female = 3). Participants “On” antiparkinsonian medications were tested before and after the CT program. Cardiorespiratory fitness level was assessed with a symptom-limited cardiopulmonary exercise test. Sleep was evaluated with polysomnography. Intracortical inhibition was assessed using transcranial magnetic stimulation measures, including short intracortical inhibition (SICI) and the cortical silent period (CSP). Explorative outcomes included hypnodensity-related metrics, subjective sleep quality, cognition, motor signs severity, and fatigue. Following CT, we observed significant improvements in cardiorespiratory fitness level, the duration of NREM sleep stage 3, NREM stable sleep (hypnodensity-derived variable), SICI, and cognitive function. In contrast, there were no significant changes in other polysomnographic sleep outcomes, subjective sleep quality, CSP, motor signs severity, and fatigue. Although our findings require replication in RCTs, they expand previous research and suggest that CT may be a long-term, cost-effective strategy to mitigate common alterations in sleep and intracortical inhibition in PD.

Background: Corticospinal excitability (CSE) is a surrogate measure of neuroplasticity within the corticospinal tract measured with transcranial magnetic stimulation (TMS). A single bout of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) cardiovascular exercise (CE) have been both demonstrated to transiently augment CSE in people with stroke. However, the effect of multiple sessions of CE and exercise intensity is unknown. Objectives: We conducted a randomized controlled trial (NCT03614585) to examine the effect of a HIIT vs. MICT CE program on CSE measures obtained using TMS applied on the ipsilesional (ILH) and contralesional (CLH) hemispheres. Methods: Fifty-six individuals with cortical and/or subcortical stroke lesions in the chronic phase of stroke recovery (>6 months) were randomly assigned to a 12-week HIIT (n = 28) or MICT (n = 28) program. CSE measures were obtained at baseline and post-intervention. Linear mixed model analyses were conducted to compare changes in CSE measures and their respective interhemispheric ratios. Results: CSE changes were not significantly different between HIIT and MICT but exploratory analyses showed that, when analyzed together, both groups increased resting motor evoked potential (MEP) amplitude ( P = .003), decreased resting motor threshold (rMT) ( P = .030), and reduced intracortical facilitation (ICF) ( P = .049) in the ILH. No CSE changes in the CLH were observed. HIIT and MICT rebalanced interhemispheric rMT ( P = .020) and ICF ratios ( P = .040), and increased resting MEP amplitude ratio ( P = .020). Conclusions: Chronic CE increases excitatory ILH CSE measures and reduces interhemispheric imbalances but intensity does not have a moderating effect. More studies are needed to determine the functional relevance of exercise-induced changes in CSE in post-stroke recovery.

Background: Following stroke, a growth-promoting response resulting in heightened neuroplasticity occurs during the early subacute stages of recovery, a period during which the brain may be more responsive to therapeutical interventions. Given its central role in regulating neuroplastic processes and brain repair in animal models, brain-derived neurotrophic factor (BDNF) has been targeted as a potential biomarker for stroke recovery in humans, with interventions upregulating BDNF holding therapeutical potential. Cardiovascular exercise (CE) has been recommended for stroke rehabilitation, partly due to its potential to induce neural adaptations, including upregulation of BDNF. Objectives: To examine the effects of CE on BDNF in individuals at early subacute stages of recovery. Methods: Seventy-six participants within 3 months of first-ever ischemic stroke were randomly assigned to 8 weeks of either CE plus standard care or standard care alone. To measure the chronic and acute responses to exercise in serum BDNF levels, blood samples were collected before and immediately after a graded exercise test conducted at baseline, 4, and 8 weeks. The potential role of the BDNF Val66Met polymorphism in modulating the BDNF response was also explored. Data were analyzed following an intention-to-treat approach. Results: Despite clinically important increases in cardiorespiratory fitness, CE did not induce significant chronic or acute changes in serum BDNF. Furthermore, the response to CE was not associated with changes in cardiorespiratory fitness and clinical outcomes or was modulated by Val66Met. Conclusions: These findings indicate that CE has a limited capacity to upregulate circulating BDNF in subacute stages of stroke recovery. Trial Registration: Exercise and Genotype in Sub-acute Stroke: https://clinicaltrials.gov/study/NCT05076747 .

: Background.: Following stroke, a growth-promoting response resulting in heightened neuroplasticity occurs during the early subacute stages of recovery, a period during which the brain may be more responsive to therapeutical interventions. Given its central role in regulating neuroplastic processes and brain repair in animal models, brain-derived neurotrophic factor (BDNF) has been investigated as a potential biomarker for stroke recovery in humans, with interventions upregulating it holding therapeutical potential. Cardiovascular exercise (CE) has been recommended for stroke rehabilitation, partly due to its potential to induce neural adaptations, including upregulation of BDNF. Objectives.: To examine the effects of CE on BDNF in individuals at early subacute stages of recovery. Methods.: 76 participants within 3 months of first-ever ischemic stroke were randomly assigned to eight weeks of either CE plus standard care or standard care alone. To measure the chronic and acute responses to exercise in serum BDNF levels, blood samples were collected before and immediately after a graded exercise test conducted at baseline, four and eight weeks. The potential role of the BDNF Val66Met polymorphism in modulating the BDNF response to CE was also explored. Results.: Despite significant increases in cardiorespiratory fitness, CE did not induce any significant chronic or acute changes in BDNF concentration. Similarly, the BDNF response to CE was not modulated by the Val66Met polymorphism or associated with changes in cardiorespiratory fitness and clinical outcomes. Conclusions.: These findings indicate limited effects of CE in modulating circulating BDNF in subacute stages of stroke recovery. Trial Registration: Exercise and Genotype in Sub-acute Stroke: https://clinicaltrials.gov/study/NCT05076747