Beatriz Fernández‐Rodríguez

Background: Cognitive fluctuations (CF) are spontaneous alterations in cognition, attention, and arousal, which are core clinical features in Lewy body dementia. A 4‐item scale from the Dementia Cognitive Fluctuation Scale (4‐item DCFS) is used in demented patients to identify CF. However, this has not been applied to non‐demented patients with Parkinson's disease (PD). Objectives: We applied the 4‐item DCFS in non‐demented PD patients to evaluate its relationship to neuropsychological tests and to determine whether this score is associated with cognitive deterioration. Methods: Fifty‐one patients underwent prospective neuropsychological assessments. Those who scored ≥3 in the 4‐item DCFS were recognized as CF positive. The Bayesian Kendall correlation test was applied to assess the relationship between the 4‐item DCFS score, cognitive tests, and amyloid burden. Forty‐five patients were followed up for 3 years. Results: Thirty‐two patients scored 0 (62.7%, no positive answers), 11 (21.6%) scored 1, 4 (7.8%) scored 2, and 4 (7.8%) scored 3 points on the 4‐item DCFS. Moderate or strong evidence showed that the 4‐item‐DCFS score correlated with worse performance on the Trail Making Test B (Bayes factor, BF ₊₀ = 4), delayed visual recall test (BF ₋₀ = 12.9), and higher amyloid burden (BF ₊₀ = 13.6). All patients who scored ≥3 converted to PD‐mild cognitive impairment or dementia at follow‐up, whereas only 29% without CFs had converted to a worse cognitive status. Conclusions: A higher score on the 4‐item DCFS is related to lower scores in executive and memory function, along with a potential connection to amyloid pathology. Patients with lower scores are less likely to develop a worse cognitive state, although larger sample sizes are needed to confirm this relationship.

Social cognition (SC) encompasses a set of cognitive functions that enable individuals to understand and respond appropriately to social interactions. Although focused ultrasound subthalamotomy (FUS‐STN) effectively treats Parkinson's disease (PD) clinical motor features, its impact and safety on cognitive‐behavioral interactions/interpersonal awareness are unknown. This study investigated the effects of unilateral FUS‐STN on facial emotion recognition (FER) and affective and cognitive theory of mind (ToM) in PD patients from a randomized sham‐controlled trial (NCT03454425). Subjects performed SC evaluation before and 4 months after the procedure while still under blind assessment conditions. The SC assessment included the Karolinska Directed Emotional Faces task for FER, the Reading the Mind in the Eyes (RME) test for affective ToM, and The Theory of Mind Picture Stories Task (ToM PST) (order, questions, and total score) for cognitive ToM. The active treatment group showed anecdotal‐to‐moderate evidence of no worsening in SC after FUS‐STN. Anecdotal evidence for an improvement was recognized in the SC score changes, from baseline to post‐treatment, for the active treatment group compared with sham for the RME, ToM PST order, ToM PST total, FER total, and recognition of fear, disgust, and anger. This study provides the first evidence that unilateral FUS‐STN does not impair social cognitive abilities, indicating that it can be considered a safe treatment approach for this domain in PD patients. Furthermore, the results suggest FUS‐STN may even lead to some improvement in social cognitive outcomes, which should be considered as a preliminary finding requiring further investigation with larger samples sizes. © 2024 International Parkinson and Movement Disorder Society.

Background The nigrostriatal system is especially vulnerable to neurodegeneration in Parkinson’s disease (PD) and the blood-brain barrier (BBB) is a limiting factor for delivery of therapeutic agents to the brain. This pilot study aimed to demonstrate safety, feasibility and tissue penetration (by 18F-Choline-positron emission tomography (PET)) of MR-guided focused ultrasound (MRgFUS) simultaneous BBB opening (BBB-O) in the substantia nigra (SN) and putamen in PD. Methods Three patients underwent MRgFUS for midbrain and putamen BBB-O. Patients were evaluated clinically and underwent brain MRI with gadolinium (baseline, 24 hours, 14 days and 3 months postprocedure). In two patients, BBB-O was repeated after 2–3 weeks, and 18F-Choline-PET was performed immediately after. Results The right SN and putamen were simultaneously opened unilaterally in 3 patients once and the left SN in 1 patient in a different session. No severe clinical or neuroimaging adverse events developed in any patient. 18F-Choline-PET uptake was enhanced in the targeted SN and putamen regions. Conclusion BBB-O of the nigrostriatal system is a feasible and well-tolerated approach in patients with PD. 18F-Choline-PET uptake indicates penetration into the parenchyma after BBB-O, which suggests that the opening is functionally effective. This minimally invasive technique could facilitate delivery of putative neurorestorative molecules to brain regions vulnerable to neurodegeneration.

Background: Cognitive reserve (CR) is the mismatch between preserved cognition and neuropathological damage. Amyloidopathy in Parkinson's disease (PD) could be associated with faster progression to dementia, but the putative protective effect of CR is unknown.Objectives: To evaluate the effect of CR on β‐amyloid burden and brain metabolism in non‐demented PD subjects.Methods: Participants with PD (n = 53) underwent a clinical evaluation, [¹⁸F]‐fluorodeoxyglucose and [¹⁸F]‐flutemetamol positron emission tomography magnetic resonances, and were classified according to CR. The metabolic pattern of 16 controls was compared to PD subjects.Results: The PD subjects showed hypometabolism mainly in the bilateral posterior cortex. Superior‐CR subjects (n = 22) exhibited better cognitive performance, increased amyloid burden, and higher metabolism in several right hemisphere areas compared to low‐medium‐CR subjects (n = 31).Conclusions: Higher CR in non‐demented PD is associated with better cognitive performance, which might reduce vulnerability to the effect of β‐amyloid. Whether superior CR leads to protection against metabolic deterioration, and predominantly right hemisphere involvement, deserves further exploration.

Background: Parkinson's disease (PD) exhibits a high prevalence of dementia as disease severity and duration progress. Focused ultrasound (FUS) has been applied for transient blood–brain barrier (BBB) opening of cortical regions in neurodegenerative disorders. The striatum is a primary target for delivery of putative therapeutic agents in PD.Objective: Here, we report a prospective, single‐arm, nonrandomized, proof‐of‐concept, phase I clinical trial (NCT03608553 amended) in PD with dementia to test the safety and feasibility of striatal BBB opening in PD patients.Methods: Seven PD patients with cognitive impairment were treated for BBB opening in the posterior putamen. This was performed in two sessions separated by 2 to 4 weeks, where the second session included bilateral putamina opening in 3 patients. Primary outcome measures included safety and feasibility of focal striatal BBB opening. Changes in motor and cognitive functions, magnetic resonance imaging (MRI), ¹⁸F‐fluorodopa (FDOPA), and β‐amyloid PET (positron emission tomography) images were determined.Results: The procedure was feasible and well tolerated, with no serious adverse events. No neurologically relevant change in motor and cognitive (battery of neuropsychological tests) functions was recognized at follow‐up. MRI revealed putamen BBB closing shortly after treatment (24 hours to 14 days) and ruled out hemorrhagic and ischemic lesions. There was a discrete but significant reduction in β‐amyloid uptake in the targeted region and no change in FDOPA PET.Conclusions: These initial results indicate that FUS‐mediated striatal BBB opening is feasible and safe and therefore could become an effective tool to facilitate the delivery of putative neurorestorative molecules in PD. © 2022 International Parkinson and Movement Disorder Society.

Objective: To evaluate the predictive and prognostic value of total tumor load (TTL) in sentinel lymph nodes (SLNs) in patients with infiltrating breast cancer after neoadjuvant systemic therapy (NST). Methods: This retrospective multicenter study used data from a Spanish Sentinel Lymph Node database. Patients underwent intraoperative SLN biopsy after NST. TTL was determined from whole nodes using a one-step nucleic acid amplification (OSNA) assay and defined as the total sum of CK19 mRNA copies in all positive SLNs. Cox-regression models identified independent predictive variables, which were incorporated into a nomogram to predict axillary non-SLN metastasis, and identified prognostic variables for incorporation into a disease-free survival (DFS) prognostic score. Results: A total of 314 patients were included; most had no lymph node involvement prior to NST (cN0; 75.0% of patients). Most received chemotherapy with or without biologic therapy (91.7%), and 81 patients had a pathologic complete response. TTL was predictive of non-SLN involvement (area under the concentration curve = 0.87), and at a cut-off of 15,000 copies/µL had a negative predictive value of 90.5%. Nomogram parameters included log (TTL + 1), maximum tumor diameter and study-defined NST response. TTL was prognostic of disease recurrence and DFS at a cut-off of 25,000 copies/µL. After a 5-year follow-up, DFS was higher in patients with ≤ 25,000 copies/µL than those with > 25,000 (89.9% vs. 70.0%; p = 0.0017). Conclusions: TTL > 15,000 mRNA copies/µL was predictive of non-SLN involvement and TTL > 25,000 mRNA copies/µL was associated with a higher risk of disease recurrence in breast cancer patients who had received NST.