Genotype-phenotype correlation in PRKN-associated Parkinson's disease.

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson's disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials.

Differences in Survival across Monogenic Forms of Parkinson's Disease.

OBJECTIVE: Survival of patients with monogenic Parkinson's disease may depend on the causative genes associated with the disease. In this study, we compare survival of patients with Parkinson's disease according to the presence of SNCA, PRKN, LRRK2, or GBA mutations. METHODS: Data from the French Parkinson Disease Genetics national multicenter cohort study were used. Patients with sporadic and familial Parkinson's disease were recruited between 1990 and 2021. Patients were genotyped for the presence of mutations in the SNCA, PRKN, LRRK2, or GBA genes. Vital status was collected from the National death register for participants born in France. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using multivariable Cox proportional hazards regression. RESULTS: Of the 2,037 patients with Parkinson's disease, 889 had died after a follow-up of up to 30 years. Patients with PRKN (n = 100, HR = 0.41; p = 0.001) and LRRK2 mutations (n = 51, HR = 0.49; p = 0.023) had longer survival than those without any mutation, whereas patients with SNCA (n = 20, HR = 9.88; p < 0.001) or GBA mutations (n = 173, HR = 1.33; p = 0.048) had shorter survival. INTERPRETATION: Survival differs across genetic forms of Parkinson's disease, with higher mortality for patients with SNCA or GBA mutations, and lower mortality for those with PRKN or LRRK2 mutations. Differences in severity and disease progression among monogenic forms of Parkinson's disease likely explain these findings, which has important consequences for genetic counselling and choice of end points for future clinical trials for targeted therapies. ANN NEUROL 2023;94:123-132.

The wide spectrum of COVID-19 neuropsychiatric complications within a multidisciplinary centre.

A variety of neuropsychiatric complications has been described in association with COVID-19 infection. Large scale studies presenting a wider picture of these complications and their relative frequency are lacking. The objective of our study was to describe the spectrum of neurological and psychiatric complications in patients with COVID-19 seen in a multidisciplinary hospital centre over 6 months. We conducted a retrospective, observational study of all patients showing neurological or psychiatric symptoms in the context of COVID-19 seen in the medical and university neuroscience department of Assistance Publique Hopitaux de Paris-Sorbonne University. We collected demographic data, comorbidities, symptoms and severity of COVID-19 infection, neurological and psychiatric symptoms, neurological and psychiatric examination data and, when available, results from CSF analysis, MRI, EEG and EMG. A total of 249 COVID-19 patients with a de novo neurological or psychiatric manifestation were included in the database and 245 were included in the final analyses. One-hundred fourteen patients (47%) were admitted to the intensive care unit and 10 (4%) died. The most frequent neuropsychiatric complications diagnosed were encephalopathy (43%), critical illness polyneuropathy and myopathy (26%), isolated psychiatric disturbance (18%) and cerebrovascular disorders (16%). No patients showed CSF evidence of SARS-CoV-2. Encephalopathy was associated with older age and higher risk of death. Critical illness neuromyopathy was associated with an extended stay in the intensive care unit. The majority of these neuropsychiatric complications could be imputed to critical illness, intensive care and systemic inflammation, which contrasts with the paucity of more direct SARS-CoV-2-related complications or post-infection disorders.

Role of Epileptic Activity in Older Adults With Delirium, a Prospective Continuous EEG Study.

Background/Objectives: Delirium occurs in up to 50 % of hospitalized old patients and is associated with increased morbidity and mortality. Acute medical conditions favor delirium, but the pathophysiology is unclear. Preliminary evidence from retrospective and prospective studies suggests that a substantial minority of old patients with unexplained delirium have non-convulsive seizures or status epilepticus (NCSE). Yet, seeking epileptic activity only in unexplained cases of delirium might result in misinterpretation of its actual prevalence. We aimed to systematically investigate the role of epileptic activity in all older patients with delirium regardless of the underlying etiology. Design, Setting: Prospective observational study in a tertiary medical center. Adults >65 years with delirium underwent at least 24 h of continuous electro-encephalographic monitoring (cEEG). Background patterns and ictal and interictal epileptic discharges were identified, as well as clinical and biological characteristics. Participants: Fifty patients were included in the study. Results: NCSE was found in 6 (12%) patients and interictal discharges in 15 (30%). There was no difference in the prevalence of epileptic activity rates between delirium associated with an acute medical condition and delirium of unknown etiology. Conclusion: Epileptic activity may play a substantial role in the pathophysiology of delirium by altering brain functioning and neuronal metabolism. No clinical or biological marker was found to distinguish delirious patients with or without epileptic activity, underlining the importance of cEEG in this context.

Structural priming in sentence comprehension: A single prime is enough.

Experiencing a syntactic structure affects how we process subsequent instances of that structure. This phenomenon, called structural priming, is observed both in language production and in language comprehension. However, while abstract syntactic structures can be primed independent of lexical overlap in sentence production, evidence for structural priming in comprehension is more elusive. In addition, when structural priming in comprehension is found, it can often be accounted for in terms of participants' explicit expectations. Participants may use the structural repetition over several sentences and build expectations, which create a priming effect. Here, we use a new experimental paradigm to investigate structural priming in sentence comprehension independent of lexical overlap and of participants' expectations. We use an outcome dependent variable instead of commonly used online measures, which allows us to more directly compare these effects with those found in sentence production studies. We test priming effects in syntactically homogeneous and heterogeneous conditions on a sentence-picture matching task that forces participants to fully parse the sentences. We observe that, while participants learn the structural regularity in the homogeneous condition, structural priming is also found in the heterogeneous condition, in which participants do not expect any particular structure. In fact, we find that a single prime is enough to trigger priming. Our results indicate that-like in sentence production-structural priming can be observed in sentence comprehension without lexical repetition and independent of participants' expectation.

The role of the striatum in sentence processing: disentangling syntax from working memory in Huntington's disease.

The role of sub-cortical structures in language processing remains controversial. In particular, it is unclear whether the striatum subserves language-specific processes such as syntax or whether it solely affects language performance via its significant role in executive functioning and/or working memory. Here, in order to address this issue, we attempted to equalize working memory constraints while varying syntactic complexity, to study sentence comprehension in 15 patients with striatal damage, namely Huntington's disease at early stage, and in 15 healthy controls. More particularly, we manipulated the syntactic relation between a name and a pronoun while holding the distance between them constant. We exploited a formal principle of syntactic theory called Principle C. This principle states that whereas in a sentence such as "Paul smiled when he entered" Paul and he can be a single person, this interpretation is blocked in sentences such as "He smiled when Paul entered". In a second experiment we varied working memory load using noun-adjective gender agreement in center-embedded and right-branching relatives (e.g., "the girl who watches the dog is green" vs. "the girl watches the dog which is green"). The results show that HD patients correctly establish name-pronoun co-reference but they fail to block it when Principle C should apply. Furthermore, they have good performance with both center-embedded and right-branching relatives, suggesting that their difficulties in sentence comprehension do not arise from memory load impairment during sentence processing. Taken together, our findings indicate that the striatum holds a genuine role in syntactic processing, which cannot be reduced to its involvement in working memory. However, it only impacts on particular aspects of syntax that may relate to complex computations whereas other operations appear to be preserved. Hypotheses about the role of the striatum in syntactic processing are discussed.