Sara Prioni

Diagnosing the different variants of primary progressive aphasia (PPA) is challenging, but more accurate characterization can improve patient management and treatment outcomes. This study aimed to identify the following: (1) which speech features, alone or combined with language assessment and gray matter volumes (GMVs), best distinguish PPA variants and (2) how connected speech evolves in PPA. This prospective study was conducted at IRCCS San Raffaele Hospital in Milan, Italy, between 2010 and 2021. We included patients with PPA who underwent neuropsychological assessments, including standard evaluation of language and the "Picnic Scene" speech test, and, when available, brain structural MRI. Clinical and language assessments were also performed at follow-up in a subgroup. Sequential feature selection models identified speech parameters that best differentiated groups, incorporating age, sex, education, standard language tests, and GMVs. In each PPA group, linear mixed-effect models analyzed speech changes over time. We included 95 patients with PPA (mean age 69 ± 9 years, 55 women [58%]; 40 with nonfluent variant PPA [nfvPPA], 35 with semantic variant PPA [svPPA], 20 with logopenic variant PPA [lvPPA]), of whom 82 underwent brain MRI and 34 had a follow-up visit after 10.2 months. Each model distinguished svPPA from the other PPA groups with high accuracy (R² range 0.93-1.00; p < 0.001). No differences in accuracy were observed among models for this distinction. In differentiating nfvPPA and lvPPA groups, the models incorporating speech parameters (R² = 0.92; p < 0.001), GMVs (R² = 0.95; p < 0.001), and their combination (speech + GMVs; R² = 0.97; p < 0.001) outperformed those using only standard language scores (R² = 0.75; p = 0.01). Over time, patients with nfvPPA showed more phonological errors, the svPPA group exhibited more semantic and morphosyntactic errors along with difficulties in naming and syntax production, and patients with lvPPA exhibited reduced number of words per second and fewer words per sentence. All models were equally effective in distinguishing the svPPA group from the other 2 PPA subtypes. However, compared with using standard measures alone, incorporating speech measures from the "Picnic Scene" speech test, GMVs, or their combination into the models significantly improved accuracy in differentiating nfvPPA and lvPPA groups. The PPA variants showed distinct speech trajectories. These variables can aid in understanding disease progression, predicting patient outcomes, and planning speech therapy interventions in clinical practice.

Familial cases of Alzheimer's disease (AD) with autosomal dominant transmission and early onset have a prevalence around 1%. Since only a small fraction of them has a monogenic inheritance due to APP, PSEN1 , and PSEN2 genes, genetic studies are ongoing to unravel the missing heritability. By sequencing panels including multiple dementia-related genes, we identified a novel likely pathogenic mutation in SORL1 in a pedigree including five members affected by AD. This loss of function mutation may lead to a reduction of SORL1 receptor, worsening amyloidogenic burden. As the contribution of SORL1 mutations to heritability of AD is presently not well established, we think that it is very important to signal new familial (likely) pathogenic SORL1 mutations in order to define the actual genetic involvement of SORL1 in AD pathogenesis.

This study aimed to evaluate the intensity of head pain associated with sonication. In particular, we were interested in identifying predictive factors of high-intensity head pain as it could be a source of interference with the procedure. Furthermore, we explored eventual dissociative or post-traumatic consequences related to high-intensity pain during MRgFUS.

Background: Magnetic resonance‐guided focused ultrasound (MRgFUS) thalamotomy is increasingly used to treat drug‐resistant essential tremor (ET). Data on MRgFUS thalamotomy in dystonic tremor (DT) are anecdotal.Objectives: To investigate efficacy, safety, and differences in target coordinates of MRgFUS thalamotomy in DT versus ET.Methods: Ten patients with DT and 35 with ET who consecutively underwent MRgFUS thalamotomy were followed for 12 months. Although in both groups the initial surgical planning coordinates corresponded to the ventralis intermediate (Vim), the final target could be modified intraoperatively based on clinical response.Results: Tremor significantly improved in both groups. The thalamic lesion was significantly more anterior in DT than ET. Considering both ET and DT groups, the more anterior the lesion, the lower the odds ratio for adverse events.Conclusions: MRgFUS thalamotomy is safe and effective in DT and ET. Compared to classical Vim coordinates used for ET, more anterior targeting should be considered for DT.

Background and Objectives. MRI connectomics is an ideal tool to test a network-based model of pathological propagation from a disease epicenter in neurodegenerative disorders. Here, we used a novel graph-theory-based MRI paradigm to explore functional connectivity reorganization, discerning between direct and indirect connections from disease epicenters, and its relationship with neurodegeneration across clinical presentations of the frontotemporal dementia (FTD) spectrum, including behavioral variant of FTD (bvFTD), non-fluent (nfvPPA) and semantic variants of primary progressive aphasia (svPPA). Methods. In this observational, cross-sectional study, disease epicenters were defined as the peaks of atrophy of a cohort of patients with high confidence of FTLD pathology (Mayo Clinic). These were used as seed regions for stepwise functional connectivity (SFC) analyses in an independent (Milan) set of FTD patients, to assess connectivity in regions directly and indirectly connected to the epicenters. Correlations between SFC architecture in healthy conditions and atrophy patterns in FTD patients were also tested. Results. As defined by comparing the 42 Mayo Clinic patients with 15 controls, disease epicenters were the left anterior insula for bvFTD, left supplementary motor area for nfvPPA, and left inferior temporal gyrus (ITG) for svPPA. Compared with 94 age-matched controls, bvFTD (n=64) and nfvPPA patients (n=34) of the Milan cohort showed widespread decreased SFC in bilateral cortical regions with direct/indirect connections with epicenters, and increased SFC either in directly connected regions, physically close to the respective seed region, or in more distant cortical/cerebellar areas with indirect connections. Across all link-steps, svPPA (n=36) showed SFC decrease mostly within the temporal lobes, with co-occurrent SFC increase in cerebellar regions at indirect link-steps. Average stepwise topological distance from the left ITG in a reference group of 50 young healthy controls correlated with regional grey matter volume in svPPA, consistent with network-based degeneration. Discussion. Our findings demonstrate that each FTD syndrome is associated with a characteristic interplay of decreased and increased functional connectivity with the disease epicenter, affecting both direct and indirect connections. SFC revealed novel insights regarding the topology of functional disconnection across FTD syndromes, holding the promise to be used to model disease progression in future longitudinal studies.

Background: Magnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy is a safe and effective procedure for drug‐resistant tremor in Parkinson's disease (PD).Objective: The aim of this study was to demonstrate that MRgFUS ventralis intermedius thalamotomy in early‐stage tremor‐dominant PD may prevent an increase in dopaminergic medication 6 months after treatment compared with matched PD control subjects on standard medical therapy.Methods: We prospectively enrolled patients with early‐stage PD who underwent MRgFUS ventralis intermedius thalamotomy (PD‐FUS) and patients treated with oral dopaminergic therapy (PD‐ODT) with a 1:2 ratio. We collected demographic and clinical data at baseline and 6 and 12 months after thalamotomy.Results: We included 10 patients in the PD‐FUS group and 20 patients in the PD‐ODT group. We found a significant increase in total levodopa equivalent daily dose and levodopa plus monoamine oxidase B inhibitors dose in the PD‐ODT group 6 months after thalamotomy.Conclusions: In early‐stage tremor‐dominant PD, MRgFUS thalamotomy may be useful to reduce tremor and avoid the need to increase dopaminergic medications. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Background and purpose: Q336H is a rare MAPT mutation, previously found in a single patient with behavioral variant frontotemporal dementia and tau pathology (Pick bodies). Here, we describe the clinical characteristics of two members of a new family carrying the Q336H MAPT mutation.Methods: Clinical, genetic, and neuroradiological assessment and follow‐up of the proband were made.Results: At age 37 years, the proband developed naming and object recognition impairment, due to a lack of knowledge. After 3 years, he developed behavioral disorders. Magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography showed the involvement of the left temporal pole. A diagnosis of semantic variant primary progressive aphasia (svPPA) was made. At follow‐up after 6 and 12 months, a rapid worsening of cognitive deficits occurred. His parent presented, at age 65 years, slowly progressive memory deficits without behavioral impairment, and, on MRI, evidence of mesial temporal atrophy, consistent with a clinical diagnosis of Alzheimer disease (AD).Conclusions: This is the second family carrying the MAPT Q336H mutation reported so far. We showed that svPPA and AD‐like phenotype can be associated with this mutation. A wide clinical variability exists at the intrafamilial level for Q336H MAPT mutation, pointing to genetic and/or environmental influencing factors on disease expression. We also confirmed that svPPA can be associated with MAPT mutations, suggesting that this gene should be analyzed also in patients with svPPA, especially with early onset. In addition, an AD‐like phenotype may be associated with this mutation, suggesting its different effects on protein misfolding and aggregation.