Wszołek, Zbigniew K.

AbstractBackgroundAs gene‐targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial‐ready cohorts is limited.ObjectiveThe objectives are to (1) establish an international cohort of affected and unaffected individuals with PD‐linked variants; (2) provide harmonized and quality‐controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.MethodsWe conducted a worldwide, systematic online survey to collect individual‐level data on individuals with PD‐linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ‐1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed.ResultsWe collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ‐1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published.ConclusionsWithin the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD‐linked variants; (2) provide harmonized and quality‐controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene‐targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

AbstractIntroductionEmpathy relies on fronto‐cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress.MethodsFour hundred thirty‐one individuals with asymptomatic genetic FTD (n = 114), genetic and sporadic bvFTD (n = 317), and 163 asymptomatic non‐carrier controls were enrolled. In sub‐samples, we investigated empathy measured by the informant‐based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n = 91), and its correspondence to underlying atrophy (n = 51).ResultsEmpathic concern (estimate = 4.38, 95% confidence interval [CI] = 2.79, 5.97; p < 0.001) and perspective taking (estimate = 5.64, 95% CI = 3.81, 7.48; p < 0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy.DiscussionLoss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials.

ABSTRACTBackgroundAdult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare neurodegenerative disorder with characteristic clinicopathological features. Identification of pathogenic mutations in CSF1R, AARS1, and AARS2 genes led to increased recognition and diagnosis of the ALSP.ObjectivesThis paper presents the first family with typical clinical, radiological, and pathological features of ALSP, yet negative for CSF1R, AARS1, and AARS2 mutations.MethodsThe index case was a 30‐year‐old male who presented with gait difficulty, followed by cognitive decline and incontinence.ResultsNeurological examination evidenced progressive dementia, dysarthria, spasticity, parkinsonism, and severe gait disturbances. Brain MRI showed confluent white matter abnormalities with scattered foci of restricted diffusion, and atrophy of the corpus callosum. He was suspected of ALSP; however, the extensive genetic work‐up did not find pathogenic mutation. He died at 33 years, and brain autopsy was performed. He had myelin staining pallor and axonal swellings, spheroids, and pigmented glia in affected white matter. His father developed similar symptoms in his early 40s and died at 46 years. Neuropathological examination also confirmed ALSP diagnosis. We found two similar cases in the literature with typical ALSP features but negative for CSF1R mutation; however, none were tested for AARS1 and AARS2 mutations.ConclusionsWe draw attention to a new entity within the ALSP disease spectrum that needs further investigation. As the disease‐modifying therapy is already available for ALSP‐CSF1R, there is a strong need to identify the genetic cause of patients such as these in the ALSP spectrum, enabling research toward implementing effective treatment.

Mutations in the CSF1R gene are the most common cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a neurodegenerative disease with rapid progression and ominous prognosis. Hematopoietic stem cell transplantation (HSCT) has been increasingly offered to patients with CSF1R-ALSP. However, different therapy results were observed, and it was not elucidated which patient should be referred for HSCT. This study aimed to determine predictors of good and bad HSCT outcomes in CSF1R-ALSP. We retrospectively analyzed 15 patients, 14 symptomatic and 1 asymptomatic, with CSF1R-ALSP that underwent HSCT. Median age of onset was 39 years, and the median age of HSCT was 43 years. Cognitive impairment was the most frequent initial manifestation (43%), followed by gait problems (21%) and neuropsychiatric symptoms (21%). Median post-HSCT follow-up was 26 months. Good outcomes were associated with gait problems as initial (p = 0.041) and predominant (p = 0.017) manifestation and younger age at HSCT (p = 0.044). Cognitive impairment as first manifestation was a predictor of a bad outcome (p = 0.016) and worsening of cognition post-HSCT (p = 0.025). In conclusion, gait problems indicated a milder phenotype with better response to HSCT and good therapy outcomes. In contrast, patients with a higher burden of cognitive symptoms were most likely not to benefit from HSCT.