Wszołek, Zbigniew K.

AbstractBackgroundUp to 30% of frontotemporal dementia (FTD) cases are due to known pathogenic mutations (f‐FTD). Little is known about the factors that predict who will choose to learn their results. Upcoming clinical trials in f‐FTD may require disclosure prior to enrollment, even before symptom onset, and thus characterizing this sample is important. Furthermore, understanding the mood impacts of genetic disclosure may guide genetic counseling practice.MethodF‐FTD participants (n=568) from families with a known pathogenic mutation (MAPT, C9orf72, GRN) were enrolled through the ARTFL/LEFFTDS Longitudinal FTD Study (ALLFTD) and provided the opportunity for disclosure. Independent‐sample t‐tests compared demographic and psychosocial factors between participants who did and did not receive their results. In participants who were asymptomatic at baseline and follow up (n=199,177 with follow‐up), linear mixed effects modeling was used to investigate pre‐ to post‐disclosure changes in the 15‐item Geriatric Depression Scale (GDS).ResultOf participants from families with a known pathogenic genetic mutation, 47% received genetic disclosure. Of the asymptomatic subset (n=386), 36% know their mutation status. Of these asymptomatic learners, 46% received disclosure through the study, and the remainder learned their genetic status prior to study enrollment. None of the analyzed demographic or psychosocial factors (i.e., sex, age, education, having children) differed between learners and non‐learners (p’s > 0.05). In the longitudinal analysis of asymptomatic participants, learners showed a pre‐ to post‐increase of 0.31 GDS points/year (95%CI: ‐0.08, 0.69, p = 0.12), whereas non‐learners showed a slight decline (‐0.15 points/year, 95%CI: ‐0.36, 0.06, p = 0.16). This difference between slopes was statistically significant (0.46, 95%CI: 0.02, 0.89, p=0.04) but represents a small clinical effect. In asymptomatic learners, slopes did not differ based on mutation status (0.28, 95%CI: ‐0.66, 1.20, p=0.55). Conclusions were based on the estimates and full range of confidence intervals.ConclusionThe majority of asymptomatic research participants do not know their genetic status, which will be a consideration for clinical trials that require disclosure. No considered demographic factors were strongly associated with the decision to receive disclosure. The findings suggest that disclosure in asymptomatic participants has minimal impact on depressive symptoms regardless of genetic results.

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates.ObjectiveThe objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD.MethodsAdvancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation.Results29% of respondents self‐reported as patients (63±10 years), 26% self‐reported as caregivers answering on behalf of patients (65±10 years), and 45% self‐reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (≧66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (≧80%) and being informed of their individual disease progression (≧75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (≧87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture (≧52%). Overall, respondents showed a positive attitude and support for research participation (≧77%) and trusted that their health information would remain confidential in a clinical trial (≧53%).ConclusionsFavorable attitudes and interest towards medical research exist among participants. To optimize participation, clinical trials should allocate funding for travel and involve participants in feedback about study results and their disease progression. Alternatives to invasive assessments may increase participation.

AbstractColony‐stimulating factor 1 receptor (CSF1R)‐related leukoencephalopathy is a rare but fatal microgliopathy. The diagnosis is often delayed due to multifaceted symptoms that can mimic several other neurological disorders. Imaging provides diagnostic clues that help identify cases. The objective of this study was to integrate the literature on neuroimaging phenotypes of CSF1R‐related leukoencephalopathy. A systematic review and meta‐analysis were performed for neuroimaging findings of CSF1R‐related leukoencephalopathy via PubMed, Web of Science, and Embase on 25 August 2021. The search included cases with confirmed CSF1R mutations reported under the previous terms hereditary diffuse leukoencephalopathy with spheroids, pigmentary orthochromatic leukodystrophy, and adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia. In 78 studies providing neuroimaging data, 195 cases were identified carrying CSF1R mutations in 14 exons and five introns. Women had a statistically significant earlier age of onset (p = 0.041, 40 vs 43 years). Mean delay between symptom onset and neuroimaging was 2.3 years. Main magnetic resonance imaging (MRI) findings were frontoparietal white matter lesions, callosal thinning, and foci of restricted diffusion. The hallmark computed tomography (CT) finding was white matter calcifications. Widespread cerebral hypometabolism and hypoperfusion were reported using positron emission tomography and single‐photon emission computed tomography. In conclusion, CSF1R‐related leukoencephalopathy is associated with progressive white matter lesions and brain atrophy that can resemble other neurodegenerative/‐inflammatory disorders. However, long‐lasting diffusion restriction and parenchymal calcifications are more specific findings that can aid the differential diagnosis. Native brain CT and brain MRI (with and without a contrast agent) are recommended with proposed protocols and pictorial examples are provided.

A rare APOE variant APOE3 -Jac reduces self-aggregation and promotes healthy brain aging.

AbstractBackground and purposePerry disease (or Perry syndrome) is an autosomal dominant neurodegenerative disorder characterized by parkinsonism, neuropsychiatric symptoms, central hypoventilation, weight loss and distinct TDP‐43 pathology. It is caused by mutations of the DCTN1 gene encoding an essential component of axonal transport. The objectives were to provide the current state of knowledge on clinical, pathological and genetic aspects of Perry disease, as well as practical suggestions for the management of the disease.MethodsData on new patients from New Zealand, Poland and Colombia were collected, including autopsy report. Also all of the published papers since the original work by Perry in 1975 were gathered and analyzed.ResultsParkinsonism was symmetrical, progressed rapidly and was poorly responsive to L‐Dopa; nonetheless, a trial with high doses of L‐Dopa is warranted. Depression was severe, associated with suicidal ideations, and benefited from antidepressants and L‐Dopa. Respiratory symptoms were the leading cause of death, and artificial ventilation or a diaphragm pacemaker prolonged survival. Weight loss occurred in most patients and was of multifactorial etiology. Autonomic dysfunction was frequent but underdiagnosed. There was a clinical overlap with other neurodegenerative disorders. An autopsy showed distinctive pallidonigral degeneration with TDP‐43 pathology. Genetic testing provided evidence of a common founder for two families. There was striking phenotypic variability in DCTN1‐related disorders. It is hypothesized that oligogenic or polygenic inheritance is at play.ConclusionsPerry disease and other DCTN1‐related diseases are increasingly diagnosed worldwide. Relatively effective symptomatic treatments are available. Further studies are needed to pave the way toward curative/gene therapy.

AbstractBackgroundColony‐stimulating factor‐1 receptor (CSF1R)‐related leukoencephalopathy is a rapidly progressive neurodegenerative disease for which there is currently no cure. Hematopoietic stem cell transplantation (HSCT) has been proposed as a disease‐modifying treatment.ObjectiveThe objective of this study was to determine the effect of HSCT on disease progression.MethodsWe collected all available clinical data from a cohort of 7 patients with CSF1R‐related leukoencephalopathy who underwent HSCT at our institutions. Clinical data included detailed neurological examination by a board‐certified neurologist, serial cognitive screens, formal neuropsychological evaluations, and serial brain magnetic resonance imaging (MRI).ResultsOur patients had an average disease duration of 27.6 months at the time of transplant, and we have 87 months of total posttransplant follow‐up time (median, 11; range, 2–27). One patient died in the periprocedural period. The remaining patients showed a variable response to treatment, with 6 of 7 patients trending toward stabilization on motor examination, cognitive scores, and/or MRI abnormalities, especially with white matter lesion burden.ConclusionsThis is the largest series of patients with CSF1R‐related leukoencephalopathy receiving HSCT. We conclude that HSCT can stabilize the disease in some patients. Variability in patient responsiveness suggests that measures of disease heterogeneity and severity need to be considered when evaluating a patient's candidacy for transplant. HSCT appears to be the first disease‐modifying therapy for CSF1R‐related leukoencephalopathy. This milestone may serve as a foothold toward better understanding the disease's pathomechanism, thus providing new opportunities for better disease‐specific therapies. © 2021 International Parkinson and Movement Disorder Society