Supplementary Material for: Ambulatory Activity Components Deteriorate Differently across Neurodegenerative Diseases: A Cross-Sectional Sensor-Based Study

<b><i>Background and Purpose:</i></b> Reduced ambulatory activity is a major burden in neurodegenerative disease (NDD), leading to severe restrictions in social participation and further deterioration of motor capacities. However, objective evidence on walking behavior patterns and components underlying this impairment and its decline with disease progression is scarce for many NDDs. We aimed to unravel the detailed metrics underlying the reduced ambulatory activity in selected NDDs, and their relation to disease duration. We hypothesized that progressively reduced ambulatory activity is a feature shared across different NDDs, characterized by changes in both common and distinct components. <b><i>Methods:</i></b> Sixty-five subjects with NDD (n = 34 degenerative ataxia; n = 15 progressive supranuclear palsy, and n = 16 Parkinson's disease) and 38 healthy older adults (total n = 103) wore a three-axial accelerometer (activPAL3™) for 7 consecutive days. Detailed metrics of ambulatory activity were calculated. <b><i>Results:</i></b> The average daily walking duration was significantly decreased in all three NDDs, yet characterized by a differential pattern of changes in number and length of walking bouts and sit-to-stand transfers. Decline in walking duration progressed with increased disease duration in all three NDDs, yet at a differing rate. This decline was associated with progressive reductions in walking bout length and walking behavior pattern diversity in all three NDDs. <b><i>Conclusions:</i></b> These findings provide objective evidence that reduced ambulatory activity is a shared feature across different NDDs. Moreover, they reveal that several underlying walking behavior components change with increasing disease duration, yet at a differing rate in different NDDs. This indicates that metric analysis of ambulatory activity might provide ecologically relevant and disease-specific progression and outcome markers in several NDDs

Supplementary Material for: Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia

<p><b><i>Background and Objective:</i></b> Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene <i>(GRN)</i>. However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to <i>GRN </i>mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in <i>GRN</i>-negative FTD. <b><i>Methods:</i></b> Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls). All FTD patients were assessed by whole-exome sequencing for <i>GRN</i> mutations, yielding a target cohort of 34 patients without pathogenic mutations in <i>GRN</i> (<i>GRN</i>-negative cohort) and 3 <i>GRN</i> mutation carriers (2 LoF variants and 1 novel missense variant). <b><i>Results:</i></b> Not only the <i>GRN</i> mutation carriers but also the <i>GRN</i>-negative patients showed decreased CSF levels of progranulin (serum levels in<i> GRN</i>-negative patients were normal). The decreased CSF progranulin levels were unrelated to patients' increased CSF levels of total tau, possibly indicating different destructive neuronal processes within FTD neurodegeneration. The patient with the novel <i>GRN</i> missense variant (c.1117C>T, p.P373S) showed substantially decreased CSF levels of progranulin, comparable to the 2 patients with <i>GRN</i> LoF mutations, suggesting a pathogenic effect of this missense variant. <b><i>Conclusions:</i></b> Our results indicate that central nervous progranulin reduction is not restricted to the relatively rare cases of FTD caused by <i>GRN</i> LoF mutations, but also contributes to the more common <i>GRN-</i>negative forms of FTD. Central nervous progranulin reduction might reflect a partially distinct pathogenic mechanism underlying FTD neurodegeneration and is not directly linked to tau alterations.</p><br

Supplementary Material for: Fatigue-related changes of daily function: most promising measures for the digital age

Background: Fatigue is a prominent symptom in many diseases, and is strongly associated with impaired daily function. The measurement of daily function is currently almost always done with questionnaires, which are subjective and imprecise. With the recent advances of digital wearable technologies, novel approaches to evaluate daily function quantitatively and objectively in real life conditions are increasingly possible. This also creates new possibilities to measure fatigue-related changes of daily function using such technologies. Summary: This review examines in immune-mediated inflammatory and neurodegenerative diseases, which parameters may have the greatest potential to reflect fatigue-related changes of daily function. Key Messages: Results of a standardized analysis of the literature reporting about perception-, capacity- and performance-evaluating assessment tools indicate that changes of the following parameters: physical activity, independence of daily living, social participation, working life, mental status, cognitive and aerobic capacity, and supervised and unsupervised mobility performance have the highest potential to reflect fatigue-related changes of daily function. These parameters thus hold the greatest potential for quantitatively measuring fatigue in representative diseases in real life conditions, e.g. with digital wearable technologies. Furthermore, to the best of our knowledge, this is a new approach to analysing evidence for the design of performance-based digital assessment protocols in human research, which may stimulate further systematic research in this area