Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course of the disease. Considering its poor prognosis with a median survival time of 2 to 4 years and limited causal treatment options, an early diagnosis of ALS plays an essential role. In the past, diagnosis has primarily been determined by clinical findings supported by electrophysiological and laboratory measurements. To increase diagnostic accuracy, reduce diagnostic delay, optimize stratification in clinical trials and provide quantitative monitoring of disease progression and treatment responsivity, research on disease-specific and feasible fluid biomarkers, such as neurofilaments, has been intensely pursued. Advances in imaging techniques have additionally yielded diagnostic benefits. Growing perception and greater availability of genetic testing facilitate early identification of pathogenic ALS-related gene mutations, predictive testing and access to novel therapeutic agents in clinical trials addressing disease-modified therapies before the advent of the first clinical symptoms. Lately, personalized survival prediction models have been proposed to offer a more detailed disclosure of the prognosis for the patient. In this review, the established procedures and future directions in the diagnostics of ALS are summarized to serve as a practical guideline and to improve the diagnostic pathway of this burdensome disease.

Background: With pathway‐specific trials in PD associated with variants in the glucocerebrosidase gene (PD_GBA) under way, we need markers that confirm the impact of genetic variants in patient‐derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read‐out for target engagement.Objective: To explore GBA‐pathway‐specific biomarker profiles cross‐sectionally (TUEPAC‐MIGAP, PPMI) and longitudinally (PPMI).Methods: We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by‐products) and CSF levels of total α‐synuclein in PD_GBA patients compared to PD_{GBA_wildtype} patients.Results: Cross‐sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PD_GBA compared to PD_{GBA_wildtype}. (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PD_GBA compared to PD_{GBA_wildtype}. (3) CSF levels of total α‐synuclein were lower in PD_GBA compared to PD_{GBA_wildtype}. All of these findings were most pronounced in PD_GBA with severe mutations (PD_{GBA_severe}). Cross‐sectionally in TUEPAC‐MIGAP and longitudinally in PPMI, CSF levels of downstream‐products (ceramides) were higher in PD_{GBA_severe}. Cross‐sectionally in TUEPAC‐MIGAP by‐products sphinganine and sphingosine‐1‐phosphate and longitudinally in PPMI species of by‐products lactosylceramides and sphingomyelin were higher in PD_{GBA_severe}.Interpretation: These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PD_GBA with severe variants. © 2021 International Parkinson and Movement Disorder Society

The worldwide prevalence of Parkinson’s disease (PD) has been constantly increasing in the last decades. With rising life expectancy, a longer disease duration in PD patients is observed, further increasing the need and socioeconomic importance of adequate PD treatment. Today, PD is exclusively treated symptomatically, mainly by dopaminergic stimulation, while efforts to modify disease progression could not yet be translated to the clinics. New formulations of approved drugs and treatment options of motor fluctuations in advanced stages accompanied by telehealth monitoring have improved PD patients care. In addition, continuous improvement in the understanding of PD disease mechanisms resulted in the identification of new pharmacological targets. Applying novel trial designs, targeting of pre-symptomatic disease stages, and the acknowledgment of PD heterogeneity raise hopes to overcome past failures in the development of drugs for disease modification. In this review, we address these recent developments and venture a glimpse into the future of PD therapy in the years to come.