Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges

No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era.

What is the Clinical Significance of Cerebrospinal Fluid Biomarkers in Parkinson's disease? Is the Significance Diagnostic or Prognostic?

The clinical diagnostic criteria of Parkinson's disease (PD) have limitations in detecting the disease at early stage and in differentiating heterogeneous clinical progression. The lack of reliable biomarker(s) for early diagnosis and prediction of prognosis is a major hurdle to achieve optimal clinical care of patients and efficient design of clinical trials for disease-modifying therapeutics. Numerous efforts to discover PD biomarkers in CSF were conducted. In this review, we describe the molecular pathogenesis of PD and discuss its implication to develop PD biomarkers in CSF. Next, we summarize the clinical utility of CSF biomarkers including alpha-synuclein for early and differential diagnosis, and prediction of PD progression. Given the heterogeneity in the clinical features of PD and none of the CSF biomarkers for an early diagnosis have been developed, research efforts to develop biomarkers to predict heterogeneous disease progression is on-going. Notably, a rapid cognitive decline followed by the development of dementia is a risk factor of poor prognosis in PD. In connection to this, CSF levels of Alzheimer's disease (AD) biomarkers have received considerable attention. However, we still need long-term longitudinal observational studies employing large cohorts to evaluate the clinical utility of CSF biomarkers reflecting Lewy body pathology and AD pathology in the brain. We believe that current research efforts including the Parkinson's Progression Markers Initiative will resolve the current needs of early diagnosis and/or prediction of disease progression using CSF biomarkers, and which will further accelerate the development of disease-modifying therapeutics and optimize the clinical management of PD patients.

Flow Starting Point and Voiding Mechanisms Measured by Simultaneous Registrations of Intravesical, Intra-abdominal, and Intraurethral Pressures in Awake Rats / 대한배뇨장애요실금학회지

PURPOSE: The aim of this study was to apply a new surgical procedure that allows for the successful monitoring of intraurethral pressure (IUP) changes in the cystometry of awake Sprague-Dawley rats. METHODS: Twenty-six female Sprague-Dawley rats were grouped according to the catheterization method (bladder only; bladder and urethra; or bladder, urethra, and abdomen). Using an arbitrarily determined initial point of the first phase among four rat micturition phases on the simultaneous curves as a reference point, we compared the time differences to the points on an intravesical pressure (IVP) and those on IUP or a detrusor pressure (DP) curve from intra-abdominal pressure (IAP). RESULTS: In awake rat, the start of urethral flow on IUP curve corresponded to the initial point of the second phase, which is same to the results on the anesthetized rat. However, certain results, such as micturition pressure (MP) and intraluminal pressure high-frequency oscillations (IPHFOs), differed between awake and anesthetized rats. Most MP values were checked after the end of urethral flow on the IUP curve, which is due to the peculiar methodology such as transvesical catheterization. Urethral flow was not completely interrupted during the IPHFOs, which suggests the presence of urethral wall tension against the flow during voiding. After removal of the superimposed effects of IAP from IVP, the DP curve clearly showed a peculiar shape, highlighting the possibility of using IAP in place of IUP to detect the flow starting point on the IVP curve. CONCLUSIONS: Awake rat cystometry results have been interpreted based on those in anesthetized rats. However, our awake cystometry data were substantially different in terms of voiding time compared to those of anesthetized rats. This discovery warrants careful interpretation of the voiding parameters in awake rat cystometry.