Clearance Mechanisms in Atypical Neurodegenerative Diseases (PeptiClear)

Cerebral Clearance Mechanisms in Atypical Neurodegenerative Diseases: A Multi-modal Study on Lymphatic, Glymphatic and Blood-brain-barrier Function

The project PeptiClear aims to investigate whether the blood-brain-barrier (BBB) and the glymphatic system are compromised in atypical neurodegenerative diseases, and whether Alzheimer´s disease (AD)-related copathology, vascular lesions or sleep disturbances modify the clinical picture or structural and/or functional features of the diseases.

Study Overview

• Status: Recruiting
• Conditions: Neurodegenerative Diseases; Frontotemporal Degeneration

Detailed Description

It is well established for the frequent sporadic (non-genetic) variant of Alzheimer´s disease (AD) that not the overproduction of a specific protein (Amyloid-beta - Aβ) is a major cause but rather the insufficient clearance of this protein from the central nervous system. On one hand, under physiological conditions, the interplay of the several cell types (cerebral endothelial cells, perivascular mural cells (pericytes), glial cells (astrocytes and microglia) and neurons) regulates the neuronal and glial cell environment and is crucial for cell function and survival. On the other hand, Aβ aggregates lead to BBB damage and activation of microglial cells. The BBB facilitates the clearance of proteins such as Aβ via the cerebrovascular system, but its association with other intracerebral Aβ drainage systems, such as the glympathic system, remains to be clarified. As the glymphatic system is mainly active during sleep, sleep disturbances could influence the clinical course. Concerning atypical neurodegenerative diseases, it is not clear whether tau or alpha-synuclein (alpha-syn) deposits also have a potential to damage the BBB. In AD Aβ aggregation and vascular changes give rise to insufficient protein clearance and thus contribute to AD pathogenesis in a synergistic fashion. However the role of copathology in atypical neurodegenerative diseases - which mainly consists of Alzheimer-related changes and vascular pathology - is elusive and remains to be clarified.

The prospective study cohort (N ~80) will include patients with Lewy Body spectrum disease, progressive supranuclear palsy, corticobasal syndrome and frontotemporal dementia. All study participants will undergo a detailed clinical and neuropsychological assessment according to a standardised protocol (i.a. magnet resonance imaging (MRI), positron emission tomography (PET), cerebrospinal fluid (CSF), actigraphy).

• Study Type: Observational
• Enrollment (Anticipated): 80

Contacts and Locations

• Study Contact: Name: Robert Perneczky, Prof. Dr.; Phone Number: +4989440055863; Email: PSY.Alzheimerzentrum@med.uni-muenchen.de
• Study Contact Backup: Name: Lena Burow, M.Sc.; Phone Number: +4989440055898; Email: lena.burow@med.uni-muenchen.de

Study Locations

• Germany
  • Bayern
    • München, Bayern, Germany, 80336
      • Recruiting
      • Klinik und Poliklinik für Psychiatrie und Psychotherapie des LMU Klinikums
      • Contact: Robert Perneczky, Prof. Dr.; Phone Number: +49 89 4400 55863; Email: PSY.Alzheimerzentrum@med.uni-muenchen.de
      • Contact: Lena Burow, M.Sc.; Phone Number: +49 89 4400 55898; Email: lena.burow@med.uni-muenchen.de
      • Sub-Investigator: Carolin Kurz, Dr.med.
      • Sub-Investigator: Boris-Stephan Rauchmann, Dr. med.
      • Sub-Investigator: Selim Gürsel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Atypical neurodegerative diseases: Lewy-Body Spectrum Diseases, Progressive Supranuclear Palsy, Corticobasal Syndrome, Frontemporal Degeneration

Description

Inclusion Criteria:

• Diagnosis of Atypical Parkinsonian Disorders or Frontotemporal Dementia
• Able to provide written informed consent
• Unchanged pharmacotherapy within 4 days prior to the study specific assessments
• Fluent in German

Exclusion Criteria:

• Unable to give informed consent or has a legal guardian
• Other severe mental disorder, e.g. schizophrenia or bipolar affective disorder
• Clinically relevant depression
• Acute suicidality
• Current alcohol, drug or medication abuse
• History of severe traumatic brain injury within 3 months prior to inclusion
• Structural lesions of the basal ganglia or brain stem
• Severe neurological disorder including (but not limited to) epilepsy, systemic disorders, stroke, repeated transient ischaemic attacks, increased brain intracranial pressure, normal pressure hydrocephalus
• Severe medical disorders including (but not limited to) heart failure, respiratory failure, uncontrolled severe arterial hypertension
• Electronic implants (e.g. cardiac pacemaker) or other MRI contraindication
• Renal failure > stage 3 (GFR < 30 mL/min)
• Pregnancy
• Unresolved malignancies within two years prior to inclusion
• Severe current infections or other chronic or systemic disorders
• Other circumstances which preclude participation based on the investigator's judgement

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Lewy Body Spectrum Diseases
Progressive Supranuclear Palsy
Corticobasal Syndrome
Frontotemporal Degeneration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disruption of the brain-blood-barrier between the subgroups	Name of Measurement: Ktrans; Measurement Tool: dynamic contrast imaging(DCI) sequence (MRI); Unit: min -1	Baseline
Clearance mechanisms and glymphatic or cerebral lymphatic system	Name of Measurement: Diffusion tensor imaging (DTI) Analysis along the perivascular space (ALPS); Measurement Tool: DTI MRI; Unit: mean (Dxpro, Dypro)/ mean (Dypro, Dzasc)	Baseline
Changes in circadian rhythms	Sleep Efficiency, proportional integration mode (PIM) ;Measurement Tool: Actigraphy; Units: counts	Baseline
Correlation between clinical symptoms, tau pathology and BBB disorder	Correlations between neuropsychological tests (e.g. Clinical Dementia Rating Sum of Boxes), CSF markers (pg/ml) and TAU PET, standardized uptake value ratio (SUVr) and Ktrans map	Baseline

Collaborators and Investigators

• Sponsor: Ludwig-Maximilians - University of Munich
• Investigators: Principal Investigator: Robert Perneczky, Prof. Dr., Klinik und Poliklinik für Psychiatrie und Psychotherapie des LMU Klinikums

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2022
• Primary Completion (Anticipated): April 1, 2024
• Study Completion (Anticipated): April 1, 2024

Study Registration Dates

• First Submitted: November 2, 2021
• First Submitted That Met QC Criteria: March 31, 2022
• First Posted (Actual): April 8, 2022

Study Record Updates

• Last Update Posted (Estimate): March 9, 2023
• Last Update Submitted That Met QC Criteria: March 8, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Sleep; Neurodegenerative diseases; Frontotemporal Degeneration; Clearance; Blood-brain-barrier; Microglial activation; Glymphatic system
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurodegenerative Diseases
• Other Study ID Numbers: 21-0106

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No