This is a Phase II, randomized, placebo-controlled, double-blind, crossover study on the CNS and pharmacodynamic effects of clenbuterol (CST-103) co-administered with nadolol (CST-107) in 4 subject populations with Neurodegenerative Disorders.

Approximately 40 subjects with Parkinson's Disease (PD) with REM Sleep Behavior Disorder (RBD) and Depressive Symptoms, Mild Cognitive Impairment (MCI) with Depressive Symptoms, Dementia with Lewy Bodies (DLB) with Cognitive Fluctuations, and Parkinson's Disease Dementia (PDD) with Cognitive Fluctuations were to be enrolled in a 2 period, 2-way crossover design following study eligibility confirmation during the screening period. The number of subjects enrolled in each cohort could change as emerging data are reviewed from this and other studies.

During each treatment period, subjects received daily doses of clenbuterol (CST-103) co-administered with nadolol (CST-107) or matching placebo for 14 days. Each treatment period was separated by a washout period of 14 days (+5-day window).

All subjects completed clinical and pharmacodynamic assessments during each treatment period and PK blood samples were collected prior to, during and after study medication administration.

Inclusion Criteria:

Subjects with PD:

• Male or female subjects ≥ 40 and ≤ 80 years of age, at time of informed consent.
• Diagnosed with Parkinson's Disease, as defined by the United Kingdom Parkinson Disease Brain Bank criteria, associated with REM sleep behavior disorder (PD)
• Modified Hoehn & Yahr ≥ stage 1 and ≤ stage 3 during "On" period as documented in the 3 months prior to Screening or completed at Screening.
• Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 28.

Subjects with MCI:

• Male or female subjects ≥ 50 and ≤ 80 years of age, at time of informed consent.
• Meet the criteria for amnestic Mild Cognitive Impairment (MCI) as per the National Institute on Aging-Alzheimer's Association core clinical criteria.
• Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 26.
• No dementia according to the International Classifications of Diseases (ICD)-10 and Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV.
• Memory complaint reported by the subject or his/her partner, family member or caregiver.
• Score of greater than or equal to one standard deviation below age and educational norms in the Digit Symbol Substitution Test (DSST) during Screening.
• Cognitive decline not primarily caused by vascular, traumatic, or medical problems.

Subjects with Dementia with Lewy Bodies (DLB) or Parkinson's Disease Dementia (PDD):

• Male or female subjects ≥ 50 and ≤ 80 years of age, at time of informed consent.
• Diagnosis of dementia associated with Dementia with Lewy Bodies or Parkinson's disease (PDD).
• Documented cognitive fluctuations endorsed on the Dementia Cognitive Fluctuation Scale (DCFS) with a combined score of ≥8 in items 4, 11, 12 and 14.
• Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 26.
• Have informant or caregiver throughout the study who will submit written consent to cooperate with this study, who routinely accompanies and/or stays with subject 12 hours or more a week, assists with treatment compliance, provides assessments and is able to escort the subject on required visits to study institution.
• Modified Hoehn & Yahr ≥ stage 1 and ≤ stage 3 during "On" period as documented in the 3 months prior to Screening or completed at Screening.
• Stable concomitant medical and/or psychiatric illnesses in the judgement of the PI.

For ALL Subjects:

• Unless confirmed to be azoospermic (vasectomized or secondary to medical cause), males must agree to use a male condom from Day 1 throughout the study when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant.
• Females of childbearing potential (i.e., not postmenopausal or surgically sterile) who have a male partner must have a negative serum pregnancy test result and must agree to one of the following from start of Screening through 30 days after the last study medication administration: use a reliable method of birth control, or monogamous relationship with a male partner of confirmed sterility, or practice complete abstinence.
• Females of non-childbearing potential may be enrolled if it is documented that they are postmenopausal.
• Body weight greater or equal to 50 kg and body mass index (BMI) between 18 and 35 kg/m2, inclusive at Screening.
• Stable medical conditions for 3 months prior to Screening visit (e.g., controlled hypertension, dyslipidemia).
• Willing to follow the protocol requirements and comply with protocol restrictions.
• Capable of providing informed consent and complying with study procedures. Subjects who are unable to provide consent may use a Legally Authorized Representative.

Exclusion Criteria:

• Poorly controlled hypertension despite lifestyle modifications and/or pharmacotherapy.
• Pulmonary disease, including asthma if requiring the use of a β2-Adrenergic bronchodilator, or evidence of clinically significant moderate or severe pulmonary symptoms.
• Clinical signs indicating syndromes such as corticobasal degeneration, supranuclear gaze palsy, multiple system atrophy, chronic traumatic encephalopathy, signs of frontal dementia, history of stroke, head injury or encephalitis, cerebellar signs, early severe autonomic involvement, or Babinski sign.
• Current evidence or history in past two years of epilepsy, focal brain lesion, head injury with loss of consciousness or meeting DSM-IV diagnostic criteria for psychotic disorders.
• Evidence of any significant clinical disorder or laboratory finding (or in the case of potassium levels below normal range) that renders the participant unsuitable for receiving an investigational drug.
• History of malignant disease, including solid tumors and hematologic malignancies (except basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured).
• Any clinically significant illness or disease as determined by medical and surgical history, physical examination, 12-lead electrocardiogram (ECG) and clinical laboratory assessments conducted at Screening.
• Clinically significant abnormalities of ECG, including QTcF > 450 ms, for males and QTcF > 470 ms for females, and/or HR < 50 beats per minute, or evidence of clinically significant bundle branch blocks, as indicated by 12-lead ECG.
• Calculated creatinine clearance of ≤70 mL/min according to the Cockcroft-Gault equation.
• Current use of any prohibited prescription medication (high-dose aspirin, paracetamol or levodopa, β-AR agonists or β-AR blockers, hypnotics or benzodiazepines other than clonazepam, monoamine oxidase inhibitors, opioids ), over-the-counter medication, or herbal supplements/products.
• Prior treatment with any investigational drug ≤90 days prior to dosing (Day 1), or ≤5 half-lives of the drug (whichever is longer), or current enrollment in any other study treatment or disease study, except for observational studies.
• Known or suspected alcohol or substance abuse within the past 12 months and/or positive test for alcohol or drugs of abuse.
• Active suicidal ideation within 3 months prior to study Screening.
• Positive screening test for hepatitis C antibody (HCV Ab) or current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] at Screening).
• Positive screening test for human immunodeficiency virus (HIV).
• Current infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
• Contraindications to wearing the BioStamp digital device sensors, which include but are not limited to implanted pacemakers, defibrillators, or other active implantable devices.
• Known allergies or hypersensitivities to adhesives or hydrogel.
• Other reasons for which the PI considers it is not in the best interest of the participant to undertake the study.

Double-Blind