Succinate / Surrogate endpoint / Symptom / Synapse

Succinate

Succinate

MOA: LPS → Succinate→ HIF-1α → IL-1β (Kumari, 2020 #1870) Es (quartile → mean/SD): PD vs HC 0.5, early PD vs HC 0.48 Correlation with IL-1b (→ Daria?) We observed an association between UPDRS motor score and concentration of succinate metabolite in PD patients (r = 0.24, p = 0.03) It has become increasingly clear that increased transcription of pro-IL-1β in response to infection or tissue injury is fueled by changes in cellular metabolism. In healthy cells, aerobic metabolism mostly occurs via an intact tricarboxylic acid (TCA) cycle and oxidative phosphorylation to generate ATP, whereas glycolysis is responsible for anaerobic metabolism. However, in response to the TLR4 agonist LPS and other proinflammatory stimuli, some immune cells can shift to a state of increased aerobic glycolysis. This metabolic shift, known as a Warburg effect, results in a rapid but low yield of ATP and production of lactate via the glycolytic pathway, with the TCA cycle reset to facilitate the accumulation of the metabolic intermediate succinate. Succinate leakage into the cytosol acts to stabilize the transcription factor HIF-1α (hypoxia-inducible factor-1α) via inhibition of prolyl hydroxylases. HIF-1α in turn translocates to the nucleus, where it interacts with the hypoxia response element to transcribe proinflammatory cytokines—in particular IL-1β—and glycolytic machinery (20, 21). The pyruvate kinase isoenzyme cytosolic PKM2 (pyruvate kinase M2) has emerged as a pivotal determinant of the Warburg effect in immune cells in response to LPS (22).

(Liu, 2020 #1875)

Surrogate endpoint

{Fleming, 2012 #2652}

Categorization of Outcome Measures, according to Level of Evidence regarding Efficacy. Composite Endpoints will be denoted by {brackets}.

Level 1 A true clinical efficacy measure (When evidence establishing risk is acceptable in the context of evidence of benefit)

• Death
• {Death or Hospitalization}, in Heart Failure
• {Death, Lung Transplantation or Hospitalization for Pulmonary Arterial Hypertension} in PAH
• {Cardiovas Death, Stroke, or Symptomatic Myocardial Infarction}, in Acute Coronary Syndrome
• {Stroke or Systemic Embolic Event}, in Atrial Fibrillation
• Progression to EDSS 7 (i.e., becoming wheel chair bound), in Multiple Sclerosis
• 15 Letter Loss in Best Corrected Visual Acuity, in Age Related Macular Degeneration
• {Cough, Dyspnea, Chest Pain, or Fever (if defined as symptomatic warmth & chills)}, in Community-Acquired Bacterial Pneumonia
• Pain or Loss of Joint Function, in Osteo-Arthritis or Rheumatoid Arthritis
• Symptomatic Bone Fractures
• Pain in the area of skin lesions, in Acute Bacterial Skin and Skin Structure Infections

Level 2 A validated surrogate (for a specific disease setting and class of interventions.) (When interventions are safe, with strong evidence that risks from off target effects are acceptable)

• H_bA_1c for clinical effects on long term risk of microvascular complications, in T2DM
• {Death or Cancer Recurrence}, in Adjuvant Colorectal Cancer, with 5-Fluorouracil based regimens
• Systolic and Diastolic Blood Pressure, in Multiple Classes of Anti-hypertensives
• >40 meter improvements in 6 Minute Walk Distance, in Pulmonary Arterial Hypertension
• HIV infection, if the mechanisms of the HIV prevention intervention only reduce susceptibility rather than impacting disease progression or infectiousness should infection occur

Level 3 A non-validated surrogate, yet one established to be ‘reasonably likely to predict clinical benefit’ (for a specific disease setting and class of interventions) (When interventions are safe, with evidence that risks from off target effects are acceptable)

• Large and Durable effects on Viral Load, in Some Treatment of HIV infection Settings
• Durable Complete Responses, in Some Hematologic Oncology Settings
• Large Effects on Progression-Free-Survival, in Some Solid Tumor Oncology Settings

Level 4 A correlate that is a measure of biological activity, but not established to be at a higher level.

• CD-4, in HIV infected patients
• Fever (if defined as elevated body temperature), in Community Acquired Bacterial Pneumonia
• Decolonization of VRE, in the Gastro-Intestinal Tract to prevent VRE bacteremia
• Decolonization of Staphylococcus aureus, in Preventing Wound or Bloodstream Infections
• Hematocrit levels, in Chemotherapy-Induced Anemia or in End Stage Renal Disease
• Antibody Levels and Cell Mediated Immune Responses, in Vaccines for Prevention of HIV
• Urine GAG and Urine KS, in Rare Disease Settings such as MPS-I, MPS-II and MPS-IV
• PSA levels or Prostate Cancer Biopsy, in Prevention of Prostate Cancer Symptoms or Death
• Detecting Asymptomatic Ulcers on Endoscopy, in Prevention of Symptomatic Ulcers
• FEV-1 and FVC, in Pulmonary Diseases
• Silent Myocardial Infarction, in Cardiovascular Disease
• Asymptomatic Fracture Rate, in Prevention of Symptomatic Disease
• Negative Cultures & Polymerase Chain Reaction Tests, in Treating Various Infectious Diseases

In Table 1, EDSS is ‘expanded disability status scale score’; T2DM is ‘type 2 diabetes mellitus’; VRE is ‘vancomycin resistant enterococci’; PSA is ‘prostate specific antigen’; FEV-1 is ‘forced expiratory volume in 1 second’; FVC is ‘forced vital capacity’; MPS is ‘mucopolysaccharidosis’

Symptom

• Burden
  • {Mammen, 2023 #2396} The three most bothersome and important symptoms were tremor, fine motor difficulties, and slow movements.
  • Symptoms had the greatest impact on sleep, job functioning, exercise, communication, relationships, and self-concept—commonly expressed as a sense of being limited by PD.
• Milestone
  • AD/PD 2023 Page 23: transcriptomics (inflammatory, Aβ, Asyn, and mt gene expression slight negative relation)

Synapse

anatomy

• the number of synapse in human brain: trillions

SYNAPSE

Pre (~1 μm)
Cleft (~20 nm)
Post (0.5-4 μm)

Legend: Receptor / Scaffold / Ca2+ channel

Synaptic vesicle proteins and plasma membrane lipids are synthesized in the endoplasmic reticulum and modified in the Golgi apparatus, where they are then packaged in secretory vesicle precursors.

Synaptic vesicle proteins	Synaptic vesicle precursors (SVPs	Synaptic vesicles (SVs
Synaptic vesicle proteins are produced and packaged into synaptic vesicle precursors (SVPs) in the cell body	Contain synaptic components such as synaptophysin, synaptotagmin, and vesicular amino acid transporters (e.g., VGLUT1), vesicle-associated membrane protein 2 (VAMP2=synaptobrevin) that replenish synaptic vesicle and active	are small, electron-lucent vesicles that are clustered at presynaptic terminals. They store neurotransmitters and release them by calcium-triggered exocytosis
	synaptic vesicle precursors (SVPs) are generated in the cell soma and need to be trafficked along the axon to presyn

Uncertain Spans

location	text/status	reason
Succinate bullet	(→ Daria?)	The annotation in parentheses is small; preserved as visible question mark.
Synapse SVPs/SVs row	column header (SVPs and (SVs	Source closes parenthesis is missing in the visible header row; preserved as written.
Bottom row of SVPs/SVs table	presyn	Word is cut off at the bottom edge of the photo; continues in the next photo.