Neurological Disorders: Therapeutics and Diagnostics Targets

What is Neurological disorders

Neurological disorders encompass a wide array of conditions that affect the nervous system, including the brain, spinal cord, and peripheral nerves. These disorders can manifest in various ways, impacting movement, speech, cognitive function, and more. They are characterized by the progressive degeneration or damage of nerve cells and structures, leading to the symptoms and complications associated with each specific condition.

Neurological disorders are also commonly referred to as "Nervous System Diseases." This alternative term broadly covers the same range of conditions, emphasizing the diseases' impact on the entire nervous system rather than focusing solely on the neurological aspects.

Nervous system diseases can be categorized into several types based on the part of the system they affect:

1. Central Nervous System Diseases:These affect the brain and spinal cord. Examples include multiple sclerosis, Alzheimer's disease, Parkinson's disease, and brain tumors.

2. Peripheral Nervous System Diseases:These affect the nerves outside the brain and spinal cord. Examples include peripheral neuropathy, Guillain-Barré syndrome, and carpal tunnel syndrome.

3. Autonomic Nervous System Diseases:These affect the part of the nervous system that controls involuntary actions, such as heart rate, blood flow, and digestion. Examples include autonomic dysfunction and multiple system atrophy.

Neurological disorders classified by MOA

Neurological disorders are classified based on their mechanism of action (MOA), which refers to the specific biochemical process through which they affect the nervous system. This classification helps in understanding the disease process and in developing targeted therapies and diagnostics. The MOA-based classification includes categories such as:

Neurodegenerative Diseases: These involve the gradual loss of neuron function and structure. The MOA often involves the accumulation of toxic proteins, oxidative stress, mitochondrial dysfunction, and inflammatory processes. Examples include Alzheimer's disease, Parkinson's disease, and Huntington's disease.

Demyelinating Diseases: In these conditions, the protective covering (myelin sheath) of nerve fibers in the brain and spinal cord is damaged, which affects the transmission of nerve impulses. This can be due to autoimmune responses, genetic factors, or unknown causes. Multiple sclerosis is a prime example of a demyelinating disease.

Neuropathies (Peripheral Nerve Disorders): These diseases affect peripheral nerves and can result from mechanical injury, metabolic imbalances, infections, and toxic exposures. The MOA often involves direct nerve damage or demyelination. Examples include diabetic neuropathy and Guillain-Barré syndrome.

Vascular Disorders: These involve conditions that affect the blood vessels supplying the nervous system, leading to issues like stroke or transient ischemic attacks (TIAs). The MOA includes artery blockage (ischemic stroke) or bleeding (hemorrhagic stroke) due to various risk factors like hypertension, atherosclerosis, and aneurysms.

Infectious Diseases: Caused by pathogens such as bacteria, viruses, fungi, or parasites, these diseases affect the nervous system through direct infection, inflammation, and damage to nervous tissue. Examples include meningitis, encephalitis, and neurosyphilis.

Functional Disorders: These are conditions where the nervous system does not work correctly, but there is no structural damage observable. The MOA can involve abnormal neural signaling or neurotransmitter imbalances. Examples include migraine headaches, fibromyalgia, and functional neurological disorder (FND).

Genetic and Developmental Disorders: These involve conditions that are present at birth or develop due to genetic mutations. The MOA can vary widely but often involves defects in genes critical for the development, maintenance, and function of the nervous system. Examples include Down syndrome, spinal muscular atrophy, and phenylketonuria (PKU).

Therapeutics and Diagnostics Targets of Neurological disorders

Biomarkers play a crucial role in diagnosing, monitoring, and understanding the progression of diseases. In the context of nervous system diseases classified by their mechanism of action (MOA), biomarkers can vary widely due to the diverse nature of these conditions. Here's a list of biomarkers associated with each MOA-based disease category:

Neurodegenerative Diseases:

Alzheimer's disease: Amyloid beta (Aβ) peptides, Tau proteins (phosphorylated Tau), and neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and blood.

Parkinson's disease: Alpha-synuclein in CSF, blood, and saliva; decreased dopamine transporter (DAT) uptake in basal ganglia detected by imaging studies.

Huntington's disease: Mutant Huntingtin (mHTT) protein and neurofilament light chain (NfL) levels in CSF and blood.

Demyelinating Diseases:

Multiple sclerosis (MS): Oligoclonal bands in CSF, elevated levels of neurofilament light chain (NfL), and myelin basic protein (MBP) as indicators of nerve damage and demyelination.

Neuropathies (Peripheral Nerve Disorders):

Diabetic neuropathy: Elevated blood glucose levels, glycosylated hemoglobin (HbA1c), and skin biopsy showing reduced nerve fiber density.

Guillain-Barré syndrome: Elevated protein levels in CSF without a corresponding increase in white blood cells (albuminocytologic dissociation).

Vascular Disorders:

Stroke: Imaging biomarkers (CT, MRI) for identifying ischemic or hemorrhagic stroke; blood biomarkers include fibrinogen levels, D-dimer, and brain natriuretic peptide (BNP).

Infectious Diseases:

Meningitis: Elevated white blood cell count in CSF, increased protein, decreased glucose in CSF; specific causative agent identified through CSF culture or PCR.

Encephalitis: Presence of pathogens in CSF (PCR, culture), antibodies against specific pathogens in blood or CSF.

Functional Disorders:

Migraine: No specific biomarkers for diagnosis; research focuses on CGRP (calcitonin gene-related peptide) levels during attacks.

Fibromyalgia: Elevated levels of substance P in CSF, abnormal functional MRI (fMRI) findings indicating increased pain sensitivity.

Genetic and Developmental Disorders:

Down syndrome: Chromosomal analysis confirming the presence of an extra chromosome 21.

Spinal muscular atrophy (SMA): Genetic testing for deletions or mutations in the SMN1 gene.

Phenylketonuria (PKU): Elevated levels of phenylalanine in blood.

Comprehensive Overview of Therapeutics, Diagnostics, and Biomarkers for Neurological Conditions

Category	Condition	Therapeutics	Diagnostics	Biomarkers	Target ID
Neurodegenerative Diseases	Alzheimer's Disease (AD)	Cholinesterase inhibitors, NMDA receptor antagonists, amyloid beta targeting treatments like aducanumab.	PET scans for amyloid and tau, CSF analysis for amyloid beta, total tau, and phosphorylated tau.	Amyloid beta (APP), Tau protein	GM-T87024, GM-T45593
	Parkinson's Disease (PD)	Dopamine precursors (levodopa), dopamine agonists, MAO-B inhibitors.	Clinical assessment, DAT imaging.	Alpha-synuclein, Dopamine transporter (SLC6A3)	GM-T03644, GM-T55959
Demyelinating Diseases	Multiple Sclerosis (MS)	Immunomodulatory drugs, monoclonal antibodies, oral treatments.	MRI, CSF analysis for oligoclonal bands, neurofilament light chain.	Myelin basic protein (MBP)	GM-T54761
Neuropathies (Peripheral Nerve Disorders)	Diabetic Neuropathy	Blood glucose control, pain management.	Clinical examination, nerve conduction studies.	-
	Guillain-Barré Syndrome (GBS)	IVIG, plasmapheresis.	Clinical presentation, NCV tests, CSF analysis.	-
Vascular Disorders	Stroke	Thrombolytics for ischemic stroke, control of hypertension for hemorrhagic stroke.	CT, MRI, carotid ultrasound, echocardiography.	-
Infectious Diseases	Meningitis and Encephalitis	Antimicrobial treatment based on the pathogen, corticosteroids.	Lumbar puncture for CSF analysis, PCR, MRI or CT.	-
Functional Disorders	Migraine	NSAIDs, triptans, beta-blockers, CGRP inhibitors.	Primarily clinical diagnosis.	CGRP	GM-T93509
	Fibromyalgia	FDA-approved drugs (duloxetine, milnacipran, pregabalin), pain management.	Based on clinical criteria; widespread pain index and symptom severity scale.	-
Genetic and Developmental Disorders	Down Syndrome	Supportive care, early intervention.	Prenatal screening, chromosomal analysis.	-
	Spinal Muscular Atrophy (SMA)	Gene therapy, antisense oligonucleotides, small molecules.	Genetic testing for SMN1 deletions or mutations.	SMN1	GM-T71907
	Phenylketonuria (PKU)	Dietary management, enzyme replacement therapy.	Newborn screening, genetic testing.	Phenylalanine hydroxylase (PAH)	GM-T76213