Neuropsychiatric Disorders I

What is Neuropsychiatry?

• The distinction between neurology and psychiatry is artificial.
• Neuropsychiatry covers:
  • Psychiatric consequences of neurological diseases.
  • Neurological substrates of psychiatric illnesses.
  • Patients presenting to neurologists with neurological symptoms that are discrepant with underlying neuropathology.

Injuries of the Brain

• Tumors, poisons, and infections
• Neurodegenerative diseases

Traumatic Brain Injury (TBI)

• Mild TBI (Concussion):
  • Injury to the head resulting in alteration of brain function (e.g., loss of consciousness, confusion).
  • Acute symptoms: headache (61%), nausea (27%), dizziness (18%), vomiting (6%).
• Severe TBI: More severe consequences than mild TBI.

Pathophysiology of TBI

• Mechanical forces generate damage in two phases:
  • Primary injury: Force of the physical impact.
  • Secondary injury: Biochemical mechanisms (e.g., Ca^{2+} → free radicals, reorganization of cytoskeleton, activation of programmed cell death).
• In mild TBI, irreversible cellular damage is rare.
  • Neurons and their projections may be shifted and their electrophysiological attributes may change.
  • These changes usually normalize in a few days.

Severe TBI

• Definition:
  • Decreased level of consciousness.
  • Amnesia.
  • Skull fracture.
  • Neurological signs.
  • Intracranial injury.
• Epidemiology (USA):
  • 600 out of 100,000 people yearly.
  • 50% need hospitalization.
  • 10% result in death.
  • 20% result in chronic disability.
• Causes:
  • Falls (35.2%).
  • Traffic accidents (17.3%).
  • Blow to the head (16.5%).
  • Fighting (10%).
  • Unknown (21%).

Pathophysiology of Severe TBI

• Primary injury:
  • Localized damage: skull fracture and arterial hematomas.
  • Diffuse damage: venous hematomas and diffuse axonal damage.
• Secondary injury: swelling, hypoxia, increased pressure, inflammation.
• Frequently damaged areas:
  • Frontal and temporal lobes.
  • Brainstem.
  • Cerebellum.

Disorders of Consciousness

• Severe TBI frequently causes disorders of consciousness.
• Coma:
  • Most severe.
  • No response to the environment.
  • Stable EEG pattern.
• Vegetative state:
  • Sleep cycles detected by EEG.
  • Eye opening may occur.
• Minimally conscious state:
  • Patient responds to certain stimuli.

Impaired Blood Flow to the Brain

• Stroke: Sudden loss of blood flow resulting in neurological deficits.
• Ischemia: Reduced blood supply.
• Infarction: Tissue damage due to loss of oxygen.
• Causes:
  • Structural changes to blood vessels.
  • Embolism.
  • Systemic decrease of blood flow.

Consequences of a Stroke

• The number of deaths is decreasing, but it's still a major health problem.
• Close to 10% of people over 60 experience a stroke.
  • Results in cognitive decline and dementia in most cases.
• Types:
  • Ischemic (87%).
  • Hemorrhagic (13%).
• Effects:
  • Cerebrum: aphasia, visual deficits, neglect, and sensorimotor problems.
  • Brainstem and cerebellum: dizziness, nausea, vomiting, and ataxia.

Brain Tumors

• Categories:
  • Primary: Tumor cells originate in the brain.
  • Secondary: Originate elsewhere and metastasize to the brain.
• Brain tumors make up 2% of all cancers.

Epidemiology of Brain Tumors

• Primary brain tumor types:
  • Glioma (50.4%).
  • Meningioma (20.8%).
  • Pituitary adenoma (15%).
  • Nerve sheath tumors (10%).
• Secondary tumors usually originate from the lung, breast, skin, kidney, or colon.
• Secondary tumors are ten times more common than primary brain tumors.

Symptoms of Brain Tumors

• Depend on location, size, and growth speed.
• Common symptoms:
  • Focal neurological symptoms.
  • Headaches.
  • Seizures.
  • Emotional instability.
  • Cognitive deficits.

Herpes Simplex Encephalitis

• Virus infects mucous membranes, entering the brain via the olfactory/trigeminal nerve.
• Mortality:
  • Untreated: 70% within 7-14 days.
  • Treated: 15%–20%.
• Mainly infects the frontal and temporal lobes.

Symptoms and Diagnosis of Herpes Simplex Encephalitis

• Infection starts on one side and spreads to the temporal lobe of the other hemisphere.
• Detection: with imaging procedures.
• EEG: abnormal in 85% of cases (epileptiform activity).
• Intelligence: usually normal.
• Amnesia: severe anterograde amnesia is characteristic.
• Klüver-Bucy syndrome: may also occur.

Heavy Metals

• Lead:
  • Crosses the blood-brain barrier and changes nerve cell activity.
  • Children are particularly sensitive.
  • Symptoms: headache, exhaustion, emotional instability, tremors, ataxia.
• Mercury:
  • May lead to erethism: aloofness, paranoia, irritability, emotional problems.
  • Movement symptoms and irritation of sensory nerves are also typical.

Neurodegenerative Disease

• Caused by the progressive loss of structure or function of neurons (neurodegeneration).
• Neuronal damage may ultimately involve cell death.

Alzheimer’s Disease

• Neurodegenerative disease that worsens progressively.
• 60–70% of dementia cases.
• Early symptom: difficulty remembering recent events.
• Later symptoms: problems with language, disorientation, mood swings, loss of motivation, self-neglect, and behavioral issues.
• Average life expectancy: 3-12 years after diagnosis.

Protein Aggregates in Alzheimer's Disease

• Abnormal amounts of amyloid beta (Aβ) accumulate extracellularly as amyloid plaques and tau proteins accumulate intracellularly as neurofibrillary tangles.
• Amyloid hypothesis: extracellular amyloid beta (Aβ) deposits as the fundamental cause.
• APP gene is on chromosome 21.
  • People with Down syndrome universally exhibit early Alzheimer's symptoms by 40.
• APOE4 is a major genetic risk factor.
  • Apolipoproteins enhance the breakdown of beta-amyloid.

Parkinson’s Disease

• Long-term neurodegenerative disease of the central nervous system.
• Symptoms emerge slowly.
• Non-motor symptoms become more common as the disease progresses.
• Usual symptoms: tremor, slowness of movement, rigidity, and difficulty with balance (parkinsonism).
• Advanced stages: Parkinson's disease dementia, falls, and neuropsychiatric problems (sleep abnormalities, psychosis, mood swings, or behavioral changes).

Misfolded Proteins in Parkinson’s Disease

• Main pathological characteristics:
  • Cell death in the basal ganglia.
  • Affecting up to 70% of dopamine-secreting neurons in the substantia nigra pars compacta.
• Alpha-synuclein becomes misfolded and clumps together.
  • Cells can't remove these clumps.
  • Alpha-synuclein becomes cytotoxic.
• Clumps are called Lewy bodies and can be seen in neurons under a microscope.

Protein Folding and Aggregation

• Protein folding reactions are described in terms of the free-energy landscape.
• Smooth funnel shape (panel i):
  • The energy landscape smoothly converges from top to bottom due to the progressive formation of native-like interactions, thereby increasingly favouring the native state of the protein.
• Rugged appearance (panel ii):
  • Proteins often undergo folding processes involving intermediate states and encounter rate-limiting steps
• Panel (iii):
  • Protein misfolding also causes proteins to stray away from their original native folding trajectory, illustrated by the presence of a side of the energy funnel where proteins become trapped in energy minima associated with aggregated protein conformations
• Panel (iv):
  • Molecular chaperones play a vital role in guiding proteins through the folding landscape, facilitating the avoidance or resolution of unproductive conformations
• Panel (v):
  • Under physiological conditions, the aggregated state of many proteins is thermodynamically more favourable than the native state.
• Panel (vi):
  • The interplay of kinetic effects, pathological interactions and structural frustration is also likely involved in amyloid polymorphism, again resulting in a rugged energy landscape.
• ~20% of natural protein sequences comprise hydrophobic segments (fewer in intrinsically disordered proteins (IDPs)).
• Aggregation-prone regions (APRs) are integral factors that facilitate the folding of soluble protein domains and frequently occur in transmembrane domains or as binding surfaces in IDPs.

The Glymphatic System

• A highly organized fluid transport system.
• (A) Vascular endfeet of astrocytes create the perivascular spaces through which CSF enters the brain and pervades its interstitium. CSF enters these perivascular spaces from the subarachnoid space and is propelled by arterial pulsatility deep into the brain, from where CSF enters the neuropil, facilitated by the dense astrocytic expression of the water channel AQP4, which is arrayed in nanoclusters within the endfeet. CSF mixes with fluid in the extracellular space and leaves the brain via the perivenous spaces, as well as along cranial and spinal nerves. Interstitial solutes, including protein waste, are then carried through the glymphatic system and exported from the CNS via meningeal and cervical lymphatic vessels.
• (B) Amyloid-b plaque formation is associated with an inflammatory response, including reactive micro- and astrogliosis with dispersal of AQP4 nanoclusters. Age-related decline in CSF production, decrease in perivascular AQP4 polarization, gliosis, and plaque formation all impede directional glymphatic flow and thereby impair waste clearance. Notably, vascular amyloidosis might be initiated by several mechanisms. Amyloid-b might be taken up from the CSF by vascular smooth muscle cells expressing the low-density lipoprotein receptor-related protein 1 (LRP1) (111). Alternatively, amyloid deposition might be initiated by the backflow of extracellular fluid containing amyloid-b into the periarterial space from the neuropil, rather than proceeding to the perivenous spaces, because of an increase in hydrostatic pressure on the venous side or an inflammation-associated loss of AQP4 localization to astrocytic endfeet.

Arterial Pulsatility and Fluid Flow

• Arterial pulsatility drives CSF transit into perivascular spaces.
• ACA, MCA, and PCA arteries transport CSF to penetrating arteries.
• Cardiovascular diseases with reduced cardiac output reduce arterial wall pulsatility and CSF flow.
• Thickening of arterial wall reduces arterial wall compliance and pulsatility.

Sleep Architecture and Glymphatic Clearance

• Deep (stage 3) NREM sleep dominates early phases of sleep for young people.
• Older individuals (over 60) have sleep interrupted by short awake episodes and less stage 3 NREM sleep.
• Lack of stage 3 NREM sleep, frequent interruptions of sleep, and shorter total sleep time decrease glymphatic activity in aging.

Model of Disorders and Glymphatic Function

• (A) Seeding and prion-like spread of protein aggregates (amyloid-b and tau) in Alzheimer’s disease and of a-synuclein in Parkinson’s disease, relative to the distribution of glymphatic influx of a CSF tracer after intrathecal delivery (67). Prion-like spread of protein aggregates includes an extracellular component and, hence, the possibility that the seeds are transported by the glymphatic system.
• (B)Diminished brain fluid clearance is associated with several conditions:
  • Normal aging is linked to decreased sleep quality and glymphatic flow.
  • Stagnation of glymphatic flow contributes to protein aggregation, leading to inflammation, neuronal loss, and dementia.