Neuropathology

1. Alzheimer's Dementia (AD)

Alzheimer's disease is the most common cause of dementia. Its pathology is characterised by a progressive loss of neurons and synapses, leading to macroscopic brain atrophy and a specific set of microscopic changes.

Gross Changes

At autopsy, or on an MRI scan, the brain of a person with advanced Alzheimer's disease shows distinct macroscopic, or "gross," changes. The extensive neuronal death causes the brain to shrink. This is seen as:

• Diffuse Atrophy: The entire brain, particularly the cerebral cortex, loses volume.
• Widened Cortical Sulci: As the gyri (ridges) of the brain shrink, the sulci (grooves) between them appear wider and more prominent.
• Enlarged Cerebral Ventricles: The fluid-filled ventricles inside the brain expand to fill the space left by the lost brain tissue. This is known as hydrocephalus ex vacuo.

Histological Changes

The gross atrophy is caused by a cascade of microscopic events. The two defining, or cardinal, pathological hallmarks of AD are senile plaques and neurofibrillary tangles. Other key histological findings include:

• Neuronal and Synaptic Loss: This is the direct cause of cognitive decline.
• Granulovacuolar Degeneration: Small vacuoles containing central granules appear in the cytoplasm of neurons, especially in the temporal lobes.
• Hirano Bodies: These are rod-shaped, eosinophilic (pink-staining) inclusions made of actin, frequently found in the pyramidal neurons of the hippocampus.
• Astrocytic Gliosis: A non-specific "scarring" process where astrocytes proliferate in response to neuronal injury.

A. Senile Plaques

These are insoluble deposits found in the extracellular space (between neurons).

• Composition: The core component of senile plaques is a protein fragment called beta-amyloid (Aβ), specifically the Aβ42 peptide. This peptide has a beta-pleated sheet structure, which makes it prone to aggregation.
• Formation: Beta-amyloid is cleaved from a larger parent protein called the Amyloid Precursor Protein (APP), which is embedded in the neuron's membrane. Two enzymes, beta-secretase and gamma-secretase, work together to cut out the Aβ peptide. This is the amyloidogenic or "bad" pathway.
• Prevention: A third enzyme, alpha-secretase, cleaves APP within the Aβ sequence, making the formation of the toxic peptide impossible. This is the non-amyloidogenic or "good" pathway.

There are two main types of plaques:

1. Neuritic Plaques: These are the clinically significant plaques. They have a dense core of aggregated amyloid fibrils and are surrounded by dystrophic (dying) neurites, activated microglia, and reactive astrocytes. They stain with Congo red, showing a characteristic "apple-green" birefringence under polarized light, which confirms the beta-pleated sheet structure.
2. Diffuse Plaques: These consist of non-fibrillar Aβ and are not surrounded by a neuritic reaction. They are not well correlated with cognitive decline and are considered an earlier stage of plaque development.

B. Neurofibrillary Tangles (NFTs)

These are insoluble deposits found inside neurons.

• Composition: NFTs are primarily composed of an abnormally hyperphosphorylated form of a protein called tau.
• Normal Function: Tau is a microtubule-associated protein. In a healthy neuron, it acts like a railroad tie, binding to and stabilising microtubules, which are the "tracks" for transporting essential materials along the axon.
• Pathology: In AD, tau becomes pathologically hyperphosphorylated (too many phosphate groups are attached). This causes it to detach from the microtubules, which then disintegrate, disrupting the neuron's transport system. The detached, hyperphosphorylated tau proteins then misfold and clump together into insoluble paired helical filaments, which form the neurofibrillary tangles. This process leads to synaptic dysfunction and ultimately, neuronal death.

Progression and Correlates of Cognitive Decline

The spread of NFT pathology follows a predictable anatomical pattern, described by the Braak stages. The pathology begins in the medial temporal lobes (entorhinal cortex and hippocampus) before spreading to the association cortices. This progression closely mirrors the clinical progression of symptoms, from early memory loss to global cognitive decline.

Early Sites of Pathology

The disease process targets specific neuronal populations very early on.

• Medial Temporal Lobes: As described by the Braak stages, the entorhinal cortex and hippocampus are the first regions to develop significant tangle pathology. This directly explains why anterograde memory impairment is the first and most prominent clinical symptom.
• Basal Nucleus of Meynert: This structure in the basal forebrain is the primary source of acetylcholine for the entire cerebral cortex. There is profound and early loss of these cholinergic neurons in AD. This cholinergic deficit is the basis for the "cholinergic hypothesis" of AD and the rationale for using acetylcholinesterase inhibitors (e.g., donepezil) as a symptomatic treatment.

Cerebral Amyloid Angiopathy (CAA)

This is a very common co-pathology in Alzheimer's disease, seen in over 90% of cases.

• Definition: Aβ protein accumulates in the walls of small and medium-sized arteries and arterioles in the cerebral cortex and overlying leptomeninges.
• Clinical Significance: This weakens the vessel walls, making them prone to rupture. CAA is a major cause of spontaneous, superficial, lobar hemorrhages (brain bleeds) in the elderly.

Genetic Factors and Biomarkers

• Down's Syndrome (Trisomy 21): The gene for Amyloid Precursor Protein (APP) is located on chromosome 21. Individuals with Down's syndrome have three copies of this chromosome, leading to a lifelong overproduction of APP and Aβ. As a result, they invariably develop AD pathology by middle age.
• Apolipoprotein E (ApoE): The ApoE gene has three alleles. The ApoE4 allele is the strongest genetic risk factor for late-onset AD. In contrast, the ApoE2 allele is considered protective.

2. Lewy Body Dementia (DLB)

Dementia with Lewy Bodies (DLB) is the second most common type of neurodegenerative dementia after Alzheimer's disease. It is part of a spectrum of disorders known as synucleinopathies, which also includes Parkinson's disease.

Distribution of Lewy Bodies

The key difference between the pathology of Parkinson's disease (PD) and DLB lies in the distribution of these inclusions.

• In Parkinson's disease, Lewy bodies are primarily confined to the brainstem, particularly the substantia nigra.
• In DLB, Lewy bodies are found not only in the brainstem but are also widespread throughout the cerebral cortex, especially in the temporal lobe, cingulate gyrus, and frontal lobes.
• Cortical Lewy Bodies: The Lewy bodies found in the cortex are often less conspicuous than those in the brainstem. They may lack the classic halo and appear as less distinct eosinophilic inclusions.

Composition and Classification

• Primary Protein: The main constituent of Lewy bodies is an aggregated and misfolded protein called alpha-synuclein.
• Synucleinopathies: Diseases defined by the aggregation of alpha-synuclein are called synucleinopathies. This group includes Parkinson's disease, DLB, and Multiple System Atrophy (MSA).
• Other Components: Lewy bodies also contain other proteins, including ubiquitin (which tags abnormal proteins for disposal) and tau protein.

Associated Pathologies

• Lewy Neurites: These are abnormal neuronal processes (axons and dendrites) that are also filled with aggregated alpha-synuclein. They are common in the hippocampus and substantia nigra.
• Co-pathology with Alzheimer's Disease: A very high proportion of patients with DLB (around 75%) also have significant Alzheimer's-type pathology, including amyloid plaques. However, the neurofibrillary tangle burden is typically less than in a case of pure AD.
• Microvacuolation: Some cases of DLB show spongiform changes (microvacuolation) in the cortex, particularly the medial temporal regions, which can create diagnostic confusion with Creutzfeldt-Jakob disease.

3. Frontotemporal Dementia (FTD)

Frontotemporal dementia refers to a group of clinical syndromes caused by the progressive degeneration of the frontal and/or anterior temporal lobes of the brain. Unlike Alzheimer's disease, which primarily affects memory, FTD typically presents with profound changes in personality, social behaviour, and language. The underlying pathology is heterogeneous.

Pathological Subtypes

FTD is associated with three main types of underlying pathology.

1. Frontal Lobe Degeneration Type: This is the most common pathological form. It is characterised by a loss of large cortical nerve cells with minimal reactive gliosis. A key microscopic feature is spongiform degeneration (or microvacuolation), particularly in the superficial layers of the cortex.
2. Pick's Type (Pick's Disease): This is the classic, though less common, form of FTD pathology.

   Pick's Disease Pathology

   • Gross Pathology: Severe, focal atrophy of the frontal and temporal lobes, described as "knife-blade" atrophy.
   • Histology: Includes the pathognomonic Pick bodies (spherical, silver-staining tau inclusions) and Pick cells (swollen, "ballooned" neurons).

3. Motor Neurone Disease (MND) Type: This form of FTD is associated with the pathology of motor neurone disease.
   • Histology: The key feature is the presence of ubiquitinated but tau-negative inclusions within neurons of the frontal cortex and hippocampus. The protein involved is most commonly TDP-43.
   • Associated Pathology: There is also evidence of motor neuron degeneration in the anterior horn cells of the spinal cord.

4. Huntington's Disease

Huntington's disease is an autosomal dominant neurodegenerative disorder caused by an expansion of a CAG trinucleotide repeat in the huntingtin gene on chromosome 4. While it is primarily known as a movement disorder, it invariably includes a progressive cognitive decline (dementia) and significant psychiatric symptoms.

5. Creutzfeldt-Jakob Disease (CJD)

Creutzfeldt-Jakob disease is a rare, rapidly progressive, and universally fatal neurodegenerative disorder. It belongs to a group of conditions known as prion diseases or transmissible spongiform encephalopathies. The clinical hallmark is a rapidly progressive dementia, often accompanied by myoclonus (sudden, jerky movements) and ataxia.

Forms of CJD

There are three main forms:

1. Sporadic (sCJD): The most common form, accounting for about 85% of cases. It occurs with no known cause.
2. Familial: An inherited form caused by a mutation in the prion protein gene.
3. Acquired: Includes variant CJD (vCJD), which is linked to the consumption of meat contaminated with bovine spongiform encephalopathy ("mad cow disease"), and iatrogenic CJD, transmitted via contaminated medical equipment or biological products.

The Prion Protein (PrP)

The cause of CJD is not a virus or bacterium, but a misfolded protein called a prion.

• Normal Protein (PrPᶜ): All mammals have a normal prion protein (PrPᶜ), encoded by a gene on chromosome 20. It is a normal cell-surface protein, rich in alpha-helical structures.
• Pathogenic Protein (PrPˢᶜ): In CJD, this normal protein undergoes a conformational change into an abnormal, misfolded shape called PrPˢᶜ. The key change is that the protein refolds from a structure rich in alpha-helices to one with a much higher beta-pleated sheet content.
• Properties: This change in shape makes PrPˢᶜ extremely stable, resistant to heat and proteases (enzymes that break down proteins), and prone to aggregation. It acts as a template, causing other normal PrPᶜ proteins to misfold into the pathogenic PrPˢᶜ form in a self-propagating chain reaction. This accumulation of abnormal PrPˢᶜ is toxic to neurons and leads to the spongiform changes.

Distinctions Between Classic CJD and Variant CJD (vCJD)

vCJD is a distinct entity from the more common classic (sporadic) CJD.

• Age of Onset: Classic CJD typically affects older adults (mean age ~68). In stark contrast, vCJD affects much younger individuals (mean age ~28).
• Clinical Presentation: Classic CJD usually begins with rapidly progressing dementia and neurological signs. vCJD often begins with prominent psychiatric symptoms (e.g., depression, psychosis) and sensory disturbances, with overt neurological signs appearing later.
• Duration: The course of classic CJD is extremely rapid (average 5 months). The course of vCJD is slightly more prolonged (average 1 year).
• EEG: Classic CJD often shows characteristic triphasic sharp waves on EEG. These are typically absent in vCJD.
• Pathology: vCJD is uniquely characterized by the presence of florid plaques—amyloid plaques of PrPˢᶜ surrounded by a halo of spongiform change.
• Tonsil Biopsy: The prion protein in vCJD accumulates in lymphoid tissue. Therefore, a tonsil biopsy is often positive in vCJD, whereas it is negative in classic CJD.
• MRI: The pulvinar sign—symmetrical high signal in the posterior thalamus on FLAIR MRI—is a highly sensitive and specific sign for vCJD and is not seen in classic CJD.

Genetics and Biomarkers

• Codon 129 Polymorphism: A polymorphism on the prion protein gene at codon 129 (methionine/M vs. valine/V) influences susceptibility. Having two copies of methionine (M/M) increases risk. Notably, 100% of vCJD patients have the M/M phenotype.
• 14-3-3 Protein: This protein can be detected in the CSF and is a marker of rapid neuronal destruction. However, it is non-specific and can be elevated in other conditions like viral encephalitis or stroke. It is less frequently found in vCJD.

6. HIV-Associated Pathology

The Human Immunodeficiency Virus (HIV) can cause significant neurological and psychiatric complications, collectively known as HIV-Associated Neurocognitive Disorders (HAND). The most severe form is HIV-associated dementia.

• Macrophage-Tropism: The strains of HIV isolated from the brain are typically "macrophage-tropic," meaning they are better at infecting macrophages and microglia than T-lymphocytes. This adaptation is crucial for establishing a persistent CNS infection.

Mechanism of Neuropathogenesis

Importantly, HIV does not directly infect neurons. The damage is indirect, caused by a cascade of inflammatory and neurotoxic events initiated by infected glial cells.

1. Direct Effects: Infected macrophages and microglia release viral proteins (such as Tat and gp120) that are directly toxic to neurons.
2. Indirect Effects: The infected glial cells also release a flood of pro-inflammatory cytokines and other neurotoxins (e.g., quinolinic acid, nitric oxide). This creates a state of chronic neuroinflammation.
3. Astrocyte Activation: These inflammatory signals activate nearby astrocytes, which in turn release their own neurotoxic substances, amplifying the damage.
4. Neuronal Injury: The combination of viral proteins and inflammatory mediators disrupts neuronal function and ultimately triggers apoptosis (programmed cell death) in neurons. This neuronal loss, particularly in subcortical regions, leads to the clinical symptoms of HAND.

Biopsy Findings

A brain biopsy from a person with advanced HAND reveals a characteristic pattern of inflammation and damage.

• Macrophage infiltration into the CNS, often clustered around blood vessels.
• Formation of small clusters of activated microglia (microglial nodules).
• Multinucleated Giant Cells: The pathognomonic finding. These are formed by the fusion of several HIV-infected macrophages and/or microglia.
• Astrocyte activation and damage (astrogliosis).
• Neuronal loss, most prominent in subcortical structures like the hippocampus, basal ganglia, and caudate nucleus.
• White matter pathology (demyelination).

7. Schizophrenia

Schizophrenia is considered a neurodevelopmental disorder, meaning that subtle abnormalities in brain structure and development are present long before the clinical onset of psychosis. Neuroimaging and post-mortem studies have identified a pattern of consistent, though often subtle, brain changes.

Gross Changes

• Ventriculomegaly: The single most robust and consistently replicated structural finding in schizophrenia is the enlargement of the lateral and third ventricles. This is not due to an overproduction of CSF but is an ex vacuo phenomenon, meaning the ventricles expand to fill the space left by a reduction in the volume of surrounding brain tissue.

• Reduced Tissue Volume: There is a widespread reduction in grey matter volume, particularly affecting temporolimbic structures like the hippocampus and amygdala, as well as the thalamus and superior temporal gyrus.
• Planum Temporale Asymmetry: In most healthy individuals, the planum temporale (a language-related area on the superior temporal gyrus) is larger on the left side than the right. A frequent finding in schizophrenia is a reduction or reversal of this normal leftward asymmetry, suggesting an abnormality in the neurodevelopmental processes that establish language lateralisation.

• Cavum Septi Pellucidi: An increased incidence of this minor neurodevelopmental anomaly (a failure of the two leaflets of the septum pellucidum to fuse) is also noted.

Histological Changes

Unlike neurodegenerative diseases like Alzheimer's, schizophrenia is not characterised by dramatic cell death or gliosis.

• No Evidence for Astrogliosis: A crucial finding is the general absence of significant astrogliosis (the "scarring" response to neuronal death). This suggests that the brain abnormalities in schizophrenia are not due to a destructive, degenerative process that starts in adulthood, but rather a more subtle, early developmental disruption.
• Neuronal and Synaptic Changes: Studies have described subtle changes in cell architecture, including:
  • Reduced neuronal size and dendritic arborization (fewer and less complex branches).
  • An increase in neuronal density in some areas (neurons are packed closer together because the space between them, the neuropil, is reduced).
  • Decrements in presynaptic markers, supporting the hypothesis of excessive synaptic pruning during adolescence, where too many connections are eliminated.

8. Mood Disorders

Structural and functional brain changes are also observed in major mood disorders, particularly in patients with severe, recurrent, or late-onset illness.

Effects of Treatment

• Lithium: Has neurotrophic and neuroprotective effects. Treatment can increase cortical grey matter volume, enhance neurogenesis, and inhibit apoptosis.
• Antidepressants: Can promote hippocampal neurogenesis and prevent the loss of dendritic spines, suggesting they may help reverse some of the structural changes associated with chronic stress and depression.

9. Alcoholic Brain Damage

Chronic alcohol misuse is directly toxic to the brain, leading to both generalized atrophy and specific focal damage.

• Wernicke's Encephalopathy: This acute neurological emergency is caused by thiamine (Vitamin B1) deficiency. The pathology consists of degenerative changes, including gliosis and small hemorrhages, in structures surrounding the third ventricle and aqueduct. Key affected areas include the mamillary bodies, hypothalamus, and mediodorsal thalamic nucleus.
• Brain Shrinkage: Even in uncomplicated alcoholism, there is significant brain shrinkage, which is largely accounted for by a loss of white matter. Some of this volume loss appears to be reversible with sustained abstinence.
• Neuronal Loss: Alcohol-related neuronal loss has been documented in specific regions, including the superior frontal association cortex and the cerebellum.

10. Autism Spectrum Disorder (ASD)

ASD is a neurodevelopmental disorder with a complex neurobiology involving atypical brain growth trajectories and connectivity.

• Cerebellar Abnormalities: One of the most consistent and classic findings in post-mortem and early imaging studies is hypoplasia (underdevelopment) of the cerebellar vermis (the midline part of the cerebellum). A significantly lower count of Purkinje cells, the main output neurons of the cerebellar cortex, has also been documented.
• Neocortical Changes: Findings in the cortex have been inconsistent. Some studies suggest an early period of brain overgrowth, possibly related to reduced or inefficient synaptic pruning, followed by a slowing of growth in later childhood.

11. Autoimmune Encephalitis

Autoimmune encephalitis is a group of inflammatory brain disorders caused by the immune system mistakenly attacking the brain. The underlying mechanism involves antibodies that target neuronal cell surface proteins, receptors, or ion channels. These conditions are critically important to recognise as they often present with acute or subacute neuropsychiatric symptoms (psychosis, memory loss, catatonia) but are potentially treatable with immunotherapy. Many forms are paraneoplastic, meaning they are triggered by an underlying cancer.

11.1 Anti-NMDA Receptor (NMDAR) Encephalitis

This is the most common type of autoimmune encephalitis.

11.2 Anti-LGI1 Encephalitis

This is another common cause of autoimmune limbic encephalitis.

• Pathophysiology: Antibodies target the LGI1 (Leucine-rich glioma-inactivated 1) protein, which is part of the voltage-gated potassium channel (VGKC) complex.
• Clinical Features:
  • Limbic Encephalitis: Presents with subacute memory loss and confusion.
  • Seizures: A core feature. A pathognomonic seizure type is faciobrachial dystonic seizures (FBDS)—brief, frequent, jerky posturing of the arm and face on one side.
  • Hyponatremia: Low blood sodium is a very common and highly specific feature, seen in over 60% of patients.

11.3 Anti-CASPR2 Encephalitis

This condition also involves antibodies against a protein in the VGKC complex and typically affects older men.

11.4 Anti-GABA-B Receptor Encephalitis

• Pathophysiology: Antibodies target the GABA-B receptor, a key inhibitory receptor in the brain.
• Clinical Features: Presents as a severe limbic encephalitis with prominent, often treatment-resistant, seizures.
• Paraneoplastic Association: There is a very strong association with small-cell lung cancer (SCLC). The presence of these antibodies should trigger a search for an underlying SCLC.

11.5 Neuromyelitis Optica Spectrum Disorder (NMOSD)

This is an inflammatory disorder that is distinct from typical autoimmune encephalitis and multiple sclerosis.

• Pathophysiology: Caused by antibodies targeting the Aquaporin-4 (AQP4) water channel, which is highly expressed on astrocytes.
• Clinical Features: The disease has a specific predilection for the optic nerves and spinal cord.
  • Optic Neuritis: Severe, often bilateral, inflammation of the optic nerve causing vision loss.
  • Transverse Myelitis: Inflammation of the spinal cord causing weakness, numbness, and bladder/bowel dysfunction.
• Radiological Hallmark: A key finding on spinal MRI is longitudinally extensive transverse myelitis (LETM), where the spinal cord lesion spans three or more vertebral segments.

12. Atypical Parkinsonian Syndromes

This group of neurodegenerative disorders shares features of parkinsonism (bradykinesia, rigidity) with Parkinson's disease, but they have additional clinical signs, typically respond poorly to levodopa therapy, and have a more rapid progression. They are caused by different underlying proteinopathies.

12.1 Progressive Supranuclear Palsy (PSP)

PSP is a primary tauopathy, specifically involving the aggregation of 4-repeat (4R) tau protein.

12.2 Multiple System Atrophy (MSA)

MSA is a primary alpha-synucleinopathy, but with a key difference from Parkinson's disease and DLB. In MSA, the alpha-synuclein protein accumulates predominantly within glial cells (oligodendrocytes), forming characteristic glial cytoplasmic inclusions (GCIs).

• Clinical Features: MSA is defined by a combination of symptoms from three domains:
  1. Autonomic Dysfunction: This is a core feature and is often severe and early. It includes orthostatic hypotension (dizziness on standing), urinary incontinence or retention, and erectile dysfunction.
  2. Parkinsonism: Bradykinesia and rigidity that respond poorly to levodopa.
  3. Cerebellar Ataxia: Gait and limb ataxia, slurred speech, and abnormal eye movements.
• Subtypes: Based on the dominant motor feature, MSA is classified as MSA-P (parkinsonian) or MSA-C (cerebellar).
• Radiological Signs: MRI can be supportive, showing putaminal atrophy in MSA-P or a "hot cross bun" sign (pontine atrophy) in MSA-C.

13. Vascular Dementia & Normal Pressure Hydrocephalus

13.1 Vascular Dementia

Vascular dementia is not a single disease but a group of cognitive disorders caused by cerebrovascular disease and ischemic or hemorrhagic brain injury.

• Pathophysiology: The cognitive decline is the result of the cumulative damage from strokes. This can be from a single large stroke in a strategic brain area (e.g., thalamus) or, more commonly, from the additive effect of multiple smaller strokes over time.
• Multi-infarct Dementia: This is the classic subtype, caused by multiple cortical and/or subcortical infarcts.
• Underlying Cause: The fundamental cause is disease of the blood vessels. The most common pathology is arteriosclerosis ("hardening of the arteries"), particularly atherosclerosis, which is the buildup of plaques in major cerebral arteries, leading to blockage or embolism.

13.2 Normal Pressure Hydrocephalus (NPH)

NPH is a crucial diagnosis to consider in older adults with cognitive decline because it is potentially reversible with treatment (CSF shunting).

Radiological Hallmark: MRI shows ventriculomegaly (enlarged ventricles) that is out of proportion to any cortical atrophy. The sulci are not significantly widened, which helps distinguish it from the hydrocephalus ex vacuo seen in Alzheimer's disease.

14. Traumatic Brain Injury (TBI) and its Sequelae

14.1 Acute TBI Prognosis

14.2 Chronic Traumatic Encephalopathy (CTE)

Also known as dementia pugilistica or "punch-drunk syndrome," CTE is a progressive neurodegenerative disease caused by repetitive head trauma, including both concussive and sub-concussive impacts.

• Pathology: CTE is definitively classified as a tauopathy.
• Histopathological Hallmark: The pathognomonic finding is the accumulation of hyperphosphorylated tau (p-tau) protein as neurofibrillary tangles (NFTs) in neurons and astrocytes.
• Unique Distribution: What distinguishes CTE from other tauopathies like Alzheimer's disease is the unique anatomical distribution of these tangles. In CTE, the p-tau pathology is characteristically found clustered around small blood vessels, particularly at the depths of the cerebral sulci.

15. Cellular Neuropathology

15.1 Microglia

• Function: Microglia are the resident immune cells of the central nervous system. They are the brain's equivalent of macrophages.
• Role: In their resting state, they constantly survey the neural environment. In response to any form of injury, infection, or pathology (like the amyloid plaques in AD), they become "activated." Activated microglia are the primary phagocytes of the CNS, responsible for clearing dead cells, cellular debris, and foreign pathogens. They also play a complex role in neuroinflammation, releasing both protective and toxic substances.

15.2 Lesion Effects and Clinical Syndromes

The location of a brain lesion produces highly specific clinical signs.

• Bitemporal Hemianopia: This specific pattern of visual field loss, often described as "tunnel vision," is caused by a lesion that compresses the center of the optic chiasm. The most common cause is a pituitary tumor (e.g., pituitary adenoma), which expands upward from the sella turcica and damages the crossing nasal retinal fibers from both eyes.
• Perseveration and Frontal Lobe Dysfunction: Perseveration is the inappropriate repetition of a particular response (a word, thought, or action) despite the absence or cessation of a stimulus. It reflects an inability to switch tasks or concepts and is a classic sign of executive dysfunction caused by damage to the prefrontal cortex, particularly the dorsolateral prefrontal cortex. It is a common feature in conditions that cause frontal lobe atrophy, such as frontotemporal dementia.
• Dissociative Amnesia: This is a psychiatric condition, not a primary neuropathological one, but it is important to differentiate from organic amnesias. It is characterized by an inability to recall important autobiographical information, usually of a traumatic or stressful nature. Unlike organic amnesia where new learning (anterograde memory) is impaired, in dissociative amnesia the capacity for new learning remains intact.
• Cerebral Palsy (CP): This is a non-progressive motor disorder caused by an insult (e.g., perinatal hypoxia) to the developing brain. The most common form, spastic diplegia, is characterized by upper motor neuron lesion (UMNL) signs in the legs, including spasticity, hyperreflexia, and a "scissoring" gait. The classic MRI finding is periventricular leukomalacia, which is damage to the white matter tracts adjacent to the ventricles that control leg movement.

15.3 Neurobiology of Psychiatric & Genetic Disorders

• Post-Traumatic Stress Disorder (PTSD): Neuroimaging studies in PTSD have revealed a consistent pattern of changes in the brain's fear and memory circuits. The most reliable structural finding is reduced hippocampal volume (atrophy). Functional findings include hyperactivity of the amygdala (the fear center) and hypoactivity of the medial prefrontal cortex (which normally inhibits the amygdala).

• MDMA ("Ecstasy") Neurotoxicity: MDMA is a potent serotonin-releasing agent and reuptake inhibitor. Chronic, heavy use is believed to be neurotoxic to the fine axon terminals of serotonergic neurons. This leads to a long-term, compensatory downregulation of the serotonin transporter (SERT). A reduction in SERT density is the most consistent structural brain change associated with long-term MDMA use.
• Williams Syndrome: This is a genetic disorder (microdeletion on chromosome 7) with a unique cognitive profile of preserved language but severe visuospatial deficits. This clinical finding has a direct radiological correlate: abnormalities of the inferior parietal lobule, a brain region critical for visuospatial processing.

15.4 Experimental Models & Key Structures

• Multiple Sclerosis (MS): MS is an autoimmune disease where T-cells attack the myelin of the CNS. The primary animal model used to study this process is Experimental Autoimmune Encephalomyelitis (EAE). In this model, animals are immunized with myelin proteins, which induces a T-cell-mediated inflammatory demyelinating disease that closely mimics the pathology of MS.

• Blood-Brain Barrier (BBB): The BBB is a complex, dynamic interface. Its integrity and function depend on a variety of molecules. Apolipoprotein E (ApoE) is a lipid-transport protein that is fundamentally important for cerebrovascular homeostasis. It helps maintain the tight junctions between endothelial cells and supports overall BBB stability. The ApoE4 allele, the major genetic risk factor for Alzheimer's disease, is associated with increased BBB breakdown.