Neuropathology: Neurocognitive Disorders

• Neuropathology involves the study of common neurocognitive disorders like different types of dementia.

Major and Mild Neurocognitive Disorders (Dementia)

• Major and mild neurocognitive disorders are collectively known as dementia.
• Early neurocognitive disorder is classified as mild.
• Late neurocognitive disorder is classified as major.
• Major neurocognitive disorder involves generalized, progressive impairment of cognitive function and impairment in activities of daily living (ADLs).
• Level of consciousness is not impaired in major neurocognitive disorder.
• Executive function, memory, and attention can all be affected in major neurocognitive disorder.

ADLs vs. IADLs

• Activities of daily living (ADLs) are basic self-care tasks like bathing.
• Instrumental activities of daily living (IADLs) are more complex and involve planning and thinking to take care of oneself and the home.

Dementia Severity

• In mild neurocognitive disorder, ADLs are not significantly impaired.
• There is a reduction in function in one or more major cognitive domains.
• Common areas affected include complex attention, executive function, learning and memory, language, perceptual-motor skills, or social cognition.
• A patient with mild neurocognitive disorder is aware of and frustrated by these deficits.
• In major neurocognitive disorder, both ADLs and iADLs are affected.
• iADLs are often impaired first, specifically shopping, food preparation, finances, and medication management.
• There is a larger impairment in one or more major cognitive domains.
• Patients are often unaware of their deterioration with major neurocognitive disorder.

Common Features of Neurodegenerative Disorders

• Neurodegenerative disorders involve a progressive loss of neurons with associated secondary changes in white matter tracts.
• This loss is selective, affecting one or more groups of neurons while leaving others intact.
• Neurons next to degenerating ones can sometimes appear completely normal.
• A common finding in neurodegenerative disorders is protein aggregates resistant to degradation through the ubiquitin-proteasome system, forming inclusions within neurons.
• Examples of common neurodegenerative disorders include Parkinson's disease and Alzheimer's disease.

Alzheimer's Disease (AD)

• It is the most common cause of dementia in the elderly, with a prevalence of 1 in 8 in older populations and 40% in the 80-90-year-old group.
• It is the 6th leading cause of death.

General Pathological Findings in AD:

• Neurofibrillary tangles are present.
• Beta-amyloid plaques form.
• Cerebral atrophy occurs.
• There is often loss of widely distributed cholinergic neurons in the nucleus basalis of Meynert.

Alzheimer Disease: Pathology

• Neuritic plaques (beta-amyloid) appear as focal, spherical collections of dilated, tortuous, neuritic processes and are often around a central amyloid core that may be surrounded by a clear halo.
• The amyloid core contains several abnormal proteins, including Aβ (a peptide derived from amyloid precursor protein, APP).
• Other proteins present in plaques in lesser abundance include components of the complement cascade and pro-inflammatory cytokines.
• Plaques range in size from 20 to 200 μm in diameter, with microglial cells and reactive astrocytes at their periphery.
• Plaques are found in the hippocampus, amygdala, and neocortex, while primary motor and sensory cortices tend to be spared.
• Neurofibrillary tangles consist of bundles of filaments in the cytoplasm of neurons that displace or encircle the nucleus and are basophilic fibrillary structures with H&E staining commonly found in cortical neurons.
• These tangles are especially in the entorhinal cortex, pyramidal cells of the hippocampus, amygdala, and basal forebrain.

Alzheimer Disease: Tangles

• Neurofibrillary tangles are insoluble and resistant to clearance in vivo.
• A major component of "tangled filaments" includes abnormally hyperphosphorylated forms of the protein tau. -Tau is defined as an axonal microtubule-associated protein that enhances microtubule assembly.
• Other components include MAP2 (another microtubule-associated protein) and ubiquitin.

Alzheimer Disease: Pathophysiology

• APP is a membrane-associated protein thought to be a receptor for an unidentified ligand and is cleaved as part of normal breakdown of cellular proteins.
• Depending on where it's cut, APP can be either soluble or insoluble; insoluble forms accumulate in the extracellular space and are thought to be important in the pathogenesis.
• Aggregates of beta-amyloid are directly neurotoxic and activate microglia and astrocytes, leading to chronic inflammatory injury to neurons.
• Accumulation of beta-amyloid is thought to be responsible for neurofibrillary tangles within neurons.

Genetic Risk Factors

• Presenilin 1 and presenilin 2 are associated with severe early-onset AD and are involved in regulating neuronal intracellular calcium levels and cleaving APP.
• Apolipoprotein E4 (ApoE4) is one of four subtypes that help transport cholesterol throughout the CNS.
• Those heterozygous for E4 have approximately double the risk of late-onset AD (LOAD), which accounts for 25% of the Caucasian population.
• Individuals who are homozygous have sixteen times the increased risk of LOAD.
• Apo E4 positivity is not as strongly causative of AD as presenilin mutations.

Infectious Theory of Alzheimer's Disease:

• Amyloid Precursor Protein (APP) may be a primitive component of the innate immune system and seems to cause the death of bacteria and viruses.
• It is linked to viruses in the herpes family.

Insulin Resistance and Type 2 Diabetes

• Type II diabetes is the most common disorder of glucose metabolism, where genetic and lifestyle factors lead to insulin resistance.
• Resistance to insulin results in fewer receptors and down regulation of intracellular signaling linked to the insulin receptor.
• Insulin increases storage of glucose via glycogenesis in the liver, decreases new production of glucose (gluconeogenesis) in the liver, and inhibits lipogenolysis.
• Type II diabetics have long-term increased blood levels of glucose and free fatty acids.
• Insulin resistance seems to be an important component of AD pathophysiology, as AD is more common in those with type 2 diabetes.
• Insulin resistance reduces synaptogenesis, as insulin has a role in normal neuronal physiology and synaptic plasticity; long-term hyperglycemia down-regulates intracellular signaling cascades, decreasing plasticity; insulin resistance also increases circulating pro-inflammatory cytokines.

Clinical Features of AD:

• Slow development of impaired cognition.
• Short-term memory and executive functions (planning, logic) impaired relatively early.
• Personality changes and loss of normal inhibitions can follow some time after.
• Language deficits and loss of learned motor skills tend to result from more advanced disease.
• Incontinence and impaired ambulation result from severe disease, and impaired mobility is related to the development of pneumonia and sepsis.
• The "4 A's" and one "D" of Alzheimer's disease include Anterograde amnesia, Aphasia, Apraxia, Agnosia, and disturbance in executive function.

Dementia with Lewy Bodies

• It is a genetically determined disorder where tau protein is mutated, resulting in its aggregation or altered interaction with microtubules.
• Frontal and temporal lobes show more marked atrophy.
• Parkinson-like movement disorder is present.
• Dementia typically antecedes the movement symptoms or presents early with Parkinson’s type symptoms.
• Lewy bodies exist in neurons as the likely aggregates of misfolded alpha-synuclein.
• It affects 0.1-5% of the general elderly population.

Clinical Features:

• There are fluctuations in cognitive function with varying levels of alertness and attention.
• Visual hallucinations are vivid.
• Parkinsonian motor features appear later or close to the onset of dementia.
• Less prominent anterograde memory loss in comparison to AD.
• More prominent executive function deficits.

Psychosis and Executive Functions

• Psychosis involves impairment in reality testing, characterized by delusions and hallucinations.

• Delusions are beliefs that are not compatible with reality or normal cultural beliefs. Audible (hearing voices) and visual (seeing things) hallucinations may be present.

• Executive functions are orchestrated by the prefrontal cortex and involve complex cognitive sets:

• Shifting effectively between tasks.

• Inhibiting behaviours.

• Selecting + paying attention to information.

• Using working memory.

• Planning tasks.

• Executive functions often rely on memory and verbal fluency and are your brain's "taskmaster" to keep you doing things effectively and appropriately.

Parkinson's Disease Dementia

• Patients with long-standing PD but without cognitive impairment slowly develop dementia.
• It is associated with visual hallucinations and fluctuating alertness.
• Lewy bodies are also present.

Frontotemporal Dementias (FTD)

• FTD is a large group with a diverse nomenclature and is characterized by deficits in executive function.
• Behavioural variants are most common:
  • Behavioural disinhibition (socially inappropriate behaviour, impulsive, careless).
  • Apathy or inertia.
  • Loss of sympathy or empathy.
  • Perseverative, stereotyped, or compulsive/ritualistic behaviour.
  • Hyperorality and dietary changes.
• FTD has prominent behavioural symptoms and little to no memory deficits compared to Alzheimers.
• Language and atypical motor symptoms will also be present
• It involves progressive inability to form words or use language.
• It follows a constant, non-fluctuating course with rapid decline.
• It is more common in younger patients, becoming less common as the patient population ages, while Alzheimer’s gets more common as the patient population ages.

Vascular Dementia

• Multiple small infarcts affecting the gray matter of the cortices or hypertension affecting white matter can present with dementia.
• It is the second most common cause after Alzheimer's disease.
• Small vessel changes may be characteristics of hypertension and hypertension or multiple emboli can cause vessel disease. Clinical Presentation
• It presents similar to Alzheimer’s.
• The difference, unlike Alzheimers, is that depression and psychosis can be prominent features
• Gait abnormalities are common, and lateralizing signs are often present.

MMSE Assessmment

• This assesses Orientation, Short/Recent memory, Sustained concentration, and Executive functions.