A 70-year-old woman is brought to the office after her nurse noticed her being apathetic, easily distracted, and starting to urinate in bed. Her medical history is relevant for hypertension, under control with medication. Physical examination reveals a blood pressure of 138/76 mm Hg, a heart rate of 70/min, and a respiratory rate 14/min and regular. On neurological examination, she has a broad-based shuffling gait, and increased muscle tone in her limbs that is reduced by distracting the patient. There is decreased coordination with exaggerated deep tendon reflexes, decreased attention and concentration, and postural tremor. Which of the following additional features would be expected to find in this patient?

Dilation of the ventricular system

Degeneration of the substantia nigra pars compacta

Accumulation of Lewy bodies in cortical cells

Accumulation of amyloid plaques and neurofibrillary tangles in the cerebral cortex

A 68-year-old man is brought to the physician by his wife because she is concerned about his speech being irregular. Specifically, she says that over the last 8 months, her husband has been saying increasingly nonsensical statements at home. In addition, he is no longer able to perform basic verbal tasks such as ordering from a menu or giving directions even though he was an English teacher prior to retirement. She also reports that he has recently started attempting to kiss strangers and urinate in public. Finally, she has also noticed that he has been frequently binge eating sweets even though he was previously very conscientious about his health. When asked about these activities, the patient does not have insight into his symptoms. Which of the following would most likely be seen in this patient?

Hyperphosphorylated tau inclusion bodies

Intracellular hyperphosphorylated tau proteins

A 52-year-old man presents with 2 months of diarrhea, abdominal pain, and fatigue. He reports a weight loss of 4 kg (8 lb). He also says his joints have been hurting recently, as well. Past medical history is unremarkable. Review of systems is significant for problems with concentration and memory. Physical examination is unremarkable. A GI endoscopy is performed with a biopsy of the small bowel. Which of the following histologic finding would most likely be seen in this patient?

Non-caseating granulomas in the small intestine

Absence of nerves in the myenteric plexus

Crypt hyperplasia with increased intraepithelial lymphocytes

A 35-year-old woman presents with headaches and seizures. MRI shows a well-circumscribed, calcified frontal lobe mass. Histology reveals oligodendroglioma with 1p/19q codeletion and IDH1 mutation. She undergoes gross total resection. Two years later, surveillance MRI shows a new enhancing nodule at the resection margin. Biopsy shows increased mitotic activity, microvascular proliferation, and retained 1p/19q codeletion but new CDKN2A/B homozygous deletion. What is the most critical factor in determining management strategy?

Retained 1p/19q codeletion predicts continued chemosensitivity to PCV regimen

The tumor has progressed to anaplastic oligodendroglioma requiring combined chemoradiation with temozolomide and RT

CDKN2A/B deletion indicates transformation to glioblastoma requiring maximal therapy

Loss of IDH1 mutation suggests new primary tumor requiring re-resection only

Microvascular proliferation mandates anti-angiogenic therapy with bevacizumab

A 55-year-old man presents with progressive supranuclear gaze palsy, axial rigidity, and frequent falls. MRI shows midbrain atrophy with hummingbird sign. He dies 7 years later. Autopsy reveals globose neurofibrillary tangles in the basal ganglia and brainstem. Tau immunostaining shows 4-repeat tau predominance. His brother had similar symptoms. Genetic testing reveals a MAPT mutation. How does this change the pathogenic understanding and potential therapeutic approach?

It confirms primary tauopathy amenable to tau-directed antisense oligonucleotide therapy

It suggests prion-like propagation requiring anti-aggregation compounds

It demonstrates autoimmune etiology requiring immunosuppression

It reveals mitochondrial dysfunction requiring coenzyme Q10 supplementation

It indicates concurrent alpha-synuclein pathology requiring dual-target therapy

A 70-year-old man with progressive dementia undergoes autopsy. Microscopy shows neuritic plaques and neurofibrillary tangles meeting criteria for Alzheimer disease (AD). However, sections also reveal Lewy bodies in the substantia nigra and cortex, moderate atherosclerosis with old lacunar infarcts, and TDP-43 positive inclusions in the hippocampus. He had no parkinsonian features clinically. What is the most appropriate neuropathologic interpretation?

Alzheimer disease with multiple contributing pathologies (mixed dementia)

Dementia with Lewy bodies with concurrent Alzheimer pathology

Vascular dementia with incidental Alzheimer changes

Frontotemporal dementia with secondary Alzheimer pathology

Primary age-related tauopathy with multiple comorbidities

Neurodegenerative diseases for USMLE Step 1: High-Yield Pathology Lessons

Neurodegeneration - Protein Power Down

Core Mechanism: Misfolded proteins lose normal function & gain toxic properties, resisting degradation and aggregating.

Key Proteinopathies:
- Alzheimer: Aβ plaques, Tau tangles
- Parkinson/LBD: α-synuclein (Lewy bodies)
- Huntington: Huntingtin (HTT)
- Prion Disease (CJD): Prion protein (PrPSc)

Protein Misfolding, Aggregation, and Fibril Formation

⭐ Prion-like Spread: Misfolded proteins like α-synuclein and tau can propagate from cell to cell, seeding aggregation in a chain reaction.

Alzheimer Disease - Plaque & Tangle Tussle

Pathology: Extracellular senile plaques (β-amyloid) & intracellular neurofibrillary tangles (hyperphosphorylated tau protein).
Clinical: Most common cause of dementia. Insidious onset with progressive memory loss (initially short-term), visuospatial deficits, and executive dysfunction.
Genetics:
- Sporadic (late-onset, >95%): Apolipoprotein E4 (ApoE4) is the major risk factor.
- Familial (early-onset): Mutations in APP (Chr 21), PSEN1 (Chr 14), PSEN2 (Chr 1).
Gross: Diffuse cortical atrophy, especially hippocampus → hydrocephalus ex vacuo.

Alzheimer’s Brain Changes: Gross and Microscopic

⭐ Patients with Down Syndrome (Trisomy 21) have an extra copy of the APP gene, leading to a significantly increased risk of early-onset Alzheimer's disease.

Synucleinopathies - The Shakes & Slips

Parkinson's Disease (PD): Core motor symptoms 📌 TRAP: Tremor (pill-rolling, at rest), Rigidity (cogwheel), Akinesia/bradykinesia, Postural instability.
- Pathophysiology: Loss of dopaminergic neurons in substantia nigra pars compacta. Intraneuronal Lewy bodies (α-synuclein aggregates).
Lewy Body Dementia (LBD): Features parkinsonism plus early cognitive decline (dementia < 1 year of motor symptoms), fluctuating cognition, and vivid visual hallucinations.
Multiple System Atrophy (MSA): Parkinsonism combined with prominent, early autonomic failure (e.g., orthostatic hypotension) or cerebellar signs.

Lewy body formation in neurons

⭐ In LBD, cognitive symptoms appear before or within 1 year of motor symptoms. In PD, dementia is a late complication.

Diverse Pathologies - FTD, HD, ALS & Prions

Frontotemporal Dementia (FTD)
- Degeneration of frontal and/or temporal lobes, leading to behavioral or language deficits.
- Pathology: Round tau inclusions (Pick bodies) or TDP-43 inclusions.
Huntington's Disease (HD)
- Autosomal dominant; ↑CAG repeats in the HTT gene (anticipation).
- Marked atrophy of the caudate and putamen.
- Loss of GABAergic medium spiny neurons.
- 📌 Choria, Aggressiveness, Grimacing = CAG.
Amyotrophic Lateral Sclerosis (ALS)
- Combined Upper (UMN) & Lower (LMN) motor neuron death.
- Pathology: TDP-43 inclusions in motor neurons; Bunina bodies (remains of autophagic vacuoles).
Prion Disease (e.g., CJD)
- Pathogenic PrPSc induces misfolding of normal PrPC.
- Causes spongiform encephalopathy (vacuolization).

Histology of Spongiform Encephalopathy in Prion Diseases

⭐ Creutzfeldt-Jakob Disease (CJD) classically presents as a rapidly progressive dementia with myoclonus and characteristic periodic sharp wave complexes on EEG.

High‑Yield Points - ⚡ Biggest Takeaways

Alzheimer's disease is defined by extracellular amyloid-β plaques and intracellular neurofibrillary tangles (hyperphosphorylated tau).

Parkinson's disease features Lewy bodies (α-synuclein) and loss of dopaminergic neurons in the substantia nigra.

Huntington's disease results from a CAG repeat expansion, leading to caudate and putamen atrophy.

ALS combines upper and lower motor neuron signs; look for TDP-43 inclusions.

Creutzfeldt-Jakob disease causes rapidly progressive dementia via spongiform encephalopathy.

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