A 62-year-old woman is brought to a physician by her husband for fluctuating changes in behavior and hallucinations over the past 2 years. On occasion, she becomes difficult to understand and her speech becomes disorganized. She also frequently sees "small people" and animals on the dining room table, which is disturbing to her. Her medical problems include hypertension and chronic obstructive pulmonary disease for which she takes amlodipine, albuterol, ipratropium, and a fluticasone inhaler. She was formerly an executive at a software company but had to retire due to frequent memory lapses. Her temperature is 98.6°F (37°C), blood pressure is 120/80 mmHg, pulse is 80/min, and respirations are 12/min. Physical exam is notable for slowed movements and difficulty with balance at rest, which were not present at her wellness visit 1 year ago. Which of the following pathological findings (Figures A-E) would most likely be seen if a brain biopsy were performed?
Figure D
Figure E
Figure B
Figure C
Figure C
This patient with fluctuating changes in behavior and cognition, visual hallucinations, memory loss, and extrapyramidal symptoms (bradykinesia, postural instability) most likely has Lewy body dementia. Lewy body dementia is characterized histologically by Lewy bodies, which are intracytoplasmic eosinophilic inclusions of alpha-synuclein (shown in Figure C).

Alpha-synuclein is normally abundantly present in its unfolded form in neurons. Abnormal folding of alpha-synuclein leads to aggregation into insoluble fibrils. These intracytoplasmic aggregates (Lewy bodies) are seen in Parkinson disease, Lewy body dementia, and multiple system atrophy, which are collectively referred to as alpha-synucleinopathies. Lewy body dementia is the second most common degenerative dementia and presents with fluctuating cognition, visual hallucinations, parkinsonism (bradykinesia, postural instability, rigidity, and a resting tremor), rapid eye movement (REM) sleep disorder, autonomic dysfunction, and sensitivity to antipsychotics. Lewy body dementia can be distinguished from Parkinson disease with dementia by the timing of symptoms. In Lewy body dementia, cognitive symptoms begin at the same time as or 1 year prior to the onset of movement symptoms whereas in Parkinson disease the cognitive symptoms classically occur over 1 year after motor symptoms. There is no cure for Lewy body dementia, and treatment is aimed at alleviating symptoms.

Arnaoutoglou et al. reviewed the epidemiology, pathology, treatment, and future directions for research of Lewy body dementia. The authors found potential genetic bases for Lewy body dementia, including mutations in the GBA gene. They recommended that further research be conducted on the therapeutic implications of these genetic findings.

Figure/Illustration A shows a hematoxylin and eosin (H&E) stained brain biopsy of a patient with Creutzfeldt-Jakob disease. Characteristic spongiform changes in neurons (yellow boxes) and agglomerated prions (orange arrows) are seen in this slide.

Figure/Illustration B shows an H&E stained brain biopsy of a patient with a small lacunar infarct on low magnification. A central area of tissue loss (yellow outline) and surrounding residual gliosis (orange arrows) are seen in this slide.

Figure/Illustration C shows a brain biopsy of a patient with Lewy body dementia stained with mouse anti-alpha-synuclein antibody and counterstained with hematoxylin. Lewy bodies (intracytoplasmic eosinophilic inclusions of alpha-synuclein) are indicated by orange arrows. Note that Lewy bodies are always found intracellularly (neurons highlighted by blue boxes).

Figure/Illustration D shows an H&E stained brain biopsy of a patient with Alzheimer disease. Extracellular neurofibrillary tangles found in Alzheimer disease are indicated by black arrows.

Figure/Illustration E shows an H&E stained brain biopsy of a patient with frontotemporal dementia. A characteristic Pick cell (red box), or ballooned neuron, with dissolved chromatin (yellow arrow), is seen in this slide.

Incorrect Answers:
Answer A: Figure A shows an H&E stained brain biopsy of a patient with Creutzfeldt-Jakob disease. Creutzfeldt-Jakob disease is a rapidly progressive dementia that manifests with poor concentration, declining executive function, startle myoclonus, 14-3-3 protein on lumbar puncture, and synchronous sharp wave complexes on electroencephalogram (EEG). Clinical decline occurs over the course of weeks and months, culminating in death within a year. Creutzfeldt-Jakob disease shows spongiform vacuolation due to the accumulation of abnormal prion protein (PrPsc).

Answer B: Figure B shows an H&E stained brain biopsy of a patient with a small lacunar infarct. Lacunar infarcts may be asymptomatic or cause focal neurologic deficits such as motor hemiparesis, pure sensory stroke, ataxic hemiparesis, or dysarthria-clumsy hand syndrome depending on the territory involved. Lacunar strokes will show diffuse eosinophilia of the affected area, followed by liquefactive necrosis with neutrophilic infiltration, followed by macrophages with surrounding reactive gliosis, finally leading to an area of tissue loss with residual gliosis.

Answer D: Figure D shows an H&E stained brain biopsy of a patient with Alzheimer disease. Alzheimer disease presents with a gradual cognitive decline with difficulty completing activities of daily living. Memory is the most prominently affected domain. Visual hallucinations, fluctuating levels of cognition, and extrapyramidal symptoms are not common in Alzheimer disease. Amyloid plaques and neurofibrillary tangles may be seen on brain biopsy.

Answer E: Figure E shows an H&E stained brain biopsy of a patient with frontotemporal dementia (Pick disease). The behavioral variant of frontotemporal dementia is associated with early-onset personality and behavioral changes, and it may be associated with extrapyramidal symptoms. Unlike Lewy body dementia, memory is usually not affected in frontotemporal dementia until late in the disease course. frontotemporal dementia is characterized by Pick cells (ballooned neurons with dissolved chromatin) and Pick bodies, round intracellular aggregates of hyperphosphorylated tau protein.

Bullet Summary:
Lewy body dementia presents with alterations in consciousness, disorganized speech, visual hallucinations, extrapyramidal symptoms, early compromise of executive functions, and eosinophilic intracytoplasmic inclusions of alpha-synuclein (Lewy bodies) on biopsy.