How would you approach a young adult with rapidly progressive cognitive-behavioral changes, marked memory impairment, spatial disorientation, and a strong family history of early dementia? What clinical, genetic, and biomarker findings would you integrate when counseling about investigational therapies and understanding the underlying etiology? Explore how advanced diagnostic evaluations can help unravel complex presentations in early-onset neurodegeneration.
VIDEO INFO
Category: Role in Alzheimer’s, Use of TPE in Dementia, Indications for Therapeutic Plasma Exchange, Therapeutic plasma exchange, Clinical Pathology
Difficulty: Expert – Expert level – For those seeking deep understanding
Question Type: Diagnosis – Identify conditions based on clinical presentation
Case Type: Complicated Condition
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QUESTION
A 24-year-old woman presents with 10 months of rapidly progressive cognitive-behavioral change. She reports misplacing items, spatial disorientation in large buildings, difficulty tracking multi-step tasks, and lapses in episodic memory. Early education and development were unremarkable. Family history is notable for her father s early dementia with myoclonus in his late 30s and death at 45; no neuropathology is available. She does not drink alcohol or use illicit drugs….
OPTIONS
A. Young-onset, biomarker-confirmed Alzheimer s disease due to a pathogenic PSEN1 mutation, with an amnestic-executive syndrome, posterior temporoparietal hypometabolism, and concordant amyloid and tau positivity.
B. Autosomal-dominant Alzheimer s disease due to APP duplication with cerebral amyloid angiopathy-predominant features, typically marked by microbleeds and lobar hemorrhage on MRI not seen here.
C. Logopenic variant primary progressive aphasia due to Alzheimer pathophysiology without autosomal-dominant mutation, despite the amnestic-predominant cognitive profile and PSEN1 pathogenicity.
D. Seronegative autoimmune limbic encephalitis causing predominant memory symptoms despite negative neuronal antibody panels, normal CSF indices, and Alzheimer-pattern molecular imaging.
CORRECT ANSWER
A. Young-onset, biomarker-confirmed Alzheimer s disease due to a pathogenic PSEN1 mutation, with an amnestic-executive syndrome, posterior temporoparietal hypometabolism, and concordant amyloid and tau positivity.
EXPLANATION
The totality of data points to autosomal-dominant Alzheimer s disease due to a pathogenic PSEN1 variant with fully concordant Alzheimer biomarkers. Clinically, the patient s amnestic-executive syndrome with topographical disorientation, impaired delayed recall, and posterior temporoparietal hypometabolism on FDG-PET is classic for Alzheimer s neurodegeneration. Molecularly, she is positive by a plasma pTau217/beta-amyloid 1-42 ratio run in a specialized laboratory, shows CSF Abeta42 low with elevated tau species, and has robust amyloid PET uptake in precuneus/posterior cingulate with supportive tau PET in temporal cortices. Genetically, a heterozygous PSEN1 pathogenic missense variant in a CLIA-certified lab with a family history of early dementia and myoclonus is diagnostic of young-onset autosomal-dominant Alzheimer s disease….
Further reading:
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