Dementia with Lewy Bodies Phenocopy in a Case of RT-QuIC Negative Creutzfeldt-Jakob Disease: Implications of Functional Anatomy

Real time quaking-induced conversion (RT-QuIC) is a highly specific test for Creutzfeldt-Jakob disease (CJD), although sensitivity varies by molecular subtype, with lower sensitivity in rare variants such as VV1 and MM2. We report a patient who presented with rapid cognitive decline found to have negative RT-QuIC, reportedly positive CSF biomarkers for Alzheimer’s disease (AD), a clinical syndrome of Posterior Cortical Atrophy (PCA) plus additional clinical characteristics of dementia with Lewy bodies (DLB). Findings at autopsy were consistent with CJD.

Case Report:

A 77-year-old male was evaluated for rapid cognitive decline over 12 months. His symptoms began as isolated visuospatial impairment, initially described as an episode of transient diplopia in the left visual field of his left eye. Ophthalmologic evaluation and MRI brain (Figure 1A) following the episode were normal. Two months later, he began to experience navigational difficulties while driving in well-known areas. This rapidly progressed over the following months to include difficulty with navigating between rooms in his home. A sleep study was performed and found severe central sleep apnea and repeat MRI brain demonstrated biparietal atrophy in the dorsal superior parietal lobule region which was notably worse compared to imaging from five months prior. Due to transient episodes of confusion, an EEG was performed and demonstrated intermittent slowing over the left frontal region without interictal abnormalities. Keppra was initiated without improvement in symptoms and was later discontinued. Lab work included CBC, CMP, B12, and TSH, which were within normal limits, as well as a negative heavy metal screen and negative paraneoplastic antibody panel.

Figure 1: Diffuse MRI and neuropathology.

Diffusion-weighted image (DWI) MRI and apparent diffusion coefficient (ADC) map from initial evaluation. (A) DWI MRI and ADC map from 5 months later which demonstrates left greater than right posterior and anterior restricted diffusion in the cortex with ADC map correlate. (B) Prion protein (PrP) immunostaining in the frontal cortex. (C) Parietal lobe section demonstrating severe spongiform degeneration. (D) Occipital cortex demonstrating severe neuronal loss and gliosis. (E) Inferior olivary nucleus showing severe neuronal loss and gliosis. (F)

Over the following two months, the patient began to have worsening difficulty with short-term memory, expressive aphasia, and executive dysfunction. An FDG-PET scan demonstrated hypometabolism in the bilateral dorsal parietal cortices, consistent with regions of cortical atrophy demonstrated on structural MRI. CSF testing was remarkable for RBC 9, WBC 4, protein 51, glucose 64, negative RT-QuIC, positive 14-3-3 protein, total-tau 2029 pg/mL. Amyloid β 42 was 3825 pg/mL and amyloid β 40 was 18903 pg/mL, though the 42/40 ratio was low at 0.20 with a reported “high risk” of AD. He was also found to have one copy of apolipoprotein epsilon 4, a genetic risk factor for Alzheimer’s disease. At this point he was referred to a subspecialty cognitive and behavioral neurology clinic, where his neurologic examination was notable for parkinsonism with bilateral upper extremity postural and resting tremor and bradykinesia. Bedside neurobehavioral status examination found him fully oriented to person, place, and time. He had difficulty with repetition of longer phrases and was mildly hypophonic. His Montreal Cognitive Assessment(1) was 18/30 and Frontal Assessment Battery(2) was 12/18. He was able to perform simple calculations correctly but struggled with more complex multiplication. He had multiple illusory misperceptions on an overlapping figure test(3) and was unable to identify two of four items. His spatial working memory was very poor, and he had difficulty with mental spatial navigation on bedside task based on the Brooks letter task(4) adapted for assessment of spatial orientation for the Brain Card^™.(5) In this task, a block letter ‘E’ is presented visually and the patient is instructed that the visual aid will be removed and then they will be asked to imagine they are at the bottom left of the letter (denoted by an ‘x’) and describe the sequence of right and left turns taken to walk the perimeter of the letter until returning to the initial position. Secondary review of his MRI was initially thought to demonstrate progressive, isolated bilateral dorsal parietal atrophy. At the time of clinical evaluation, the first (at symptom onset) and last (5 months later) MRI images were available for review and felt to show significant biparietal atrophy. The patient was diagnosed with PCA due to comorbid etiologies of AD and DLB given his initial visuospatial impairment, parkinsonism, rapid decline, and episodic fluctuations with positive biomarkers for AD neuropathologic change on CSF.

Over the following three to six months, the patient developed myoclonic jerks of his bilateral upper extremities. Routine EEG showed generalized slowing without epileptiform discharges. His aphasia worsened with increasing paraphasic errors, which progressed to minimal comprehensible verbal output. The patient became unable to navigate within a room or identify common objects including his toothbrush. He became highly anxious with any visually startling stimuli as well, and ultimately passed away less than 2 years after the initial onset of symptoms. The patient’s brain autopsy showed severe neuronal loss and gliosis in the inferior olivary nucleus and occipital lobe with transcortical spongiform changes that were most pronounced in the parieto-occipital regions. There were no amyloid plaques or Lewy bodies seen. These findings are consistent with a diagnosis of sporadic CJD. A sample was sent to the National Prion Disease Surveillance Center where an immunostain for prion protein (PrP) was positive, confirming a diagnosis of a prion disease.

In light of the misalignment between in vivo and neuropathological diagnosis, a thorough re-review of his medical record was undertaken, and it was discovered that there were two MRIs of the brain performed at month five of symptoms. The first of these had been repeated due to concern for artifactual areas of restricted diffusion (Figure 1B). The follow-up MRI performed the same day was read as having no areas of restricted diffusion, but on close inspection the same regions visible in Figure 1B were subtle, but still present.

Discussion:

CJD is a human prion disease involving the deposition of an abnormally folded and protease-resistant form of prion protein (PrPSc) within the brain. Most cases (85%) are sporadic with 5–15% of cases involving inherited mutations of the prion protein gene.(6) Sporadic CJD typically presents as rapidly progressing dementia associated with myoclonus, cerebellar manifestations, extrapyramidal signs, and deficits in higher cortical function including visual disturbances, aphasia, and apraxia.(7) CSF lab testing for CJD historically involved the detection of non-specific markers for neuronal damage such as elevated neuron-specific enolase, 14-3-3 protein, and total-tau protein.(6) RT-QuIC is a relatively new test developed in 2010 which has been reported as highly sensitive (~96%) and specific (~100%) in the detection of sporadic CJD.(8) While highly sensitive, it is nevertheless imperfect, especially in instances of more indolent disease course.(9)

Sporadic CJD has 6 clinicopathological subtypes based on the PRNP codon 129 polymorphism (M and V) and PrPSc glycotype.(10) RT-QuIC has been shown to be less sensitive in rare and slower progressive subtypes, such as MM2 and VV1, although exact numbers have not yet been established.(10) The presence of blood (>1250 × 10^6/L; the 9 RBC present in the CSF of this case would not be expected to alter testing characteristics) and elevated protein in the CSF have also been associated with false negative RT-QuIC results,(6) which makes a high index of suspicion necessary in cases with rapid decline and negative RT-QuIC. In a study which investigated RT-QuIC negative sCJD cases, 90% were found to have a positive alternative diagnostic study including positive total tau and 14-3-3, restricted diffusion in typical cortical regions and/or subcortical areas, and triphasic waves on EEG.(9) In our case, three diffusion-weighted MRI sequences were obtained prior to referral, the final two collected days apart due to the concern that regions on the diffusion sequence represented artifact. Indeed, the regions of restricted diffusion were less on repeat imaging but were still present on retrospective review. It is noteworthy that, in some instances, outside radiologic reports are unlikely to identify or consider the significance of this finding.(11) This finding, in the context of rapid progression and highly elevated total tau, should prompt a high index of suspicion for human prion disease and is a highly salient clinical pearl that subspecialists in behavioral neurology & neuropsychiatry should be aware of.

Biomarkers of neurodegenerative disease have become more common place in clinical practice with the advent and coverage of biofluid biomarkers. In this case, our patient had an extensive work-up that included CSF analysis with amyloid beta 42:40 ratio which was reported as “high risk” for a diagnosis of AD. However, the raw values for both amyloid beta 42 and 40 were at the upper limits of previously published mass spectroscopy analyses.(12) In this case, the amyloid beta 42:40 ratio was 0.2, which was right at the lower limit of ‘high risk’ for Alzheimer’s disease. The combination of these unusual factors should have raised higher skepticism that AD was a potentially misleading diagnostic conclusion.

The presentation of our case was consistent with the PCA clinical syndrome. PCA can be due to AD, Lewy body disease, corticobasal degeneration, and prion disease.(13) In our case, there was early visuospatial impairment, followed shortly thereafter by early signs that may have been referable to thalamic involvement (i.e., severe central sleep apnea). A case described by Yamashita and colleagues described a slowly progressive case of MM2-thalamic variant sCJD that had severe cortical involvement, though the clinical scenario fit with a primary thalamic variant, and authors argued that cortical atrophy occurred later in the course of their disease.(14) In our case, cortical atrophy likely occurred earlier in the disease course as initial visuospatial symptoms localized to the occipitoparietal cortex, as is seen in the Heidenhain variant of CJD.(15) Later symptoms, such as severe sleep apnea, insomnia, and fluctuations in arousal localized to the thalamo-olivary circuit. Fluctuations in attention, arousal, and sleep-wake architecture are core features of DLB and localize to the dorsal-lateral and posterior thalamus.(16) Another core feature of DLB includes parkinsonism, which is associated with brainstem and cerebellar tract involvement, including the olivary nucleus.(17)

In conclusion, our case demonstrates several critical points that practicing neuropsychiatric subspecialists should take away: a) When a high clinical suspicion for prion disease exists, careful consideration should be given to surrogate markers, in particular CSF total tau, as RT QuIC is a highly specific but imperfect test b) AD biomarkers must be interpreted cautiously, and in the context of additional clinical data automated interpretation on reports may be misleading; c) careful scrutiny of all DWI MRI images is critical and reports of artifacts should be carefully considered; and d) phenotypic presentation indexes the neuroanatomic site of injury and is transdiagnostic with regards to underlying proteinopathic etiology.