Prion Disease Pathology Surveillance Center Research Articles

Pathological findings in autoimmune encephalitis autopsy specimens from cases of suspected prion disease.

The underlying pathology of autoimmune encephalitis is not well characterized due to the limited opportunities to study tissue specimens. Autopsy specimens available at prion surveillance centers from patients with suspected Creutzfeldt-Jakob disease offer a unique opportunity to study the pathology of autoimmune encephalitis. Our objective was to describe pathological findings of autoimmune encephalitis specimens submitted to the U.S. National Prion Disease Pathology Surveillance Center. Pathology reports were obtained from the National Prion Center. Specimens negative for prion disease were screened for inflammatory pathology and those suggestive of autoimmune encephalitis were analyzed. Cases identified on autopsy were compared to institutional cases with fatal seronegative autoimmune encephalitis and available brain biopsy. Between 1998 and 2022, 7934 specimens were evaluated of which 2998 (38%) were negative for prion protein. Querying the database for alternative diagnoses of encephalitis/encephalopathy yielded 43 cases that were screened by an experienced neuropathologist yielding 14 (0.5%) cases consistent with autoimmune encephalitis. Most specimens showed diffuse inflammation involving the limbic system (86%), basal ganglia (86%), cortex (71%), diencephalon (71%), and in some cases the brainstem (43%) and cerebellum (43%). Lymphocytic inflammatory infiltrate was predominantly perivascular with parenchymal extension in 64%. Microglial activation/nodules were seen in 64% of cases. Neuronal loss was present only in 50%. Pathological findings were identical to biopsy specimens from our institutional cohort. Seronegative AE may have consistent pathology with diffuse or multifocal perivascular inflammation and microglial activation. Half the patients do not have neuronal loss suggesting a potential for neurological recovery. These findings are preliminary and require further confirmation.

Forma esporádica de enfermedad de Creutzfeldt-Jakob: reporte de dos casos

La enfermedad de Creutzfeldt-Jakob es la encefalopatía espongiforme más común en el ser humano y prototipo de las patologías causadas por priones. Se caracteriza histológicamente por astrogliosis y degeneración de la sustancia gris. Típicamente inicia con síntomas prodrómicos no específicos progresando a demencia con mioclonias y ataxia. Presentamos dos casos de mujeres en edad media con deterioro cognitivo progresivo, dificultades motrices, alteraciones del lenguaje y mioclonias que conducen a la muerte. En electroencefalogramas de ondas trifásicas lentas periódicas así como elevación de proteínas tau y 14-3-3 en LCR por apoyo del The National Prion Disease Pathology Surveillance Center - Cleveland, todos estos hallazgos definen las condiciones para el diagnóstico clínico de enfermedad por priones. El diagnóstico diferencial en el contexto de demencia rápidamente progresiva es amplio, incluyendo infecciones, intoxicaciones, trastornos metabólicos, autoinmunidad, vasculopatías y neoplasias que podrían explicar un posible subregistro en las estadísticas regionales. Existe una posible asociación de riesgo entre enfermedad por priones y médicos patólogos que, aunque discutida, podría limitar el estudio de los especímenes histológicos que son la clave del diagnóstico definitivo. A pesar de la importancia en salud pública de estas condiciones, el actual modelo de salud limita el manejo integral de los pacientes.

RT-QuIC Testing for Prions: Applying a Sensitive but Imperfect Test in Clinical Practice (P5-12.010)

<h3>Objective:</h3> Identify the clinical, laboratory, and pathologic features associated with false negative real-time quaking-induced conversion (RT-QuIC) testing for prions. <h3>Background:</h3> Heterogeneity in clinical presentation, abundant mimics, and potential for iatrogenic transmission emphasize the need for accurate diagnostic tests for Creutzfeldt-Jakob disease (CJD). While RT-QuIC is an excellent test, false negative results are recognized in clinical practice. <h3>Design/Methods:</h3> One-hundred twelve patients with probable or definite prion disease were assessed at two tertiary care centers from 2013–2021. RT-QuIC testing for prions was performed in cerebrospinal fluid (CSF) in all patients via the National Prion Disease Pathology Surveillance Center (Cleveland, OH). Demographic data, clinical features, and results of common tests and laboratory studies were abstracted from electronic medical records, and differences between RT-QuIC positive and negative patients considered using univariate statistics. <h3>Results:</h3> Initial RT-QuIC testing was negative in 12/112 patients (sensitivity 89%). Median age at presentation was younger in RT-QuIC negative patients (56.9 vs 66 years, p&lt;0.01), who were also less likely to present with ataxia (3/12 vs 61/100, p=0.03). CSF cell count, protein, and glucose levels were similar between cohorts, while rates of 14-3-3 positivity (2/12 vs 77/100, p&lt;0.01) and median CSF total tau levels were lower in RT-QuIC negative patients (2318 vs 4001 pg/mL, p&lt;0.01). RT-QuIC negative patients also had a longer median days from symptom onset to first presentation (125 vs 47, p=0.04), and longer symptomatic disease duration (530 vs 148, p&lt;0.01). Two RT-QuIC-negative patients underwent repeat testing, of which both were positive. <h3>Conclusions:</h3> RT-QuIC is a sensitive yet imperfect measure necessitating incorporation of other test results when prion disease is suspected. Patients with negative RT-QuIC had lower CSF biomarkers of neuronal damage (total-tau and 14-3-3) and longer symptomatic duration of prion disease raising the possibility that false negative RT-QuIC testing may associate with a more indolent disease course. <b>Disclosure:</b> Dr. Jones has nothing to disclose. Dr. Lazar has nothing to disclose. Dr. Porter has nothing to disclose. Dr. Prusinski has nothing to disclose. Dr. Brier has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. The institution of Dr. Brier has received research support from NIH. Dr. Bucelli has received personal compensation for serving as an employee of Biogen. Dr. Bucelli has received personal compensation for serving as an employee of Biogen. Dr. Bucelli has received personal compensation for serving as an employee of Neuroquestions. Dr. Bucelli has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen . Dr. Bucelli has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Bucelli has stock in Neuroquestions.com. An immediate family member of Dr. Bucelli has stock in Neuroquestions.com. The institution of Dr. Bucelli has received research support from Biogen. The institution of Dr. Bucelli has received research support from Ionis. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Parabon Nanolabs. The institution of Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eli Lilly. Dr. Day has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for DynaMed (EBSCO Health). Dr. Day has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Barrow Law. Dr. Day has stock in ANI Pharmaceuticals. The institution of Dr. Day has received research support from National Institutes of Health / NIA. The institution of Dr. Day has received research support from Chan Zuckerberg Initiative. The institution of Dr. Day has received research support from Alzheimer’s Association. The institution of Dr. Day has received research support from National Institutes of Health / NINDS. The institution of Dr. Day has received research support from Horizon Therapeutics. Dr. Day has received personal compensation in the range of $500-$4,999 for serving as a Presenter at Annual Meeting (CME) with American Academy of Neurology. Dr. Day has received personal compensation in the range of $500-$4,999 for serving as a Content Development (CME) with PeerView, Inc. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving as a Content Development (CME) with Continuing Education, Inc. Dr. Day has a non-compensated relationship as a Clinical Director with AntiNMDA Receptor Encephalitis Foundation that is relevant to AAN interests or activities.

Real-time quaking-induced conversion assays for prions: Applying a sensitive but imperfect test in clinical practice.

Real-time quaking-induced conversion (RT-QuIC) assays offer a sensitive and specific means for detection of prions, although false negative results are recognized in clinical practice. We profile the clinical, laboratory, and pathologic features associated with false negative RT-QuIC assays and extend these to frame the diagnostic approach to patients with suspected prion disease. A total of 113 patients with probable or definite prion disease were assessed at Mayo Clinic (Rochester, MN; Jacksonville, FL; Scottsdale, AZ) or Washington University School of Medicine (Saint Louis, MO) from 2013 to 2021. RT-QuIC testing for prions was performed in cerebrospinal fluid (CSF) at the National Prion Disease Pathology Surveillance Center (Cleveland, OH). Initial RT-QuIC testing was negative in 13 of 113 patients (sensitivity=88.5%). RT-QuIC negative patients were younger (median=52.0 years vs. 66.1 years, p< 0.001). Other demographic and presenting features, and CSF cell count, protein, and glucose levels were similar in RT-QuIC negative and positive patients. Frequency of 14-3-3 positivity (4/13 vs. 77/94, p< 0.001) and median CSF total tau levels were lower in RT-QuIC negative patients (2517 vs. 4001 pg/mL, p= 0.020), and time from symptom onset to first presentation (153 vs. 47 days, p= 0.001) and symptomatic duration (710 vs. 148 days, p= 0.001) were longer. RT-QuIC is a sensitive yet imperfect measure necessitating incorporation of other test results when evaluating patients with suspected prion disease. Patients with negative RT-QuIC had lower markers of neuronal damage (CSF total tau and protein 14-3-3) and longer symptomatic duration of disease, suggesting that false negative RT-QuIC testing associates with a more indolent course.

Distinct conformers of amyloid beta accumulate in the neocortex of patients with rapidly progressive Alzheimer's disease

Amyloid beta (Aβ) deposition in the neocortex is a major hallmark of Alzheimer's disease (AD), but the extent of deposition does not readily explain phenotypic diversity and rate of disease progression. The prion strain–like model of disease heterogeneity suggests the existence of different conformers of Aβ. We explored this paradigm using conformation-dependent immunoassay (CDI) for Aβ and conformation-sensitive luminescent conjugated oligothiophenes (LCOs) in AD cases with variable progression rates. Mapping the Aβ conformations in the frontal, occipital, and temporal regions in 20 AD patients with CDI revealed extensive interindividual and anatomical diversity in the structural organization of Aβ with the most significant differences in the temporal cortex of rapidly progressive AD. The fluorescence emission spectra collected in situ from Aβ plaques in the same regions demonstrated considerable diversity of spectral characteristics of two LCOs—quatroformylthiophene acetic acid and heptaformylthiophene acetic acid. Heptaformylthiophene acetic acid detected a wider range of Aβ deposits, and both LCOs revealed distinct spectral attributes of diffuse and cored plaques in the temporal cortex of rapidly and slowly progressive AD and less frequent and discernible differences in the frontal and occipital cortex. These and CDI findings indicate a major conformational diversity of Aβ accumulating in the neocortex, with the most notable differences in temporal cortex of cases with shorter disease duration, and implicate distinct Aβ conformers (strains) in the rapid progression of AD.

Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion.

Genetic prion disease accounts for 10–15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an unclear pathogenicity. The goal of this case series was to provide an insight into the characteristics of the 2-octapeptide repeat genetic variant and to provide insight into the risk for Creutzfeldt–Jakob disease in asymptomatic carriers. 2-octapeptide repeat insertion prion disease cases were collected from the National Prion Disease Pathology Surveillance Center (US), the National Prion Clinic (UK), and the National Creutzfeldt–Jakob Disease Registry (Australia). Three largescale population genetic databases were queried for the 2-octapeptide repeat insertion allele. Eight cases of 2-octapeptide repeat insertion were identified. The cases were indistinguishable from the sporadic Creutzfeldt–Jakob cases of the same molecular subtype. Western blot characterization of the prion protein in the absence of enzymatic digestion with proteinase K revealed that 2-octapeptide repeat insertion and sporadic Creutzfeldt–Jakob disease have distinct prion protein profiles. Interrogation of large-scale population datasets suggested the variant is of very low penetrance. The 2-octapeptide repeat insertion is at most a low-risk genetic variant. Predictive genetic testing for asymptomatic blood relatives is not likely to be justified given the low risk.

Subtype Diagnosis of Sporadic Creutzfeldt-Jakob Disease with Diffusion Magnetic Resonance Imaging.

ObjectiveSporadic Creutzfeldt–Jakob disease (sCJD) comprises several subtypes as defined by genetic and prion protein characteristics, which are associated with distinct clinical and pathological phenotypes. To date, no clinical test can reliably diagnose the subtype. We established two procedures for the antemortem diagnosis of sCJD subtype using diffusion magnetic resonance imaging (MRI).MethodsMRI of 1,458 patients referred to the National Prion Disease Pathology Surveillance Center were collected through its consultation service. One neuroradiologist blind to the diagnosis scored 12 brain regions and generated a lesion profile for each MRI scan. We selected 487 patients with autopsy‐confirmed diagnosis of “pure” sCJD subtype and at least one positive diffusion MRI examination. We designed and tested two data‐driven procedures for subtype diagnosis: the first procedure—prion subtype classification algorithm with MRI (PriSCA_MRI)—uses only MRI examinations; the second—PriSCA_MRI + Gen—includes knowledge of the prion protein codon 129 genotype, a major determinant of sCJD subtypes. Both procedures were tested on the first MRI and the last MRI follow‐up.ResultsPriSCA_MRI classified the 3 most prevalent subtypes with 82% accuracy.PriSCA_MRI + Gen raised the accuracy to 89% and identified all subtypes.Individually, the 2 most prevalent sCJD subtypes, MM1 and VV2, were diagnosed with sensitivities up to 95 and 97%, respectively. The performances of both procedures did not change in 168 patients with longitudinal MRI studies when the last examination was used.InterpretationThis study provides the first practical algorithms for antemortem diagnosis of sCJD subtypes. MRI diagnosis of subtype is likely to be attainable at early disease stages to prognosticate clinical course and design future therapeutic trials. ANN NEUROL 2021;89:560–572

Human Prion Disease Surveillance in Washington State, 2006-2017

Human prion disease surveillance is critical to detect possible cases of variant Creutzfeldt-Jakob disease and other acquired forms of prion disease in the United States. Results are presented here that describe 12 years of surveillance in Washington, the only US state that has reported the presence of classic bovine spongiform encephalopathy, an animal prion disease that has been shown to transmit to humans. To describe the current prion disease surveillance system in Washington and the epidemiological and clinical results of surveillance from 2006 through 2017. This cross-sectional study reports findings from the human prion disease surveillance system in place in Washington state from January 1, 2006, through December 31, 2017. Participants included Washington residents with a clinical suspicion of human prion disease or suggestive test results from the National Prion Disease Pathology Surveillance Center or with prion disease listed as a cause of death on the death certificate. Data for this report were analyzed from June 1, 2016, to July 1, 2020. Human prion disease diagnosis. The main outcome was incidence of human prion disease cases, including identification of variant Creutzfeldt-Jakob disease. A total of 143 human prion disease cases were detected during the study period, none of which met criteria for a variant Creutzfeldt-Jakob disease diagnosis. Among 137 definite or probable cases, 123 (89.8%) occurred in persons aged 55 years or older, with a median age at death of 66 years (range, 38-84 years). Most patients were White (124 [92.5%] among 134 with reported race), and slightly over half were male (70 [51.1%]). The average annual age-adjusted prion disease incidence was 1.5 per million population per year, slightly higher than the national rate of 1.2 per million. A total of 99 cases (69.2%) were confirmed by neuropathology. Sporadic prion disease was the most common diagnosis, in 134 cases (93.7%), followed by familial prion disease in 8 cases (5.6%). One iatrogenic prion disease case (0.7%) was also reported. The findings of this cross-sectional study suggest that demographic characteristics of patients with prion disease in Washington are consistent with national findings. The slightly higher incidence rate may be due to the state's enhanced surveillance activities, including close collaboration with key partners and educational efforts targeted toward health care providers. Results indicate that surveillance will continue to be beneficial for monitoring epidemiological trends, facilitating accurate diagnoses, and detecting variant Creutzfeldt-Jakob disease or other emerging human prion disease cases.

Diagnosis of prion diseases by RT-QuIC results in improved surveillance.

To present the National Prion Disease Pathology Surveillance Center's (NPDPSC's) experience using CSF real-time quaking-induced conversion (RT-QuIC) as a diagnostic test, to examine factors associated with false-negative RT-QuIC results, and to investigate the impact of RT-QuICs on prion disease surveillance. Between May 2015 and April 2018, the NPDPSC received 10,498 CSF specimens that were included in the study. Sensitivity and specificity analyses were performed on 567 autopsy-verified cases. Prion disease type, demographic characteristics, specimen color, and time variables were examined for association with RT-QuIC results. The effect of including positive RT-QuIC cases in prion disease surveillance was examined. The diagnostic sensitivity and specificity of RT-QuIC across all prion diseases were 90.3% and 98.5%, respectively. Diagnostic sensitivity was lower for fatal familial insomnia, Gerstmann-Sträussler-Scheinker disease, sporadic fatal insomnia, variably protease sensitive prionopathy, and the VV1 and MM2 subtypes of sporadic Creutzfeldt-Jakob disease. Individuals with prion disease and negative RT-QuIC results were younger and had lower tau levels and nonelevated 14-3-3 levels compared to RT-QuIC-positive cases. Sensitivity was high throughout the disease course. Some cases that initially tested RT-QuIC negative had a subsequent specimen test positive. Including positive RT-QuIC cases in surveillance statistics increased laboratory-based case ascertainment of prion disease by 90% over autopsy alone. RT-QuIC has high sensitivity and specificity for diagnosing prion diseases. Sensitivity limitations are associated with prion disease type, age, and related CSF diagnostic results. RT-QuIC greatly improves laboratory-based prion disease ascertainment for surveillance purposes. This study provides Class III evidence that second-generation RT-QuIC identifies prion disease with a sensitivity of 90.3% and specificity of 98.5% among patients being screened for these diseases due to concerning symptoms.

Evaluation of a New Criterion for Detecting Prion Disease With Diffusion Magnetic Resonance Imaging

Early diagnosis is a requirement for future treatment of prion diseases. Magnetic resonance imaging (MRI) with diffusion-weighted images and improved real-time quaking-induced conversion (RT-QuIC) in cerebrospinal fluid (CSF) have emerged as reliable tests. To assess the sensitivity and specificity of diffusion MRI for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) with a new criterion (index test) of at least 1 positive brain region among the cortex of the frontal, parietal, temporal, and occipital lobes; the caudate; the putamen; and the thalamus. This diagnostic study with a prospective and a retrospective arm was performed from January 1, 2003, to October 31, 2018. MRIs were collected from 1387 patients with suspected sCJD consecutively referred to the National Prion Disease Pathology Surveillance Center as part of a consultation service. Magnetic resonance imaging. Four neuroradiologists blinded to the diagnosis scored the MRIs of 200 randomly selected patients. One neuroradiologist scored the MRIs of all patients. Sensitivity and specificity of the index test compared with currently used criteria and CSF diagnostic (improved RT-QuIC, 14-3-3, and tau CSF tests). A total of 872 patients matched the inclusion criteria (diffusion MRI and autopsy-confirmed diagnosis), with 619 having sCJD, 102 having other prion diseases, and 151 having nonprion disease. The primary analysis included 200 patients (mean [SD] age, 63.6 [12.9] years; 100 [50.0%] male). Sensitivity of the index test of 4 neuroradiologists was 90% to 95% and superior to sensitivity of current MRI criteria (69%-76%), whereas specificity was 90% to 100% and unchanged. Interrater reliability of the 4 neuroradiologists was high (κ = 0.81), and individual intrarater reliability was excellent (κ ≥0.87). The sensitivity of the index test of 1 neuroradiologist for 770 patients was 92.1% (95% CI, 89.7%-94.1%) and the specificity was 97.4% (95% CI, 93.4%-99.3%) compared with a sensitivity of 69.8% (95% CI, 66.0%-73.4%; P < .001) and a specificity of 98.0% (95% CI, 94.3%-99.6%; P > .99) according to the current criteria. For 88 patients, index test sensitivity (94.9%; 95% CI, 87.5%-98.6%) and specificity (100%; 95% CI, 66.4%-100%) were similar to those of improved RT-QuIC (86.1% [95% CI, 76.5%-92.8%] and 100% [95% CI, 66.4%-100%], respectively). Lower specificities were found for 14-3-3 and tau CSF tests in 452 patients. In this study, the diagnostic performance of diffusion MRI with the new criterion was superior to that of current standard criteria and similar to that of improved RT-QuIC. These results may have important clinical implications because MRI is noninvasive and typically prescribed at disease presentation.

Prion disease incidence in the United States: 2003-2015.

To report the incidence of prion disease in the United States. Prion disease decedents were retrospectively identified from the US national multiple cause-of-death data for 2003-2015 and matched with decedents in the National Prion Disease Pathology Surveillance Center (NPDPSC) database through comparison of demographic variables. NPDPSC decedents with neuropathologic or genetic test results positive for prion disease for whom no match was found in the multiple cause-of-death data were added as cases for incidence calculations; those with cause-of-death data indicating prion disease but with negative neuropathology results were removed. Age-specific and age-adjusted average annual incidence rates were then calculated. A total of 5,212 decedents were identified as having prion disease, for an age-adjusted average annual incidence of 1.2 cases per million population (range 1.0 per million [2004 and 2006] to 1.4 per million [2013]). The median age at death was 67 years. Ten decedents were <30 years of age (average annual incidence of 6.2 per billion); only 2 of these very young cases were sporadic forms of prion disease. Average annual incidence among those ≥65 years of age was 5.9 per million. Prion disease incidence can be estimated by augmenting mortality data with the results of neuropathologic and genetic testing. Cases <30 years of age were extremely rare, and most could be attributed to exogenous factors or the presence of a genetic mutation. Continued vigilance for prion diseases in all age groups remains prudent.

Co-occurrence of chronic traumatic encephalopathy and prion disease

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive traumatic brain injury (TBI). CTE is generally found in athletes participating in contact sports and military personnel exposed to explosive blasts but can also affect civilians. Clinically and pathologically, CTE overlaps with post-traumatic stress disorder (PTSD), a term mostly used in a clinical context. The histopathology of CTE is defined by the deposition of hyperphosphorylated tau protein in neurons and astrocytes preferentially with perivascular distribution and at the depths of the cortical sulci. In addition to hyperphosphorylated tau, other pathologic proteins are deposited in CTE, including amyloid β (Aβ), transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) and α-synuclein. However, the coexistence of prion disease in CTE has not been observed. We report three cases of histopathologically validated CTE with co-existing sporadic prion disease. Two were identified in a cohort of 55 pathologically verified cases of CTE submitted to the CTE Center of Boston University. One was identified among brain tissues submitted to the National Prion Disease Pathology Surveillance Center of Case Western Reserve University. The histopathological phenotype and properties of the abnormal, disease-related prion protein (PrPD) of the three CTE cases were examined using lesion profile, immunohistochemistry, electrophoresis and conformational tests. Subjects with sporadic Creutzfeldt-Jakob disease (sCJD) matched for age, PrP genotype and PrPD type were used as controls. The histopathology phenotype and PrPD properties of the three CTE subjects showed no significant differences from their respective sCJD controls suggesting that recurring neurotrauma or coexisting CTE pathology did not detectably impact the prion disease phenotype and PrPD conformational characteristics. Based on the reported incidence of sporadic prion disease, the detection of two cases with sCJD in the CTE Center series of 55 CTE cases by chance alone would be highly unlikely (p = 8.93*10− 6). Nevertheless, examination of a larger cohort of CTE is required to conclusively determine whether the risk of CJD is significantly increased in patients with CTE.

Rapidly Progressive Alzheimer's Disease inTwo Distinct Autopsy Cohorts.

A rapidly progressive phenotype of Alzheimer's disease (AD) has been described in some prion disease cohorts. Limited information regarding rapidly progressive AD (rpAD) is available from longitudinal national cohorts. To compare the clinical characteristics of rpAD in two different national cohorts. A retrospective analysis was performed on AD subjects with available neuropathology in the National Alzheimer's Coordinating Center (NACC) database and among neuropathologically characterized AD cases from the National Prion Disease Pathology Surveillance Center (NPDPSC) that were evaluated for suspected prion disease. In the NACC cohort, rpAD was delineated by the lower 10th percentile of follow up duration from pre-dementia to death duration among subjects meeting pathological diagnosis of AD. rpAD from the NPDPSC had a shorter mean symptom duration than the NACC identified rpAD cases (11.6 months versus 62.4 months) and were also younger at the time of their death (60.0 versus 81.8 years). NACC identified rpAD subjects, beginning from a predementia stage, had slower rate of MMSE change per year than NPDPSC cases (2.5 versus 6.0 points). rpAD constitute an important subset of AD subjects in whom a rapid course of symptomatic clinical decline is noted, as confirmed in both national cohorts. rpAD was best characterized by survival time (≤3 years), as there were clear differences between the rpAD cohorts in terms of symptom duration, age at death, and MMSE change per year, likely due to the strong selection biases. rpAD could shed light on the biology of rate of progression in AD.

A Practical Primer on Prion Pathology.

Prion diseases comprise a group of transmissible degenerative encephalopathies resulting from propagation of a misfolded cellular protein of uncertain function. As is generally the case with rare diseases, lack of institutional experience compromises individual familiarity with the varying, and apparently protean, manifestations of prion diseases, both clinically and pathologically. Coupled with the documented transmissibility of these diseases both within and between species, the Centers for Disease Control and Prevention (CDC) has established the National Prion Disease Pathology Surveillance Center to both aid with diagnosis of prion disease and to survey the United States for evidence of zoonotic transmission. We have assembled this primer with the hope that our accumulated experience will enable the neuropathological community to help the CDC "save lives and protect people."

FLORTAUCIPIR TAU-PET SPECIFICITY IS MAINTAINED IN PATIENTS WITH PATHOLOGICALLY CONFIRMED CREUTZFELDT-JAKOB DISEASE

[18F]AV-1451 (Flortaucipir) exhibits good specificity for binding neurofibrillary tangles (NFTs) in Alzheimer disease (AD). It is unknown whether this specificity is maintained in neurodegenerative diseases associated with profound neuronal lysis and elevations in soluble tau (i.e. Creutzfeldt-Jakob disease; CJD). [18F]AV-1451 PET neuroimaging was performed in 5 consecutive patients who presented with sporadic Creutzfeldt-Jakob disease (CJD). At autopsy, patients were evaluated for AD neuropathologic change (ADNC) and CJD (CJD subtyping performed by the National Prion Disease Pathology Surveillance Center, Case Western University; Cleveland, Ohio). Tauopathy was quantified by study authors blinded to imaging findings using anti-phosphorylated tau (PHF1) immunohistochemistry. [18F]AV-1451 retention was compared between CJD patients (median age, 66 [63–74] years) and amyloid-beta-negative cognitively normal (CN) controls (n=44; median age, 68 [63–74] years), and participants with very mild AD dementia (n=8; median age, 77 [63–90]). All CJD patients presented with rapidly progressive dementia leading to death within 9 months of symptom onset. The median interval from [18F]AV-1451 PET to autopsy was 4 (1–14) weeks. Restricted diffusion within the cortical ribbon and/or deep-gray structures, and elevations of CSF tau (median=6519; range=1528–13240 pg/mL) were observed in all cases, suggestive of rapid neuronal loss. No unique pattern of 18F-AV1451 retention was observed on visual inspection. Standardized uptake value ratios (SUVRs; referenced to cerebellar cortex; partial volume corrected) were summarized across known regions that are often affected in symptomatic AD dementia (i.e., amygdala, entorhinal, inferotemporal, and lateral occipital cortices). Summary SUVRs in CJD patients (1.17, 1.08–1.36) were indistinguishable from those observed in CN controls (1.14, 0.84–1.54; p=0.6), and well below levels measured in AD participants (2.23, 1.60–3.04; p=<0.01). Focal [18F]AV-1451 retention was observed within the temporal lobes of one CJD patient (1.45 standard units above the mean observed in CN controls; p=0.15; Fig. 1A). Microscopy demonstrated a moderately dense focus of NFTs within the temporal isocortex, in the context of Braak NFT stage I and low-level ADNC (A1B1C0; NIA-AA criteria). Flortaucipir retention was not seen in another case (Fig. 1B) with Braak NFT stage III and intermediate-level ADNC (A2B2C1/2).

FLORTAUCIPIR TAU-PET SPECIFICITY IS MAINTAINED IN PATIENTS WITH PATHOLOGICALLY CONFIRMED CREUTZFELDT-JAKOB DISEASE

[18F]AV-1451 (Flortaucipir) exhibits good specificity for binding neurofibrillary tangles (NFTs) in Alzheimer disease (AD). It is unknown whether this specificity is maintained in neurodegenerative diseases associated with profound neuronal lysis and elevations in soluble tau (i.e. Creutzfeldt-Jakob disease; CJD). [18F]AV-1451 PET neuroimaging was performed in 5 consecutive patients who presented with sporadic Creutzfeldt-Jakob disease (CJD). At autopsy, patients were evaluated for AD neuropathologic change (ADNC) and CJD (CJD subtyping performed by the National Prion Disease Pathology Surveillance Center, Case Western University; Cleveland, Ohio). Tauopathy was quantified by study authors blinded to imaging findings using anti-phosphorylated tau (PHF1) immunohistochemistry. [18F]AV-1451 retention was compared between CJD patients (median age, 66 [63–74] years) and amyloid-beta-negative cognitively normal (CN) controls (n=44; median age, 68 [63–74] years), and participants with very mild AD dementia (n=8; median age, 77 [63–90]). All CJD patients presented with rapidly progressive dementia leading to death within 9 months of symptom onset. The median interval from [18F]AV-1451 PET to autopsy was 4 (1–14) weeks. Restricted diffusion within the cortical ribbon and/or deep-gray structures, and elevations of CSF tau (median=6519; range=1528–13240 pg/mL) were observed in all cases, suggestive of rapid neuronal loss. No unique pattern of 18F-AV1451 retention was observed on visual inspection. Standardized uptake value ratios (SUVRs; referenced to cerebellar cortex; partial volume corrected) were summarized across known regions that are often affected in symptomatic AD dementia (i.e., amygdala, entorhinal, inferotemporal, and lateral occipital cortices). Summary SUVRs in CJD patients (1.17, 1.08–1.36) were indistinguishable from those observed in CN controls (1.14, 0.84–1.54; p=0.6), and well below levels measured in AD participants (2.23, 1.60–3.04; p=<0.01). Focal [18F]AV-1451 retention was observed within the temporal lobes of one CJD patient (1.45 standard units above the mean observed in CN controls; p=0.15; Fig. 1A). Microscopy demonstrated a moderately dense focus of NFTs within the temporal isocortex, in the context of Braak NFT stage I and low-level ADNC (A1B1C0; NIA-AA criteria). Flortaucipir retention was not seen in another case (Fig. 1B) with Braak NFT stage III and intermediate-level ADNC (A2B2C1/2).

The Case Files

The Case Files

Accuracy of administrative diagnostic data for pathologically confirmed cases of Creutzfeldt-Jakob disease in Massachusetts, 2000-2008

Creutzfeldt-Jakob disease (CJD) is a transmissible disorder that is monitored by public health authorities at the state and national levels in the United States. Little is known about the current accuracy and concurrence of CJD diagnoses across national and state sources of surveillance data. Using multiple sources, including the National Prion Disease Pathology Surveillance Center (NPDPSC) registry, we sought to identify all deceased Massachusetts patients with pathologically diagnosed CJD between 2000 and 2008. Pathologically verified CJD cases were then matched to their respective records in the Massachusetts hospital discharge and death certificate datasets. Using these data, we also aimed to estimate the sensitivity and specificity of death certificate diagnoses. Death certificate and hospital discharge dataset diagnoses of CJD combined accounted for 80% (35 of 44) of pathologically confirmed cases. The estimated sensitivity and specificity for death certificate diagnoses alone were 71% (27 of 38) and 75% (9 of 12), respectively. Death certificate diagnoses were less sensitive for pathologically confirmed CJD than reported previously. Increasing reliance on autopsy over biopsy and an expanding spectrum of health care delivery may be responsible for this discrepancy. The findings reported here underscore the value of using multiple mechanisms in national CJD surveillance.

Treatable neurological disorders misdiagnosed as Creutzfeldt‐Jakob disease

Heightened awareness of Creutzfeldt-Jakob disease (CJD) among physicians and the lay public has led to its frequent consideration in the differential diagnosis of patients with rapidly progressive dementia (RPD). Our goal was to determine which treatable disorders are most commonly mistaken for CJD. We performed a retrospective clinical and neuropathological review of prion-negative brain autopsy cases referred to the US National Prion Disease Pathology Surveillance Center at Case Western Reserve University from January 2006 through December 2009. Of 1,106 brain autopsies, 352 (32%) were negative for prion disease, 304 of which had adequate tissue for histopathological analysis. Alzheimer disease (n = 154) and vascular dementia (n = 36) were the 2 most frequent diagnoses. Seventy-one patients had potentially treatable diseases. Clinical findings included dementia (42 cases), pyramidal (n = 20), cerebellar (n = 14), or extrapyramidal (n = 12) signs, myoclonus (n = 12), visual disturbance (n = 9), and akinetic mutism (n = 5); a typical electroencephalogram occurred only once. Neuropathological diagnoses included immune-mediated disorders (n = 26), neoplasia (n = 25, most often lymphoma), infections (n = 14), and metabolic disorders (n = 6). In patients with RPD, treatable disorders should be considered and excluded before diagnosing CJD. Misdiagnosed patients often did not fulfill World Health Organization criteria. RPD with positive 14-3-3 cerebrospinal fluid protein should not be regarded as sufficient for the diagnosis of CJD. Adherence to revised criteria for CJD, which include distinctive magnetic resonance imaging features of prion disease, is likely to improve diagnostic accuracy.

Variably protease‐sensitive prionopathy: A new sporadic disease of the prion protein

The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with "variably protease-sensitive prionopathy" (VPSPr). None of the subjects had mutations in the PrP gene coding region. Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease.