RESUMEN
The current classification of sporadic Creutzfeldt-Jakob disease identifies six major subtypes mainly defined by the combination of the genotype at polymorphic codon 129 (methionine/M or valine/V) of the prion protein gene and the type (1 or 2) of misfolded prion protein accumulating in the brain (e.g. MM1, MM2, MV1, MV2, etc.). Here, we systematically characterized the clinical and histo-molecular features associated with the third prevalent subtype, the MV2 subtype with kuru plaques (MV2K), in the most extensive series collected to date. We evaluated neurological histories, cerebrospinal biomarkers, brain MRI and EEG results in 126 patients. The histo-molecular assessment included misfolded prion protein typing, standard histologic staining and immunohistochemistry for prion protein in several brain areas. We also investigated the prevalence and topographic extent of coexisting MV2-cortical features, the number of cerebellar kuru plaques and their effect on clinical phenotype. Systematic regional typing revealed a western blot profile of misfolded prion protein comprising a doublet of 19 and 20 kDa unglycosylated fragments, with the former more prominent in neocortices and the latter in the deep grey nuclei. The 20/19 kDa fragment ratio positively correlated with the number of cerebellar kuru plaques. The mean disease duration was exceedingly longer than in the typical MM1 subtype (18.0 versus 3.4 months). Disease duration correlated positively with the severity of pathologic change and the number of cerebellar kuru plaques. At the onset and early stages, patients manifested prominent, often mixed, cerebellar symptoms and memory loss, variably associated with behavioural/psychiatric and sleep disturbances. The cerebrospinal fluid prion real-time quaking-induced conversion assay was positive in 97.3% of cases, while 14-3-3 protein and total-tau positive tests were 52.6 and 75.9%. Brain diffusion-weighted MRI showed hyperintensity of the striatum, cerebral cortex and thalamus in 81.4, 49.3 and 33.8% of cases, and a typical profile in 92.2%. Mixed histotypes (MV2K + MV2-cortical) showed an abnormal cortical signal more frequently than the pure MV2K (64.7 versus 16.7%, P = 0.007). EEG revealed periodic sharp-wave complexes in only 8.7% of participants. These results further establish MV2K as the most common 'atypical' subtype of sporadic Creutzfeldt-Jakob disease, showing a clinical course that often challenges the early diagnosis. The plaque-type aggregation of the misfolded prion protein accounts for most of the atypical clinical features. Nonetheless, our data strongly suggest that the consistent use of the real-time quaking-induced conversion assay and brain diffusion-weighted MRI allows an accurate early clinical diagnosis in most patients.
Asunto(s)
Síndrome de Creutzfeldt-Jakob , Kuru , Neocórtex , Priones , Humanos , Síndrome de Creutzfeldt-Jakob/diagnóstico por imagen , Síndrome de Creutzfeldt-Jakob/genética , Kuru/metabolismo , Kuru/patología , Proteínas Priónicas/genética , Proteínas Priónicas/metabolismo , Encéfalo/patología , Priones/genética , Fenotipo , Neocórtex/patologíaRESUMEN
We investigated the biomarker profile of neurodegeneration, Alzheimer's and Lewy body pathology in the CSF of 148 polysomnography-confirmed patients with isolated REM sleep behavior disorder (IRBD), a condition that precedes Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We assessed misfolded α-synuclein (AS) by RT-QuIC assay, amyloid-beta peptides (Aß42 and Aß40), phosphorylated tau (p-tau), and total tau (t-tau) by CLEIA and neurofilament light chain (NfL) by ELISA. We detected AS in 75.3% of patients, pathologically decreased Aß42/Aß40 ratio in 22.5%, increased p-tau in 15.5%, increased t-tau in 14.9%, and elevated NfL in 14.7%. After a mean follow-up of 2.48 ± 2.75 years, 47 (38.1%) patients developed PD (n = 24) or DLB (n = 23). At CSF collection, AS positivity [HR 4.05 (1.26-12.99), p = 0.019], mild cognitive impairment [3.86 (1.96-7.61), p < 0.001], and abnormal DAT-SPECT [2.31 (1.09-4.91), p < 0.030] were independent predictors of conversion to PD and DLB. Among the other CSF markers, only elevated p-tau/Aß42 was predictive of conversion, although only to DLB and not as an independent variable. In IRBD, CSF AS assessment by RT-QuIC provides an added value in defining the risk of short-term conversion to PD and DLB independent of clinical and instrumental investigations. Positive Alzheimer's disease (AD) pathology markers and elevated NfL occur in a subgroup of patients, but p-tau/Aß42 is the only marker that predicts short-term conversion to DLB. Longer follow-up is needed to assess if AD biomarkers predict the later development of PD and DLB in IRBD.
RESUMEN
BACKGROUND AND OBJECTIVES: Real-time quaking-induced conversion (RT-QuIC) assay detects misfolded α-synuclein (AS) in the skin and CSF of patients with the synucleinopathies Parkinson disease and dementia with Lewy bodies. Isolated REM sleep behavior disorder (IRBD) constitutes the prodromal stage of these synucleinopathies. We aimed to compare the ability of RT-QuIC to identify AS in the skin and CSF of patients with IRBD. METHODS: This was a cross-sectional study where consecutive patients with polysomnographic-confirmed IRBD and age-matched controls without RBD underwent skin biopsy and lumbar puncture the same day. Three-millimeter skin punch biopsies were obtained bilaterally in the cervical region from dorsal C7 and C8 dermatomes and in distal legs. RT-QuIC assessed AS in these 6 skin sites and the CSF. RESULTS: We recruited 91 patients with IRBD and 41 controls. In the skin, sensitivity to detect AS was 76.9% (95% CI 66.9-85.1), specificity 97.6% (95% CI 87.1-99.9) positive predictive value 98.6% (95% CI 91.0-99.8), negative predictive value 65.6% (95% CI 56.6-73.6), and accuracy 83.3% (95% CI 75.9-89.3). In the CSF, the sensitivity was 75.0% (95% CI 64.6-83.6), the specificity was 97.5% (95% CI 86.8-99.9), the positive predictive value was 98.5% (95% CI 90.5-99.8), the negative predictive value was 63.9% (95% CI 55.2-71.9), and the accuracy was 82.0% (95% CI 74.3-88.3). Results in the skin and CSF samples showed 99.2% agreement. Compared with negative patients, RT-QuIC AS-positive patients had a higher likelihood ratio of prodromal Parkinson disease (p < 0.001) and showed more frequently hyposmia (p < 0.001), dopamine transporter imaging single-photon emission CT deficit (p = 0.002), and orthostatic hypotension (p = 0.014). No severe or moderate adverse effects were reported. There was no difference between the percentage of participants reporting mild adverse events secondary to skin biopsy or lumbar puncture (9.1% vs 17.2%; p = 0.053). One hundred and ten (83%) and 104 (80%) participants, respectively, stated they would accept to undergo skin biopsy and lumbar puncture again for research purposes. DISCUSSION: Our study in IRBD shows that (1) RT-QuIC detects AS in the skin and CSF with similar high sensitivity, specificity, and agreement, (2) AS RT-QuIC positivity is associated with supportive features and biomarkers of synucleinopathy, and (3) skin punch biopsy and lumbar puncture have comparable mild adverse effects, tolerance, and acceptance. RT-QuIC in the skin or CSF might represent a patient selection strategy for future neuroprotective trials targeting AS in IRBD. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that RT-QuIC-detected AS in the skin and CSF distinguishes patients with IRBD from controls.
Asunto(s)
Enfermedad de Parkinson , Trastorno de la Conducta del Sueño REM , Sinucleinopatías , Humanos , alfa-Sinucleína , Sinucleinopatías/diagnóstico , Trastorno de la Conducta del Sueño REM/diagnóstico , Estudios TransversalesRESUMEN
There is poor knowledge about the clinical effects of Lewy body (LB) pathology in patients with cognitive impairment, especially when coexisting with Alzheimer's disease (AD) pathology (amyloid-ß and tau). Using a seed amplification assay, we analyzed cerebrospinal fluid for misfolded LB-associated α-synuclein in 883 memory clinic patients with mild cognitive impairment or dementia from the BioFINDER study. Twenty-three percent had LB pathology, of which only 21% fulfilled clinical criteria of Parkinson's disease or dementia with Lewy bodies at baseline. Among these LB-positive patients, 48% had AD pathology. Fifty-four percent had AD pathology in the whole sample (17% of mild cognitive impairment and 24% of patients with dementia were also LB-positive). When examining independent cross-sectional effects, LB pathology but not amyloid-ß or tau, was associated with hallucinations and worse attention/executive, visuospatial and motor function. LB pathology was also associated with faster longitudinal decline in all examined cognitive functions, independent of amyloid-ß, tau, cognitive stage and a baseline diagnosis of dementia with Lewy bodies/Parkinson's disease. LB status provides a better precision-medicine approach to predict clinical trajectories independent of AD biomarkers and a clinical diagnosis, which could have implications for the clinical management of cognitive impairment and the design of AD and LB drug trials.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Humanos , Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/diagnóstico , Enfermedad por Cuerpos de Lewy/patología , Enfermedad de Parkinson/patología , Estudios Transversales , Enfermedad de Alzheimer/patología , Disfunción Cognitiva/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeoRESUMEN
α-Synuclein aggregates constitute the pathology of Lewy body (LB) disease. Little is known about the effects of LB pathology in preclinical (presymptomatic) individuals, either as isolated pathology or coexisting with Alzheimer's disease (AD) pathology (ß-amyloid (Aß) and tau). We examined the effects of LB pathology using a cerebrospinal fluid α-synuclein-seed amplification assay in 1,182 cognitively and neurologically unimpaired participants from the BioFINDER study: 8% were LB positive, 26% Aß positive (13% of those were LB positive) and 16% tau positive. LB positivity occurred more often in the presence of Aß positivity but not tau positivity. LB pathology had independently negative effects on cross-sectional and longitudinal global cognition and memory and on longitudinal attention/executive function. Tau had cognitive effects of a similar magnitude, but these were less pronounced for Aß. Participants with both LB and AD (Aß and tau) pathology exhibited faster cognitive decline than those with only LB or AD pathology. LB, but not AD, pathology was associated with reduced sense of smell. Only LB-positive participants progressed to clinical LB disease over 10 years. These results are important for individualized prognosis, recruitment and choice of outcome measures in preclinical LB disease trials, but also for the design of early AD trials because >10% of individuals with preclinical AD have coexisting LB pathology.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad por Cuerpos de Lewy , Humanos , alfa-Sinucleína , Cuerpos de Lewy/patología , Proteínas tau/líquido cefalorraquídeo , Estudios Transversales , Enfermedad de Alzheimer/patología , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Enfermedad por Cuerpos de Lewy/complicaciones , Enfermedad por Cuerpos de Lewy/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Cognición , Disfunción Cognitiva/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Tomografía de Emisión de PositronesRESUMEN
BACKGROUND: Increasing evidence supports the use of plasma biomarkers of neurodegeneration and neuroinflammation to screen and diagnose patients with dementia. However, confirmatory studies are required to demonstrate their usefulness in the clinical setting. METHODS: We evaluated plasma and cerebrospinal fluid (CSF) samples from consecutive patients with frontotemporal dementia (FTD) (n = 59), progressive supranuclear palsy (PSP) (n = 31), corticobasal syndrome (CBS) (n = 29), dementia with Lewy bodies (DLB) (n = 49), Alzheimer disease (AD) (n = 97), and suspected non-AD physiopathology (n = 51), as well as plasma samples from 60 healthy controls (HC). We measured neurofilament light chain (NfL), phospho-tau181 (p-tau181), and glial fibrillary acid protein (GFAP) using Simoa (all plasma biomarkers and CSF GFAP), CLEIA (CSF p-tau181), and ELISA (CSF NfL) assays. Additionally, we stratified patients according to the A/T/N classification scheme and the CSF α-synuclein real-time quaking-induced conversion assay (RT-QuIC) results. RESULTS: We found good correlations between CSF and plasma biomarkers for NfL (rho = 0.668, p < 0.001) and p-tau181 (rho = 0.619, p < 0.001). Plasma NfL was significantly higher in disease groups than in HC and showed a greater increase in FTD than in AD [44.9 (28.1-68.6) vs. 21.9 (17.0-27.9) pg/ml, p < 0.001]. Conversely, plasma p-tau181 and GFAP levels were significantly higher in AD than in FTD [3.2 (2.4-4.3) vs. 1.1 (0.7-1.6) pg/ml, p < 0.001; 404.7 (279.7-503.0) vs. 198.2 (143.9-316.8) pg/ml, p < 0.001]. GFAP also allowed discriminating disease groups from HC. In the distinction between FTD and AD, plasma p-tau181 showed better accuracy (AUC 0.964) than NfL (AUC 0.791) and GFAP (AUC 0.818). In DLB and CBS, CSF amyloid positive (A+) subjects had higher plasma p-tau181 and GFAP levels than A- individuals. CSF RT-QuIC showed positive α-synuclein seeding activity in 96% DLB and 15% AD patients with no differences in plasma biomarker levels in those stratified by RT-QuIC result. CONCLUSIONS: In a single-center clinical cohort, we confirm the high diagnostic value of plasma p-tau181 for distinguishing FTD from AD and plasma NfL for discriminating degenerative dementias from HC. Plasma GFAP alone differentiates AD from FTD and neurodegenerative dementias from HC but with lower accuracy than p-tau181 and NfL. In CBS and DLB, plasma p-tau181 and GFAP levels are significantly influenced by beta-amyloid pathology.
Asunto(s)
Enfermedad de Alzheimer , Demencia Frontotemporal , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Demencia Frontotemporal/líquido cefalorraquídeo , Demencia Frontotemporal/diagnóstico , Proteína Ácida Fibrilar de la Glía , Humanos , alfa-Sinucleína , Proteínas tau/líquido cefalorraquídeoRESUMEN
BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a clinico-radiological syndrome of elderly individuals likely sustained by different neurodegenerative changes as copathologies. Since iNPH is a potentially reversible condition, assessing neurodegenerative pathologies in vitam through CSF biomarkers and their influence on clinical features and surgical outcome represents crucial steps. METHODS: We measured α-synuclein seeding activity related to Lewy body (LB) pathology by the real-time quaking-induced conversion assay (RT-QuIC) and Alzheimer disease core biomarkers (proteins total-tau, phospho-tau, and amyloid-beta) by immunoassays in the cerebrospinal fluid (CSF) of 293 iNPH patients from two independent cohorts. To compare the prevalence of LB copathology between iNPH participants and a control group representative of the general population, we searched for α-synuclein seeding activity in 89 age-matched individuals who died of Creutzfeldt-Jakob disease (CJD). Finally, in one of the iNPH cohorts, we also measured the CSF levels of neurofilament light chain protein (NfL) and evaluated the association between all CSF biomarkers, baseline clinical features, and surgery outcome at 6 months. RESULTS: Sixty (20.5%) iNPH patients showed α-synuclein seeding activity with no significant difference between cohorts. In contrast, the prevalence observed in CJD was only 6.7% (p = 0.002). Overall, 24.0% of iNPH participants showed an amyloid-positive (A+) status, indicating a brain co-pathology related to Aß deposition. At baseline, in the Italian cohort, α-synuclein RT-QuIC positivity was associated with higher scores on axial and upper limb rigidity (p = 0.003 and p = 0.011, respectively) and lower MMSEc scores (p = 0.003). A+ patients showed lower scores on the MMSEc (p = 0.037) than A- patients. Higher NfL levels were also associated with lower scores on the MMSEc (rho = -0.213; p = 0.021). There were no significant associations between CSF biomarkers and surgical outcome at 6 months (i.e. responders defined by decrease of 1 point on the mRankin scale). CONCLUSIONS: Prevalent LB- and AD-related neurodegenerative pathologies affect a significant proportion of iNPH patients and contribute to cognitive decline (both) and motor impairment (only LB pathology) but do not significantly influence the surgical outcome at 6 months. Their effect on the clinical benefit after surgery over a more extended period remains to be determined.
Asunto(s)
Péptidos beta-Amiloides , Hidrocéfalo Normotenso , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Humanos , Hidrocéfalo Normotenso/líquido cefalorraquídeo , Hidrocéfalo Normotenso/epidemiología , Hidrocéfalo Normotenso/cirugía , Cuerpos de Lewy , Fragmentos de Péptidos/líquido cefalorraquídeo , Prevalencia , alfa-Sinucleína , Proteínas tau/líquido cefalorraquídeoRESUMEN
The methionine (M)-valine (V) polymorphic codon 129 of the prion protein gene (PRNP) plays a central role in both susceptibility and phenotypic expression of sporadic Creutzfeldt-Jakob diseases (sCJD). Experimental transmissions of sCJD in humanized transgenic mice led to the isolation of five prion strains, named M1, M2C, M2T, V2, and V1, based on two major conformations of the pathological prion protein (PrPSc, type 1 and type 2), and the codon 129 genotype determining susceptibility and propagation efficiency. While the most frequent sCJD strains have been described in codon 129 homozygosis (MM1, MM2C, VV2) and heterozygosis (MV1, MV2K, and MV2C), the V1 strain has only been found in patients carrying VV. We identified six sCJD cases, 4 in Catalonia and 2 in Italy, carrying MV at PRNP codon 129 in combination with PrPSc type 1 and a new clinical and neuropathological profile reminiscent of the VV1 sCJD subtype rather than typical MM1/MV1. All patients had a relatively long duration (mean of 20.5 vs. 3.5 months of MM1/MV1 patients) and lacked electroencephalographic periodic sharp-wave complexes at diagnosis. Distinctive histopathological features included the spongiform change with vacuoles of larger size than those seen in sCJD MM1/MV1, the lesion profile with prominent cortical and striatal involvement, and the pattern of PrPSc deposition characterized by a dissociation between florid spongiform change and mild synaptic deposits associated with coarse, patch-like deposits in the cerebellar molecular layer. Western blot analysis of brain homogenates revealed a PrPSc type 1 profile with physicochemical properties reminiscent of the type 1 protein linked to the VV1 sCJD subtype. In summary, we have identified a new subtype of sCJD with distinctive clinicopathological features significantly overlapping with those of the VV1 subtype, possibly representing the missing evidence of V1 sCJD strain propagation in the 129MV host genotype.