SQSTM1 Pro392Leu presenting as a corticobasal syndrome with progressive nonfluent aphasia.

Corticobasal syndrome is generally considered to be a sporadic condition. There are familial and isolated genetic cases, associated with GRN, MAPT, c9orf72 or PNRP variants. Some reports implicate other genes: LRRK2, CHMP2B, GBA, CYP27A1, PSEN1, APP, TARDBP and TBK1. Here, we report a case of a patient carrying a SQSTM1 Pro392Leu variant. We report a 57-year-old right-handed-woman with a history of progressive speech impairment, marked right side rigidity and bradykinesia, with rest tremor and stimulus sensitive myoclonus. She had predominantly right-sided apraxia. She had right side agraphestesia and astereognosis. MRI showed asymmetrical left frontotemporoparietal atrophy. DaTSCAN showed predominantly left involvement, PiB-PET was negative. CSF NfL was of 9356.5pg/mL. She carried a heterozygous variant P392L in SQSTM1. This case report expands the spectrum of phenotypes associated with SQSTM1 pathogenic variants. It also expands the list of genes associated with corticobasal syndrome, supporting the involvement of the ubiquitin-proteasome system in this condition.

Towards a neurocognitive profile in familial cerebral cavernous malformations.

BACKGROUND: Familial cerebral cavernous malformations (FCCM) is a rare autosomal dominant disease, characterized by vascular malformations that can lead to macro and microhemorrhages. The neurocognitive impact of FCCM is still underrecognized. METHODS: We report the clinical, neurocognitive, imaging and genetic data of a three generation family with FCCM. RESULTS: A 63-year-old man (proband) had progressive memory impairment since the last year. Neurologic exam was unremarkable. Brain MRI showed multiple large cavernomas (mainly in the pons, left temporal, and right temporo-parietal) and scattered microhemorrhages. Neuropsychological assessment mainly revealed left frontal and right temporo-parietal dysfunction. A 41-year-old daughter, presented with headache, vertigo and memory complaints in the last 2 years. Neurological examination revealed left central facial paralysis. Brain MRI showed two small right parietal and internal capsule cavernomas, as well as microhemorrhages. Neuropsychological assessment showed moderate temporal neocortical left dysfunction. A 34-year-old daughter had recurrent headache and memory complaints, with unremarkable neurological exam. Brain MRI revealed two large cavernomas (left fronto-orbitary and inferior temporal), with few microhemorrhages. Neuropsychological assessment was normal. A granddaughter had mild headaches and a small right cerebellar cavernoma, without microhemorrhages. Neuropsychological assessment showed mild temporal neocortical left dysfunction. A nonsense variant, c.55C > T; p.R19* generating a premature stop codon in CCM2 gene shared by all affected family members was identified. CONCLUSIONS: Neuropsychological evaluation showed that memory complaints and cognitive impairment could be an important unrecognized finding in FCCM. Its pathophysiological mechanisms are still unknown but the role of recurrent microhemorrhages could provide an interesting hypothesis.

Montreal Cognitive Assessment in Mild Cognitive Impairment: Relationship with Cerebrospinal Fluid Biomarkers and Conversion to Dementia.

BACKGROUND: Mild cognitive impairment (MCI) is considered a prodromal state of dementia. Abnormal values of cerebrospinal fluid Alzheimer's disease biomarkers (CSF-AD-b) have been associated with a higher risk of conversion to dementia (due to Alzheimer's disease), but studies evaluating the ability of Montreal Cognitive Assessment (MoCA) in this task are lacking. OBJECTIVE: This study aims to investigate the relationship between MoCA and CSF-AD-b, as well as the ability of those tools to predict conversion to dementia. METHODS: Taking advantage of our MCI cohort with biological characterization on longitudinal follow-up (180 patients followed for 62.6 months during which 41.3% converted), we computed MoCA and MMSE z-scores, using Portuguese normative data. The performance in MoCA z-score was correlated with CSF-AD-b and the relative time to conversion and risk according to baseline characteristics were analyzed using Kaplan-Meier analysis and Cox regression models. RESULTS: MoCA z-scores were correlated with Aß42 (p = 0.026), t-tau (p = 0.033), and p-tau (p = 0.01). Impaired MMSE (p < 0.001) and MoCA z-scores (p = 0.019), decreased Aß42 (p < 0.001) and increased t-tau (p < 0.001) and p-tau (p < 0.001) were associated with shorter estimated time of conversion. Aß42 (p < 0.001) and MMSE z-scores (p = 0.029) were independent predictors of conversion. For those with at least 9 years of education, MoCA z-score (p = 0.004) (but not MMSE) was an independent predictor of conversion as well as Aß42. CONCLUSIONS: This study confirms the role of CSF-AD-b, namely Aß42, in predicting conversion from MCI to dementia and suggests the utility of MoCA in predicting conversion in highly educated subjects, supporting its use in the evaluation of MCI patients.

Establishing a HOPE Program in a Real-life Setting: A Brazilian Case Series.

Background: Although hypothermic oxygenated perfusion (HOPE) improves posttransplant outcomes, setting up machine perfusion programs may be subjected to specific obstacles under different conditions. This study aims to describe the establishment of HOPE in a real-life setting in Brazil. Methods: Extended criteria donors in donation after brain death organs preserved by HOPE were accepted for higher-risk candidates needing expedited transplantation, perceived as those who would benefit most from the technique because of its limited availability. Extended criteria donors was defined by the Eurotransplant criteria. High-risk transplant candidates were characterized by suboptimal surgical conditions related to the recipient or the procedure. Results: Six HOPE-preserved grafts were transplanted from February 2022 to August 2022. The mean donor risk index was 1.7 (SD 0.5). One organ was severely steatotic, and 3 had an anticipated cold ischemia time above 12 h. Recipients' mean model for end-stage liver disease was 28.67 (SD 6.79), with 1 case of retransplant, 1 of refractory ascites, and 1 of acute-on-chronic liver failure. The mean cold ischemia time was 5 h 42 min (SD 82 min), HOPE 6 h 3 min (SD 150 min), and total preservation time 11 h 46 min (SD 184 min). No case had early allograft dysfunction. The mean length of hospital stay was 10 d with 100% graft and patient survival and no ischemic cholangiopathies at a median follow-up of 15 mo (min 12, max 18). Costs and country-specific legal regulations for device utilization were the major hurdles to implementing the program. Conclusion: We presented a pathway to introduce and rationalize the use of HOPE in a scenario of challenging donor-recipient matching with good results. These findings may aid in implementing machine perfusion programs, especially in settings with limited resources or complex transplant logistics.

Serum Neurofilament Light Chain in the Diagnostic Evaluation of Patients with Cognitive Symptoms in the Neurological Consultation of a Tertiary Center.

Serum light-chain neurofilaments (sNfL) have been investigated as a potential minimally invasive biomarker that could help in the diagnosis of patients with cognitive symptoms. We assessed the correlation between sNfL and cerebrospinal fluid (CSF) biomarkers (sNfL versus CSF NfL, ρ= 0.70, p < 0.001), the performance of sNfL in distinguishing controls from patients (controls versus frontotemporal dementia, area under curve 0.86), and sNfL differences in mild cognitive impairment according to amyloid-ß (Aß) deposition (Aß versus non-Aß, p = 0.017). Our results support the role of this biomarker in the screening and risk stratification of patients followed in a neurological consultation of a tertiary center.

Genomics and Antimicrobial Susceptibility of Clinical Pseudomonas aeruginosa Isolates from Hospitals in Brazil.

Pseudomonas aeruginosa, an opportunistic pathogen causing infections in immunocompromised patients, usually shows pronounced antimicrobial resistance. In recent years, the frequency of carbapenemases in P. aeruginosa has decreased, which allows use of new beta-lactams/combinations in antimicrobial therapy. Therefore, the in vitro evaluation of these drugs in contemporary isolates is warranted. We evaluated the antimicrobial susceptibility and genomic aspects of 119 clinical P. aeruginosa isolates from 24 different hospitals in Brazil in 2021-2022. Identification was performed via MALDI-TOF-MS, and antimicrobial susceptibility was identified through broth microdilution, gradient tests, or disk diffusion. Whole-genome sequencing was carried out using NextSeq equipment. The most active drug was cefiderocol (100%), followed by ceftazidime-avibactam (94.1%), ceftolozane-tazobactam (92.4%), and imipenem-relebactam (81.5%). Imipenem susceptibility was detected in 59 isolates (49.6%), and the most active aminoglycoside was tobramycin, to which 99 (83.2%) isolates were susceptible. Seventy-one different sequence types (STs) were detected, including twelve new STs described herein. The acquired resistance genes blaCTX-M-2 and blaKPC-2 were identified in ten (8.4%) and two (1.7%) isolates, respectively. Several virulence genes (exoSTUY, toxA, aprA, lasA/B, plcH) were also identified. We found that new antimicrobials are effective against the diverse P. aeruginosa population that has been circulating in Brazilian hospitals in recent years.

Eleven hours of hypothermic oxygenated machine perfusion (HOPE) for complex liver retransplantation: A case report.

This case report describes the longest reported HOPE treatment ever for an extended criteria donor organ in donation after brain death performed to enable the transplantation of a surgically complex retransplant case. Although further evidence is required, HOPE may facilitate liver retransplantation, expanding the donor organ pool and reducing time constraints on the operation.

Blood biomarkers in mild cognitive impairment patients: Relationship between analytes and progression to Alzheimer disease dementia.

BACKGROUND AND PURPOSE: Blood-based biomarkers are promising tools for the diagnosis of Alzheimer disease (AD) at prodromal stages (mild cognitive impairment [MCI]) and are hoped to be implemented as screening tools for patients with cognitive complaints. In this work, we evaluated the potential of peripheral neurological biomarkers to predict progression to AD dementia and the relation between blood and cerebrospinal fluid (CSF) AD markers in MCI patients referred from a general neurological department. METHODS: A group of 106 MCI patients followed at the Neurology Department of Coimbra University Hospital was included. Data regarding baseline neuropsychological evaluation, CSF levels of amyloid ß 42 (Aß42), Aß40, total tau (t-Tau), and phosphorylated tau 181 (p-Tau181) were available for all the patients. Aß42, Aß40, t-Tau, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) levels were determined in baseline stored serum and plasma samples by commercial SiMoA (Single Molecule Array) assays. Progression from MCI to AD dementia was assessed at follow-up (mean = 5.8 ± 3.4 years). RESULTS: At baseline, blood markers NfL, GFAP, and p-Tau181 were significantly increased in patients who progressed to AD at follow-up (p < 0.001). In contrast, plasma Aß42/40 ratio and t-Tau showed no significant differences between groups. NfL, GFAP, and p-Tau181 demonstrated good diagnostic accuracy to identify progression to AD dementia (area under the curve [AUC] = 0.81, 0.80, and 0.76, respectively), which improved when combined (AUC = 0.89). GFAP and p-Tau181 were correlated with CSF Aß42. Association of p-Tau181 with NfL was mediated by GFAP, with a significant indirect association of 88% of the total effect. CONCLUSIONS: Our findings highlight the potential of combining blood-based GFAP, NfL, and p-Tau181 to be applied as a prognostic tool in MCI.

Neuropsychological Assessment in the Distinction Between Biomarker Defined Frontal-Variant of Alzheimer's Disease and Behavioral-Variant of Frontotemporal Dementia.

BACKGROUND: Frontal-variant of Alzheimer's disease (fvAD) was purposed for patients with AD pathology that, despite the typical amnestic presentation, show early and progressive deterioration of behavior and executive functions, closely resembling the behavioral-variant of frontotemporal dementia (bvFTD). This leads to a challenging differential diagnosis where neuropsychological evaluation and in vivo pathological evidence are essential. OBJECTIVE: To evaluate the contribution of a comprehensive neuropsychological assessment (NP) battery in distinguishing between fvAD-dementia and bvFTD supported by cerebrospinal fluid (CSF) biomarkers. METHODS: We included 40 patients with a baseline NP profile with prominent early executive and/or behavioral dysfunction, who meet both diagnosis of bvFTD and fvAD-dementia, according to international criteria. All patients underwent comprehensive NP assessment and CSF-AD biomarker evaluation. Neuropsychological domains as well as clinical and sociodemographic features, and APOE genotype were compared between groups. RESULTS: 21 patients (52.5%) met the biological criteria for AD (decreased Aß42 together with increased T-tau or P-tau in CSF) and were therefore classified as fvAD (mean age was 64.57, with 47.6% female). There were no differences between groups regarding age/age-at-onset, gender, or educational level. Regarding neuropsychological profile, performances in language and memory functions were equivalent in both groups. Significant differences were found in visuo-constructional abilities (p = 0.004), Trail Making Test A (p < 0.001), and Raven's Colored Progressive Matrices (p = 0.019), with fvAD patients showing worst performances. CONCLUSION: In patients with an early prominent frontal profile, a higher impairment in attention and visuo-spatial functions, signaling additional right hemisphere fronto-parietal dysfunction, point towards a diagnosis of fvAD-dementia and may be useful in clinical practice.

Toulouse-Piéron Cancellation Test: Normative scores for the portuguese population.

The Toulouse-Piéron Cancelation Test (TP) is a classic psychometric tool for the assessment of selective/sustained attention, processing speed and visuo-perceptual abilities. It is commonly used in neurological disorders such as epilepsy, multiple sclerosis or Alzheimer's disease. It encompasses two main indexes: Work-Efficiency (WE) and Dispersion-Index (DI). The aim of this study is to provide normative scores for the TP in a sample of Portuguese healthy adults. The TP was administered to a convenience sample of 357 cognitively-dwelling subjects aged between [45 and 86] years old, following a standard assessment protocol. The normative scores were adjusted for age and education. Education was the main predictor of TP-WE (R2 = .310), whereas the influence of age on this score was lower (R2 = .191). These two variables explained 50.1% of the variance of the results. Regarding TP-DI, education was also the main predictor of the results (R2 = .039), whereas age was responsible for R2 = .011 and together, they explained 5% of the variance of TP-DI. TP performances are strongly influenced by age and education. This is the first study focused on the establishment of normative data after the age of 45 in the Portuguese population, allowing a reliable assessment in both clinical and research contexts.

Characterization of Progranulin Gene Mutations in Portuguese Patients with Frontotemporal Dementia.

In Portugal, heterozygous loss-of-function mutations in the progranulin (GRN) gene account for approximately half of the genetic mediated forms of frontotemporal dementia (FTD). GRN mutations reported thus far cause FTD through a haploinsufficiency disease mechanism. Herein, we aim to unveil the GRN mutation spectrum, investigated in 257 FTD patients and 19 family members from the central/north region of Portugal using sequencing methods. Seven different pathogenic variants were identified in 46 subjects including 40 patients (16%) and 6 relatives (32%). bvFTD was the most common clinical presentation among the GRN mutation patients, who showed a global pattern of moderate-to-severe frontotemporoparietal deficits in the neuropsychological evaluation. Interestingly, two mutations were novel (p.Thr238Profs*18, p.Leu354Profs*16), and five were previously described, although three of them only in the Portuguese population, suggesting a population-specific GRN mutational spectrum. The subjects harboring a GRN mutation showed a significant reduction in serum PGRN levels, supporting the pathogenic nature of these variants. This work broadens the mutation spectrum of GRN and the identification of the underlying GRN mutations provided an accurate genetic counselling and allowed the enrolment of subjects with GRN mutations (both asymptomatic and symptomatic) in ongoing clinical trials, which is essential to test new drugs for the disease.

Portuguese version of the CDR plus NACC FTLD: Validation studies.

Introduction: The CDR Dementia Staging Instrument PLUS National Alzheimer's Coordinating Center (CDR plus NACC FTLD) was developed by adding to the standard CDR two extra domains focused on the main features of frontotemporal lobar degeneration (FTLD): language and behavior/personality. We intended to perform the validation studies for the European-Portuguese population. Methods: A total of 105 participants matched for age, education, and disease staging (35 bvFTD, 35 AD, and 35 controls) were included. A translated-version of the CDR and the two added domains was administered by a neuropsychologist who was blinded to the diagnosis. Results: The bvFTD group had higher baseline CDR plus NACC FTLD scores compared to the AD and controls. Only the sum-of-boxes (SB) score, the behavior/personality, and language domains were able to distinguish between clinical groups. Logistic regression analyses showed that adding the behavior/personality domain with or without language significantly enhanced the discriminating ability. Discussion: Results show that the CDR plus NACC FTLD is a reliable tool in the diagnostic process of bvFTD patients and has an added value in distinguishing them from patients with AD.

Alzheimer's Disease Diagnosis Based on the Amyloid, Tau, and Neurodegeneration Scheme (ATN) in a Real-Life Multicenter Cohort of General Neurological Centers.

BACKGROUND: The ATN scheme was proposed as an unbiased biological characterization of the Alzheimer's disease (AD) spectrum, grouping biomarkers into three categories: brain Amyloidosis-A, Tauopathy-T, Neurodegeneration-N. Although this scheme was mainly recommended for research, it is relevant for diagnosis. OBJECTIVE: To evaluate the ATN scheme performance in real-life cohorts reflecting the inflow of patients with cognitive complaints and different underlying disorders in general neurological centers. METHODS: We included patients (n = 1,128) from six centers with their core cerebrospinal fluid-AD biomarkers analyzed centrally. A was assessed through Aß42/Aß40, T through pTau-181, and N through tTau. Association between demographic features, clinical diagnosis at baseline/follow-up and ATN profiles was assessed. RESULTS: The prevalence of ATN categories was: A-T-N-: 28.3%; AD continuum (A + T-/+N-/+): 47.8%; non-AD (A- plus T or/and N+): 23.9%. ATN profiles prevalence was strongly influenced by age, showing differences according to gender, APOE genotype, and cognitive status. At baseline, 74.6% of patients classified as AD fell in the AD continuum, decreasing to 47.4% in mild cognitive impairment and 42.3% in other neurodegenerative conditions. At follow-up, 41% of patients changed diagnosis, and 92% of patients that changed to AD were classified within the AD continuum. A + was the best individual marker for predicting a final AD diagnosis, and the combinations A + T+ (irrespective of N) and A + T+N+ had the highest overall accuracy (83%). CONCLUSION: The ATN scheme is useful to guide AD diagnosis in real-life neurological centers settings. However, it shows a lack of accuracy for patients with other types of dementia. In such cases, the inclusion of other markers specific for non-AD proteinopathies could be an important aid to the differential diagnosis.

Co-production of Classes A and B Carbapenemases BKC-1 and VIM-2 in a Clinical Pseudomonas Putida Group Isolate from Brazil.

Emergence of resistance to classical antimicrobial agents is a public health issue, especially in countries with high antimicrobial consumption rates. Carbapenems have been employed as first-choice option for empirical treatment complicated infections. However, in the last decades, frequency of carbapenemase-producing Gram-negative bacteria has rising, demanding the use of alternative antimicrobial agents. By sequencing the entire genomes with short and long reads technologies, we report the isolation and genomic characterization of a carbapenem-resistant Pseudomonas clinical isolate. The identification based on average nucleotide identity indicates a putative new species into the Pseudomonas putida Group, which carries both the blaBKC-1 and blaVIM-2 carbapenemase genes. The blaBKC-1 was found to be on a transferable IncQ plasmid backbone, whereas blaVIM-2 was found in a new integron, In2126 (intl1∆-blaVIM-2-aacA7-blaVIM-2∆-aacA27-3'CS), described in this study. Our findings indicate that co-occurrence of classes A and B carbapenemase enzymes underscores the evolving emergence of more complex antimicrobial resistance in opportunistic pathogens.

Septuagenarian Donors and Recipients in Deceased Donor Liver Transplantation: A Brazilian Single Center Experience and Literature Review.

BACKGROUND: The number of elderly patients who have end-stage liver disease and require liver transplantation has dramatically increased. On the other hand, liver grafts from elderly donors have been offered more frequently for transplantation. The present study aims to analyze the results of liver transplants performed with donors and recipients aged ≥70 years. METHODS: We performed a single-center retrospective study of deceased donors liver transplants that involved recipients aged ≥7070 years or recipients who received grafts from donors aged ≥70 years from 2011 to 2021. A literature review on the results of liver transplantation in elderly recipients was also performed. RESULTS: Thirty septuagenarian recipients were included; their overall 1- and 5-years survival was 80% and 76.6%, respectively. The prevalence of recipients aged ≥70 years in our department was 2.65%. Twenty recipients received grafts form septuagenarian donors; their overall 1- and 5-years survival was 75%. The prevalence of donors aged ≥70 years in our department was 1%. In the literature review, 17 articles were analyzed. The 5-years survival of recipients aged ≥70 years ranged from 47.1% to 78.5%. CONCLUSIONS: Septuagenarian recipients and patients who received grafts from elderly brain-dead donors present adequate overall survival after liver transplantation. Optimized donor-recipient matching is paramount for achieving good outcomes. The combination of high-risk donors with septuagenarian recipients should be avoided as well as using grafts of elderly donors that present others risk factors. Thus, the age of the donor or recipient alone cannot be considered an absolute contraindication for liver transplantation.

Incidence of Donor Hepatic Artery Thrombosis in Liver Grafts Recognized During Organ Procurement and Backtable: A Rare but Treacherous Pitfall In Liver Transplantation.

INTRODUCTION: Donor hepatic artery thrombosis (dHAT) identified during liver procurement and backtable is a rare and little-reported event that can make liver transplants unfeasible. METHODS: This is a retrospective study of dHAT identified during liver grafts procurements or backtable procedures. All grafts were recovered from brain-dead donors. The demographic characteristics of the donors and the incidence of dHAT were analyzed. The data were also compared to a cohort of donors without dHAT. RESULTS: There was a total of 486 donors during the study period. The incidence of dHAT was 1.85% (n = 9). The diagnosis of dHAT was made during procurement in 5 cases (55.5%) and during the backtable in 4 (44.4%). Most donors were female (n = 5), with an average BMI of 28.14 ± 6.9 kg/m2, hypertensive (n = 5), and with stroke as cause of brain death (n = 8). The most prevalent site of dHAT was a left hepatic artery originating from the left gastric artery (n = 4). Of the 9 cases reported, 2 livers were used for transplantation, and 7 were discarded. Comparing those cases to a cohort of 260 donors without dHAT, we found a higher incidence of anatomic variations in the hepatic artery (P = .01) and of stroke as cause of brain death (P = .05). CONCLUSION: The occurrence of dHAT before liver procurement is a rare event, however it may become a treacherous pitfall if the diagnosis is late. Grafts with anatomic variations recovered from women with brain death due to stroke and with past history of hypertension seem to be at a higher risk of presenting dHAT.

Serum GFAP differentiates Alzheimer's disease from frontotemporal dementia and predicts MCI-to-dementia conversion.

OBJECTIVE: Reactive astrogliosis is a hallmark of Alzheimer's disease (AD) and frontotemporal dementia (FTD) but differences between the diseases and time course are unclear. Here, we used serum levels of the astroglial marker glial fibrillary acidic protein (GFAP) to investigate differences in patients with AD dementia, mild cognitive impairment (MCI)-AD and behavioural variant FTD (bvFTD). METHODS: This multicentre study included serum samples from patients diagnosed with AD dementia (n=230), MCI-AD (n=111), bvFTD (n=140) and controls (n=129). A subgroup of patients with MCI-AD (n=32) was longitudinally followed-up for 3.9±2.6 years after sample collection. Serum levels of GFAP, neurofilament light chain (NfL) and pTau181 were measured by Simoa (Quanterix) and Ella (ProteinSimple). RESULTS: In total, samples from 610 individuals from four clinical centres were investigated in this study. Serum GFAP levels in AD dementia were increased (median 375 pg/mL, IQR 276-505 pg/mL) compared with controls (167 pg/mL, IQR 108-234 pg/mL) and bvFTD (190 pg/mL, IQR 134-298 pg/mL, p<0.001). GFAP was already increased in the early disease phase (MCI-AD, 300 pg/mL, IQR 232-433 pg/mL, p<0.001) and was higher in patients with MCI-AD who developed dementia during follow-up (360 pg/mL, IQR 253-414 pg/mL vs 215 pg/mL, IQR 111-266 pg/mL, p<0.01, area under the curve (AUC)=0.77). Diagnostic performance of serum GFAP for AD (AUC=0.84, sensitivity 98%, specificity 60%, likelihood ratio 2.5) was comparable to serum pTau181 (AUC=0.89, sensitivity 80%, specificity 87%, likelihood ratio 6.0) but superior to serum NfL (AUC=0.71, sensitivity 92%, specificity 49%, likelihood ratio 1.8). CONCLUSIONS: Our data indicate a different type of reactive astrogliosis in AD and bvFTD and support serum GFAP as biomarker for differential diagnosis and prediction of MCI-to-dementia conversion.

Rare variants in TP73 in a frontotemporal dementia cohort link this gene with primary progressive aphasia phenotypes.

BACKGROUND AND PURPOSE: TP73 was recently reported to cause amyotrophic lateral sclerosis (ALS). ALS and frontotemporal dementia (FTD) are considered to form part of a continuum. We aimed to investigate whether TP73 variants may be associated with FTD. METHODS: We studied a thoroughly investigated cohort of 65 Portuguese patients with frontotemporal dementia using whole-exome sequencing. The patients had no other known genetic cause for their disease (C9orf72 expansion was also excluded). RESULTS: Of the 65 patients studied, two had rare variants in TP73 (p.Gly605Ser and p.Arg347Trp). Both variants had minor allele frequency <0.001 and were predicted to be pathogenic in silico. The two patients displayed a phenotype that included predominant language impairment, suggestive of non-fluent progressive aphasia. CONCLUSION: We show that two thoroughly studied patients without other known genetic changes harbored TP73 rare variants, which are pathogenic in silico. This adds evidence to support the role of TP73 in the ALS-FTD spectrum, especially in primary progressive aphasia cases.

The European Portuguese version of the Oxford Cognitive Screening (OCS-Pt): a screening test for acute stroke patients.

In Portugal, there is no gold standard test to assess acute stroke patients in the hospital context. However, cognitive deficits are common after a stroke episode and are followed by a negative impact on a patient's quality of life and rehabilitation. Here, we first aimed to adapt the Oxford Cognitive Screening to European Portuguese speakers (OCS-Pt), develop normative data cut-offs, and report the psychometric properties of the OCS-Pt. The second aim was to test the incidence of impairments in acute stroke patients. We tested 137 healthy participants aged between 25 and 92 years old, and we report normative cut-offs based on the 5th and 95th percentile, and on the patterns for age and education level. Our results are similar to other European OCS versions, and results using convergent and divergent validity show satisfactory values ranged between moderate to high. Additionally, 146 acute stroke patients, in the first week after the stroke episode, performed the OCS-Pt. Results show that this is an inclusive test and allows to discriminate between impaired and preserved functions. In conclusion, OCS-Pt is a promising cognitive screening tool to assess acute stroke survivors to be used in stroke care in Portugal.

Serum neurofilament light chain as a surrogate of cognitive decline in sporadic and familial frontotemporal dementia.

BACKGROUND AND PURPOSE: Neurofilament light chain (NfL) has recently been proposed as a promising biomarker in frontotemporal dementia (FTD). We investigated the correlation of both cerebrospinal fluid (CSF) and serum NfL with detailed neuropsychological data and cognitive decline in a cohort of sporadic and familial FTD. METHODS: CSF and serum NfL, as well as conventional CSF Alzheimer's disease (AD) biomarkers (Aß42, t-Tau, p-Tau181), were determined in 63 FTD patients (30 sporadic-FTD, 20 with progranulin (GRN) mutations [FTD-GRN], 13 with chromosome 9 open reading frame 72 [C9orf72] expansions [C9orf72-FTD]), 37 AD patients, and 31 neurologic controls. Serum NfL was also quantified in 37 healthy individuals. Correlations between baseline CSF and serum NfL levels, standardized neuropsychological tests, and the rate of cognitive decline in FTD patients were assessed. RESULTS: CSF and serum NfL presented with significantly higher levels in FTD than in AD patients and both control groups. Within FTD subtypes, genetic cases, and particularly FTD-GRN, had higher CSF and serum NfL levels. Significant correlations between NfL levels and overall cognitive function, abstract reasoning (CSF and serum), executive functions, memory, and language (serum) were found. A relationship between increased baseline CSF and serum NfL and a decay in cognitive performance over time was also observed. CONCLUSIONS: Our findings highlight the potential of serum NfL as a useful surrogate end point of disease severity in upcoming targeted treatments.