Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.

BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.

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.

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.

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.

Reconsidering the role of blood-brain barrier in Alzheimer's disease: From delivery to target.

The existence of a selective blood-brain barrier (BBB) and neurovascular coupling are two unique central nervous system vasculature features that result in an intimate relationship between neurons, glia, and blood vessels. This leads to a significant pathophysiological overlap between neurodegenerative and cerebrovascular diseases. Alzheimer's disease (AD) is the most prevalent neurodegenerative disease whose pathogenesis is still to be unveiled but has mostly been explored under the light of the amyloid-cascade hypothesis. Either as a trigger, bystander, or consequence of neurodegeneration, vascular dysfunction is an early component of the pathological conundrum of AD. The anatomical and functional substrate of this neurovascular degeneration is the BBB, a dynamic and semi-permeable interface between blood and the central nervous system that has consistently been shown to be defective. Several molecular and genetic changes have been demonstrated to mediate vascular dysfunction and BBB disruption in AD. The isoform ε4 of Apolipoprotein E is at the same time the strongest genetic risk factor for AD and a known promoter of BBB dysfunction. Low-density lipoprotein receptor-related protein 1 (LRP-1), P-glycoprotein, and receptor for advanced glycation end products (RAGE) are examples of BBB transporters implicated in its pathogenesis due to their role in the trafficking of amyloid-ß. This disease is currently devoid of strategies that change the natural course of this burdening illness. This unsuccess may partly be explained by our misunderstanding of the disease pathogenesis and our inability to develop drugs that are effectively delivered to the brain. BBB may represent a therapeutic opportunity as a target itself or as a therapeutic vehicle. In this review, we aim to explore the role of BBB in the pathogenesis of AD including the genetic background and detail how it can be targeted in future therapeutic research.

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.

Whole-exome sequencing reveals PSEN1 and ATP7B combined variants as a possible cause of early-onset Lewy body dementia: a case study of genotype-phenotype correlation.

Dementia with Lewy bodies is a neurodegenerative disease, sharing features with Parkinson's and Alzheimer's diseases. We report a case of a patient dementia with Lewy bodies carrying combined PSEN1 and ATP7B mutations. A man developed dementia with Lewy bodies starting at the age of 60 years. CSF biomarkers were of Alzheimer's disease and DaTSCAN was abnormal. Whole-exome sequencing revealed a heterozygous p.Ile408Thr PSEN1 variant and a homozygous p.Arg616Trp ATP7B variant. This case reinstates the need of considering ATP7B mutations when evaluating a patient with parkinsonism and supports p.Ile408Thr as a pathogenic PSEN1 variant.

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.

Exome Sequencing of a Portuguese Cohort of Frontotemporal Dementia Patients: Looking Into the ALS-FTD Continuum.

Introduction: Frontotemporal dementia (FTD) is considered to be part of a continuum with amyotrophic lateral sclerosis (ALS). Many genes are associated with both ALS and FTD. Yet, many genes associated with ALS have not been shown to cause FTD. We aimed to study a Portuguese cohort of FTD patients, searching for variants in genes associated with both FTD and/or ALS. Methods: We included 57 thoroughly characterized index FTD patients from our memory clinic, who were not carriers of pathogenic variants in GRN, MAPT or C9orf72. We performed exome sequencing and 1) prioritized potential FTD and ALS causing variants by using Exomiser to annotate and filter results; and 2) looked specifically at rare variability in genes associated with FTD (excluding GRN, MAPT and C9ORF72) and/or ALS. Results: We identified 13 rare missense variants in 10 patients (three patients had two variants) in the following genes: FUS, OPTN, CCNF, DCTN1, TREM2, ERBB4, ANG, CHRNA4, CHRNB4 and SETX. We found an additional frameshift variant on GLT8D1 in one patient. One variant (ERBB4 p.Arg1112His) gathered enough evidence to be classified as likely pathogenic by the ACMG criteria. Discussion: We report, for the first time, an expanded study of genes known to cause FTD-ALS, in the Portuguese population. Potentially pathogenic variants in ERBB4, FUS, SETX, ANG, CHRNA4 and CHRNB4 were identified in FTD patients. These findings provide additional evidence for the potential role of rare variability in ALS-associated genes in FTD, expanding the genetic spectrum between the two diseases.

Lewy body dementia is associated with an increased risk of atrial fibrillation: A case-control study.

BACKGROUND: Lewy bodies are a hallmark of Dementia with Lewy Bodies. They can also be found in the sinoatrial node and may be associated with heart disease. OBJECTIVES: We aimed to investigate a possible association between Lewy Body dementia and atrial fibrillation. METHODS: We performed a case-control study based on our centre's cohort of degenerative dementia (Dementia with Lewy Bodies and Alzheimer's disease) patients. The possible association between Lewy Body dementia and atrial fibrillation was studied through a binomial logistic regression, which adjusted for comorbidity data. RESULTS: We included 461 patients. 45 of the 398 (11.3%) with Alzheimer's disease and 14 of the 63 with Dementia with Lewy Bodies (22.2%) had atrial fibrillation. Heart failure (OR = 3.345, 95%CI = [1.618, 6.916], p = 0.001), hypertension (OR = 2.547, 95%CI = [1,137, 5.703], p = 0.023), stroke (OR = 2.274, 95%CI = [1.013, 5.103], p = 0.046) and Dementia with Lewy Bodies (OR = 2.536, 95%CI = [1.105, 5.822], p = 0.028) were associated with atrial fibrillation. CONCLUSIONS: We found an association between Dementia with Lewy bodies and Atrial Fibrillation.

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.

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.

Apolipoprotein E genotype does not influence the risk of symptomatic hemorrhage in acute ischemic stroke.

BACKGROUND: APOE ε4 is independently associated with lobar intracranial hemorrhages (ICH). Although the ε4 allele enhances amyloid deposition in blood vessels, the ε2 allele predisposes to vasculopathic changes leading to rupture of amyloid laden vessels. Thus, ε4 and ε2 carriers might have increased susceptibility to ICH. We aimed to study the impact of the apolipoprotein E alleles in the development of symptomatic ICH (sICH). METHODS: We included 384 consecutive ischemic anterior circulation stroke patients submitted to thrombolysis between January 2014 and March 2016. Admission CT-scans were reviewed to calculate the ASPECTS. Patients were followed for up to at least 6 months post-stroke or until death. Outcome was development of sICH, defined according to the ECASS III. RESULTS: Considering APOE genotyping, three patients had ε2/ε2, four had ε2/ε4, 38 had ε2/ε3, 284 had ε3/ε3, 51 had ε3/ε4 and four had ε4/ε4. sICH was associated with sex and diabetes. In multivariate analysis, sICH was not associated with carrying one or more ε4 alleles (OR: 0.483, 95%CI = [0.059, 3.939], p = 0.497) nor with carrying one or more ε2 alleles (OR: 1.369, 95%CI = [0.278, 6.734], p = 0.699). CONCLUSION: No association was found between APOE genotype and the development of symptomatic intracranial hemorrhage.

Neuropsychological profile of amyloid-positive versus amyloid-negative amnestic Mild Cognitive Impairment.

INTRODUCTION: Patients diagnosed with amnestic mild cognitive impairment (aMCI) are at high risk of progressing to dementia. It became possible, through the use of biomarkers, to diagnose those patients with aMCI who have Alzheimer's disease. However, it is presently unfeasible that all patients undergo biomarker testing. Since neuropsychological testing is required to make a formal diagnosis of aMCI, it would be interesting if it could be used to predict the amyloid status of patients with aMCI. METHODS: Participants with aMCI, known amyloid status (Aß+ or Aß-) and a comprehensive neuropsychological evaluation, were selected from the Cognitive Complaints Cohort database for this study. Neuropsychological tests were compared in Aß+ and Aß- aMCI patients. A binary logistic regression analysis was conducted to model the probability of being amyloid positive. RESULTS: Of the 216 aMCI patients studied, 117 were Aß+ and 99 were Aß-. Aß+ aMCI patients performed worse on several memory tests, namely Word Total Recall, Logical Memory Immediate and Delayed Free Recall, and Verbal Paired Associate Learning, as well as on Trail Making Test B, an executive function test. In a binary logistic regression model, only Logical Memory Delayed Free Recall retained significance, so that for each additional score point in this test, the probability of being amyloid positive decreased by 30.6%. The resulting model correctly classified 64.6% of the aMCI cases regarding their amyloid status. CONCLUSIONS: The neuropsychological assessment remains an essential step to diagnose and characterize patients with aMCI; however, neuropsychological tests have limited value to distinguish the aMCI patients who have amyloid pathology from those who might suffer from other clinical conditions.

Neurology training and research in the COVID-19 pandemic: a survey of the Resident and Research Fellow Section of the European Academy of Neurology.

BACKGROUND AND PURPOSE: The COVID-19 (SARS-CoV-2) outbreak has disrupted residency programmes due to university and hospitals' priorities to face this emergency at all cost. Most research projects and clinical trials were temporarily stopped or postponed. The Resident and Research Fellow Section (RRFS) of the European Academy of Neurology (EAN) has decided to assess the impact of the COVID-19 pandemic on neurology training. METHODS: All EAN RRFS members were invited to fill out an online questionnaire of 40 items concerning their clinical involvement during the COVID-19 emergency, and the impact of the pandemic on their training (Appendix S1). RESULTS: Of the 227 RRFS members who completed the questionnaire, 222 were from Europe, and of those 111 were from Portugal, Italy or France. Responders highlighted that severe restrictions have been imposed to face this pandemic, including reduction of inpatient beds, prohibition of in-person visits and limitation to hospital access for patients' relatives. This was accompanied by an increase in email correspondence and phone calls with 50% of countries allowing telemedicine to reach outpatients. Seventy-nine per cent of the respondents felt that the pandemic will probably have a serious impact on their training and career. CONCLUSION: The pandemic led to a disruption of neurology activities, including medical training and research. The long-run impact of these changes remains unknown, but it will probably change the way neurology practice and training will be organized for future generations.

Neuropsychological features of progranulin-associated frontotemporal dementia: a nested case-control study.

The distinction between sporadic and genetic behavioural-variant frontotemporal dementia (bvFTD) regarding some neuropsychological (NP) features remains challenging. Specifically, progranulin (GRN)-associated bvFTD frequently presents with early episodic memory impairment and some degree of parietal dysfunction which are supporters of Alzheimer's disease (AD) diagnosis. In this context, we aimed to characterize the NP profile of GRN-bvFTD as compared to sporadic-bvFTD and AD in patients with mild dementia (Mini-Mental State Examination score ≥ 17 and Clinical Dementia Rating Scale score ≤ 1. We identified 21 patients at Centro Hospitalar e Universitário de Coimbra, Portugal with GRN mutations belonging to fifteen different families. As our focus was bvFTD variants, FTD-related aphasic forms (3 patients) were excluded. The remaining 18 GRN-bvFTD were further matched with 18 sporadic-bvFTD and 18 AD patients according to disease staging, age and education. All patients completed the Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA) and a comprehensive NP assessment battery. Results were converted into z-scores. Differences between groups in individual NP measures and NP domains were assessed through non-parametric tests (Kruskal-Wallis test analysis) and eta squared (ŋ2) was calculated as a measure of effect size. Group comparisons show that GRN patients have worse performances on verbal retrieval processes (P = 0.039, ŋ2 = 0.110) and visuoconstructive abilities (P = 0.039, ŋ2 = 0.190) than sporadic bvFTD forms. When compared to AD, GRN patients present a higher impairment in frontal (P = 0.001, ŋ2 = 0.211) and parietal (P = 0.041, ŋ2 = 0.129) measures and a better performance in memory tasks (P = 0.020, ŋ2 = 0.120). Sporadic-bvFTD forms are worse than AD in frontal measures (P = 0.032, ŋ2 = 0.200), being better in both memory (P = 0.010, ŋ2 = 0.131) and visuospatial skills (P = 0.023, ŋ2 = 0.231). Considering these results, we conclude that GRN-bvFTD patients present a NP profile that associates the typical patterns of FTD and AD deficits. This is particularly expressive in visuoconstructive abilities, which was the more discriminative feature between groups, followed by episodic verbal memory. This study was approved by the Institutional Ethics Committee of Centro Hospitalar e Universitário de Coimbra, Portugal (CE-029/2019) on June 24, 2019.