Remote versus face-to-face neuropsychological testing for dementia research: a comparative study in people with Alzheimer's disease, frontotemporal dementia and healthy older individuals.

OBJECTIVES: We explored whether adapting neuropsychological tests for online administration during the COVID-19 pandemic was feasible for dementia research. DESIGN: We used a longitudinal design for healthy controls, who completed face-to-face assessments 3-4 years before remote assessments. For patients, we used a cross-sectional design, contrasting a prospective remote cohort with a retrospective face-to-face cohort matched for age/education/severity. SETTING: Remote assessments were conducted using video-conferencing/online testing platforms, with participants using a personal computer/tablet at home. Face-to-face assessments were conducted in testing rooms at our research centre. PARTICIPANTS: The remote cohort comprised 25 patients (n=8 Alzheimer's disease (AD); n=3 behavioural variant frontotemporal dementia (bvFTD); n=4 semantic dementia (SD); n=5 progressive non-fluent aphasia (PNFA); n=5 logopenic aphasia (LPA)). The face-to-face patient cohort comprised 64 patients (n=25 AD; n=12 bvFTD; n=9 SD; n=12 PNFA; n=6 LPA). Ten controls who previously participated in face-to-face research also took part remotely. OUTCOME MEASURES: The outcome measures comprised the strength of evidence under a Bayesian framework for differences in performances between testing environments on general neuropsychological and neurolinguistic measures. RESULTS: There was substantial evidence suggesting no difference across environments in both the healthy control and combined patient cohorts (including measures of working memory, single-word comprehension, arithmetic and naming; Bayes Factors (BF)01 >3), in the healthy control group alone (including measures of letter/category fluency, semantic knowledge and bisyllabic word repetition; all BF01 >3), and in the combined patient cohort alone (including measures of working memory, episodic memory, short-term verbal memory, visual perception, non-word reading, sentence comprehension and bisyllabic/trisyllabic word repetition; all BF01 >3). In the control cohort alone, there was substantial evidence in support of a difference across environments for tests of visual perception (BF01=0.0404) and monosyllabic word repetition (BF01=0.0487). CONCLUSIONS: Our findings suggest that remote delivery of neuropsychological tests for dementia research is feasible.

Neuropsychological assessments for dementia research in the COVID-19 era: comparing remote and face-to-face testing (preprint)

Objectives: We explored whether adapting traditional neuropsychological tests for online administration against the backdrop of COVID-19 was feasible for people with diverse forms of dementia and healthy older controls. We compared face-to-face and remote settings to ascertain whether remote administration affected performance. Design: We used a longitudinal design for healthy older controls who completed face-to-face neuropsychological assessments between three and four years before taking part remotely. For patients, we used a cross-sectional design, contrasting a prospective remote cohort with a retrospective face-to-face cohort matched in age, education, and disease duration. Setting: Remote assessments were performed using video-conferencing and online testing platforms, with participants using a personal computer or tablet and situated in a quiet room in their own home. Face-to-face assessments were carried out in dedicated testing rooms in our research centre. Participants: The remote cohort comprised ten healthy older controls (also seen face-to-face 3-4 years previously) and 25 patients (n=8 Alzheimer's disease (AD); n=3 behavioural variant frontotemporal dementia (bvFTD); n=4 semantic dementia (SD); n=5 progressive nonfluent aphasia (PNFA); n=5 logopenic aphasia (LPA)). The face-to-face patient cohort comprised 64 patients (n=25 AD; n=12 bvFTD; n=9 SD; n=12 PNFA; n=6 LPA). Primary and secondary outcome measures: The outcome measures comprised the strength of evidence under a Bayesian analytic framework for differences in performances between face-to-face and remote testing environments on a general neuropsychological (primary outcomes) and neurolingustic battery (secondary outcomes). Results: There was evidence to suggest comparable performance across testing environments for all participant groups, for a range of neuropsychological tasks across both batteries. Conclusions: Our findings suggest that remote delivery of neuropsychological tests for dementia research is feasible.

SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer's-like neuropathology (preprint)

Major cell entry factors of SARS-CoV-2 are present in neurons; however, the neurotropism of SARS-CoV-2 and the phenotypes of infected neurons are still unclear. Acute neurological disorders occur in many patients, and one-third of COVID-19 survivors suffer from brain diseases. Here, we show that SARS-CoV-2 invades the brains of five patients with COVID-19 and Alzheimers, autism, frontotemporal dementia or no underlying condition by infecting neurons and other cells in the cortex. SARS-CoV-2 induces or enhances Alzheimers-like neuropathology with manifestations of beta-amyloid aggregation and plaque formation, tauopathy, neuroinflammation and cell death. SARS-CoV-2 infects mature but not immature neurons derived from inducible pluripotent stem cells from healthy and Alzheimers individuals through its receptor ACE2 and facilitator neuropilin-1. SARS-CoV-2 triggers Alzheimers-like gene programs in healthy neurons and exacerbates Alzheimers neuropathology. A gene signature defined as an Alzheimers infectious etiology is identified through SARS-CoV-2 infection, and silencing the top three downregulated genes in human primary neurons recapitulates the neurodegenerative phenotypes of SARS-CoV-2. Thus, SARS-CoV-2 invades the brain and activates an Alzheimers-like program.

TREM2 variants as a possible cause of frontotemporal dementia with distinct neuroimaging features.

BACKGROUND AND PURPOSE: Nasu-Hakola disease (NHD) is a rare, autosomal recessive disorder characterized by skeletal and neurological symptoms. Behavioral symptoms with cognitive impairment may mimic the behavioral variant of frontotemporal dementia (bvFTD) and other early-onset dementias. Our patients were analyzed and the literature was reviewed to delineate neurological and neuroimaging findings suggestive of NHD. METHOD: Fourteen patients carrying a pathogenic mutation in the TREM2 gene were found in our database. Demographic, clinical, laboratory and radiological data were retrieved and analyzed. RESULTS: The presenting clinical picture was behavioral changes with cognitive decline resembling bvFTD in all patients. The mean age was 37.1 ± 4.97 years and the mean duration of the disease was 8.9 ± 3.51 years. Only two patients had typical bone cysts. Seven patients had bilateral calcification of the basal ganglia in computed tomography of the brain. Magnetic resonance imaging of the brain revealed severe atrophy of the corpus callosum, enlargement of the ventricles, atrophy of the caudate nuclei and periventricular white matter changes in all patients. Symmetrical global atrophy of the brain mainly affecting frontoparietal and lateral temporal regions were observed in all cases, and 13 patients had atrophy of the hippocampus. Cerebrospinal fluid examination of 10 patients showed elevated protein levels in six and the presence of oligoclonal bands in four patients. CONCLUSION: A combination of white matter changes, enlarged ventricles, atrophy of the caudate nuclei and thinning of the corpus callosum in magnetic resonance imaging strongly suggests NHD in patients with FTD syndrome. Molecular genetic analysis should be performed in suspected cases, and families should receive genetic counseling.

Comparison of FTD SARS-CoV-2 Assay and RealStar RT-PCR kit 1.0 for the detection of SARS-CoV-2.

The aim of the study was to evaluate the clinical performance of FTD SARS-CoV-2 compared to the RealStar RT-PCR kit 1.0. The analysis of 100 nasopharyngeal swabs showed an overall agreement of 88 %. The positive percentage agreement was 85.6 % and the negative percentage agreement was 91 %. In conclusion we observed a substantial agreement among the two methods, with discrepancies mainly observed in specimens with relatively low amount of viral RNA.

Autoantibodies against Progranulin and IL-1 receptor antagonist in critically ill COVID-19 (preprint)

INTRODUCTION: Hyperinflammation is frequently observed in patients with severe COVID-19. Inadequate and defective IFN type I responses against SARS-CoV-2, caused by autoantibodies in a proportion of patients, lead to severe courses. In addition, hyperactive responses of the humoral immune system have been described so far. RATIONALE: In the current study we investigated a possible role of neutralizing autoantibodies against anti-inflammatory mediators. Plasma from patients with severe and critical COVID-19 was screened by ELISA for antibodies against PGRN, IL-10, IL-18BP, IL-22BP and IL-1-RA. Autoantibodies were characterized and the antigens were analyzed for immunogenic alterations. RESULTS: PGRN-autoantibodies were detected with high titers in 11 of 30 (36.7%), and IL 1-RA-autoantibodies in 14 of 30 (46.7%) patients of a discovery cohort with severe to critical COVID-19. In a validation cohort of 41 patients with critical COVID-19 high-titered PGRN-Abs were detected in 12 (29.3%) and IL-1-RA-Abs in 19 of 41 patients (46.2%). PGRN-Abs and IL-1-RA-Abs belonged to IgM and several IgG subclasses. In separate cohorts with non-critical COVID-19, PGRN-Abs and IL-1-RA-Abs were detected significantly less frequently and at low titers. Neither PGRN- nor IL-1-RA-Abs were found in 40 healthy controls vaccinated against SARS-CoV-2. PGRN-Abs were not cross-reactive against SARS-CoV-2 structural proteins or against IL-1-RA. Plasma levels of both free PGRN and IL-1-RA were significantly decreased in autoantibody-positive patients compared to Ab-negative and non-COVID controls. Functionally, PGRN-Abs from patients reduced PGRN-dependent inhibition of TNF- signaling in vitro. The pSer81 hyperphosphorylated PGRN isoform was exclusively detected in patients with high-titer PGRN-Abs; likewise, a yet unidentified hyperphosphorylated IL-1-RA isoform was only found in patients with high-titer IL-1-RA-Abs. No autoantibodies against IL-10, IL-18BP or IL-22BP were found. CONCLUSION: To conclude, neutralizing autoantibodies to IL-1-RA and PGRN occur in a significant proportion of patients with critical COVID-19, with a concomitant decrease in circulating PGRN and IL-1-RA, which is indicative of a misdirected, proinflammatory autoimmune response. The break of self-tolerance is likely caused by atypical isoforms of both antigens due to hyperphosphorylation. It remains to be determined whether these secondary modifications are induced by the SARS-CoV-2-infection itself, or are preexisting and predispose for a critical course.

NMDA and AMPA Receptor Autoantibodies in Brain Disorders: From Molecular Mechanisms to Clinical Features.

The role of autoimmunity in central nervous system (CNS) disorders is rapidly expanding. In the last twenty years, different types of autoantibodies targeting subunits of ionotropic glutamate receptors have been found in a variety of patients affected by brain disorders. Several of these antibodies are directed against NMDA receptors (NMDAR), mostly in autoimmune encephalitis, whereas a growing field of research has identified antibodies against AMPA receptor (AMPAR) subunits in patients with different types of epilepsy or frontotemporal dementia. Several in vitro and in vivo studies performed in the last decade have dramatically improved our understanding of the molecular and functional effects induced by both NMDAR and AMPAR autoantibodies at the excitatory glutamatergic synapse and, consequently, their possible role in the onset of clinical symptoms. In particular, the method by which autoantibodies can modulate the localization at synapses of specific target subunits leading to functional impairments and behavioral alterations has been well addressed in animal studies. Overall, these preclinical studies have opened new avenues for the development of novel pharmacological treatments specifically targeting the synaptic activation of ionotropic glutamate receptors.

Death Rate Due to COVID-19 in Alzheimer's Disease and Frontotemporal Dementia.

We aimed to evaluate the frequency and mortality of COVID-19 in patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD). We conducted an observational case series. We enrolled 204 patients, 15.2% of whom were diagnosed with COVID-19, and 41.9% of patients with the infection died. Patients with AD were older than patients with FTD (80.36±8.77 versus 72.00±8.35 years old) and had a higher prevalence of arterial hypertension (55.8% versus 26.3%). COVID-19 occurred in 7.3% of patients living at home, but 72.0% of those living at care homes. Living in care facilities and diagnosis of AD were independently associated with a higher probability of death. We found that living in care homes is the most relevant factor for an increased risk of COVID-19 infection and death, with AD patients exhibiting a higher risk than those with FTD.

Analysis of twenty-week time-series of confirmed cases of New Coronavirus COVID-19 and their simple short-term prediction for Georgia and Neighboring Countries (Armenia, Azerbaijan, Turkey, Russia) in amid of a global pandemic (preprint)

Results of a comparative statistical analysis of the daily data associated with New coronavirus COVID-19 infection of confirmed cases ([C]) of the population in Georgia (GEO), Armenia (ARM), Azerbaijan (AZE), Turkey (TUR) and Russia (RUS) amid a global pandemic (WLD) in the period from March 14 to July 31, 2020 are presented. The analysis of data is carried out with the use of the standard statistical analysis methods of random events and methods of mathematical statistics for the non-accidental time-series of observations. In particular, a correlation and autocorrelation analysis of the observational data was carried out, the periodicity in the time- series of [C] were revealed, the calculation of the interval prediction values of [C] taking into account the periodicity in the time-series of observations from August 1 to 31, 2020 (ARM, AZE) and from August 1 to September 11, 2020 (WLD, GEO, TUR, RUS) were carried out. Comparison of real and calculated predictions data on [C] in the study sites from August 1 to August 31, 2020 is carried out. It was found that daily, monthly and mean weekly real values of [C] for all the studied locations practically fall into the 99% confidence interval of the predicted values of [C] for the specified time period. A dangerous situation with the spread of coronavirus infection may arise when the mean weekly values of [C] of the 99% upper level of the forecast confidence interval are exceeded within 1-2 weeks. Favorable - when the mean weekly values of [C] decrease below 99% of the lower level of the forecast confidence interval.