The Clinical Aspects of COVID and Alzheimer's Disease: A Round-Up of Where Things Stand and Are Headed.

 The link between long COVID-19 and brain/cognitive impairments is concerning and may foster a worrisome worldwide emergence of novel cases of neurodegenerative diseases with aging. This review aims to update the knowledge, crosstalk, and possible intersections between the Post-COVID Syndrome (PCS) and Alzheimer's disease (AD). References included in this review were obtained from PubMed searches conducted between October 2023 and November 2023. PCS is a very heterogenous and poorly understood disease with recent evidence of a possible association with chronic diseases such as AD. However, more scientific data is required to establish the link between PCS and AD.

Long COVID: neurological manifestations - an updated narrative review / COVID longa: manifestações neurológicas - uma revisão narrativa atualizada

ABSTRACT. Infection with the SARS-CoV-2 virus can lead to neurological symptoms in the acute phase and in the Long COVID phase. These symptoms usually involve cognition, sleep, smell disorders, psychiatric manifestations, headache and others. This condition is more commonly described in young adults and women. This symptomatology can follow severe or mild cases of the disease. The importance of this issue resides in the high prevalence of neurological symptoms in the Long COVID phase, which entails significant morbidity in this population. In addition, such a condition is associated with high health care costs, with some estimates hovering around 3.7 trillion US dollars. In this review, we will sequentially describe the current knowledge about the most prevalent neurological symptoms in Long COVID, as well as their pathophysiology and possible biomarkers.

RESUMO. A infecção pelo vírus SARS-CoV-2 pode levar a sintomas neurológicos na fase aguda e na fase de COVID longa. Esses sintomas geralmente envolvem cognição, sono, distúrbios do olfato, manifestações psiquiátricas, dor de cabeça e outros. Esta condição é mais comumente descrita em adultos jovens e mulheres. A sintomatologia pode acompanhar casos graves ou leves da doença. A importância desta questão reside na elevada prevalência de sintomas neurológicos na fase de COVID longa, o que acarreta morbilidade significativa nesta população. Além disso, tal condição está associada a elevados custos de cuidados de saúde, com algumas estimativas em torno de 3,7 trilhões de dólares americanos. Nesta revisão, descrevemos sequencialmente o conhecimento atual sobre os sintomas neurológicos mais prevalentes na COVID longa, bem como sua fisiopatologia e possíveis biomarcadores.

Post-COVID-19 Cognitive Decline and Apoe Polymorphism: Towards a Possible Link?

APOE ε4 polymorphism has been recently described as a possible association with cognitive deficits in COVID-19 patients. This research aimed to establish the correlation between COVID-19 and cognitive impairment, and the APOE gene polymorphism among outpatients. We performed a cross-sectional study with confirmed COVID-19 patients and neurological symptoms that persisted for more than three months from onset. APOE genotypes were determined. The final number of patients included in this study was 219, of which 186 blood samples were collected for APOE genotyping, evaluated 4.5 months after COVID-19. Among the participants, 143 patients (65.3%) reported memory impairment symptoms as their primary concern. However, this complaint was objectively verified through screening tests (Addenbrooke Cognitive Examination-Revised and Mini-Mental State Examination) in only 36 patients (16.4%). The group experiencing cognitive decline exhibited a higher prevalence of the APOE ε4 allele than the normal group (30.8% vs. 16.4%, respectively, p = 0.038). Furthermore, the APOE ε4 allele and anxiety symptoms remained significant after multivariate analysis. This study assessed an outpatient population where cognitive changes were the primary complaint, even in mild cases. Moreover, the ε4 allele, sleep disorders, and anxiety symptoms were more frequent in the cognitive decline group.

Thyroid axis participates in high-temperature-induced male sex reversal through its activation by the stress response.

Environmental changes alter the sex fate in about 15% of vertebrate orders, mainly in ectotherms such as fish and reptiles. However, the effects of temperature changes on the endocrine and molecular processes controlling gonadal sex determination are not fully understood. Here, we provide evidence that thyroid hormones (THs) act as co-players in heat-induced masculinization through interactions with the stress axis to promote testicular development. We first demonstrated that the thyroid axis (through thyroid-related genes and T3 levels) is highly active in males during the gonadal development in medaka (Oryzias latipes). Similarly, T3 treatments promoted female-to-male sex reversal in XX embryos. Subsequently, embryonic exposure to temperature-induced stress up-regulated the genes related to the thyroid and stress axes with a final increase in T3 levels. In this context, we show that blocking the stress axis response by the loss of function of the corticotropin-releasing hormone receptors suppresses thyroid-stimulating hormone expression, therefore, heat-induced activation of the thyroid axis. Thus, our data showed that early activation of the stress axis and, in consequence, the TH axis, too, leaves us with that both being important endocrine players in inducing female-to-male reversal, which can help predict possible upcoming physiological impacts of global warming on fish populations.

Post nirmatrelvir/ritonavir erythema multiforme in a patient with coronavirus disease infection.

Erythema multiforme (EM), an immune-mediated skin condition, can occur after infection or following the use of medications. In this study, we describe a patient who developed EM after nirmatrelvir/ritonavir administration. An 81-year-old woman presented with fever and dyspnea. Laboratory investigations showed positive coronavirus disease (COVID-19) based on polymerase chain reaction assay, and she received a 5-day regimen of nirmatrelvir/ritonavir. We observed development of EM after this treatment and initiated prednisone (1 mg/kg) therapy, which led to rapid improvement. Our study is the first to report EM in a patient with COVID-19, who received nirmatrelvir/ritonavir and showed a favorable response.

Cogan's sign in a patient with suspected post-COVID-19 vaccine-associated myasthenia gravis.

The Cogan's sign is indicative of myasthenia gravis. This is the first report of neurological signs in a patient with post-COVID-19 vaccine-associated myasthenia gravis in Brazil. In this case, a previously healthy 68-year-old woman presented with proximal limb weakness, left ptosis, and diplopia 1 month after receiving her fourth dose of the COVID-19 vaccine. Neurological examination revealed the presence of Cogan's sign, and she recovered rapidly after treatment. To our knowledge, this is the first reported case of myasthenia gravis associated with the COVID-19 vaccine in Brazil.

Parinaud syndrome due to cofirmed neurotuberculosis in a lupus eritematosis systemic patient.

INTRODUCTION: This article aims to describe a patient with Parinaud syndrome due to neurotuberculosis confirmed by cerebrospinal fluid analysis. CASE REPORT: Initially, patient sought medical care, performed a chest x-ray and later a chest CT scan, with a probable diagnosis of miliary tuberculosis. In addition, she presented binocular diplopia worse at right lateral gaze, paresis of vertical gaze, light near-dissociation and convergent retraction nystagmus and presence of mycobacterium tuberculosis on PCR Xpert MTB/RIF. The treatment of miliary tuberculosis was interrupted due to pharmacodermia, but after diagnosis of neurotuberculosis, it was restarted with isoniazid, pyrazinamide and ethambutol with partial visual symptoms improvement. DISCUSSION: This case demonstrates the importance of pursuing diagnosis through more accurate techniques, especially in a patient with previous treatment pharmacoderma, whose absence of proper diagnosis and treatment would be extremely deleterious.

Cogan's sign in a patient with suspected post-COVID-19 vaccine-associated myasthenia gravis

ABSTRACT The Cogan's sign is indicative of myasthenia gravis. This is the first report of neurological signs in a patient with post-COVID-19 vaccine-associated myasthenia gravis in Brazil. In this case, a previously healthy 68-year-old woman presented with proximal limb weakness, left ptosis, and diplopia 1 month after receiving her fourth dose of the COVID-19 vaccine. Neurological examination revealed the presence of Cogan's sign, and she recovered rapidly after treatment. To our knowledge, this is the first reported case of myasthenia gravis associated with the COVID-19 vaccine in Brazil.

Post nirmatrelvir/ritonavir erythema multiforme in a patient with coronavirus disease infection

ABSTRACT Erythema multiforme (EM), an immune-mediated skin condition, can occur after infection or following the use of medications. In this study, we describe a patient who developed EM after nirmatrelvir/ritonavir administration. An 81-year-old woman presented with fever and dyspnea. Laboratory investigations showed positive coronavirus disease (COVID-19) based on polymerase chain reaction assay, and she received a 5-day regimen of nirmatrelvir/ritonavir. We observed development of EM after this treatment and initiated prednisone (1 mg/kg) therapy, which led to rapid improvement. Our study is the first to report EM in a patient with COVID-19, who received nirmatrelvir/ritonavir and showed a favorable response.

Central hypersomnia and chronic insomnia: expanding the spectrum of sleep disorders in long COVID syndrome - a prospective cohort study.

INTRODUCTION: Long-onset COVID syndrome has been described in patients with COVID-19 infection with persistence of symptoms or development of sequelae beyond 4 weeks after the onset of acute symptoms, a medium- and long-term consequence of COVID-19. This syndrome can affect up to 32% of affected individuals, with symptoms of fatigue, dyspnea, chest pain, cognitive disorders, insomnia, and psychiatric disorders. The present study aimed to characterize and evaluate the prevalence of sleep symptoms in patients with long COVID syndrome. METHODOLOGY: A total of 207 patients with post-COVID symptoms were evaluated through clinical evaluation with a neurologist and specific exams in the subgroup complaining of excessive sleepiness. RESULTS: Among 189 patients included in the long COVID sample, 48 (25.3%) had sleep-related symptoms. Insomnia was reported by 42 patients (22.2%), and excessive sleepiness (ES) was reported by 6 patients (3.17%). Four patients with ES were evaluated with polysomnography and test, multiple sleep latencies test, and actigraphic data. Two patients had a diagnosis of central hypersomnia, and one had narcolepsy. A history of steroid use was related to sleep complaints (insomnia and excessive sleepiness), whereas depression was related to excessive sleepiness. We observed a high prevalence of cognitive complaints in these patients. CONCLUSION: Complaints related to sleep, such as insomnia and excessive sleepiness, seem to be part of the clinical post-acute syndrome (long COVID syndrome), composing part of its clinical spectrum, relating to some clinical data.

Long-covid cognitive impairment: Cognitive assessment and apolipoprotein E (APOE) genotyping correlation in a Brazilian cohort.

Introduction: Few studies have objectively evaluated cognitive deficits after the acute phase of COVID-19 disease. Moreover, the role of apolipoprotein E (APOE) genotypes in cognitive decline in patients with COVID-19 has not been evaluated yet. Methods: This cross-sectional study was conducted in confirmed cases of COVID-19 patients with neurological symptoms that persisted for more than 3 months from the onset. We determined APOE genotypes. Results: The final sample consisted of 141 patients. The most frequent APOE genotype was E3/E3 (N = 95; 67.3%). In total, 93 patients (65.9%) had memory impairment symptoms as the main complaint, objectively confirmed through screening tests in 25 patients (17.7%). Patients with cognitive impairment had a lower frequency of anosmia than the normal and subjective cognitive decline (SCD) groups (p = 0.005). In addition, depression was recurrent in the cognitive impairment group and the SCD group (p = 0.046). Cognitive impairment was significantly more frequent in hospitalized patients and those with a lower education level. Cognitive status was not associated with APOE genotypes. Discussion: Hospitalized patients had more severe infection with a greater possibility of systemic complications, greater inflammatory response, and prolonged hospitalization, which could impact cognitive performance. Cognitive impairment in patients with COVID-19 does not necessarily involve specific APOE polymorphisms. However, psychiatric disorders may also be responsible for cognitive complaints. Cognitive complaints are frequent in patients with COVID-19, even after the acute phase of the disease and in mild cases. Hospitalized participants and depressed patients may have a higher risk of cognitive impairment. APOE genotypes or haplotypes may not significantly play a role in COVID-19 cognitive impairment.

Diagnostic approach in a patient with Creutzfeldt-Jakob disease / Abordagem diagnóstica em uma paciente com doença de Creutzfeldt-Jakob

ABSTRACT Prion diseases are an important cause of rapidly progressive dementias. Among them, the most common is sporadic Creutzfeldt-Jakob disease (CJD). It is a rare and incurable disease, with rapid progression to death. Objective: To describe the diagnostic approach of a patient with Creutzfeldt-Jakob disease. Methods: The diagnosis is established through the clinical picture associated with characteristic changes in the brain magnetic resonance imaging, the electroencephalogram, and analysis of specific changes in the cerebrospinal fluid. Results: The present report describes the case of a 53-year-old patient in the city of Fortaleza-CE. The diagnosis was made based on the clinical condition and through diagnostic tests, including 14-3-3 protein and RT QUIC analysis. Differential diagnosis was performed with other rapidly progressive causes, such as infectious and immune-mediated diseases. Conclusions: The diagnosis of probable sporadic CJD was established.

RESUMO As doenças priônicas são uma importante causa de demências rapidamente progressivas. Entre elas, a mais comum é a doença de Creutzfeldt-Jakob (DCJ) esporádica. É uma enfermidade rara e incurável, com rápida progressão para óbito. Objetivo: Descrever a abordagem diagnóstica de uma paciente com doença de Creutzfeldt-Jakob. Métodos: O diagnóstico é estabelecido pelo quadro clínico associado a alterações características na ressonância magnética cerebral, no eletroencefalograma e pela análise de alterações específicas no líquido cefalorraquidiano. Resultados: O presente relato descreve o caso de um paciente de 53 anos na cidade de Fortaleza (CE). O diagnóstico foi feito com base na condição clínica e por meio de testes diagnósticos, incluindo proteína 14-3-3 e análise Real-Time Quaking-Induced Conversion (RT QUIC). O diagnóstico diferencial foi realizado com outras causas rapidamente progressivas, como doenças infecciosas e imunomediadas. Conclusões: Por fim, foi estabelecido o diagnóstico de provável DCJ esporádica.

COVID-19 associated cognitive impairment: A systematic review.

INTRODUCTION: COVID-19 has a wide range of clinical manifestations. Neurological manifestations in COVID-19 patients were demonstrated during the pandemic, including cognitive impairment. This study aimed to determine any relationship between COVID-19 and cognitive complaints, such as dementia, mild cognitive impairment (MCI), or subjective cognitive decline (SCD). METHODS: We performed a systematic review of MEDLINE via Ebsco, Cochrane EMBASE, SCOPUS, and LILACS electronic databases of observational studies with COVID-19 patients confirmed by serology or PCR who developed new cognitive impairment or deteriorated from previous cognitive impairment after infection. This review protocol was recorded on PROSPERO with registration number CRD 42021241590. RESULTS: A total of 3.520 articles were retrieved and read. Twenty-two studies were selected for our review. A wide range of cognitive assessment tools (n = 25) was used. The most described affected domains in these studies were executive functions, attention, and episodic memory. Thirteen studies showed a pattern of cognitive impairment in processing speed, inattention, or executive dysfunction assessed through working memory. CONCLUSION: This review highlights the high frequency of cognitive impairment after COVID-19 infection. However, we were unable to differentiate whether the cognitive impairment found corresponded to mild cognitive impairment or dementia through data from selected studies, and this issue serves as one objective of future studies to be addressed on this topic.

Diagnostic approach in a patient with Creutzfeldt-Jakob disease.

Prion diseases are an important cause of rapidly progressive dementias. Among them, the most common is sporadic Creutzfeldt-Jakob disease (CJD). It is a rare and incurable disease, with rapid progression to death. Objective: To describe the diagnostic approach of a patient with Creutzfeldt-Jakob disease. Methods: The diagnosis is established through the clinical picture associated with characteristic changes in the brain magnetic resonance imaging, the electroencephalogram, and analysis of specific changes in the cerebrospinal fluid. Results: The present report describes the case of a 53-year-old patient in the city of Fortaleza-CE. The diagnosis was made based on the clinical condition and through diagnostic tests, including 14-3-3 protein and RT QUIC analysis. Differential diagnosis was performed with other rapidly progressive causes, such as infectious and immune-mediated diseases. Conclusions: The diagnosis of probable sporadic CJD was established.

As doenças priônicas são uma importante causa de demências rapidamente progressivas. Entre elas, a mais comum é a doença de Creutzfeldt-Jakob (DCJ) esporádica. É uma enfermidade rara e incurável, com rápida progressão para óbito. Objetivo: Descrever a abordagem diagnóstica de uma paciente com doença de Creutzfeldt-Jakob. Métodos: O diagnóstico é estabelecido pelo quadro clínico associado a alterações características na ressonância magnética cerebral, no eletroencefalograma e pela análise de alterações específicas no líquido cefalorraquidiano. Resultados: O presente relato descreve o caso de um paciente de 53 anos na cidade de Fortaleza (CE). O diagnóstico foi feito com base na condição clínica e por meio de testes diagnósticos, incluindo proteína 14-3-3 e análise Real-Time Quaking-Induced Conversion (RT QUIC). O diagnóstico diferencial foi realizado com outras causas rapidamente progressivas, como doenças infecciosas e imunomediadas. Conclusões: Por fim, foi estabelecido o diagnóstico de provável DCJ esporádica.

Characterization of Headache in COVID-19: a Retrospective Multicenter Study.

Headache is the most common neurological symptom in COVID-19, reported in 6.5 to 34% of patients. Few studies have analyzed its characteristics, and some of them included cases without laboratory confirmation or reported only critical patients. We aimed to analyze the clinical characteristics of COVID-19 associated headache in laboratory-confirmed cases. We conducted a retrospective evaluation of patients with COVID-19 and neurological symptoms. Patients who reported headache answered an interview about its clinical characteristics. Twenty-four patients with COVID-19 associated headache completed the interview. Mean age of patients was 53.8 (standard deviation-17.44), and 14 out of 24 (58.3%) were male. The majority (75%) had no previous history of headache. Fever was documented in 19 out of the 24 patients (79.1%). Headache was predominantly bifrontal or holocranial, in pressure, during hours, worsening with cough or physical activity. COVID-19 headache tends to appear in the first days of symptoms, be either frontal or holocranial and last for days. The quality of pain in pressure and the worsening with cough or physical activity were reported in most cases. We have not found any characteristic that could differentiate COVID-19 associated headache from other causes of headache, possibly because of its multifactorial mechanism.

Clinical characteristics and diagnostic accuracy of the revised Addenbrooke Cognitive Examination (ACE-R) in older adults with a low educational level / Características clínicas e acurácia do Exame Cognitivo Addenbrooke Versão revisada (ACE-R) em idosos com baixa escolaridade

ABSTRACT Objective: To determine the diagnostic accuracy of the Addenbrooke's Cognitive Examination Revised (ACE-R) as a cognitive screening tool for older adults with low levels of schooling and healthy aging, MCI and dementia in Brazil. Methods: All participants underwent neurological and psychiatric examinations and were administered a validated version of ACE-R. Results: A total of 85 participants were evaluated; most were females (84.7%, n = 72). The post hoc analysis showed statistical differences in ACE-R total scores between older adults with mild cognitive impairment (MCI) and controls (p < 0.001) and in subitem scores including verbal fluency, language, visuospatial skills and attention (p < 0.001). The visual-spatial skills subitem was the most strongly correlated with schooling level (r = 0.509, p < 0.001), whereas late, immediate recall and recognition memory were not influenced by schooling. The ACE-R had the best diagnostic accuracy in discriminating between MCI and controls = 0.69 (<57.5; 80/66), MD and controls = 0.98 (<50; 100/96), MCI and MD = 0.86 (<49.5; 100/74). Conclusions: ACE-R and Mini-Mental State Examination (MMSE) scores for older adults with MCI and controls were significantly lower than those reported in similar studies. These preliminary findings support the need for establishing reliable cut-off scores for cognitive assessment of older Brazilian adults with low schooling at risk for dementia taking into consideration ecological and local variables.

RESUMO Objetivo: Determinar a precisão diagnóstica do Exame Cognitivo de Addenbrooke (ACE-R) como uma ferramenta de triagem cognitiva para adultos idosos com baixos níveis de educação e envelhecimento saudável, MCI e demência no Brasil. Métodos: Os indivíduos submeteram-se à avaliação clínica e psiquiátrica e foi administrada uma versão validada da versão revisada da bateria cognitiva ACE-R (ACE-R). Resultados: Oitenta e cinco indivíduos foram avaliados, predominando as mulheres (84,7%, n = 72). Na análise post hoc, controles e CCL exibiram diferenças estatísticas nos escores globais do ACE-R (p < 0,001) e seus subdomínios, incluindo fluência verbal, linguagem, habilidades visuoespaciais e atenção (p < 0,001). A habilidade visuoespacial foi o item mais correlacionado com a escolaridade (r = 0,509, p < 0,001), enquanto a memória tardia, de recordação e reconhecimento não foi influenciada pela educação. A precisão do ACE-R produziu melhores resultados para CCL versus controles = 0,69 (<57,5; 80/66), demência versus controles = 0,98 (<50; 100/96), CCL versus demência = 0,86 (<49,5; 100/74). Conclusões: Os escores de ACE-R e MMSE para controles e CCL foram consideravelmente inferiores aos encontrados em estudos semelhantes. Resultados preliminares confirmam a necessidade de estudos brasileiros estabelecerem pontos de corte confiáveis para baterias cognitivas em idosos com baixa escolaridade e em risco de demência, reconhecendo variáveis ecológicas e regionais.