Enhancing cognitive flexibility and working memory in individuals with mild cognitive impairment: Exploring the impact of virtual reality on daily life activities.

Mild Cognitive Impairment (MCI) serving as a transitional stage between normal aging and dementia. This study aimed to explore the impact of virtual reality (VR) on enhancing cognitive flexibility, working memory, and daily life activities. Forty participants diagnosed with MCI were randomly assigned to either an intervention group (N = 20) or a control group (N = 20). Evaluations were at baseline, post-training, and three months post-training using various cognitive assessment tools. Results showed that the VR-based cognitive rehabilitation significantly improved instrumental activities of daily living performance, visual and verbal working memory, and reduced anxiety and depression symptoms. While cognitive flexibility did not exhibit significant improvement, these findings highlight VR interventions as a potential avenue for improving cognitive and functional aspects, and alleviating psychological symptoms in individuals with MCI. Further research with larger sample sizes and extended follow-up periods is recommended to establish the long-term effectiveness of such interventions.

"Split-day syndrome", a patient with frontotemporal dementia who lives two days in the span of one: a case report and review of articles.

Frontotemporal dementia (FTD) is among the most prevalent causes of young-onset dementia  . Along with the frontotemporal and striate atrophy, dopamine dysregulation is also present in FTD. The dopamine system controls mechanisms of time perception. Its depletion can cause miscalculations in the perception of time. We present a 72-year-old man with a unique profile of disorientation in time, such that he split each day into two, 12-h intervals. Although through each 12-h period, he went by his daily activities as if a complete day had passed, e.g., he had two sets of breakfast, lunch, and dinner  , hence the designated "split-day syndrome."

Chronic fatigue syndrome and cognitive deficit are associated with acute-phase neuropsychiatric manifestations of COVID-19: A 9-month follow-up study.

The preva lence of long-COVID symptoms is rising but it is not still possible to predict which patients will present them, and which types of symptoms they will present. We followed up 95 patients with confirmed COVID-19 for 9 months to identify and characterize long-COVID symptoms. Easy fatigability was the most common symptom (51.04%), followed by anxiety (38.54%), dyspnea (38.54%), and new-onset headache (38.54%). There was no association between COVID-19 severity in the acute phase and the number of long-COVID symptoms (F(1,93) = 0.75, p = 0.45), and cognitive function (MoCA) scores (F(1,90) = 0.073, p = 0.787) at follow-up. Being female (F(1,92) = - 2.27, p = 0.02), having a higher number of symptoms (F(1,93) = 2.76, p = 0.0068), and experiencing constitutional neuropsychiatric symptoms (F(1,93) = 2.529, p = 0.01) in the acute phase were associated with having chronic fatigue syndrome at follow-up. Moreover, constitutional neuropsychiatric symptoms in the acute phase were associated with a lower MoCA score (F(1,93) = 10.84, p = 0.001) at follow-up. Specific clinical presentations such as constitutional neuropsychiatric symptoms in the acute phase might be predictors of debilitating long-COVID symptoms such as chronic fatigue syndrome and cognitive deficits.

Sour aversion in frontotemporal dementia: a case report and review on physiologic-anatomic mechanisms.

Frontotemporal dementia (FTD) is a common cause of early-onset dementia characterized by behavioral and personality changes, as well as, altered eating habits. FTD is associated with complex changes in neural networks of gustatory processing which may be responsible for eating abnormalities. Here, we present a 66-years-old lady suffered from behavioral variant of FTD with an interesting symptom of food aversion, typically sour foods.

The role of transcranial sonography in differentiation of dementia subtypes: an introduction of a new diagnostic method.

PURPOSE: Transcranial sonography (TCS) is increasingly used for the diagnosis of neurodegenerative disorders. We assessed the role of third ventricle width (TVW), midbrain area (MA), and midbrain circumference (MC) by TCS for diagnosis and differentiation of dementia. METHODS: A cross-sectional study was designed in 59 patients with dementia including 19 patients with Alzheimer's disease (AD), 10 Dementia with Lewy bodies (DLB), 23 Frontotemporal dementia (FTD) and 7 Vascular dementia (VaD), and 22 normal-cognition individuals. Both case and control groups were matched by age, sex, and educational level. The dementia patients were divided into two subgroups: cortical-dominant dementia (CDD) including AD and FTD; and subcortical-dominant dementia (SDD) including DLB and VaD. TCS was performed through a temporal window, in which the size of TVW and midbrain was measured by trans-thalamic and trans-mesencephalic planes, respectively. RESULTS: The mean TVW was 0.85 ± 0.3 cm and 0.66 ± 0.2 cm in dementia patients and the control group, respectively (p < 0.01). The MA/MC were smaller in dementia patients compared with the control group (p < 0.05 and p < 0.01). The TVW in CDD (p = 0.003) and SDD (p = 0.027), but only MA/MC in SDD (p < 0.05), was statistically different compared with the control group. CONCLUSION: The measurement of TVW and midbrain size by TCS can be used for diagnosis and differentiation of dementia. Patients with CDD and SDD have larger TVW than the control group, whereas patients with SDD have smaller midbrain sizes.

Effectiveness of Serious Games in Evaluating Cognitive Status of the Elderly: A Systematic Review And Meta-Analysis.

Early diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD) is very important in better management of these diseases, and serious games play an effective role in helping to diagnose these diseases more accurately owing to their innovative features. With respect to the diversity of available games, the purpose of this study was to investigate the effectiveness of using serious games to assess the cognitive status of the elderly at risk of MCI/AD. A systematic review was conducted and the correlation of serious game results with cognitive test scores were extracted from eligible studies for meta-analysis. We analyzed the correlation between the results of serious games with the scores of mini-mental state examination (MMSE), Addenbrooke's Cognitive Examination-revised edition (ACE-R), and Montreal Cognitive Assessment (MoCA) tests to evaluate cognitive status of the elderly at risk of MCI/AD, as well as the cognitive aspects examined by these tests. The random-effects model was used to obtain the overall correlation coefficient to assess the relationship between the results of serious games and the above mentioned paper-and-pencil tests. The correlation of game results with the MMSE, ACE-R, and MoCA was 0.604, 0.682, with 0.682, respectively. The correlation between the results of the games with the score of each cognitive aspect was also calculated. Overall, there is a positive correlation between serious game scores in terms of accurate patients' reactions with the scores of MMSE, ACE-R, and MoCA tests. Among the cognitive aspects, the highest correlation was obtained for fluency (0.591). For abstraction, however, the correlation was the lowest (0.036). In all three tests, the correlation was >0.6 and in cognitive aspects was <0.6. Thus, more studies should be conducted to develop serious games that are more in line with cognitive tests.

Neutrophil to lymphocyte ratio in Alzheimer's disease: A systematic review and meta-analysis.

BACKGROUND: The Neutrophil-to-Lymphocyte Ratio (NLR) is a clinical indicator of peripheral inflammation that is easily accessible. It is worth noting that the formation of amyloid-ß (Aß) plaques and neurofibrillary tangles has been linked to inflammation and immune dysregulation. The main objective of this systematic review and meta-analysis is to comprehensively evaluate the existing body of research concerning the NLR in the context of Alzheimer's disease (AD) and mild cognitive impairment (MCI). METHOD: We conducted a comprehensive online search and included studies that evaluated the NLR in 1) patients with AD or MCI and 2) healthy control (HC) participants. We also pooled mean and standard deviation (SD) data for each group. RESULTS: Ultimately, 12 studies encompassed 1,309 individuals diagnosed with AD with mean NLR levels of 2.68, 1,929 individuals with MCI with mean NLR levels of 2.42, and 2,064 HC with mean NLR levels of 2.06 were included in this systematic review and meta-analysis. The mean NLR was 0.59 higher in AD patients compared to HC participants (mean difference (MD) = 0.59 [0.38; 0.80]). Similarly, the mean NLR was higher in AD than MCI patients (MD = 0.23 [0.13; 0.33]). Additionally, the mean NLR was higher in individuals with MCI compared to HC participants (MD = 0.37 [0.22; 0.52]). In the subgroup meta-analysis based on the Mini-Mental State Examination (MMSE), AD patients with lower MMSE scores (using a cut-off of 20) exhibited significantly higher mean NLR (3.10 vs. 2.70, with a p-value for subgroup differences < 0.01). CONCLUSION: The NLR, which serves as a marker of peripheral inflammation, shows increased levels in individuals with AD and MCI compared to HC participants. Furthermore, our study indicates that NLR levels are significantly higher in AD than MCI. Additionally, our novel finding suggests significantly higher NLR levels among AD patients with more severe cognitive decline compared to AD patients with less severe cognitive decline. So, it can be concluded that the higher cognitive decline in humans is accompanied by higher NLR levels. Further longitudinal researches are needed to explore more details about the relationship between inflammation and dementia.

A Deep Learning-Based Ensemble Method for Early Diagnosis of Alzheimer's Disease using MRI Images.

Recently, the early diagnosis of Alzheimer's disease has gained major attention due to the growing prevalence of the disease and the resulting costs imposed on individuals and society. The main objective of this study was to propose an ensemble method based on deep learning for the early diagnosis of AD using MRI images. The methodology of this study consisted of collecting the dataset, preprocessing, creating the individual and ensemble models, evaluating the models based on ADNI data, and validating the trained model based on the local dataset. The proposed method was an ensemble approach selected through a comparative analysis of various ensemble scenarios. Finally, the six best individual CNN-based classifiers were selected to combine and constitute the ensemble model. The evaluation showed an accuracy rate of 98.57, 96.37, 94.22, 99.83, 93.88, and 93.92 for NC/AD, NC/EMCI, EMCI/LMCI, LMCI/AD, four-way and three-way classification groups, respectively. The validation results on the local dataset revealed an accuracy of 88.46 for three-way classification. Our performance results were higher than most reviewed studies and comparable with others. Although comparative analysis showed superior results of ensemble methods against individual architectures, there were no significant differences among various ensemble approaches. The validation results revealed the low performance of individual models in practice. In contrast, the ensemble method showed promising results. However, further studies on various and larger datasets are required to validate the generalizability of the model.

Parkinsonism as an initial presentation of Creutzfeldt-Jakob disease: A case report and review of literature.

Key Clinical Message: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, fatal neurodegenerative disorder. This case highlights parkinsonism as a rare initial manifestation of sporadic CJD (sCJD), emphasizing the need for heightened clinical awareness to prevent misdiagnosis. Early and accurate diagnosis of sCJD is crucial for preventing potential iatrogenic transmission and optimizing patient management. Abstract: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative illness. While movement disorders may be present at the onset of the disease in about half of those with sporadic CJD (sCJD), parkinsonism is a rare initial presentation. In this article, we report a case of CJD with parkinsonism as the initial presentation of the disease. We report a 69-year-old lady with initial symptoms of gait difficulty, tremor, and bradykinesia. Later, she developed cognitive impairment, ataxia, chin tremor, and myoclonic jerks. Her condition worsened to the point of akinetic mutism. She was diagnosed with probable sCJD after detecting protein 14-3-3 in her cerebrospinal fluid and observing typical imaging features.This case report illustrates important aspects of an inevitably fatal and rapidly progressing disease's early presentation and clinical features. The uncommon initial presentations of sCJD should be considered with the intent of preventing misdiagnosis in the future. Early diagnosis of sCJD can prevent possible iatrogenic disease transmission and improve patient care.

Is Montreal Cognitive Assessment a valuable test for the differentiation of Alzheimer's disease, frontotemporal dementia, dementia with Lewy body, and vascular dementia?

Dementia is one of the growing diseases in the world and has different types based on its definition. The Montreal Cognitive Assessment (MoCA) test has been employed to screen patients with dementia, cognitive impairment, and disruption of daily activities. Objective: This study examined the diagnostic value of the total MoCA score and its subscores in differentiating Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy body (DLB), and vascular dementia (VaD). Methods: A total of 241 patients (AD=110, FTD=90, DLB=28, and VaD=13) and 59 healthy persons, who were referred to a dementia clinic with memory impairment in Firoozgar Hospital, were included in this study. MoCA tests were performed in all patients and normal persons. Results: By using the receiver operating characteristic (ROC) curve and measuring the area under the curve (AUC) for the total MoCA score in each group, AUC was 0.616, 0.681, 0.6117, and 0.583 for differentiating AD, FTD, DLB, and VaD patients, respectively. Among the groups, just the VaD group showed no significant usefulness in using the total MoCA score to differentiate it. To compare MoCA subscores, AD patients had higher scores in digit span, literal fluency, and abstraction but lower delayed recall scores compared with FTD patients. Conclusion: The total MoCA score and its subscores could not differentiate people with different types of dementia in the setting of screening.

A demência é uma das doenças que mais cresce no mundo e possui diferentes tipos de acordo com sua definição. O teste de Avaliação Cognitiva de Montreal (Montreal Cognitive Assessment ­ MoCA) tem sido empregado para a triagem de pacientes com demência, comprometimento cognitivo e perturbação das atividades diárias. Objetivo: Este estudo examinou o valor diagnóstico da pontuação total do MoCA e seus subescores na diferenciação entre doença de Alzheimer (DA), demência frontotempotal (DFT), demência com corpos de Lewy (DCL) e demência vascular (DV). Métodos: Este estudo incluiu 241 pacientes (DA=110, DFT=90, DCL=28 e DV=13) e 59 pessoas saudáveis, encaminhados à clínica de demência com comprometimento de memória no Hospital Firoozgar. O teste MoCA foi realizado em todos os pacientes e pessoas normais. Resultados: Usando a curva característica de operação do receptor (ROC) e medindo a área sob a curva (AUC) para a pontuação total do MoCA em cada grupo, a AUC foi de 0,616, 0,681, 0,6117 e 0,583 para diferenciar pacientes com DA, DFT, DCL e DV, respectivamente. Entre os grupos, apenas o grupo DV não mostrou utilidade significativa no uso do escore total do MoCA para diferenciá-lo. Para comparar os subescores do MoCA, os pacientes com DA tiveram pontuações mais altas em amplitude de dígitos, fluência verbal e abstração, mas menor pontuação de recordação tardia em comparação com pacientes com DFT. Conclusão: A pontuação total do MoCA e seus subescores não conseguiram diferenciar pessoas com diferentes tipos de demência no contexto da triagem.

Treatment of verb tense inflection and sentence production in Persian individuals with agrammatism.

Production of verb morphology, especially tense inflection, is usually impaired in individuals with agrammatism. There have been relatively few studies on treatment of verb tense inflection in agrammatic aphasia. In this study we adapted ACTION (a linguistically motivated treatment) to Persian language, to treat the production of regular and irregular verbs separately in sentence context. A single-subject multiple-baseline across behaviors design was used to establish the treatment effect. Using a non-probable convenience sampling, four Persian agrammatic patients with Broca's aphasia resulting from cerebrovascular accident (CVA) were recruited for this study. Two participants received treatment first for regular verbs (Phase 1, 4 weeks), and then for irregular verbs (Phase 2, 4 weeks). The other two participants received treatment in reverse order. In the final phase of treatment (Phase 3, 4 weeks), all 4 participants underwent a sentence construction treatment. All participants showed improvement in the production of trained tenses. Treatment also generalized to production of untrained regular verbs while generalization to irregular verbs was modest. Furthermore, improvement was found on narrative scores (e.g. MLU) after treatment. These findings suggest that Persian individuals with agrammatism could be trained to correctly apply temporal information to verb inflection in elicited speech.

Validity and reliability of the Persian version of Mini-Addenbrooke's Cognitive Examination among Iranian highly educated older adults.

BACKGROUND: Limited studies have examined psychometric properties of dementia screening tools in university-educated older adults. We aimed to examine this population's diagnostic accuracy of the Iranian version of Mini-Addenbrooke's Cognitive Examination (M-ACE). MATERIALS & METHODS: Eighty-seven participants with over 60 years with university education were divided into three groups: Major neurocognitive disorder, mild neurocognitive disorder, and healthy control. The Iranian version of M-ACE, the Mini-Mental State Examination (MMSE), the Geriatric Depression Scale (GDS), the Activities of Daily Living-Instrumental Activities of Daily Living (ADL-IADL) scale and Diagnostic and Statistical Manual of Mental Disorders 5th edition-Text Revision (DSM-5) were used. RESULTS: A high internal reliability of questionnaire was confirmed by Cronbach's alpha coefficient. One-way ANOVA and post hoc analysis confirmed a significant difference between study groups. The scores of M-ACE were found to have a high positive correlation with MMSE, IADL, ADL, and a moderate correlation with GDS. The optimal cutoff score of M-ACE to screen for mild and major neurocognitive disorders were 27.5 and 20.5, respectively. CONCLUSION: The M-ACE was a concise and reliable tool used to identify neurocognitive disorders in highly educated older adults, but they should be evaluated at a higher traditional cut score in earlier stages.

Language abnormalities in Alzheimer's disease indicate reduced informativeness.

OBJECTIVE: This study aims to elucidate the cognitive underpinnings of language abnormalities in Alzheimer's Disease (AD) using a computational cross-linguistic approach and ultimately enhance the understanding and diagnostic accuracy of the disease. METHODS: Computational analyses were conducted on language samples of 156 English and 50 Persian speakers, comprising both AD patients and healthy controls, to extract language indicators of AD. Furthermore, we introduced a machine learning-based metric, Language Informativeness Index (LII), to quantify empty speech. RESULTS: Despite considerable disparities in surface structures between the two languages, we observed consistency across language indicators of AD in both English and Persian. Notably, indicators of AD in English resulted in a classification accuracy of 90% in classifying AD in Persian. The substantial degree of transferability suggests that the language abnormalities of AD do not tightly link to the surface structures specific to English. Subsequently, we posited that these abnormalities stem from impairments in a more universal aspect of language production: the ability to generate informative messages independent of the language spoken. Consistent with this hypothesis, we found significant correlations between language indicators of AD and empty speech in both English and Persian. INTERPRETATION: The findings of this study suggest that language impairments in AD arise from a deficit in a universal aspect of message formation rather than from the breakdown of language-specific morphosyntactic structures. Beyond enhancing our understanding of the psycholinguistic deficits of AD, our approach fosters the development of diagnostic tools across various languages, enhancing health equity and biocultural diversity.

Nonconvulsive status epilepticus as an unusual presentation of tuberculous meningoencephalitis: A case report.

We describe a 50-year-old woman who was recently diagnosed with tuberculosis, with acute alteration in mental status. EEG showed nonconvulsive status epilepticus features. Brain MRI revealed multiple ring-enhancing lesions. She responded well to treatment for both status epilepticus and tuberculosis. Her level of consciousness improved and she became fully aware.

Mononeuropathy multiplex as an uncommon presentation of intravascular lymphoma: A case report.

Key Clinical Message: Although intravascular lymphoma rarely presents with peripheral neuropathy, learning about this presentation can lead to timely diagnosis and improved prognosis in patients with intravascular lymphoma. Abstract: A 64-year-old man presented with asymmetric paresthesia and subsequent weakness of his feet and a 10 kg weight loss over 40 days. Electrodiagnostic studies revealed distal axonal sensory-motor polyneuropathy with ongoing axonal loss. A peroneal nerve biopsy showed intravascular proliferation of CD-20 positive lymphocytes, which suggested intravascular large B-cell lymphoma.

Alzheimer's Disease and Mild Cognitive Impairment Serious Games: A Systematic Analysis in Smartphone Application Markets.

BACKGROUND: Patients with Alzheimer's disease and mild cognitive impairment can employ serious games to assess and improve their cognitive status. OBJECTIVES: To determine the cognitive aspects of the MMSE and ACE-R tests that are supported by available games. METHODS: We searched cognitive games available in online application markets (Play Store, Galaxy Store, and App Store) using keywords: Alzheimer's Disease, dementia, and mild cognitive impairment. Game scenarios were extracted and assessed by a neurologist to determine the appropriateness of the scenarios for patients and cognitive aspects supported by the games. RESULTS: We found 416 games; 135 of them were duplicates, and 237 of them were completely irrelevant to the study objective. A neurologist evaluated the remaining scenarios to see if aspects of each scenario matched the MMSE and ACE- R tests. There were 37 scenarios left in the end. These scenarios are associated with 18 different games. Most of the available scenarios are suitable for attention and orientation. CONCLUSION: Existing cognitive games may be used to several different cognitive aspects. Some of these scenarios have been used to assess cognitive status, while others have been used to improve it. The majority of available cognitive games have not been subjected to any research. As a result, it is unclear what impact they could have on the cognitive condition of the elderly with cognitive impairment. As a result, it is critical to assess these games.

Repetitive Suicidal Behaviors in a Case With a New Mutation of Wolfram Syndrome: A Jump From the Gene to the Behavior.

Wolfram syndrome (WS) is a rare autosomal recessive neurodegenerative disease with variable symptoms, including neuropsychiatric manifestations. A 26-year-old man was reported with classic symptoms of WS and repetitive psychiatric hospitalizations and at least 16 suicidal attempts. The genetic study demonstrated a novel homozygous stop-codon mutation on the WFS1 gene. This special type of mutation may be related to repetitive suicidal behaviors in this case of WS. Psychological support should be a routine practice in patients with WS.

Cerebral venous sinus thrombosis associated with COVID-19: a case series and literature review.

BACKGROUND: Since the emergence of COVID-19 pandemic, several cases of cerebral venous sinus thrombosis (CVST) have been reported in SARS-CoV-2 infected individuals. METHODS: Consecutive patients with documented SARS-CoV-2 infection, as well as clinical and radiological characteristics of CVST, were reported from three teaching hospitals in the South West, North West, and the center of Iran between June and July 2020. We also searched the abstract archives until the end of August 2020 and gathered 28 reported cases. The diagnostic criteria for SARS-CoV-2 infection were determined according to SARS-CoV-2 detection in oropharyngeal or nasopharyngeal samples in clinically suspected patients. Demographics, prominent COVID-19 symptoms, confirmatory tests for SARS-CoV-2 infection diagnosis, the interval between the diagnosis of SARS-CoV-2 infection and CVST, clinical and radiological features of CVST, therapeutic strategies, CVST outcomes, rate of hemorrhagic transformation, and mortality rate were investigated. RESULTS: Six patients (31-62 years-old) with confirmed CVST and SARS-CoV-2 infection were admitted to our centers. Four patients had no respiratory symptoms of SARS-CoV-2 infection. Five patients developed the clinical manifestations of CVST and SARS-CoV-2 infection simultaneously. Three patients had known predisposing factors for CVST. Despite receiving CVST and SARS-CoV-2 infection treatments, four patients died. SARS-COV-2 associated CVST patients were older (49.26 vs. 37.77 years-old), had lower female/male ratio (1.42 vs. 2.19), and higher mortality rate (35.29% vs. 6.07%) than CVST not associated with COVID-19. CONCLUSIONS: The role of SARS-CoV-2 as a "cause" versus an "additive contributor" remains to be elucidated. Practitioners should be aware of the possibility of CVST in SARS-CoV-2 infection.

Agenesis of the corpus callosum: a rare association with Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome (EDS) is a rare congenital disorder of connective tissues which involves the skin and musculoskeletal system. There are also some reports for the involvement of the central and peripheral nervous systems. We want to present a very rare coassociation of EDS, spondylolisthesis, and Agenesis of the corpus callosum in an Iranian lady.

Neuropsychiatric manifestations of COVID-19 can be clustered in three distinct symptom categories.

Several studies have reported clinical manifestations of the new coronavirus disease. However, few studies have systematically evaluated the neuropsychiatric complications of COVID-19. We reviewed the medical records of 201 patients with confirmed COVID-19 (52 outpatients and 149 inpatients) that were treated in a large referral center in Tehran, Iran from March 2019 to May 2020. We used clustering approach to categorize clinical symptoms. One hundred and fifty-one patients showed at least one neuropsychiatric symptom. Limb force reductions, headache followed by anosmia, hypogeusia were among the most common neuropsychiatric symptoms in COVID-19 patients. Hierarchical clustering analysis showed that neuropsychiatric symptoms group together in three distinct groups: anosmia and hypogeusia; dizziness, headache, and limb force reduction; photophobia, mental state change, hallucination, vision and speech problem, seizure, stroke, and balance disturbance. Three non-neuropsychiatric cluster of symptoms included diarrhea and nausea; cough and dyspnea; and fever and weakness. Neuropsychiatric presentations are very prevalent and heterogeneous in patients with coronavirus 2 infection and these heterogeneous presentations may be originating from different underlying mechanisms. Anosmia and hypogeusia seem to be distinct from more general constitutional-like and more specific neuropsychiatric symptoms. Skeletal muscular manifestations might be a constitutional or a neuropsychiatric symptom.