Monthlong Intubated Patient with Life-Threatening COVID-19 and Cerebral Microbleeds Suffers Only Mild Cognitive Sequelae at 8-Month Follow-up: A Case Report.

OBJECTIVE: To elaborate on possible cognitive sequelae related to COVID-19, associated cerebrovascular injuries as well as the general consequences from intensive care. COVID-19 is known to have several, serious CNS-related consequences, but neuropsychological studies of severe COVID-19 are still rare. METHODS: M., a 45-year-old man, who survived a severe COVID-19 disease course including Acute Respiratory Distress Syndrome (ARDS), cerebral microbleeds, and 35 days of mechanical ventilation, is described. We elaborate on M's recovery and rehabilitation process from onset to the 8-month follow-up. The cognitive functions were evaluated with a comprehensive screening battery at 4 weeks after extubation and at the 8-month follow-up. RESULTS: Following extubation, M. was delirious, reported visual hallucinations, and had severe sleeping difficulties. At about 3 months after COVID-19 onset, M. showed mild to moderate deficits on tests measuring processing speed, working memory, and attention. At assessments at 8 months, M. performed better, with results above average on tests measuring learning, memory, word fluency, and visuospatial functions. Minor deficits were still found regarding logical reasoning, attention, executive functioning, and processing speed. There were no lingering psychiatric symptoms. While M. had returned to a part-time job, he was not able to resume previous work-tasks. CONCLUSION: This case-study demonstrates possible cognitive deficits after severe COVID-19 and emphasizes the need of a neuropsychological follow-up, with tests sensitive to minor deficits. The main findings of this report provide some support that the long-term prognosis for cognition in severe COVID-19 may be hopeful.

Frontotemporal dementia-amyotrophic lateral sclerosis complex is simulated by neurodegeneration with brain iron accumulation.

We describe a case of late onset neurodegeneration with brain iron accumulation (NBIA) presenting as frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS). A male patient presented at age 66 with change of personality: disinhibition, emotional blunting, and socially inappropriate behavior, coupled with dysarthria, dystonia, and corticospinal tract involvement. Magnetic resonance imaging showed general cortical atrophy, iron deposits in the globus pallidus, and the "eye of the tiger" sign. Neuropsychologic performance was globally reduced, especially executive functions. Fluorodeoxyglucose positron emission tomography showed hypometabolism predominantly in frontal and temporal areas. Repeated neurophysiologic examinations showed signs of chronic denervation. The patient was diagnosed with NBIA but fulfilled consensus criteria for FTD and had a clinical picture of ALS, without neurophysiologic confirmation. Our finding introduces NBIA as a possible cause of FTD and as a differential diagnosis of the FTD-ALS complex.

Comparing Traditional and Digitized Cognitive Tests Used in Standard Clinical Evaluation - A Study of the Digital Application Minnemera.

The purpose of this study was to compare a new digitized cognitive test battery, Minnemera, with its correspondent traditional paper-based cognitive tests. Eighty-one healthy adults between the ages of 21 and 85 participated in the study. Participants performed the two different test versions (traditional paper-based and digitized) with an interval of four weeks between the tests. Test presentation (the order of the test versions presented) was counterbalanced in order to control for any possible test learning effects. The digitized tests were constructed so that there were only minor differences when compared to the traditional paper-based tests. Test results from the paper-based and digitized versions of the cognitive screening were compared within individuals by means of a correlation analysis and equivalence tests. The effects of demographic variables (age, gender and level of education) and test presentation were explored for each test measure and each test version through linear regression models. For each test measure, a significant correlation between traditional and digitized version was observed ranging between r = 0.34 and r = 0.67 with a median of r = 0.53 (corresponding to a large effect size). Score equivalence was observed for five out of six tests. In line with previous traditional cognitive studies, age was found to be the most prominent predictor of performance in all digitized tests, with younger participants performing better than older adults. Gender was the second strongest predictor, where women outperformed men in tests measuring verbal memory; men performed better than women in tests with a strong visual component. Finally, the educational level of the test subjects had an effect on executive functions, with a higher educational level linked to a better inhibition response and working memory span. This study suggests that the tests in the Minnemera cognitive screening battery are acceptably comparable to the traditional paper-based counterparts.

In vivo amyloid imaging with PET in frontotemporal dementia.

BACKGROUND: N-methyl[11C]2-(4'methylaminophenyl)-6-hydroxy-benzothiazole (PIB) is a positron emission tomography (PET) tracer with amyloid binding properties which allows in vivo measurement of cerebral amyloid load in Alzheimer's disease (AD). Frontotemporal dementia (FTD) is a syndrome that can be clinically difficult to distinguish from AD, but in FTD amyloid deposition is not a characteristic pathological finding. PURPOSE: The aim of this study is to investigate PIB retention in FTD. METHODS: Ten patients with the diagnosis of FTD participated. The diagnosis was based on clinical and neuropsychological examination, computed tomography or magnetic resonance imaging scan, and PET with 18 Fluoro-2-deoxy-d-glucose (FDG). The PIB retention, measured in regions of interest, was normalised to a reference region (cerebellum). The results were compared with PIB retention data previously obtained from 17 AD patients with positive PIB retention and eight healthy controls (HC) with negative PIB retention. Statistical analysis was performed with a students t-test with significance level set to 0.00625 after Bonferroni correction. RESULTS: Eight FTD patients showed significantly lower PIB retention compared to AD in frontal (p < 0.0001), parietal (p < 0.0001), temporal (p = 0.0001), and occipital (p = 0.0003) cortices as well as in putamina (p < 0.0001). The PIB uptake in these FTD patients did not differ significantly from the HC in any region. However, two of the 10 FTD patients showed PIB retention similar to AD patients. CONCLUSION: The majority of FTD patients displayed no PIB retention. Thus, PIB could potentially aid in differentiating between FTD and AD.

Anosognosia and anosodiaphoria in mild cognitive impairment and Alzheimer's disease.

AIMS: To evaluate the occurrence of anosognosia (lack of awareness) and anosodiaphoria (insouciance) in mild cognitive impairment (MCI) and Alzheimer's disease (AD) and to evaluate the influence of a worsening of dementia on these phenomena. METHODS: A self-evaluation scale was used assessing degrees of anosognosia and anosodiaphoria; furthermore, a neuropsychological assessment and statistical analyses with nonparametric tests which could cope with data on an ordinal scale level and small samples were employed. RESULTS: Cognitive ability was lower in AD (n = 9) than in MCI patients (n = 12), but AD patients self-rated lower cognitive disabilities, which is interpreted as one relative sign of anosognosia in AD. Awareness of the reasons for cognitive problems was also lower in AD, which is considered as another sign of anosognosia. The main pattern in MCI found that the higher the awareness, the lower the cognitive ability. In AD low awareness paralleled low cognitive functioning. Anosodiaphoria was present in AD but not in MCI. CONCLUSION: According to the literature anosognosia and anosodiaphoria seem to increase with progression of dementia from MCI as a result of right hemispheric alterations.

Increasing CSF phospho-tau levels during cognitive decline and progression to dementia.

BACKGROUND: Little is known about longitudinal changes of cerebrospinal fluid (CSF) biomarkers during cognitive decline in neurodegenerative disease progression. OBJECTIVE: To investigate longitudinal changes in CSF biomarkers--total-tau (T-tau), phospho-tau (P-tau) and beta-amyloid (Abeta42)--during cognitive decline. METHODS: Forty memory clinic patients (47.5% females), aged 61.3+/-7.6 (S.D.) years, non-demented at baseline, underwent lumbar puncture and neuropsychological testing at two occasions. Baseline mean MMSE-score was 28.3+/-1.8. Patients were divided into three groups based on baseline memory functioning; severely impaired (SIM), moderately impaired (MIM) and no impairment (NIM). RESULTS: There was a significant increase in P-tau in the SIM-group during follow-up, while P-tau in MIM and NIM did not change. Eighty-three percent of the SIM-patients converted to dementia (80% AD), while most MIM- and NIM-patients remained non-demented. T-tau- and Abeta42-levels did not change in any of the memory groups during follow-up. CONCLUSION: Increasing P-tau levels during cognitive decline and conversion to dementia suggest that P-tau may be useful as a longitudinal marker of the neurodegenerative process.

Insight in frontotemporal dementia: conceptual analysis and empirical evaluation of the consensus criterion "loss of insight" in frontotemporal dementia.

The objective of this study was to suggest a new formulation of the core research diagnostic consensus criterion "loss of insight" in frontotemporal dementia (FTD). Eight patients with FTD (diagnoses made by interviews, medical and neuropsychological examination, CT scan, and regional cerebral glucose metabolism measured by positron emission tomography (PET) participated in the study). The results indicated that insight was present in three out of eight patients, and that insight appears to be a heterogeneous concept. Two types of insight emerged: Emotional insight associated with frontotemporal functions, and cognitive insight, related to posterior cognitive functions. These results suggest that loss of insight should not serve as a core criterion on FTD, but serves well as a supportive criterion of the disease.

Differential CSF biomarker levels in APOE-epsilon4-positive and -negative patients with memory impairment.

OBJECTIVES: To investigate the relationships between episodic memory, APOE genotype, CSF markers (total tau, T-tau; phospho-tau, P-tau; beta-amyloid, Abeta42) and longitudinal cognitive decline. METHODS: 124 memory clinic patients were retrospectively divided into 6 groups based on (i) episodic memory function (Rey Auditory Verbal Learning Test, RAVLT): severe, moderate or no impairment (SIM, MIM or NIM), and (ii) APOE genotype (epsilon4+ or epsilon4-). CSF marker levels and cognitive decline were compared across groups. RESULTS: Episodic memory function, according to RAVLT scores, was significantly correlated with CSF marker levels only among epsilon4+ subjects and not among epsilon4- subjects. When comparing the 6 subgroups, SIM epsilon4+ and MIM epsilon4+ groups showed significantly lower Abeta42 levels than the other groups. T-tau and P-tau levels were significantly increased in SIM epsilon4+ when compared to all the other groups, including the SIM epsilon4- group. However, both SIM epsilon4+ and SIM epsilon4- declined cognitively during the follow-up. CONCLUSION: It remains to be determined whether APOE genotype affects the expression of biomarkers in CSF, or whether the different biomarker patterns reflect different types of disease processes in patients with progressive cognitive dysfunction.

Identifying patients at high and low risk of cognitive decline using Rey Auditory Verbal Learning Test among middle-aged memory clinic outpatients.

OBJECTIVES: To investigate whether application of cutoff levels in an episodic memory test (Rey Auditory Verbal Learning Test, RAVLT) is a useful method for identifying patients at high and low risk of cognitive decline and subsequent dementia. METHODS: 224 patients with memory complaints (mean age = 60.7 years, mean MMSE = 28.2) followed-up at a memory clinic over approximately 3 years were assigned retrospectively to one of three memory groups from their baseline results in RAVLT [severe (SIM), moderate (MIM) or no impairment (NIM)]. These groups were investigated regarding cognitive decline. RESULTS: Patients assigned to SIM showed significant cognitive decline and progressed to dementia at a high rate, while a normal performance in RAVLT at baseline (NIM) predicted normal cognition after 3 years. Patients with MIM constituted a heterogeneous group; some patients deteriorated cognitively, while the majority remained stable or improved. CONCLUSIONS: The application of cutoff levels in RAVLT at baseline showed that patients with severely impaired RAVLT performance were at a high risk of cognitive decline and progression to dementia, while patients with normal RAVLT results did not show cognitive decline during 3 years. Furthermore, the initial degree of memory impairment was decisive in the cognitive prognosis 3 years later.

Clinical and molecular aspects of frontotemporal dementia.

Frontotemporal dementia (FTD) is a neurodegenerative disease and next to Alzheimer's disease and vascular dementia, the third most common cause of early-onset progressive dementia. FTD leads to neurodegeneration in the frontal and temporal neocortex and usually encompasses both sides of the frontal and anterior temporal lobes. Psychologically, FTD is characterized by personality changes such as lack of insight, inappropriate behaviour, disinhibition, apathy, executive disabilities and a decline in cognitive functions, with large clinical and neuropathological variations among cases. Neuropathological characteristics include gliosis or microvacuolation of cortical nerve cells. Inclusions staining for tau protein and/or ubiquitin are also common findings. Both sporadic and hereditary forms of FTD have been identified and 30-50% of the FTD cases have a familial background. So far, at least three genetic loci for FTD have been identified, at human chromosomes 3, 9 and 17 in familial forms of the disease. A large number of the familial forms have been linked to chromosome 17q21 and referred to as frontotemporal dementia and Parkinsonism linked to chromosome 17. In the majority of these families, pathogenic mutations in the tau gene were identified. However, tau mutations seem to be a rare cause of disease in the general FTD population. Thus, other genes and/or environmental factors are yet to be identified, which will give further clues to this complex and heterogeneous disorder.