Short- and long-term outcome and predictors in an international cohort of patients with neuro-COVID-19.

BACKGROUND AND PURPOSE: Despite the increasing number of reports on the spectrum of neurological manifestations of COVID-19 (neuro-COVID), few studies have assessed short- and long-term outcome of the disease. METHODS: This is a cohort study enrolling adult patients with neuro-COVID seen in neurological consultation. Data were collected prospectively or retrospectively in the European Academy of Neurology NEuro-covid ReGistrY ((ENERGY). The outcome at discharge was measured using the modified Rankin Scale and defined as 'stable/improved' if the modified Rankin Scale score was equal to or lower than the pre-morbid score, 'worse' if the score was higher than the pre-morbid score. Status at 6 months was also recorded. Demographic and clinical variables were assessed as predictors of outcome at discharge and 6 months. RESULTS: From July 2020 to March 2021, 971 patients from 19 countries were included. 810 (83.4%) were hospitalized. 432 (53.3%) were discharged with worse functional status. Older age, stupor/coma, stroke and intensive care unit (ICU) admission were predictors of worse outcome at discharge. 132 (16.3%) died in hospital. Older age, cancer, cardiovascular complications, refractory shock, stupor/coma and ICU admission were associated with death. 262 were followed for 6 months. Acute stroke or ataxia, ICU admission and degree of functional impairment at discharge were predictors of worse outcome. 65/221 hospitalized patients (29.4%) and 10/32 non-hospitalized patients (24.4%) experienced persisting neurological symptoms/signs. 10/262 patients (3.8%) developed new neurological complaints during the 6 months of follow-up. CONCLUSIONS: Neuro-COVID is a severe disease associated with worse functional status at discharge, particularly in older subjects and those with comorbidities and acute complications of infection.

Transcranial magnetic stimulation and amyloid markers in mild cognitive impairment: impact on diagnostic confidence and diagnostic accuracy.

BACKGROUND: The development of diagnostic tools capable of accurately identifying the pathophysiology of mild cognitive impairment (MCI) has become a crucial target considering the claim that disease-modifying treatments should be administered as early as possible in the disease course. Transcranial magnetic stimulation (TMS) protocols have demonstrated analytical validity in discriminating different forms of dementia; however, its value in daily clinical practice in MCI subjects is still unknown. OBJECTIVE: To evaluate the clinical value of TMS compared to amyloid markers on diagnostic confidence and accuracy in MCI subjects, considering clinicians' expertise. METHODS: One hundred seven MCI subjects were included and classified as MCI-Alzheimer disease (MCI-AD), MCI-frontotemporal dementia (MCI-FTD), MCI-dementia with Lewy bodies (MCI-DLB), or MCI-other in a three-step process based on (i) demographic, clinical, and neuropsychological evaluation (clinical work-up); (ii) clinical work-up PLUS amyloidosis markers or clinical work-up PLUS TMS measures; and (iii) clinical work-up PLUS both markers. Two blinded neurologists with different clinical expertise were asked to express a diagnostic confidence for each MCI subgroup, and ROC curve analyses were performed at each step. RESULTS: The addition of TMS markers to clinical work-up significantly increased the diagnostic confidence for MCI-AD (p = 0.003), MCI-FTD (p = 0.044), and MCI-DLB (p = 0.033) compared to clinical work-up alone, but not for MCI-other (p > 0.05). No significant differences between the add-on effect of TMS and the add-on effect of amyloid markers to clinical work-up were observed (p > 0.732), while the diagnostic confidence further increased when both markers were available. The greater the clinical expertise, the greater the flexibility in considering alternative diagnosis, and the greater the ability to modify diagnostic confidence with TMS and amyloid markers. CONCLUSIONS: TMS in addition to routine clinical assessment in MCI subjects has a significant effect on diagnostic accuracy and confidence, comparable to well-established biomarkers of amyloidosis.

The impact of transcranial magnetic stimulation on diagnostic confidence in patients with Alzheimer disease.

BACKGROUND: Cholinergic dysfunction is a key abnormality in Alzheimer disease (AD) that can be detected in vivo with transcranial magnetic stimulation (TMS) protocols. Although TMS has clearly demonstrated analytical validity, its clinical utility is still debated. In the present study, we evaluated the incremental diagnostic value, expressed in terms of diagnostic confidence of Alzheimer disease (DCAD; range 0-100), of TMS measures in addition to the routine clinical diagnostic assessment in patients evaluated for cognitive impairment as compared with validated biomarkers of amyloidosis. METHODS: One hundred twenty patients with dementia were included and scored in terms of DCAD in a three-step assessment based on (1) demographic, clinical, and neuropsychological evaluations (clinical work-up); (2) clinical work-up plus amyloid markers (cerebrospinal fluid or amyloid positron emission tomographic imaging); and (3) clinical work-up plus TMS intracortical connectivity measures. Two blinded neurologists were asked to review the diagnosis and diagnostic confidence at each step. RESULTS: TMS measures increased the discrimination of DCAD in two clusters (AD-like vs FTD-like) when added to the clinical and neuropsychological evaluations with levels comparable to established biomarkers of brain amyloidosis (cluster distance of 55.1 for clinical work-up alone, 76.0 for clinical work-up plus amyloid markers, 80.0 for clinical work-up plus TMS). Classification accuracy for the "gold standard" diagnosis (dichotomous - AD vs FTD - variable) evaluated in the three-step assessment, expressed as AUC, increased from 0.82 (clinical work-up alone) to 0.98 (clinical work-up plus TMS) and to 0.99 (clinical work-up plus amyloidosis markers). CONCLUSIONS: TMS in addition to routine assessment in patients with dementia has a significant effect on diagnosis and diagnostic confidence that is comparable to well-established amyloidosis biomarkers.

Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly.

The pathway leading from amyloid-ß deposition to cognitive impairment is believed to be a cornerstone of the pathogenesis of Alzheimer's disease (AD). However, what drives amyloid buildup in sporadic nongenetic cases of AD is still unknown. AD brains feature an inflammatory reaction around amyloid plaques, and a specific subset of the gut microbiota (GMB) may promote brain inflammation. We investigated the possible role of the GMB in AD pathogenesis by studying the association of brain amyloidosis with (1) GMB taxa with pro- and anti-inflammatory activity; and (2) peripheral inflammation in cognitively impaired patients. We measured the stool abundance of selected bacterial GMB taxa (Escherichia/Shigella, Pseudomonas aeruginosa, Eubacterium rectale, Eubacterium hallii, Faecalibacterium prausnitzii, and Bacteroides fragilis) and the blood expression levels of cytokines (pro-inflammatory cytokines: CXCL2, CXCL10, interleukin [IL]-1ß, IL-6, IL-18, IL-8, inflammasome complex (NLRP3), tumor necrosis factor-alpha [TNF-α]; anti-inflammatory cytokines: IL-4, IL-10, IL-13) in cognitively impaired patients with (n = 40, Amy+) and with no brain amyloidosis (n = 33, Amy-) and also in a group of controls (n = 10, no brain amyloidosis and no cognitive impairment). Amy+ patients showed higher levels of pro-inflammatory cytokines (IL-6, CXCL2, NLRP3, and IL-1ß) compared with both controls and with Amy- patients. A reduction of the anti-inflammatory cytokine IL-10 was observed in Amy+ versus Amy-. Amy+ showed lower abundance of E. rectale and higher abundance of Escherichia/Shigella compared with both healthy controls (fold change, FC = -9.6, p < 0.001 and FC = +12.8, p < 0.001, respectively) and to Amy- (FC = -7.7, p < 0.001 and FC = +7.4, p = 0.003). A positive correlation was observed between pro-inflammatory cytokines IL-1ß, NLRP3, and CXCL2 with abundance of the inflammatory bacteria taxon Escherichia/Shigella (rho = 0.60, p < 0.001; rho = 0.57, p < 0.001; and rho = 0.30, p = 0.007, respectively) and a negative correlation with the anti-inflammatory E. rectale (rho = -0.48, p < 0.001; rho = -0.25, p = 0.024; rho = -0.49, p < 0.001). Our data indicate that an increase in the abundance of a pro-inflammatory GMB taxon, Escherichia/Shigella, and a reduction in the abundance of an anti-inflammatory taxon, E. rectale, are possibly associated with a peripheral inflammatory state in patients with cognitive impairment and brain amyloidosis. A possible causal relation between GMB-related inflammation and amyloidosis deserves further investigation.

Assessment of the Incremental Diagnostic Value of Florbetapir F 18 Imaging in Patients With Cognitive Impairment: The Incremental Diagnostic Value of Amyloid PET With [18F]-Florbetapir (INDIA-FBP) Study.

IMPORTANCE: Cerebral amyloidosis is a key abnormality in Alzheimer disease (AD) and can be detected in vivo with positron emission tomography (PET) ligands. Although amyloid PET has clearly demonstrated analytical validity, its clinical utility is debated. OBJECTIVE: To evaluate the incremental diagnostic value of amyloid PET with florbetapir F 18 in addition to the routine clinical diagnostic assessment of patients evaluated for cognitive impairment. DESIGN, SETTING, AND PARTICIPANTS: The Incremental Diagnostic Value of Amyloid PET With [18F]-Florbetapir (INDIA-FBP) Study is a multicenter study involving 18 AD evaluation units from eastern Lombardy, Northern Italy, 228 consecutive adults with cognitive impairment were evaluated for AD and other causes of cognitive decline, with a prescan diagnostic confidence of AD between 15% and 85%. Participants underwent routine clinical and instrumental diagnostic assessment. A prescan diagnosis was made, diagnostic confidence was estimated, and drug treatment was provided. At the time of this workup, an amyloid PET/computed tomographic scan was performed, and the result was communicated to physicians after workup completion. Physicians were asked to review the diagnosis, diagnostic confidence, and treatment after the scan. The study was conducted from August 5, 2013, to December 31, 2014. MAIN OUTCOMES AND MEASURES: Primary outcomes were prescan to postscan changes of diagnosis, diagnostic confidence, and treatment. RESULTS: Of the 228 participants, 107 (46%) were male; mean (SD) age was 70.5 (7) years. Diagnostic change occurred in 46 patients (79%) having both a previous diagnosis of AD and an amyloid-negative scan (P < .001) and in 16 (53%) of those with non-AD diagnoses and an amyloid-positive scan (P < .001). Diagnostic confidence in AD diagnosis increased by 15.2% in amyloid-positive (P < .001; effect size Cohen d = 1.04) and decreased by 29.9% in amyloid-negative (P < .001; d = -1.19) scans. Acetylcholinesterase inhibitors and memantine hydrochloride were introduced in 61 (65.6%) patients with positive scan results who had not previously received those drugs, and the use of the drugs was discontinued in 6 (33.3%) patients with negative scan results who were receiving those drugs (P < .001). CONCLUSIONS AND RELEVANCE: Amyloid PET in addition to routine assessment in patients with cognitive impairment has a significant effect on diagnosis, diagnostic confidence, and drug treatment. The effect on health outcomes, such as morbidity and mortality, remains to be assessed.

Course and management of allogeneic stem cell transplantation in patients with mitochondrial neurogastrointestinal encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase (TP). Allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as a treatment for patients with MNGIE and a standardized approach to HSCT in this condition has recently been developed. We report on the transplant course, management and short-term follow-up in two MNGIE patients who underwent HSCT. The source of stem cells was bone marrow taken from an HLA 9/10 allele-matched unrelated donor in the first patient and from an HLA 10/10 allele-matched sibling donor in the second. Both patients achieved full donor chimerism, and we observed restoration of buffy coat TP activity and lowered urine nucleoside concentrations in both of them. The post-transplant clinical follow-up showed improvement in gastrointestinal dysmotility, abdominal cramps and diarrhea. Neurological assessment remained unchanged. However, the first patient died 15 months after HSCT due to gastrointestinal obstruction and shock; the second patient died 8 months after the procedure due to respiratory distress following septic shock. Although HSCT corrects biochemical abnormalities and improves gastrointestinal symptoms, the procedure can be risky in subjects already in poor medical condition as are many MNGIE patients. Since transplant-related morbidity and mortality increases with progression of the disease and number of comorbidities, MNGIE patients should be submitted to HSCT when they are still relatively healthy, in order to minimize the complications of the procedure. Anyway, there is still incomplete knowledge on the natural history of the disease in many affected patients and it is not yet clear when the best time to do a transplant is. Further clues to the therapeutic potential of HSCT could result from a prolonged observation in a greater number of non-transplanted and transplanted patients, which would allow us to answer the questions of if, how and when MNGIE patients require HSCT treatment.

Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency with unknown genetic defect.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare autosomal recessively inherited disorder of fatty acid metabolism due to ETFA, ETFB or ETFDH mutations. Riboflavin treatment ameliorates symptoms and metabolic profile in ETFDH-related MADD patients. We report on a 20-year-old boy with an 8-year history of progressive difficulty in walking, running and climbing stairs. Muscle biopsy showed a lipid myopathy and the acylcarnitine profile analysis was suggestive of MADD. Nevertheless, no evidence of molecular defects in the ETFA, ETFB and ETFDH exons or intron-exon boundaries was found. Treatment with riboflavin for 1 year resulted in a clear improvement in motor functions. Our report shows that some cases of MADD are not linked to ETFA, ETFB and ETFDH exon or intron-exon boundary changes. They could be due to quite rare promoter or deep intronic mutations or, most likely, to some unknown genetic defect. We therefore suggest to extend in these cases molecular studies to cDNA analysis and indicate the need of extensive pedigree studies to identify other possible disease-related loci. Most important, treatment of these cases with riboflavin can also be effective. Therefore, early diagnosis is essential to achieve the best treatment response.

Pitfalls in diagnosing mitochondrial neurogastrointestinal encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase and is characterized by external ophthalmoparesis, gastrointestinal dysmotility, leukoencephalopathy, and neuropathy. The availability of new therapeutic options (peritoneal dialysis, allogeneic stem cell transplantation, enzyme replacement) makes it necessary to diagnose the disease early, which is not always achieved due to the difficulty in recognizing this disorder, especially in case of atypical presentation. We describe three MNGIE patients with atypical onset of the disease. In the first patient the main symptoms were long-standing chronic fever, recurrent acute migrant arthritis, and gastrointestinal disorders mimicking autoimmune or inflammatory intestinal diseases; the second patient complained only of exercise intolerance and muscle cramps, and the third patient had a CIDP-like polyneuropathy. This study stresses the insidious heterogeneous clinical onset of some cases of MNGIE, expands the spectrum of the phenotype, and suggests considering MNGIE in the differential diagnosis of enteropathic arthritis, isolated exercise intolerance, and inflammatory polyneuropathies not responsive to the usual treatment. A better understanding of the clinical heterogeneity of MNGIE is necessary in order to diagnose atypical cases and promote early diagnosis, which is now absolutely necessary in view of the new available therapies.

Current options in the treatment of mitochondrial diseases.

Mitochondrial diseases (MD) are disorders caused by an impairment of the mitochondrial respiratory chain function. They are usually progressive, isolated or multi-system diseases and have variable times of onset. Because mitochondria have their own DNA (mtDNA), MD can be caused by mutations in both mtDNA and nuclear DNA (nDNA). The complexity of genetic control of mitochondrial function is in part responsible for the intra- and inter-familiar clinical heterogeneity of this class of diseases. Despite the remarkable progress in understanding of the molecular bases of these disorders, therapy of MD is quite inadequate. Present options of treatment mainly include physical, pharmacological and gene therapy approaches. Aerobic exercise and physical therapy is useful to prevent or correct deconditioning and may improve exercise tolerance. Pharmacological approach is based on removing noxious metabolites, using reactive oxygen species scavengers and administrating vitamins and cofactors which is especially important in case of primary deficiencies of specific compounds such as Coenzyme Q10. Gene therapy is fascinating but it is difficult to apply because of polyplasmy and heteroplasmy. Experimental methods include gene shifting, allotopic expression, mitochondrial transfection or correcting mtDNA mutations with specific restriction endonucleases. Here, we discussed some recent patents. Progresses in each of these fields may open interesting perspectives for the future.