Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies.

Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer's Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.

Cognitive symptoms progress with limbic-predominant age-related TDP-43 encephalopathy stage and co-occurrence with Alzheimer disease.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a neuropathologic entity characterized by transactive response DNA-binding protein of 43-kDa (TDP-43)-immunoreactive inclusions that originate in the amygdala and then progress to the hippocampi and middle frontal gyrus. LATE-NC may mimic Alzheimer disease clinically and often co-occurs with Alzheimer disease neuropathologic change (ADNC). This report focuses on the cognitive effects of isolated and concomitant LATE-NC and ADNC. Cognitive/neuropsychological, neuropathologic, genetic, and demographic variables were analyzed in 28 control, 31 isolated LATE-NC, 244 isolated ADNC, and 172 concurrent LATE-NC/ADNC subjects from the National Alzheimer's Coordinating Center. Cases with LATE-NC and ADNC were significantly older than controls; cases with ADNC had a significantly higher proportion of cases with at least one APOE ε4 allele. Both LATE-NC and ADNC exhibited deleterious effects on overall cognition proportional to their neuropathological stages; concurrent LATE-NC/ADNC exhibited the worst overall cognitive effect. Multivariate logistic regression analysis determined an independent risk of cognitive impairment for progressive LATE-NC stages (OR 1.66; p = 0.0256) and ADNC levels (OR 3.41; p < 0.0001). These data add to the existing knowledge on the clinical consequences of LATE-NC pathology and the growing literature on the effects of multiple concurrent neurodegenerative pathologies.

Successful treatment with subcutaneous ofatumumab in an adolescent patient with refractory myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disease (MOGAD).

Preventing relapse of myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disease (MOGAD) with steroids and immunosuppressants is sometimes difficult. There is no standard treatment for refractory cases. We present the case of a 17-year-old female patient with longitudinally extensive myelitis, asymptomatic bilateral optic neuritis, and positive serum MOG-IgG. While taking steroids and several immunosuppressants during the following 14 months, she suffered from two symptomatic relapses in the cerebrum and spinal cord, and multiple asymptomatic relapses in the cerebrum. The patient was negative for MOG-IgG at the second relapse of myelitis. Subcutaneous ofatumumab has suppressed relapse for 13 months. Ofatumumab can be considered a therapeutic option for refractory MOGAD.

High-dose immunoglobulin-dependent chronic demyelinating inflammatory polyneuropathy successfully managed with subcutaneous immunoglobulin using pharmacokinetic analysis.

Immunoglobulin G therapy for chronic inflammatory demyelinating polyneuropathy (CIDP) often requires individual dose adjustments because of the heterogeneity of pathogenesis and varying catabolic rates. However, currently available pharmacokinetic studies of immunoglobulin G therapy do not consider individual differences. We conducted a pharmacokinetic study of both intravenous immunoglobulin and subcutaneous immunoglobulin in a single patient with CIDP who was dependent on high-dose immunoglobulin treatment. This patient-a 77-year-old man with symmetrical limb weakness, diffuse demyelination determined by a nerve conduction study, and lacking autoantibodies-was treated with intravenous immunoglobulin and experienced severe fluctuations in symptoms. We transitioned him to subcutaneous immunoglobulin: his serum immunoglobulin G levels stabilised and he experienced symptomatic relief. Monitoring of serum immunoglobulin G concentrations revealed volatile changes following intravenous immunoglobulin administration which stabilised following subcutaneous immunoglobulin treatment. This suggests that subcutaneous immunoglobulin is a preferable long-term treatment option, especially for high-dose immunoglobulin-dependent patients with CIDP.

Isolated progression of miliary brain metastasis in a patient with stable lung adenocarcinoma successfully treated with whole-brain radiotherapy: A case report.

Miliary brain metastasis is a rare form of metastasis commonly associated with advanced stages of cancer. In this article, we report a case of a 38-year-old male with solitary progression of miliary brain metastasis originating from stage 4 EML-ALK-positive lung adenocarcinoma. Multiple brain lesions were first detected upon the patient's inclusion in a brigatinib clinical trial. The brain lesions dissipated, and the lung and bone lesions decreased in size after starting the brigatinib therapy; however, the brain lesions later increased in number. A biopsy revealed miliary brain metastasis of lung adenocarcinoma. The patient was successfully treated with whole brain therapy, in addition to brigatinib. This case suggests that it is possible for an isolated miliary brain metastasis to occur during the effective suppression of systemic cancer progression. Whole brain radiotherapy while continuing effective systemic therapy is a good strategy for such patients.

Neurological Manifestations and Long-term Sequelae in Hospitalized Patients with COVID-19.

Objective Various neurological manifestations have been increasingly reported in coronavirus disease 2019 (COVID-19). We determined the neurological features and long-term sequelae in hospitalized COVID-19 patients. Methods We retrospectively studied 95 consecutive hospitalized patients with COVID-19 between March 1 and May 13, 2020. Acute neurological presentations (within two weeks of the symptom onset of COVID-19) were compared between 60 non-severe and 35 severely infected patients who required high-flow oxygen. In the 12 ventilated patients (the most severe group), we evaluated neurological complications during admission, subacute neurological presentations, and neurological sequelae (51 and 137 days from the onset [median], respectively). Results Of the 95 patients (mean age 53 years old; 40% women), 63% had acute neurological presentations, with an increased prevalence in cases of severe infections (83% vs. 52%, p<0.001). Impaired consciousness and limb weakness were more frequent in severe patients than in non-severe ones (0% vs. 49%; p<0.001, and 0% vs. 54%; p<0.001, respectively). In the most severe group (mean age 72 years old; 42% women), 83% of patients had neurological complications [cerebrovascular disease (17%), encephalopathy (82%), and neuropathy (55%)], and 92% had subacute neurological presentations [impaired consciousness (17%), higher brain dysfunction (82%), limb weakness (75%), and tremor (58%)]. Neurological sequelae were found in 83% of cases, including higher brain dysfunction (73%), limb weakness (50%), and tremor (58%). Conclusions Neurological manifestations are common in COVID-19, with the possibility of long-lasting sequelae.