KCNA2 IgG autoimmunity in neuropsychiatric diseases.

BACKGROUND: Autoantibodies against the potassium voltage-gated channel subfamily A member 2 (KCNA2) have been described in a few cases of neuropsychiatric disorders, but their diagnostic and pathophysiological role is currently unknown, imposing challenges to medical practice. DESIGN / METHODS: We retrospectively collected comprehensive clinical and paraclinical data of 35 patients with KCNA2 IgG autoantibodies detected in cell-based and tissue-based assays. Patients' sera and cerebrospinal fluid (CSF) were used for characterization of the antigen, clinical-serological correlations, and determination of IgG subclasses. RESULTS: KCNA2 autoantibody-positive patients (n = 35, median age at disease onset of 65 years, range of 16-83 years, 74 % male) mostly presented with cognitive impairment and/or epileptic seizures but also ataxia, gait disorder and personality changes. Serum autoantibodies belonged to IgG3 and IgG1 subclasses and titers ranged from 1:32 to 1:10,000. KCNA2 IgG was found in the CSF of 8/21 (38 %) patients and in the serum of 4/96 (4.2 %) healthy blood donors. KCNA2 autoantibodies bound to characteristic anatomical areas in the cerebellum and hippocampus of mammalian brain and juxtaparanodal regions of peripheral nerves but reacted exclusively with intracellular epitopes. A subset of four KCNA2 autoantibody-positive patients responded markedly to immunotherapy alongside with conversion to seronegativity, in particular those presenting an autoimmune encephalitis phenotype and receiving early immunotherapy. An available brain biopsy showed strong immune cell invasion. KCNA2 autoantibodies occurred in less than 10 % in association with an underlying tumor. CONCLUSION: Our data suggest that KCNA2 autoimmunity is clinically heterogeneous. Future studies should determine whether KCNA2 autoantibodies are directly pathogenic or develop secondarily. Early immunotherapy should be considered, in particular if autoantibodies occur in CSF or if clinical or diagnostic findings suggest ongoing inflammation. Suspicious clinical phenotypes include autoimmune encephalitis, atypical dementia, new-onset epilepsy and unexplained epileptic seizures.

Driving Problems in the Elderly and Cognitively Impaired.

Driving ability in the elderly and cognitively impaired is of growing demographic relevance. Driving represents a complex task for which multiple central resources are needed. In mild cognitive impairment and dementia, we need to closely monitor driving ability, as it gets irrecoverably lost in the course of the disease. In normal aging, people are often able to self-regulate driving behavior with respect to their medical conditions. Some studies demonstrated that older drivers perform well compared with younger drivers. Others suggest a decline of driving ability in the process of normal aging and an increasing involvement of older drivers in car crashes. However, these findings have been questioned because of several possible biases. Therefore, unnecessary driving restrictions need to be avoided. The reliable evaluation of driving ability requires a specialist assessment with detailed neurocognitive evaluation, investigation of medical history and medical history by proxy, as well as on-the-the-road tests. Highlighting current knowledge in this field, we would like to increase our readers' awareness for the complexity of driving-associated challenges in an aging population.

Radiation Therapy in Alzheimer's Disease: A Systematic Review.

PURPOSE: Pathophysiological hallmarks of Alzheimer's disease (AD) include extracellular amyloid plaques and intracellular neurofibrillary tangles. Recent studies also demonstrated a role of neuroinflammation in the progression of the disease. Clinical trials and animal studies using low-dose radiation therapy (LDRT) have shown therapeutic potential for AD. This systematic review summarizes the current evidence on the use of LDRT for the treatment of AD, outlines potential mechanisms of action, and discusses current challenges in the planning of future trials. METHODS AND MATERIALS: A systematic review of human and animal studies as well as registered clinical trials describing outcomes for RT in the treatment of AD was conducted. We followed the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles published until July 1, 2023, were included. RESULTS: The initial search yielded 993 articles. After the removal of duplicates and ineligible publications, a total of 16 (12 animal, 4 human) studies were included. Various dose regimens were utilized in both animal and human trials. The results revealed that LDRT reduced the number of amyloid plaques and neurofibrillary tangles, and it has a role in the regulation of genes and protein expression involved in the pathological progression of AD. LDRT has demonstrated reduced astro- and microgliosis, anti-inflammatory and neuroprotective effects, and an alleviation of symptoms of cognitive deficits in animal models. Most studies in humans suggested improvements in cognition and behavior. None of the trials or studies described significant (>grade 2) toxicity. CONCLUSIONS: Preclinical studies, animal studies, and early clinical trials in humans have shown a promising role for LDRT in the treatment of AD pathologies, although the underlying mechanisms are yet to be fully explored. Phase I/II/III trials are needed to assess the long-term safety, efficacy, and optimal treatment parameters of LDRT in AD treatment.

Immunoreactivity to astrocytes in different forms of dementia: High prevalence of autoantibodies to GFAP.

Objective: To study the prevalence of autoantibodies to glial and neuronal antigens with a focus on glial acidic fibrillary protein (GFAP) in patients with dementia. Methods: Sera of 127 patients with different forms of dementia and sera of 82 age-matched patients with various neurological diseases except for dementia, as well as sera from 15 age-matched healthy controls were analyzed for anti-glial or anti-neuronal IgG using 1) primary murine embryonic hippocampus cell cultures, 2) murine brain sections, 3) immunoblotting on mouse brain homogenates and 4) astrocyte cultures. Sera reacting with astrocytes in hippocampus cell cultures were further analyzed using HEK293 cells transfected with human GFAP. Results: IgG in serum from 45 of 127 (35.5%) patients with dementia but only 8 of 97 (8.2%, p ≤ 0.001) controls bound to either glial or neuronal structures in cultured murine hippocampus cells. In these cultures antibodies to astrocytes were detected in 35 of 127 (27.5%) of the dementia patients, whereas in controls antibodies to astrocytes were detected in 4 sera only (4.1%, p ≤ 0.001). Among the sera exhibiting reactivity to astrocytes, 14 of 35 (40%) showed immunoreaction to HEK293 cells transfected with GFAP in dementia patients, representing 11% of all sera. Within the 4 immunoreactive control sera reacting with astrocytes one reacted with GFAP (1.0% of total immunoreactivity, p = 0.003). Conclusions: Autoantibodies to glial epitopes in general and to GFAP in particular are more frequent in patients with dementia than in age-matched controls without dementia, thus indicating the need for further investigations regarding the potential pathophysiological relevance of these antibodies.

Pathological Delta Oscillations in Hallucinogen Persisting Perception Disorder: A Case Report.

Background: Hallucinogen persisting perception disorder (HPPD) is characterized by spontaneous recurrence of visual hallucinations or disturbances after previous consumption of hallucinogens, such as lysergic acid diethylamide (LSD). The underlying physiological mechanisms are unknown and there is no standardized treatment strategy available. Case Presentation: A 33-year-old male patient presented with persistent visual distortions (halos around objects, intensified colors, positive after images, and trails following moving objects) that developed after repeated use of hallucinogenic drugs at the age of 18. Symptoms developed gradually and worsened several months later, resulting in various pharmacological and psychosocial treatment attempts that remained unsuccessful, however. At presentation, 32-channel electroencephalography (EEG) showed increased delta activity over the occipital brain regions, reminiscent of occipital intermittent rhythmic delta activity (OIRDA) usually seen in children. Two sessions of cathodal (inhibitory) transcranial direct current stimulation (tDCS) over 30 min attenuated visual hallucinations and occipital delta activity by approximately 60%. The response persisted for over four weeks. Conclusion: Pathological delta activity over occipital brain regions may play an important role in the development and perpetuation of HPPD and can be attenuated by non-invasive brain stimulation.

Subjective memory impairment in glioma patients with curative radiotherapy.

BACKGROUND: Radiotherapy in patients with primary brain tumors may affect hippocampal structure and cause dyscognitive side-effects. PATIENTS AND METHODS: Using structural MRI and comprehensive neurocognitive evaluation, we investigated associations between hippocampal structure and memory deficits in 15 patients with WHO grade 3 and grade 4 gliomas receiving standard radio(chemo)therapy. RESULTS: We did not find changes in hippocampal thickness or cognitive abilities three months after completing radiotherapy. However, subjective memory impairment was associated with symptoms of depression, but not with objective memory performance, cortical thickness of the hippocampus or radiation dose. CONCLUSIONS: Irrespective of whether there is a bidirectional relationship between affective changes and subjective cognitive dysfunction in these patients, depressive symptoms remain a target for intervention to improve their quality of life. The results of our pilot study highlight that future assessment of side effects of radiotherapy concerning memory should include assessments of depressive symptoms.

Relation of retinal and hippocampal thickness in patients with amnestic mild cognitive impairment and healthy controls.

OBJECTIVE: Investigating retinal thickness may complement existing biological markers for dementia and other neurodegenerative diseases. Although retinal thinning is predictive for cognitive decline, it remains to be investigated if and how this feature aligns with neurodegeneration elsewhere in the brain, specifically in early disease stages. METHODS: Using optical coherence tomography and magnetic resonance imaging, we examined retinal thickness as well as hippocampal structure in patients with amnestic mild cognitive impairment and healthy controls. RESULTS: The groups did not differ in hippocampal and retinal thickness measures. However, we detected a correlation of peripapillary retinal nerve fiber layer thickness and hippocampal thickness in healthy people but not in cognitively impaired patients. The ratio of hippocampus to retina thickness was significantly smaller in patients with mild cognitive impairment and correlated positively with cognitive performance. CONCLUSIONS: Different temporal trajectories of neurodegeneration may disrupt transregional brain structure associations in patients with amnestic mild cognitive impairment.

Risk factors for dementia are not associated with cognitive dysfunction in young people with major depressive disorder.

BACKGROUND: Hippocampal thinning and carrying the ε4 allele of the apolipoprotein E (APOE) are associated with reduced cognitive performance in older people. Although cognitive impairment is also frequent during and after depressive episodes, it may occur irrespective of age, which makes it difficult to determine, whether this symptom indicates a risk for or shared mechanisms with neurodegeneration. We therefore investigated the influence of genetic and brain imaging risk factors for dementia on cognitive impairment in young people with major depressive disorder. METHODS: We used magnetic resonance imaging, APOE genotyping and neurocognitive assessments to examine young adults (mean age: 29.1 ±â€¯6.3 years) with major depressive disorder and a current depressive episode, presenting with or without cognitive deficits. RESULTS: Neither hippocampal thickness nor APOE genotype predicted cognitive impairment. Patients with objective cognitive deficits reported a greater number of previous depressive episodes. LIMITATIONS: Our results have to be interpreted with caution. The small sample size could have prevented the detection of effects. Complementing research methods and investigations across the life span would be necessary to reveal possible interactions between risk factors for dementia, neurodegeneration, depression, and age. CONCLUSIONS: In young adults, recurrent depressive episodes may increase the likelihood for cognitive deficits, while common risk factors for dementia do not.

Extrinsic and Intrinsic Help-Seeking Motivation in the Assessment of Cognitive Decline.

Diagnostic assessments for dementia include the evaluation of subjective memory impairment, dementia worries, or depressive symptoms. Data on the predictive value of these factors remain unclear, and varying help-seeking behavior may contribute to this finding. We investigate whether differentiating help-seeking motivation from other psychological factors associated with cognitive impairment would enhance the prediction of diagnostic outcomes in a memory clinic. We obtained information on help-seeking motivation from 171 patients who underwent routine diagnostic assessments. Utilizing a discriminant correspondence analysis, our results indicate that extrinsic motivation increases the likelihood of receiving a dementia diagnosis, whereas depression or the duration of deficits carries discriminatory information to further guide the differentiation of prodromal dementia. Recognizing motivational aspects of help-seeking behavior can complement the clinical evaluation of cognitive performance.

Cognitive impairment and medial temporal lobe structure in young adults with a depressive episode.

BACKGROUND: Cognitive deficits are common in patients with a depressive episode although the predictors for their development and severity remain elusive. We investigated whether subjective and objective cognitive impairment in young depressed adults would be associated with cortical thinning in medial temporal subregions. METHODS: High-resolution magnetic resonance imaging, cortical unfolding data analysis, and comprehensive assessments of subjective and objective cognitive abilities were performed on 27 young patients with a depressive episode (mean age: 29.0 ±â€¯5.8 years) and 23 older participants without a history of a depressive disorder but amnestic mild cognitive impairment (68.5 ±â€¯6.6 years) or normal cognition (65.2 ±â€¯8.7 years). RESULTS: Thickness reductions in parahippocampal, perirhinal and fusiform cortices were associated with subjective memory deficits only among young patients with a depressive episode and a measurable cognitive impairment. LIMITATIONS: Long-term longitudinal data would be desirable to determine the trajectories of cognitive impairment associated with depression in patients with or without cortical structure changes. CONCLUSIONS: The presence of clinically significant cognitive deficits in young people with a depressive episode may identify a patient population with extrahippocampal cortical thinning.

Family History of Alzheimer's Disease and Subjective Memory Performance.

People with a first-degree family history of Alzheimer's disease are at an increased risk of developing dementia. Subjective memory impairment among individuals with no measurable cognitive deficits may also indicate elevated dementia risk. It remains unclear whether nondemented people with a positive family history of Alzheimer's disease are more likely to experience cognitive deficits and whether such an association reflects underlying neuropathology. We therefore investigated subjective memory impairment and hippocampal cortical thickness in 40 healthy older adults and 35 patients with amnestic mild cognitive impairment. We found greater subjective memory impairment and left hemispheric hippocampal cortical thinning associated with a first-degree family history of Alzheimer's disease in healthy older adults. This suggests that subjective memory impairment could reflect preclinical stage neurodegeneration among individuals with the family history risk factor.