Happiness, positive emotions, and subjective well-being in dementia.

Research on non-cognitive features of dementia traditionally focusses on neuropsychiatric symptoms and challenging behavior and thus on negative aspects of the disease. Despite the clinical observation that many patients frequently report subjective well-being and often express positive emotions there is only little research on the definition, measurement and determinants of subjective well-being and happiness in people living with dementia. Furthermore, the few studies there are, examined happiness using retrospective questionnaires and the accounts of relatives or caregivers. However, in dementia, the experiencing self becomes more significant since past and future thinking are fading into the background. Here, we review the relative scarce literature in this field, discuss different psychological constructs and their applicability for dementia research, and suggest methods for measuring the addressed constructs in people with dementia. In particular, we propose methodology to study happiness and positive emotions in the experienced moment of the participants using ecological momentary assessments (EMA). We believe that adequate measures of momentary subjective well-being might become an important outcome parameter in clinical dementia trials beyond the currently used quality of life measures.

Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS.

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.

The impact of COVID-19-related distress on levels of depression, anxiety and quality of life in psychogeriatric patients.

Within the elderly population, psychogeriatric patients may be particularly susceptible to negative mental health effects of the coronavirus crisis. Detailed information about the psychosocial well-being of psychogeriatric patients during the pandemic is still sparse. Here we examined which aspects of subjective experience of the COVID-19 pandemic especially affect levels of depression, anxiety and quality of life in psychogeriatric patients with and without cognitive impairment. A cross-sectional paper survey was conducted during the first German lockdown among patients with a diagnosed psychiatric disorder (≥ 60 years) or a diagnosed neurodegenerative disease (regardless of their age) from the department for neurodegenerative diseases and geriatric psychiatry at the University of Bonn. The WHO-5-, GAD-7- and WHOQOL-old score were used to determine levels of depression, anxiety and quality of life. The second part obtained information about the subjective experience of the COVID-19 pandemic. Statistical analysis included among others principal component analysis and multiple linear regression analysis. COVID-19-related, immediate distress was a strong predictor of elevated symptoms of depression, anxiety and a reduced quality of life. COVID-19-related concerns regarding health and financial security, however, were not significantly associated with negative mental health outcomes. The overall prevalence of symptoms of depression (50.8% [95% CI 43.8-57.6%]) and anxiety (32.7% [95% CI 26.4-39.2%]) among psychogeriatric patients was high. Our findings indicate that psychogeriatric patients are not significantly affected by COVID-19-related concerns but are primarily suffering from emotional consequences resulting from changed living conditions due to the pandemic.

Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies.

Pathological tau aggregation leads to filamentous tau inclusions and characterizes neurodegenerative tauopathies such as Alzheimer's disease and frontotemporal dementia and parkinsonism linked to chromosome 17. Tau aggregation coincides with clinical symptoms and is thought to mediate neurodegeneration. Transgenic mice overexpressing mutant human P301S tau exhibit many neuropathological features of human tauopathies including behavioral deficits and increased mortality. Here, we show that the di-phenyl-pyrazole anle138b binds to aggregated tau and inhibits tau aggregation in vitro and in vivo. Furthermore, anle138b treatment effectively ameliorates disease symptoms, increases survival time and improves cognition of tau transgenic PS19 mice. In addition, we found decreased synapse and neuron loss accompanied by a decreased gliosis in the hippocampus. Our results suggest that reducing tau aggregates with anle138b may represent an effective and promising approach for the treatment of human tauopathies.

Function of inhibitory micronetworks is spared by Na+ channel-acting anticonvulsant drugs.

The mechanisms of action of many CNS drugs have been studied extensively on the level of their target proteins, but the effects of these compounds on the level of complex CNS networks that are composed of different types of excitatory and inhibitory neurons are not well understood. Many currently used anticonvulsant drugs are known to exert potent use-dependent blocking effects on voltage-gated Na(+) channels, which are thought to underlie the inhibition of pathological high-frequency firing. However, some GABAergic inhibitory neurons are capable of firing at very high rates, suggesting that these anticonvulsants should cause impaired GABAergic inhibition. We have, therefore, studied the effects of anticonvulsant drugs acting via use-dependent block of voltage-gated Na(+) channels on GABAergic inhibitory micronetworks in the rodent hippocampus. We find that firing of pyramidal neurons is reliably inhibited in a use-dependent manner by the prototypical Na(+) channel blocker carbamazepine. In contrast, a combination of intrinsic and synaptic properties renders synaptically driven firing of interneurons essentially insensitive to this anticonvulsant. In addition, a combination of voltage imaging and electrophysiological experiments reveal that GABAergic feedforward and feedback inhibition is unaffected by carbamazepine and additional commonly used Na(+) channel-acting anticonvulsants, both in control and epileptic animals. Moreover, inhibition in control and epileptic rats recruited by in vivo activity patterns was similarly unaffected. These results suggest that sparing of inhibition is an important principle underlying the powerful reduction of CNS excitability exerted by anticonvulsant drugs.