Afferent vagal stimulation via gastric electrical stimulation alters sympathetic-vagal balance in domestic pigs - a pilot trial.

The disturbance of the sympathetic-vagal balance with increasing sympathetic activity and consecutive increase in cytokine release is a major threat in numerous hyperinflammatory syndromes. Therapeutic interventions that modulate the activity in the sympathetic-vagal system are suggested as an effective treatment in these incidences. The purpose of this pilot study was to investigate the effect of electrical stimulation of the gastric wall on sympathetic-vagal balance. German domestic pigs (n=5) were prepared with a modified gastric tube (mGT) for repetitive gastric electrical stimulation (GES). Electrocardiogram was recorded continuously and heart rate variability (HRV) as measure of sympathetic-vagal activity was calculated for three-minute epochs at baseline condition before GES and during GES condition. In comparison to baseline, activity of the autonomic nervous system (ANS) shifted significantly toward increased dominance of vagal activity during GES with a decrease of normalized low frequency (nLF from 58.00 to 25.52) as marker of sympathetic dominance and parallel increase of normalized high frequency (nHF from 41.48 to 74.16) as marker of vagal dominance. During GES, compared to baseline, no difference in heart rate was found. These results indicate that electrical stimulation of the gastric wall may result in shifting the sympathetic-vagal balance toward a parasympathetic predominance.

Autonomic balance determines the severity of COVID-19 courses.

COVID-19 has left mankind desperately seeking how to manage dramatically rising infection rates associated with severe disease progressions. COVID-19 courses range from mild symptoms up to multiple organ failure and death, triggered by excessively high serum cytokine levels (IL 1ß, IL 6, TNF α, IL 8). The vagally driven cholinergic anti-inflammatory pathway (CAP) stops the action of nuclear factor κB (NF-κB), the transcriptional factor of pro-inflammatory cytokines. Thus, well-balanced cytokine release depends on adequate vagal signaling. Coronaviruses replicate using NF-κB transcriptional factor as well. By degrading the cytoplasmatic inhibitor of NF-κB subunits (IκB), coronaviruses induce unrestricted NF-κB expression accelerating both, virus replication and cytokine transcription.We hypothesize that CAP detriment due to depressed vagal tone critically determines the severity of COVID-19.

Higher body mass index is linked to altered hypothalamic microstructure.

Animal studies suggest that obesity-related diets induce structural changes in the hypothalamus, a key brain area involved in energy homeostasis. Whether this translates to humans is however largely unknown. Using a novel multimodal approach with manual segmentation, we here show that a higher body mass index (BMI) selectively predicted higher proton diffusivity within the hypothalamus, indicative of compromised microstructure in the underlying tissue, in a well-characterized population-based cohort (n1 = 338, 48% females, age 21-78 years, BMI 18-43 kg/m²). Results were independent from confounders and confirmed in another independent sample (n2 = 236). In addition, while hypothalamic volume was not associated with obesity, we identified a sexual dimorphism and larger hypothalamic volumes in the left compared to the right hemisphere. Using two large samples of the general population, we showed that a higher BMI specifically relates to altered microstructure in the hypothalamus, independent from confounders such as age, sex and obesity-associated co-morbidities. This points to persisting microstructural changes in a key regulatory area of energy homeostasis occurring with excessive weight. Our findings may help to better understand the pathomechanisms of obesity and other eating-related disorders.

Hypothalamus enlargement in mood disorders.

OBJECTIVE: The purpose of this study was to determine, in vivo, whether the hypothalamus volume is reduced in patients with mood disorders. METHODS: The cross-sectional study included 20 unmedicated (MDDu) and 20 medicated patients with major depressive disorder, 21 patients with bipolar disorder, and 23 controls. Twenty of the controls were matched to the MDDu. Seven Tesla, T1-weighted magnetic resonance images were acquired and processed using methods specifically developed for high-precision volumetry of the hypothalamus. RESULTS: An overall group difference was observed for the left hypothalamus volume corrected for intracranial volume. Planned contrasts identified that the left hypothalamus was approximately 5% larger in each patient group compared with the control group. A paired t-test with the 20 matched pairs of MDDu and controls and without correction for covariates confirmed the larger left hypothalamus volume in MDDu. CONCLUSIONS: Contrary to our expectations, the hypothalamus volume was increased in patients with uni- and bipolar affective disorders. The effect was left-sided and independent of medication status or statistical correction for covariates. Supported by emerging evidence that the stress response may be related to structural and functional asymmetry in the brain, our finding suggests a crucial role of the hypothalamus in mood disorders.

Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'.

BACKGROUND: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. OBJECTIVE: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). METHODS: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid ß peptide 1-42 (Aß42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated. RESULTS: Prodromal AD was found in 55 aMCI patients defined by low Aß42 in the cerebrospinal fluid (Aß positive). Compared to the aMCI group with high Aß42 levels (Aß negative), Aß positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03). CONCLUSION: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.

Prevalence of minor depression in elderly persons with and without mild cognitive impairment: a systematic review.

BACKGROUND: Minor depression (MinD) and mild cognitive impairment (MCI) are common disorders in late life that often coexist. The aim of the present review is to demonstrate prevalence rates of minor depression in older patients with and without MCI. METHODS: Electronic database searches were performed through Medline, ISI Web of Knowledge, Psycinfo, and Cochrane library. Two independent reviewers extracted the original studies based on inclusion criteria: representative study population aged 55 and older, diagnostics of MinD according to DSM. Data on prevalence rates, risk factors, comorbidity and health care usage were analyzed. RESULTS: Point prevalence for MinD is higher in medical settings (median 14.4%) than in the community-based settings (median 10.4%) and primary care patients (median 7.7%). Although minor depression is rarely investigated in elderly persons with MCI, nearly 20% of patients with MCI seem to suffer from MinD. No data was found on the prevalence of MCI in patients with MinD. Risk factors associated with MinD include female gender, history of cerebrovascular diseases, generalized anxiety disorder, loneliness, and long-term institutional care. LIMITATIONS: Methodological differences of included studies resulted in a broad range of prevalence rates. No data is shown regarding the prevalence of MCI in MinD group due to insufficient evidence. CONCLUSIONS: Our review indicates that MinD is frequent in elderly population. MCI among those subjects has not been sufficiently investigated. Future studies based on clinical structured interviews should be performed in longitudinal design in order to differentiate late-life depression from progressive MCI or early manifestation of Alzheimer's disease.

Cholesterol in mild cognitive impairment and Alzheimer's disease in a birth cohort over 14 years.

Animal epidemiological and clinical studies suggest that cholesterol is a risk factor for Alzheimer's disease (AD). Nevertheless, the relation of cholesterol to mild cognitive impairment (MCI), influence of APOE genotype and its changes in lifespan is controversial. We investigated the potential impact of plasma total cholesterol (TC) on development of MCI and AD in the interdisciplinary longitudinal study on adult development and aging, a representative birth cohort (born 1930-1932), examined in 1993/1994 (VT1), 1997/1998 (VT2), and 2005/2007 (VT3). Of 500 participants at baseline, 381 survived and were examined at VT3. After exclusion of participants with lifetime prevalence of major psychiatric diseases or mild cognitive disorder due to a medical condition, 222 participants were included in the analysis. At VT3, 82 participants had MCI, 22 participants had AD, and 118 were in good health. Participants with MCI and AD at VT3 evidenced higher TC levels at VT1 than those who were healthy. Higher TC levels at baseline were associated with an increased risk for cognitive disorders at VT3 (highest vs. lowest quartile: OR 2.64, 95 % CI 1.12-6.23, p < 0.05). Over the 14 year follow-up, TC levels declined in those with MCI and AD, but remained stable in those who remained healthy. These findings were not modified by APOE genotype or use of cholesterol-lowering medications. Our findings demonstrate that higher TC levels are observed long before the clinical manifestation of MCI and AD in patients without psychiatric or somatic comorbidities and are independent of APOE genotype.

[Adjustment disorders in internal medicine diseases]. / Anpassungsstörungen bei internistischen Erkrankungen.

It is only possible to diagnose an adjustment disorder if there is an explicit connection to a stressful life event. Clinically this disorder is marked by a wide variability of symptoms (e.g. depressive mood, anxiety). The prodromal symptoms have not been unequivocally differentiated from those of other mental disorders and normal adaptation processes. Nevertheless, the diagnosis is often made in clinical practice and, in particular, in primary care. Against this background, its significance is to be examined in association with internal medicine diseases.

Premorbid personality traits and their course in mild cognitive impairment: results from a prospective population-based study in Germany.

BACKGROUND: Personality traits contribute to cognitive functioning. We present a study comparing personality traits in normal ageing and mild cognitive impairment (MCI). METHODS: We conducted a representative longitudinal study including 222 subjects from a cohort born between 1930 and 1932 (n = 500) examined at three examination waves (t1: 1993/1994; t2: 1997/1998; t3: 2005/2007). Personality traits were assessed with the NEO-Five-Factor Inventory questionnaire. RESULTS: Healthy controls and patients with MCI showed a significant (p < 0.05) decrease concerning their levels of neuroticism and extraversion over time. MCI subjects scored significantly higher on neuroticism at baseline and lower on openness at all examinations compared to healthy controls. Subjects with higher baseline neuroticism showed a 2.24 times higher risk of developing MCI at the third follow-up (odds ratio = 2.24, 95% confidence interval = 1.12-4.45 - scores adjusted for education and sex). CONCLUSIONS: MCI subjects differ in their premorbid personality traits compared to healthy controls. According to our study, higher neuroticism should be considered a risk factor for the development of MCI.

[Symptoms and imaging diagnostics of neurodegenerative dementia]. / Klinik und bildgebende Diagnostik neurodegenerativer Demenzen.

A variety of neurodegenerative diseases can underlie dementia syndromes. In addition to Alzheimer's disease (AD) and its prodromal stages, these include in particular frontotemporal degeneration, Lewy body dementia and Parkinson's dementia, progressive supranuclear paresis, corticobasal degeneration and chorea Huntington. Although not classified as a neurodegenerative brain disease, for all clinical diagnoses there must be a differential diagnostic separation from vascular forms of dementia. Furthermore an exclusion of affective disorders, such as minor depression is necessary from a clinical psychiatric perspective. Moreover the preclinical stages of AD often present with uncharacteristic symptoms. Especially affective symptoms can occur in addition to initial cognitive deficits such as memory decline. In summary, clinical and neuropsychological procedures together with functional imaging techniques allow a detailed diagnostic assessment of neurodegenerative dementia syndromes which can be additionally supported by neurochemical biomarkers and innovative imaging procedures, such as diffusion imaging or magnetic resonance spectroscopy.

[Subdiagnostic depression. Are there treatments with clinically relevant effects?]. / Subdiagnostische Depressionen. Gibt es Behandlungen mit klinisch relevanten Effekten?

Minor depression, subsyndromal depression and subthreshold depression are frequent conditions in primary care which do not fulfil the criteria of a depressive disorder but are associated with functional disability, impairment of quality of life, and health care use. This paper reviews studies on the clinical evidence of pharmacotherapy, psychotherapy, and interventions to improve primary care. In this regard, whether clinical relevance of antidepressant therapies can be concluded from differences between placebo and active treatment is critically discussed. Due to lacking clinical evidence, aspects of a pragmatic therapeutic approach in those patients are presented.

[MCI-plus: mild cognitive impairment with rapid progression. Part II: Biomarkers and research methods]. / MCI-plus: leichte kognitive Beeinträchtigung mit rascher Progredienz. Teil II: Biomarker und Untersuchungsmethoden.

Long-term studies will be pivotal in order to examine the efficacy of preventive and early therapeutic interventions during the preclinical phase of dementia. Biomarkers will be of importance due to the large sample sizes and the necessary logistic efforts, high drop-out rates and slow clinical progression. The validity of functional and even structural imaging methods is currently investigated with early and promising results; it is presently unclear whether conventional csf-markers of Alzheimer's disease (beta-amyloid and tau-proteins) are sufficiently sensitive to monitor the effects of early interventions. It also remains doubtful whether modifications of these methods will ever be useful and available for practical purposes.

[MCI-plus: mild cognitive impairment with rapid progression. Part I: prevention and therapy]. / MCI-plus: leichte kognitive Beeinträchtigung mit rascher Progredienz. Teil I: Prävention und Therapie.

Mild Cognitive Impairment (MCI) is a prevalent problem in the elderly and many patients show predictors of rapid cognitive decline ("MCI-plus"). MCI-plus represents a syndrome with growing importance in an ageing society, which will increasingly affect primary medicine and most other clinical specialties. We will have to face the dilemma of fast progress in the field of neurodiagnostics with innovative therapeutic strategies lagging behind. Psychological and medical co-morbidity in MCI-plus will therefore offer important opportunities to delay and to avoid the manifestation of dementia. We will review and discuss current training and treatment options including symptomatic and causal interventions.

[Manic behavior as an autoregulatory attempt to stabilize vigilance]. / Ist manisches Verhalten ein autoregulatorischer Versuch zur Vigilanzstabilisierung?

In situations with low external stimulation, manic patients often present rapid declines in vigilance, with microsleeps occurring even in the 1st min of EEG recordings (lability of vigilance regulation). We postulate that manic symptoms creating a high level of external stimulation serve to stabilize vigilance. Theoretical arguments and empirical results are presented, showing that both mania and ADHD should be interpreted as vigilance autostabilization syndromes. The therapeutic effects of psychostimulants can be explained by their vigilance-stabilizing properties. They are well proven for ADHD and have repeatedly been shown to have a paradoxical effect in manic patients. The proposed concept opens new approaches for the treatment of acute mania.

[Mild cognitive impairment with predictors of rapid decline]. / Leichte kognitive Beeinträchtigung mit Vorzeichen rascher Verschlechterung.

Half the patients with mild cognitive impairment (MCI) will develop dementia over a four-year period. The scientific literature was searched and analysed for predictors of rapid decline (MCI-plus) in patients with MCI. The most important predictors of fast cognitive deterioration were found to be: old age, previous rapid decline, severity and multiplicity of cognitive deficits, somatic co-morbidity, vascular and Alzheimer-type changes in the brain, Alzheimer-type cerebrospinal fluid findings and apolipoprotein E4 polymorphism. Many patients with MCI suffer from anxiety, depression or apathy and subtle, but subjectively significant, difficulties in the activities of daily living. It is concluded that MCI-plus offers a window for medical and psychological prophylaxis and rehabilitation.

Multicenter assessment of CSF-phosphorylated tau for the prediction of conversion of MCI.

BACKGROUND: The measurement of hyperphosphorylated tau (p-tau) in CSF has been proposed as a biomarker candidate for the prediction of Alzheimer disease (AD) in patients with mild cognitive impairment (MCI). However, a standard quantitative criterion of p-tau has not been evaluated. OBJECTIVE: To assess in a multicenter study the predictive accuracy of an a priori defined criterion of tau phosphorylated at threonine 231 (p-tau(231)) for the prediction of conversion from MCI to AD during a short-term observation interval. METHODS: The study included 43 MCI converters, 45 stable MCI (average follow-up interval = 1.5 years), and 57 healthy controls (at baseline only). Subjects were recruited at four international expert sites in a retrospective study design. Cox regression models stratified according to center were used to predict conversion status. Bootstrapped 95% CIs of classification accuracy were computed. RESULTS: Levels of p-tau(231) were a significant predictor of conversion (B = 0.026, p = 0.001), independent of age, gender, Mini-Mental State Examination, and ApoE genotype. For an a priori-defined cutoff point (27.32 pg/mL), sensitivity ranged between 66.7 and 100% and specificity between 66.7 and 77.8% among centers. The bootstrapped mean percentage of correctly classified cases was 79.95% (95% CI = 79.9 to 80.00%). Post hoc defined cutoff values yielded a mean bootstrapped classification accuracy of 80.45% (95% CI = 80.24 to 80.76%). CONCLUSIONS: An a priori defined cutoff value of p-tau(231) yields relatively stable results across centers, suggesting a good feasibility of a standard criterion of p-tau(231) for the prediction of Alzheimer disease.

[Mild cognitive impairment and Alzheimer's disease: an investigation of the CERAD-NP test battery]. / Neuropsychologische Profile in der Demenzdiagnostik: Eine Untersuchung mit der CERAD-NP-Testbatterie.

To investigate the psychometric properties of the German version of the CERAD-NP, neuropsychological deficits were compared between 49 patients with mild cognitive impairment (MCI), 80 patients with Alzheimer's disease (AD), 36 with major depression (MD), and 26 elderly controls. All participants were outpatients of the memory clinic of the Section of Geriatric Psychiatry, Heidelberg University. Diagnoses were established based on clinical examination, laboratory testing, neuroimaging, and routine neuropsychological testing according to the criteria of aging-associated cognitive decline (AACD) for MCI, NINCDS-ADRDA for AD, and DSM-IV for MD, respectively. All CERAD-NP subtests discriminated between controls and AD patients with the latter showing significantly (p< or = 0.05) lower test scores. The subtests verbal fluency and constructive apraxia differed significantly between mildly and moderately AD, while the subtests assessing declarative (epsisodic) memory performance showed only minor, non-significant differences between the respective groups. The LKB patients took an intermediate position between controls and AD patients with significantly lower scores in verbal fluency and declarative memory performance than the controls. When compared with the AD patients, MCI patients were significantly impaired in all subtests except constructive apraxia. Relative to the controls, the patients with MD showed a decreased episodic memory performance but no evidence suggesting an impairment in other neuropsychological domains. Our results indicate that the CERAD-NP is a psychometric instrument which allows a sensitive discrimination between mild and moderate AD, MCI, MD and healthy controls. However, sensitivity of discrimination between different stages of dementia varies with respect to the different subtest. While the subtest for episodic memory showed floor effects already for mild dementia, subtests for verbal fluency and constructive apraxia were able to discriminate even between more advanced stages of the disease.

[Working memory in healthy subjects and schizophrenics: studies using BOLD fMRT]. / Das Arbeitsgedächtnis bei Gesunden und bei Schizophrenen: Untersuchungen mit BOLD-fMRT.

Functional magnetic resonance imaging uses the blood oxygen level-dependent effect (BOLD MRI) for noninvasive display of cerebral correlatives of cognitive function. The importance for the understanding of physiological and pathological processes is demonstrated by investigations of working memory in schizophrenics and healthy controls. Working memory is involved in processing rather than storage of information and therefore is linked to complex processes such as learning and problem solving. In schizophrenic psychosis, these functions are clearly restricted. Training effects in the working memory task follow an inverse U-shape function, suggesting that cerebral activation reaches a peak before economics of the brain find a more efficient method and activation decreases.

[Neuropsychological correlates of cerebral atrophy in Alzheimer's dementia]. / Neuropsychologische Korrelate zerebraler Atrophie bei der Alzheimer-Demenz.

This study aims to systematically analyze the relationship between neuropsychological deficits and regional cerebral atrophic changes in Alzheimer's dementia (AD). As an extension of previous studies we not only investigated substructures of the medial temporal lobe but also included other relevant cerebral regions such as frontal, temporal, and parietal lobes. This approach was based on the assumption that morphological correlates of global and specific cognitive dysfunction might reflect to a certain degree the neuronal basis of the respective function. Accordingly, the functional role assigned to a certain cerebral structure or region can be further elucidated which might lead to a better understanding of the clinical and neuropsychological heterogeneity of AD. Fifty patients with AD (NINCDS-ADRDA criteria) and 20 healthy elderly control subjects were included. All patients and controls were examined on a standardized neuropsychological test battery. In addition, magnetic resonance imaging (MRI) of the brain was performed. Volumes of the whole brain, CSF-spaces, amygdala-hippocampus complex, frontal lobes, temporal lobes, and parietal lobes were measured using a standardized protocol. AD-patients were characterized by neuropsychological deficits with respect to memory, language, praxia, cognitive speed as well as attention and concentration. These deficits were differentially correlated with regional atrophic changes. In particular, volumes of the right amygdala-hippocampus complex were correlated with declarative memory performance in the non-verbal visual domain. Furthermore, an association between left temporo-parietal regions and aspects of semantic memory, as well as verbal recall and left frontal regions could be established. The validity of our results is supported by recent findings from neuropathological and functional neuroimaging studies. In conclusion, our data indicate that MRI-based volumetry can be successfully used to detect morphological correlates of neuropsychological heterogeneity in AD and that this methodological approach allows to fruitfully study the neuronal basis of cognitive functions.