Peter Hermann

Effects of hypervolemia and hypertension on regional cerebral blood flow, intracranial pressure, and brain tissue oxygenation after subarachnoid hemorrhage.

Objective:Hypertensive, hypervolemic, hemodilution therapy (triple-H therapy) is a generally accepted treatment for cerebral vasospasm after subarachnoid hemorrhage. However, the particular role of the three components of triple-H therapy remains controversial. The aim of the study was to investigate the influence of the three arms of triple-H therapy on regional cerebral blood flow and brain tissue oxygenation. Design:Animal research and clinical intervention study. Setting:Surgical intensive care unit of a university hospital. Subjects and Patients:Experiments were carried out in five healthy pigs, followed by a clinical investigation of ten patients with subarachnoid hemorrhage. Interventions:First, we investigated the effect of the three components of triple-H therapy under physiologic conditions in an experimental pig model. In the next step we applied the same study protocol to patients following aneurysmal subarachnoid hemorrhage. Mean arterial pressure, intracranial pressure, cerebral perfusion pressure, cardiac output, regional cerebral blood flow, and brain tissue oxygenation were continuously recorded. Intrathoracic blood volume and central venous pressure were measured intermittently. Vasopressors and/or colloids and crystalloids were administered to stepwise establish the three components of triple-H therapy. Measurements and Main Results:In the animals, neither induced hypertension nor hypervolemia had an effect on intracranial pressure, brain tissue oxygenation, or regional cerebral blood flow. In the patient population, induction of hypertension (mean arterial pressure 143 ± 10 mm Hg) resulted in a significant (p < .05) increase of regional cerebral blood flow and brain tissue oxygenation at all observation time points. In contrast, hypervolemia/hemodilution (intrathoracic blood volume index 1123 ± 152 mL/m2) induced only a slight increase of regional cerebral blood flow while brain tissue oxygenation did not improve. Finally, triple-H therapy failed to improve regional cerebral blood flow more than hypertension alone and was characterized by the drawback that the hypervolemia/hemodilution component reversed the effect of induced hypertension on brain tissue oxygenation. Conclusions:Vasopressor-induced elevation of mean arterial pressure caused a significant increase of regional cerebral blood flow and brain tissue oxygenation in all patients with subarachnoid hemorrhage. Volume expansion resulted in a slight effect on regional cerebral blood flow only but reversed the effect on brain tissue oxygenation. In view of the questionable benefit of hypervolemia on regional cerebral blood flow and the negative consequences on brain tissue oxygenation together with the increased risk of complications, hypervolemic therapy as a part of triple-H therapy should be applied with utmost caution.

CSF Biomarkers and Neuropsychological Profiles in Patients with Cerebral Small-Vessel Disease

Despite existing criteria, differential diagnosis of Vascular Dementia (VD) and Alzheimers disease (AD) remains difficult. The aim of this study is to figure out cognitive and biomarker profiles that may help to distinguish between VD, AD and AD + Cerebral Small Vessel Disease (CSVD). We examined a cohort of patients with CSVD (n = 92). After stratification of cognitive impaired patients (n = 59) using the standard CSF beta-amyloid 42/40 ratio cut-off point of 0.975, we obtained two groups which differed with respect to several features: 32 patients with normal beta-amyloid 42/40 ratio (>0.975) showed markedly impaired blood-brain-barrier function as indicated by an elevated albumin ratio (median 8.35). They also differed in cognitive profiles when compared to 27 patients with AD typical beta-amyloid ratio and normal albumin ratio. We also enrolled an additional group of patients with AD (no significant CSVD on MRI, n = 27) which showed no impairment of the blood-brain-barrier. We showed a negative correlation between the albumin ratio and executive cognitive function (p = 0.016) and a negative correlation between memory function and typical AD markers like Tau (p = 0.004) and p181-Tau (p = 0.023) in our cohort. We suppose that the group of patients with normal beta-amyloid ratio represents VD while patients in the other groups represent AD+CSVD and pure AD. Our results support the idea that a dysfunction of the blood-brain-barrier might be contributing factor in the development of cognitive decline in CSVD as it seems to be of more importance than the severity of white matter lesions.

Investigating the Association of ApoE Genotypes with Blood-Brain Barrier Dysfunction Measured by Cerebrospinal Fluid-Serum Albumin Ratio in a Cohort of Patients with Different Types of Dementia

Background Since more than a decade ApoE is known to be a strong risk factor for Alzheimers disease (AD); however, molecular pathways mediating this risk are still unclear. In recent years it has been hypothesized that ApoE might play a role in the disintegration of blood-brain barrier (BBB). In the present study we addressed the question if ApoE genotypes might be associated with BBB function measured by albumin ratio (QAlb) in a large cohort of patients with different types of dementia. Methods Five hundred twenty (520) patients with Creutzfeldt-Jakob disease (CJD, n = 350), Alzheimers disease (n = 71) and cerebral small vessel disease (n = 99) were assessed for their ApoE genotype. BBB function was measured in all patients using QAlb and was compared between ApoE genotypes. Dominant and additive genetic models were assumed in order to investigate the potential effect of ApoE on BBB function. Results We observed no systematic differences in QAlb between ApoE genotypes within the present study. Increased QAlb levels were shown for those without E3 allele in the subgroup of CJD patients when assuming a dominant genetic model (p = 0.035). This could not be confirmed for patients with other forms of dementia (p = 0.234). Discussion Although there was some evidence for a protective effect of E3 alleles in CJD patients, this study does not support the hypothesis of a systematic role of ApoE genotypes in BBB function in individuals with a diagnosis of dementia. Thus, changes in BBB function do not seem to contribute to the increased risk of cognitive decline associated with certain ApoE genotypes. The interpretation of the results of this study must take into account that BBB function was only assessed by measuring QAlb which has been shown to be a good marker for overall BBB integrity but might not reflect all qualities of the barrier.

Cerebrospinal fluid neurofilament light levels in neurodegenerative dementia: Evaluation of diagnostic accuracy in the differential diagnosis of prion diseases.

Neurofilament light (NFL) levels in the cerebrospinal fluid are increased in several neurodegenerative dementias. However, their diagnostic accuracy in the differential diagnostic context is unknown.

Increased albumin CSF/serum ratio in dementia with Lewy bodies

BACKGROUND Alterations in the CSF/serum albumin ratio (Qalb) is currently recognized as one of the most reliable markers of blood-brain barrier impairment and blood-CSF barrier permeability, but its potential role as a biomarker in the differential diagnosis of neurological diseases has been poorly analysed. METHODS We evaluated Qalb and core CSF biomarkers (Tau, p-Tau and Aβ42) in a large patient population of neurological and neurodegenerative cases. Diagnostic test evaluation was assessed by ROC-AUC analysis. RESULTS In the differential diagnostic analysis, increased Qalb was found in dementia with Lewy bodies (DLB) patients compared to other diseases, either individually or stratified in non-dementia and dementia groups. When clinical groups were analysed individually and compared to controls, Qalb was also increased in stroke and Parkinsons disease dementia (PDD) cases, but not in Parkinsons disease (PD). Qalb in DLB cases correlate with CSF Aβ42 levels but not with Tau and p-Tau levels. Due to the lower CSF Aβ42 levels in DLB compared to PD and PDD, the potential clinical applicability of Qalb with respect to the DLB diagnosis is increased in combination with CSF Aβ42 analysis. CONCLUSIONS The present study demonstrates increased Qalb in synucleinopathies associated with dementia revealing a potential new clinical approach for the differential diagnosis of DLB.

Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Show Different but Partially Overlapping Profile Compared to Vascular Dementia

Vascular factors increase the risks of developing Alzheimers disease (AD) and they contribute to AD pathology. Since amyloid beta (Aβ) deposits can be observed in both diseases, there is an overlap which impedes a clear discrimination and difficult clinical diagnosis. In the present study, we compared cerebrospinal fluid (CSF) profiles of neurodegenerative and inflammatory biomarkers in a patient cohort of controls (n = 50), AD (n = 65) and vascular dementia (VaD) (n = 31) cases. Main results were validated in a second cohort composed of AD (n = 26), rapidly progressive AD (rpAD) (n = 15), VaD (n = 21), and cognitively unimpaired patients with vascular encephalopathy (VE) (n = 25) cases. In the study, cohort significant differences were detected in tau, p-tau, and Aβ1-42 (Aβ42) levels between AD and VaD patients, but not for the neuron-specific enolase (NSE), S100B protein, 14-3-3 and YKL-40. Differential tau, p-tau, and Aβ42 levels between AD and VaD were confirmed in the validation cohort, which additionally showed no differences between AD and rpAD, nor between VaD and VE. The evaluation of the biomarker performance in discrimination between AD and VaD patients revealed that the best diagnostic accuracy could be obtained when tau, p-tau, and Aβ42 were combined in form of Aβ42/p-tau (AUC 0.84–0.90, sensitivity 77–81%, specificity 80–93%) and (tau × p-tau)/Aβ42 ratio (AUC 0.83–0.87, sensitivity 73–81%, specificity 78–87%). Altogether, our studies provided neurodegenerative biomarker profiles in two cohorts of AD and VaD patients favoring the combination of CSF biomarker to differentiate between diseases.

Validation and utilization of amended diagnostic criteria in Creutzfeldt-Jakob disease surveillance

Objective To validate an amended protocol for clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) including real-time quaking-induced conversion (RT-QuIC) and to observe its use in CJD surveillance. Methods In the framework of a prospective epidemiologic study, all neuropathologically confirmed cases with sCJD who received CSF RT-QuIC analysis during diagnostic workup (n = 65) and a control group of individuals without CJD (n = 118) were selected to investigate the accuracy of an amended diagnostic protocol. The patients had been referred to the German National Reference Center for Transmissible Spongiform Encephalopathies. The influence of the amended protocol on incidence figures was evaluated in the context of 3 years of surveillance activity (screened cases using 14-3-3 test n = 18,789, highly suspicious cases of CJD n = 704). Annual incidences were calculated with current criteria and the amended protocol. Results The amended protocol showed a sensitivity of 97% and a specificity of 99%. When it was applied to all suspected cases who were referred to the reference center, the assessed incidence of CJD increased from 1.7 to 2.2 per million in 2016. Conclusion CJD surveillance remains challenging because information from external health care institutions can be limited. RT-QuIC shows excellent diagnostic accuracy when applied in the clinical setting to symptomatic patients. Data for RT-QuIC alone when applied as a general screening test are not available yet. We propose an amended research protocol that improves early and accurate clinical diagnosis of sCJD during surveillance activities. The use of this protocol will probably lead to a significant increase of the incidence rate. Classification of evidence This study provides Class III evidence that for patients with suspected sCJD, criteria for clinical diagnosis plus the CSF RT-QuIC accurately identifies patients with sCJD (sensitivity 97%, specificity 99%).

Age of onset in genetic prion disease and the design of preventive clinical trials

Regulatory agencies worldwide have adopted programs to facilitate drug development for diseases where the traditional approach of a randomized trial with a clinical endpoint is expected to be prohibitively lengthy or difficult. Here we provide quantitative evidence that this criterion is met for the prevention of genetic prion disease. We assemble age of onset or death data from N=1,094 individuals with high penetrance mutations in the prion protein gene (PRNP), generate survival and hazard curves, and estimate statistical power for clinical trials. We show that, due to dramatic and unexplained variability in age of onset, randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials. Instead, the characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Biomarker-based trials may require post-marketing studies to confirm clinical benefit. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a post-marketing study could provide opportunities for subsequent determination of clinical benefit.

Distinct microglia profile in Creutzfeldt-Jakob disease and Alzheimer's disease is independent of disease kinetics: Microglia activation profile in dementia

Activated microglia represent a common pathological feature of neurodegenerative diseases. Sporadic Creutzfeldt–Jakob disease (sCJD) patients show more pronounced microglial activation than Alzheimers disease (AD) patients. Whether these differences are due to differences in disease kinetics or represent disease‐specific changes is unknown. We investigated microglial phenotypes in brains of rapidly progressive AD (rpAD) and sCJD patients matched for clinical presentation, including disease duration. We immunostained the frontal cortex, basal ganglia and cerebellum in 16 patients with rpAD and sCJD using antibodies against markers of microglia and recruited monocytes (ionized calcium‐binding adaptor molecule 1, human leukocyte antigen DPQR, Cluster of Differentiation 68), an antibody unique to brain‐resident microglia (transmembrane protein 119 (TMEM119)), in addition to antibodies against a marker of astrocytes (glial fibrillary acidic protein), amyloid‐β (Aβ) and pathological prion protein. rpAD patients showed a distinct microglial phenotype with a high abundance of TMEM119‐positive microglia in all investigated regions. Presence of Aβ deposits seen in a sCJD patient with concomitant deposition of Aβ led to increase of TMEM119‐positive microglia. Our data suggest that in rpAD, activation of brain‐resident microglia significantly contributes to microgliosis, whereas in sCJD the TMEM119 signature of resident microglial cells is barely detectable. This is irrespective of disease duration and may indicate disease‐specific microglial reaction.

Cerebrospinal Fluid Total and Phosphorylated α-Synuclein in Patients with Creutzfeldt–Jakob Disease and Synucleinopathy

High levels of total α-synuclein (t-α-synuclein) in the cerebrospinal fluid (CSF) were reported in sporadic Creutzfeldt–Jakob disease (sCJD). The potential use of t-α-synuclein in the discrimination of Lewy body dementias (i.e., Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB)) is still under investigation. In addition, phospho-serine-129 α-synuclein (p-α-synuclein) has been described to be slightly increased in the CSF of synucleinopathies. Here, we analyzed t-α-synuclein and p-α-synuclein concentrations and their ratio in the context of differential diagnosis of neurodegenerative diseases. We quantified the levels of CSF t-α-synuclein and p-α-synuclein in a cohort of samples composed of neurological controls (NC), sCJD, PDD, and DLB by means of newly developed specific enzyme-linked immunosorbent assays. T-α-synuclein and p-α-synuclein were specifically elevated in sCJD compared to other disease groups. The area under the curve (AUC) values for t-α-synuclein were higher for the discrimination of sCJD from dementias associated to Lewy bodies as compared to the use of p-α-synuclein. A combination of both markers even increased the diagnostic accuracy. An inverse correlation was observed in CSF between t-α-synuclein and p-α-synuclein, especially in the DLB group, indicating a disease-relevant association between both markers. In conclusion, our data confirm t-α-synuclein and p-α-synuclein as robust biomarkers for sCJD and indicate the potential use of colorimetric t-α-synuclein ELISAs for differential diagnosis of dementia types.