Jurgen A.H.R. Claassen

Cerebral Autoregulation: An Overview of Current Concepts and Methodology with Special Focus on the Elderly

Cerebral autoregulation (CA) refers to the properties of the brain vascular bed to maintain cerebral perfusion despite changes in blood pressure (BP). Whereas classic studies have assessed CA during changes in BP that have a gradual onset, dynamic studies quantify the fast modifications in cerebral blood flow (CBF) in relation to rapid alterations in BP. There is a lack of standardization in the assessment of dynamic CA. This review provides an overview of the methods that have been applied, with special focus on the elderly. We will discuss the relative merits and shortcomings of these methods with regard to the aged population. Furthermore, we summarize the effects of variability in BP on CBF in older people. Of the various dynamic assessments of CA, a single sit-to-stand procedure is a feasible and physiologic method in the elderly. The collection of spontaneous beat-to-beat changes in BP and CBF allows estimation of CA using the technique of transfer function analysis. A thorough search of the literature yielded eight studies that have measured dynamic CA in the elderly aged <75 years. Regardless of the methods used, it was concluded from these studies that CA was preserved in this population.

MicroRNAs in Alzheimer's disease: differential expression in hippocampus and cell-free cerebrospinal fluid

MicroRNAs (miRNAs) are small, noncoding RNAs that function in complex networks to regulate protein expression. In the brain, they are involved in development and synaptic plasticity. In this study, we aimed to identify miRNAs with a differential expression in either hippocampus or cerebrospinal fluid (CSF) from Alzheimers disease (AD) patients and age-matched nondemented control subjects using quantitative polymerase chain reaction. In hippocampus, we also differentiated between AD patients with an intermediate stage, according to Braak III/IV stage, and a late stage, characterized according to Braak VI stage. Eight selected miRNAs were analyzed in hippocampus, and the expression of miR-16, miR-34c, miR-107, miR-128a, and miR-146a were differentially regulated. In CSF, out of 8 selected miRNAs only miR-16 and miR-146a could be reliably detected. In addition, we identified an effect of blood contamination on the CSF levels of miR-16, miR-24, and miR-146a. For group comparisons, we therefore selected CSF samples absent of, or containing only low numbers of blood cells. Levels of miR-146a were significantly decreased in CSF of AD patients. In conclusion, the abnormal expression of several miRNAs in hippocampus of intermediate- and late-stage AD patients suggests their involvement in AD pathogenesis, and low levels of miR-146a in CSF were associated with AD.

Effect of 1 Night of Total Sleep Deprivation on Cerebrospinal Fluid β-Amyloid 42 in Healthy Middle-Aged Men: A Randomized Clinical Trial

IMPORTANCE Increasing evidence suggests a relationship between poor sleep and the risk of developing Alzheimer disease. A previous study found an effect of sleep on β-amyloid (Aβ), which is a key protein in Alzheimer disease pathology. OBJECTIVE To determine the effect of 1 night of total sleep deprivation on cerebrospinal fluid Aβ42 protein levels in healthy middle-aged men. DESIGN, SETTING, AND PARTICIPANTS The Alzheimer, Wakefulness, and Amyloid Kinetics (AWAKE) study at the Radboud Alzheimer Center, a randomized clinical trial that took place between June 1, 2012, and October 1, 2012. Participants were cognitively normal middle-aged men (40-60 years of age) with normal sleep (n = 26) recruited from the local population. INTERVENTIONS Participants were randomized to 1 night with unrestricted sleep (n = 13) or 1 night of total sleep deprivation (24 hours of wakefulness) (n = 13). MAIN OUTCOMES AND MEASURES Sleep was monitored using continuous polysomnographic recording from 3 pm until 10 am. Cerebrospinal fluid samples were collected using an intrathecal catheter at defined times to compare cerebral Aβ42 concentrations between evening and morning. RESULTS A night of unrestricted sleep led to a 6% decrease in Aβ42 levels of 25.3 pg/mL (95% CI [0.94, 49.6], P = .04), whereas sleep deprivation counteracted this decrease. When accounting for the individual trajectories of Aβ42 over time, a difference of 75.8 pg/mL of Aβ42 was shown between the unrestricted sleep and sleep deprivation group (95% CI [3.4, 148.4], P = .04). The individual trajectories of evening and morning Aβ42 concentrations differed between the unrestricted sleep and sleep deprivation groups (P = .04) in contrast to stable Aβ40, tau, and total protein levels. CONCLUSIONS AND RELEVANCE Sleep deprivation, or prolonged wakefulness, interferes with a physiological morning decrease in Aβ42. We hypothesize that chronic sleep deprivation increases cerebral Aβ42 levels, which elevates the risk of Alzheimer disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01194713.

Transfer function analysis of dynamic cerebral autoregulation: A white paper from the International Cerebral Autoregulation Research Network

Cerebral autoregulation is the intrinsic ability of the brain to maintain adequate cerebral perfusion in the presence of blood pressure changes. A large number of methods to assess the quality of cerebral autoregulation have been proposed over the last 30 years. However, no single method has been universally accepted as a gold standard. Therefore, the choice of which method to employ to quantify cerebral autoregulation remains a matter of personal choice. Nevertheless, given the concept that cerebral autoregulation represents the dynamic relationship between blood pressure (stimulus or input) and cerebral blood flow (response or output), transfer function analysis became the most popular approach adopted in studies based on spontaneous fluctuations of blood pressure. Despite its sound theoretical background, the literature shows considerable variation in implementation of transfer function analysis in practice, which has limited comparisons between studies and hindered progress towards clinical application. Therefore, the purpose of the present white paper is to improve standardisation of parameters and settings adopted for application of transfer function analysis in studies of dynamic cerebral autoregulation. The development of these recommendations was initiated by (but not confined to) the Cerebral Autoregulation Research Network (CARNet – www.car-net.org).

Vascular Aspects of Cognitive Impairment and Dementia

Hypertension and stroke are highly prevalent risk factors for cognitive impairment and dementia. Alzheimers disease (AD) and vascular dementia (VaD) are the most common forms of dementia, and both conditions are preceded by a stage of cognitive impairment. Stroke is a major risk factor for the development of vascular cognitive impairment (VCI) and VaD; however, stroke may also predispose to AD. Hypertension is a major risk factor for stroke, thus linking hypertension to VCI and VaD, but hypertension is also an important risk factor for AD. Reducing these two major, but modifiable, risk factors—hypertension and stroke—could be a successful strategy for reducing the public health burden of cognitive impairment and dementia. Intake of long-chain omega-3 polyunsaturated fatty acids (LC-n3-FA) and the manipulation of factors involved in the renin-angiotensin system (e.g. angiotensin II or angiotensin-converting enzyme) have been shown to reduce the risk of developing hypertension and stroke, thereby reducing dementia risk. This paper will review the research conducted on the relationship between hypertension, stroke, and dementia and also on the impact of LC-n3-FA or antihypertensive treatments on risk factors for VCI, VaD, and AD.

β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer’s disease

Alzheimer’s disease (AD) and vascular dementia are responsible for up to 90% of dementia cases. According to the World Health Organization (WHO), a staggering number of 35.6 million people are currently diagnosed with dementia. Blocking disease progression or preventing AD altogether is desirable for both social and economic reasons and recently focus has shifted to a new and promising drug: the β-secretase inhibitor. Much of AD research has investigated the amyloid cascade hypothesis, which postulates that AD is caused by changes in amyloid beta (Aβ) stability and aggregation. Blocking Aβ production by inhibiting the first protease required for its generation, β-secretase/BACE1, may be the next step in blocking AD progression. In April 2012, promising phase I data on inhibitor MK-8931 was presented. This drug reduced Aβ cerebral spinal fluids (CSF) levels up to 92% and was well tolerated by patients. In March 2013 data was added from a one week trial in 32 mild to moderate AD patients, showing CSF Aβ levels decreased up to 84%. However, β-site APP cleaving enzyme 1 (BACE1) inhibitors require further research. First, greatly reducing Aβ levels through BACE1 inhibition may have harmful side effects. Second, BACE1 inhibitors have yet to pass clinical trial phase II/III and no data on possible side effects on AD patients are available. And third, there remains doubt about the clinical efficacy of BACE1 inhibitors. In moderate AD patients, Aβ plaques have already been formed. BACE1 inhibitors prevent production of new Aβ plaques, but hypothetically do not influence already existing Aβ peptides. Therefore, BACE1 inhibitors are potentially better at preventing AD instead of having therapeutic use.

Cerebral autoregulation in Alzheimer's disease

Cerebral autoregulation aims to stabilize blood flow to the brain during variations in perfusion pressure, thus protecting the brain against the risks of low or high systemic blood pressure. This vital mechanism is severely impaired in the transgenic mouse model of Alzheimers disease (AD) that abundantly produces amyloid-β peptide β1-42. These observations have been extrapolated to human AD, wherein impairment of autoregulation could have important implications for the clinical management and prevention of AD. Research on cerebral autoregulation in human AD, however, has only recently become available. Contrary to the animal models, preliminary studies suggest that cerebral autoregulation is preserved in patients with AD. Further research is urgently needed to elucidate this discrepancy in the current literature, given the accumulating evidence that implicates cerebrovascular pathology in AD.

Impaired cerebral autoregulation and vasomotor reactivity in sporadic Alzheimer's disease.

BACKGROUND Understanding the relationship between vascular disease and Alzheimers disease (AD) will enhance our insight into this disease and pave the way for novel therapeutic research. Cerebrovascular dysfunction, expressed as impaired cerebral autoregulation and cerebral vasomotor reactivity, has been observed in transgenic mouse models for AD. Translation to human AD is limited and conflicting however. OBJECTIVE To investigate if impaired cerebral autoregulation and cerebral vasomotor reactivity, found in animal models for AD, are present in human sporadic AD. METHODS In 12 patients with mild to moderate AD (75 SD 4 yr) and 24 controls matched for age and history of hypertension, all without diabetes, we measured blood pressure (Finapres) and cerebral blood flow-velocity (transcranial Doppler). Cerebral autoregulation was assessed during changes in blood pressure induced by single and repeated sit-stand maneuvers. Cerebral vasomotor reactivity was assessed during hyperventilation and inhalation of 5 % carbon dioxide. RESULTS During single sit-stands, controls had a 4% (SD 8) decrease in cerebrovascular resistance during a reduction in blood pressure, and an 8 % (SD 11) increase during a rise in blood pressure, indicating normal cerebral autoregulation. These changes were not seen in AD (p=0.04). During repeated sit-stands, blood pressure fluctuated by 20 % of baseline. This led to larger fluctuations in cerebral blood flow in AD (27 (6) %) than in controls (22 (6) %, p < 0.05). Cerebral vasomotor reactivity to hypercapnia was reduced in AD (42.7 % increase in CBFV, versus 79.5 % in controls, p = 0.03). CONCLUSION Observations of impaired cerebrovascular function (impaired autoregulation and vasoreactivity) in transgenic mouse models for AD were confirmed in patients with sporadic AD.

Reciprocal interactions between sleep, circadian rhythms and Alzheimer's disease: focus on the role of hypocretin and melatonin

AD, sleep and circadian rhythm physiology display an intricate relationship. On the one hand, AD pathology leads to sleep and circadian disturbances, with a clear negative influence on quality of life. On the other hand, there is increasing evidence that both sleep and circadian regulating systems exert an influence on AD pathology. In this review we describe the impairments of both sleep regulating systems and circadian rhythms in AD and their link to clinical symptoms, as this may increase knowledge on appropriate diagnosis and adequate treatment of sleep problems in AD. Furthermore we discuss how sleep regulating systems, and especially neurotransmitters such as melatonin and hypocretin, may affect AD pathophysiology, as this may provide a role for lack of sleep and circadian rhythm deterioration in the onset of AD.

The cerebrovascular role of the cholinergic neural system in Alzheimer's disease.

The intrinsic cholinergic innervation of the cortical microvessels contains both subcortical pathways and local cortical interneurons mediated by muscarinic and nicotinic acetylcholine receptors. Stimulation of this system leads to vasodilatation. In the extrinsic innervation, choline acts as a selective agonist for the α7-nicoticinic acetylcholine receptor on the sympathetic nerves to cause vasodilatation, and through this mechanism, cholinergic modulation may affect this sympathetic vasodilatation. Alzheimers disease is characterized by a cerebral cholinergic deficit and cerebral blood flow is diminished. Cholinesterase inhibitors, important drugs in the treatment of Alzheimers disease, could influence the cerebral blood flow through stimulation of the intrinsic cholinergic cerebrovascular innervation. Indeed, cholinesterase inhibitors improve cerebral blood flow in Alzheimer patients who respond to treatment. Further, cerebrovascular reactivity and neurovascular coupling are impaired in Alzheimers disease and both can be improved by cholinesterase inhibitors. Conversely, cholinesterase inhibitors inhibit the α7-nicoticinic acetylcholine receptor on extrinsic sympathetic nerves and thus may impair vasodilatation. The net outcome of these opposing effects in clinical practice remains unknown. Moreover, it is uncertain whether the regulation of cerebral blood flow during blood pressure changes (cerebral autoregulation) is impaired in patients with Alzheimers disease. Technological developments now allow us to dynamically measure blood pressure, cerebral blood flow, and cerebral cortical oxygenation. Using simple maneuvers like single sit-stand and repeated sit-stand maneuvers, the regulation of cerebral perfusion in patients with Alzheimers disease can easily be measured. Sit-stand maneuvers can be considered as a provocation test for cerebral autoregulation, and provide excellent opportunities to study the cerebrovascular effects of cholinesterase inhibitors.