Blood-Brain Barrier Breakdown in Relationship to Alzheimer and Vascular Disease.

OBJECTIVE: Blood-brain barrier (BBB) breakdown has been suggested to be an early biomarker in human cognitive impairment. However, the relationship between BBB breakdown and brain pathology, most commonly Alzheimer disease (AD) and vascular disease, is still poorly understood. The present study measured human BBB function in mild cognitive impairment (MCI) patients on 2 molecular scales, specifically BBB's permeability to water and albumin molecules. METHODS: Fifty-five elderly participants were enrolled, including 33 MCI patients and 22 controls. BBB permeability to water was measured with a new magnetic resonance imaging technique, water extraction with phase contrast arterial spin tagging. BBB permeability to albumin was determined using cerebrospinal fluid (CSF)/serum albumin ratio. Cognitive performance was assessed by domain-specific composite scores. AD pathology (including CSF Aß and ptau) and vascular risk factors were examined. RESULTS: Compared to cognitively normal subjects, BBB in MCI patients manifested an increased permeability to small molecules such as water but was no more permeable to large molecules such as albumin. BBB permeability to water was found to be related to AD markers of CSF Aß and ptau. On the other hand, BBB permeability to albumin was found to be related to vascular risk factors, especially hypercholesterolemia, but was not related to AD pathology. BBB permeability to small molecules, but not to large molecules, was found to be predictive of cognitive function. INTERPRETATION: These findings provide early evidence that BBB breakdown is related to both AD and vascular risks, but their effects can be differentiated by spatial scales. BBB permeability to small molecules has a greater impact on cognitive performance. ANN NEUROL 2021;90:227-238.

Association of Vascular Risk Factors With ß-Amyloid Peptide and Tau Burdens in Cognitively Unimpaired Individuals and Its Interaction With Vascular Medication Use.

Importance: Vascular risk factors are associated with increased risk of Alzheimer disease (AD), but it is unclear whether there is a direct association of these risk factors with AD pathogenesis. Objectives: To assess the associations of vascular risk factors with AD pathogenesis in asymptomatic individuals, and to test whether this association is moderated among individuals who use vascular medications. Design, Setting, and Participants: This cross-sectional study used data from the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) cohort of cognitively unimpaired individuals aged 55 to 82 years with a parental or multiple-sibling history of sporadic AD, who were recruited via advertisement from the greater Montreal, Quebec, Canada, metropolitan area. Participants were enrolled between September 9, 2011, to May, 3, 2017, and stratified by use vs no use of vascular medications. Data were analyzed July 1, 2018, to April 5, 2019. Main Outcomes and Measures: Principal analyses investigated associations of total, high-density lipoprotein, and low-density lipoprotein cholesterol levels, systolic and diastolic blood pressure, pulse pressure, and a combined vascular risk score (measured using the Framingham Coronary Risk Profile) with global ß-amyloid peptide (Aß) and entorhinal tau burden as measured by positron emission tomography (PET). Potential moderating associations of use of vascular medications with these associations were examined. Secondary similar analyses considered cerebrospinal fluid (CSF) Aß1-42 and phosphorylated tau levels. Results: Among 215 participants (mean [SD] age, 62.3 [5.0] years; 161 [74.8%] women), 120 participants underwent PET, including 75 participants (62.5%) who were not using vascular medications, and 162 participants underwent CSF assessment, including 113 participants (69.8%) who were not using vascular medications. There was an overlap of 67 participants who underwent PET and CSF assessment. Interaction analyses showed that among participants not using vascular medications, higher Aß deposition as measured by PET was associated with higher total cholesterol level (ß = -0.002 [SE, 0.001]; P = .02), low-density lipoprotein cholesterol level (ß = -0.002 [SE, 0.001]; P = .006), systolic blood pressure (ß = -0.006 [SE, 0.002]; P = .02), pulse pressure (ß = -0.007 [SE, 0.002]; P = .004), and Framingham Coronary Risk Profile score (ß = -0.038 [SE, 0.011]; P = .001), but such associations were absent in participants who used vascular medications. Interactions were also found between vascular medication use and high-density lipoprotein cholesterol (ß = -3.302 [SE, 1.540]; P = .03), low-density lipoprotein cholesterol (ß = 1.546 [SE, 0.754]; P = .04), and Framingham Coronary Risk Profile score (ß = 23.102 [SE, 10.993]; P = .04) on Aß1-42 burden as measured in CSF. Higher Framingham Coronary Risk Profile scores were associated with reduced tau burden among participants using vascular medications but not among participants not using vascular medications (interaction, ß = -0.010 [SE, 0.005]; P = .046). Conclusions and Relevance: These findings corroborate previously reported associations of vascular risk factors with Aß burden but not tau burden. However, these associations were found only among individuals who were not using vascular medications. These results suggest that medication use or other control of vascular risk factors should be considered in Alzheimer disease prevention trials.

Vascular hyperpermeability as a hallmark of phacomatoses: is the etiology angiogenesis comparable with mechanisms seen in inflammatory pathways? Part I: historical observations and clinical perspectives on the etiology of increased CSF protein levels, CSF clotting, and communicating hydrocephalus: a comprehensive review.

Phacomatoses are a special group of familial hamartomatous syndromes with unique neuro-cutaneous manifestations as well as disease characteristic tumors. Neurofibromatosis 2 (NF2) and tuberous sclerosis complex (TSC) are representatives of this family. Vestibular schwannoma (VS) and subependymal giant cell tumor (SGCT) are two of the most common intracranial tumors associated with NF2 and TSC, respectively. These tumors can present with obstructive hydrocephalus due to their location adjacent to or in the ventricles. However, both tumors are also known to have a unique association with an elevated protein concentration in the cerebrospinal fluid (CSF), sometimes in association with non-obstructive (communicating) hydrocephalus (HCP), the causality of which has been unclear. Furthermore, SGCTs have repeatedly been shown to have a predisposition for CSF clotting, causing debilitating obstructions and recurrent malfunctions in shunted patients. However, the exact relation between high protein levels and spontaneous clotting of the CSF is not clear, nor is the mechanism understood by which CSF may clot in SGCTs. Elevated protein levels in the CSF are thought to be caused by increased vascular permeability and dysregulation of the blood-brain barrier. The two presumed underlying pathophysiologic mechanisms for that, in the context of tumorigenesis, are angiogenesis and inflammation. Both mechanisms are correlated to the Pi3K/Akt/mTOR pathway which is a major tumorigenesis pathway in nearly all phacomatoses. In this review, we discuss the influence of angiogenesis and inflammation on vascular permeability in VSs and SGCTs at the phenotypic level as well as their possible genetic and molecular determinants. Part I describes the historical perspectives and clinical aspects of the relationship between vascular permeability, abnormal CSF protein levels, clotting of the CSF, and communicating HCP. Part II describes different cellular and molecular pathways involved in angiogenesis and inflammation in these two tumors and the correlation between inflammation and coagulation. Interestingly, while increased angiogenesis can be observed in both VS and SGCT, inflammatory processes seem more prominent in SGCT. Both pathologies are characterized by different subgroups of tumor-associated macrophages (TAM): the pro-inflammatory, M1 type is predominating in SGCTs while pro-angiogenetic, M2 type is predominating in VSs. We suggest that lack of NF2 protein in VS and lack of TSC1/2 proteins in SGCT determine this fundamental difference between the two tumor types, by defining the predominant TAM type. Since inflammatory reactions and coagulation processes are tightly connected, a "pro-inflammatory state" of SGCT can be used to explain the observed associated enhanced CSF clotting process. These distinct cellular and molecular differences may have direct therapeutic implications on tumors that are unique to certain phacomatoses or those with similar genetics.

Vascular diseases and bleedings.

Diseases of the central nervous system that are caused by an underlying vascular pathology typically result in either hemorrhage or ischemia. Most prominent entities include spontaneous subarachnoid hemorrhage, spontaneous intracerebral hemorrhage, and ischemic stroke. For anatomic reasons, cerebrospinal fluid (CSF) qualifies as body fluid for the exploration of biomarkers in these disorders. Even though in subarachnoid hemorrhage a few CSF parameters have been established for routine diagnostic purposes, there is still an unmet need and broad interest in the identification of molecules that would allow further insight into disease mechanisms and supplement patients' medical care. This chapter provides an overview on what is presently known about CSF biomarkers in spontaneous subarachnoid hemorrhage, spontaneous intracerebral hemorrhage, and ischemic stroke. We recapitulate current evidence on established diagnostic tests, discuss the role of various CSF molecules in the pathophysiology of these diseases, and illuminate their potential use in future clinical practice. Furthermore, we address methodologic aspects as well as shortcomings of research in this field.

Cerebrospinal fluid biomarkers for Alzheimer's and vascular disease vary by age, gender, and APOE genotype in cognitively normal adults.

BACKGROUND: This study sought to evaluate gender and APOE genotype-related differences in the concentrations of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) and cerebrovascular injury across the life span of cognitively normal adults. METHODS: CSF amyloid beta1-42 (Aß42), phospho-tau-181 (p-tau181), and total tau were measured in 331 participants who were between the ages of 21 and 100. CSF E-selectin and vascular cell adhesion protein 1 (VCAM1) were measured in 249 participants who were between the ages of 50 and 100. RESULTS: CSF total tau and p-tau181 increased with age over the adult life span (p < 0.01) with no gender differences in those increases. CSF Aß42 concentration varied according to age, gender, and APOE genotype (interaction of age × gender × Îµ4, p = 0.047). CSF VCAM1, but not E-selectin, increased with age (p < 0.01), but both were elevated in men compared to women (p < 0.01). CONCLUSIONS: Female APOE-ε4 carriers appear at higher risk for AD after age 50. In contrast, men may experience a relatively higher rate of cerebrovascular injury in middle and early old age.

Plasma ß-amyloid in Alzheimer's disease and vascular disease.

Implementation of amyloid biomarkers in clinical practice would be accelerated if such biomarkers could be measured in blood. We analyzed plasma levels of Aß42 and Aß40 in a cohort of 719 individuals (the Swedish BioFINDER study), including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer's disease (AD) dementia and cognitively healthy elderly, using a ultrasensitive immunoassay (Simoa platform). There were weak positive correlations between plasma and cerebrospinal fluid (CSF) levels for both Aß42 and Aß40, and negative correlations between plasma Aß42 and neocortical amyloid deposition (measured with PET). Plasma levels of Aß42 and Aß40 were reduced in AD dementia compared with all other diagnostic groups. However, during the preclinical or prodromal AD stages (i.e. in amyloid positive controls, SCD and MCI) plasma concentration of Aß42 was just moderately decreased whereas Aß40 levels were unchanged. Higher plasma (but not CSF) levels of Aß were associated with white matter lesions, cerebral microbleeds, hypertension, diabetes and ischemic heart disease. In summary, plasma Aß is overtly decreased during the dementia stage of AD indicating that prominent changes in Aß metabolism occur later in the periphery compared to the brain. Further, increased levels of Aß in plasma are associated with vascular disease.

Neuroinflammation and complexes of 17ß-hydroxysteroid dehydrogenase type 10--amyloid ß in Alzheimer's disease.

Multifunctional mitochondrial enzyme 17ß-hydroxysteroid dehydrogenase type 10 plays a role in the development of Alzheimer's disease. However, changes in its expression in the brain or cerebrospinal fluid are not fully specific for this type of dementia. Our previous study revealed that complexes of the enzyme and amyloid ß in cerebrospinal fluid could serve as a more specific biomarker of Alzheimer's disease than either the enzyme or amyloid ß individually when compared to autoimmune multiple sclerosis. In this study, enzyme-linked immunosorbent assay and the surface plasmon resonance biosensor method were used to analyse cerebrospinal fluid of patients with various neuroinflammatory diseases. Significant differences in the levels of the total enzyme, complexes, amyloid ß 1-42 and total τ/phospho-τ were found in Alzheimer's disease patients while differences in complexes, total amyloid ß and amyloid ß 1- 42 were observed in patients with neuroinflammatory diseases (except for multiple sclerosis) when compared to non-neuroinflammatory controls. The interactions of the enzyme with amyloid ß appeared to depend strongly on neuroinflammation-sensitive amyloid ß. Our data demonstrated that oligomerisation/aggregation of intracellular amyloid ß peptides was important in Alzheimer's disease while extracellular amyloid ß could play a role in neuroinflammatory diseases. Phospho-τ is currently the best biomarker of Alzheimer's disease.

Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system.

Human narcolepsy is a chronic sleep disorder affecting 1:2000 individuals. The disease is characterized by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep, such as sleep paralysis and hypnagogic hallucinations. Recently, it was discovered that the pathophysiology of (idiopathic) narcolepsy-cataplexy is linked to hypocretin ligand deficiency in the brain and cerebrospinal fluid (CSF), as well as the positivity of the human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602). The symptoms of narcolepsy can also occur during the course of other neurological conditions (i.e. symptomatic narcolepsy). We define symptomatic narcolepsy as those cases that meet the International Sleep Disorders Narcolepsy Criteria, and which are also associated with a significant underlying neurological disorder that accounts for excessive daytime sleepiness (EDS) and temporal associations. To date, we have counted 116 symptomatic cases of narcolepsy reported in literature. As, several authors previously reported, inherited disorders (n=38), tumors (n=33), and head trauma (n=19) are the three most frequent causes for symptomatic narcolepsy. Of the 116 cases, 10 are associated with multiple sclerosis, one case of acute disseminated encephalomyelitis, and relatively rare cases were reported with vascular disorders (n=6), encephalitis (n=4) and degeneration (n=1), and hererodegenerative disorder (three cases in a family). EDS without cataplexy or any REM sleep abnormalities is also often associated with these neurological conditions, and defined as symptomatic cases of EDS. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, review of the literature reveals numerous unquestionable cases of symptomatic narcolepsy. These include cases with HLA negative and/or late onset, and cases in which the occurrences of the narcoleptic symptoms are parallel with the rise and fall of the causative disease. A review of these cases (especially those with brain tumors), illustrates a clear picture that the hypothalamus is most often involved. Several cases of symptomatic cataplexy (without EDS) were also reported and in contrast, these cases appear to be often associated with non-hypothalamic structures. CSF hypocretin-1 measurement were also carried out in a limited number of symptomatic cases of narcolepsy/EDS, including narcolepsy/EDS associated with tumors (n=5), head trauma (n=3), vascular disorders (n=5), encephalopathies (n=3), degeneration (n=30), demyelinating disorder (n=7), genetic/congenital disorders (n=11) and others (n=2). Reduced CSF hypocretin-1 levels were seen in most symptomatic narcolepsy cases of EDS with various etiologies and EDS in these cases is sometimes reversible with an improvement of the causative neurological disorder and an improvement of the hypocretin status. It is also noted that some symptomatic EDS cases (with Parkinson diseases and the thalamic infarction) appeared, but they are not linked with hypocretin ligand deficiency. In contrast to idiopathic narcolepsy cases, an occurrence of cataplexy is not tightly associated with hypocretin ligand deficiency in symptomatic cases. Since CSF hypocretin measures are still experimental, cases with sleep abnormalities/cataplexy are habitually selected for CSF hypocretin measures. Therefore, it is still not known whether all or a large majority of cases with low CSF hypocretin-1 levels with CNS interventions, exhibit EDS/cataplexy. It appears that further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiological mechanisms for the occurrence of EDS and cataplexy.

Oligoclonal immunoglobulins in cerebrospinal fluid during varicella zoster virus (VZV) vasculopathy are directed against VZV.

Limited analyses of cerebrospinal fluid from patients with central nervous system infections have shown that the oligoclonal IgG is antibody directed against the agent that causes disease. Using a new method involving binding of IgG to beads coated with lysates prepared from candidate infectious antigens, we showed that the oligoclonal IgG in cerebrospinal fluid of a patient with chronic varicella zoster virus vasculopathy is directed against the causative virus. This approach holds promise in identifying and purifying the relevant oligoclonal IgGs in inflammatory central nervous system diseases of unknown cause.

Multifocal vasculopathy due to Varicella-Zoster Virus (VZV): serial analysis of VZV DNA and intrathecal synthesis of VZV antibody in cerebrospinal fluid.

Recognition of multifocal vasculopathy due to varicella-zoster virus (VZV) is often problematic. We describe a human immunodeficiency virus-infected patient who had progressive central nervous system disease for >3 months. Both VZV DNA and antibody were detected in cerebrospinal fluid (CSF) specimens; serial polymerase chain reaction analyses confirmed the diagnosis and guided the duration of therapy. Reduced ratios of VZV antibody in serum to that in CSF were also demonstrated.

Cerebrospinal fluid apolipoprotein E level is increased in late-onset Alzheimer's disease.

Worldwide evidence has recently shown that the allele epsilon4 of apolipoprotein E (ApoE) is a genetic risk factor for Alzheimer's disease (AD) underlining the possible role of apoE in the physiopathology of AD. To evaluate the usefulness of apoE concentration in pathogenesis of AD, we measured the cerebrospinal fluid (CSF) levels of apoE. CSF apoE level was significantly higher in 38 patients with late-onset AD than in 31 control patients and 47 patients suffering from other neurological and related diseases. Higher levels of CSF apoE were also present in a subset of patients with meningoencephalitis, motor neuron disease, and low back pain. The increase of CSF-apoE in AD is in agreement with results from studies that find an increase of mRNA apoE in the brains of AD patients. Compared to other works, these results underline the importance and the difficulties of the selection of the controls. The CSF apoE level seems to be a reflection of neuronal damage and/or an inflammatory reaction that may be common to AD and other neurological and related diseases.

Concentration of catecholamines and indoleamines in the cerebrospinal fluid of patients with vascular parkinsonism compared to Parkinson's disease patients.

The concentration of catecholamines and indoleamines in the cerebrospinal fluid of patients with vascular parkinsonism (VP) was compared to that in patients with Parkinson's disease (PD) and controls. Compared to the controls, the concentration of tyrosine was significantly higher, and the concentration of L-dopa and 3-O-methyldopa (3-OMD) was significantly lower in both VP and PD patients. The balance between the 3-OMD/L-dopa and dopamine (DA)/L-dopa ratios was changed in favor of 3-OMD/L-dopa in both VP patients and PD patients suggesting the preservation of a compensatory mechanism. All these changes were less marked in VP patients than in PD patients. A remarkable finding was that in contrast to PD patients the concentration of DA and norepinephrine (NE) was significantly higher in VP patients than in the controls. The decrease in the concentration of 5-hydroxytryptamine (5-HT) was significantly greater in VP patients than in PD patients. In PD patients, the concentration of DA, NE, and 5-HT showed significant correlation with the severity of motor symptoms. In VP patients, the concentration of 5-HT alone showed significant correlation with the severity of motor symptoms and cognitive dysfunction. These findings suggest that VP patients may have similar disturbances in the DA synthesis pathway as PD patients, but differ from PD patients in that the concentrations of DA and NE are elevated and the decrease in the 5-HT concentration is greater in VP patients.

The amino terminal portion of cerebrospinal fluid cystatin C in hereditary cystatin C amyloid angiopathy is not truncated: direct sequence analysis from agarose gel electropherograms.

The isolated amyloid substance in hereditary cystatin C amyloid angiopathy (HCCAA) is mainly composed of a cystatin C variant devoid of the 10 amino terminal amino acid residues of extracellular cystatin C from healthy individuals. We have developed a procedure for protein sequencing directly from agarose gel electropherograms and used this in conjunction with isoelectric focusing to investigate the amino terminal sequence of cerebrospinal fluid (CSF) cystatin C in HCCAA patients. The amino-terminal sequence determined for cystatin C from a HCCAA patient CSF sample, Xaa-Ser-Pro-Gly-Lys-Pro-Pro-Xaa-Leu-Val-Gly-Gly-Pro-Met-Xaa-Ala-Xaa-Val, showed that the protein was not amino-terminally truncated. CSF cystatin C from all nine HCCAA patients investigated was found to have an isoelectric point identical to that of native cystatin C, and the truncated form of cystatin C isolated from amyloid deposits was shown to contribute to less than 1% of the total amount of cystatin C in CSF. The total cysteine proteinase inhibitory capacity of CSF from HCCAA patients was lower than that of CSF from other patients. This decreased CSF inhibitory capacity in HCCAA patients was caused by decreased levels of cystatin C, since the levels of the other two cysteine proteinase inhibitors found in CSF, alpha 2-macroglobulin and kininogen, were significantly higher than in CSF from non-HCCAA patients.

Interpretation of cerebrospinal fluid proteins by gel electrophoresis.

The use of polyacrylamide gel electrophoresis (PAGE) for the separation of proteins in cerebrospinal fluid (CSF) results in greater definition than does a "routine" method such as cellulose acetate electrophoresis. Unconcentrated CSF is easily separated into as many as 18 bands by the use of PAGE. By means of a modified PAGE method described in this paper, unconcentrated and untreated CSF is quickly and conveniently analyzed for protein constituents. This modification involves a continuous buffer environment, a pore-size concentration gradient and CSF in amounts of 0.1 to 0.4 ml. Sucrose addition is not necessary in this procedure. Whereas most central nervous system (CNS) disease states do not yield consistently distinctive protein patterns, some diseases, such as vascular disease, infectious meningitis and some metastatic tumors, yield significantly altered patterns. It is suggested that the chief value of CSF protein electrophoresis at the present time is to follow the course of a CNS disease.