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2.
Neurology ; 94(24): e2545-e2554, 2020 06 16.
Article in English | MEDLINE | ID: mdl-32354749

ABSTRACT

OBJECTIVE: To characterize a cohort of patients with neurosarcoidosis with particular focus on CSF analysis and to investigate whether CSF values could help in distinguishing it from multiple sclerosis (MS). METHODS: This retrospective cohort study enrolled 85 patients with a diagnosis of neurosarcoidosis (possible, probable, or definite). CSF total protein, white cell count, and angiotensin-converting enzyme levels were measured. CSF and serum oligoclonal immunoglobulin G (IgG) patterns were analyzed with the use of odds ratios and binary logistic regression. RESULTS: Eighty patients had a probable (nonneural positive histology) or definite (neural positive histology) diagnosis of neurosarcoidosis. Most frequent findings on MRI were leptomeningeal enhancement (35%) and white matter and spinal cord involvement (30% and 23%). PET scan showed avid areas in 74% of cases. CSF analysis frequently showed lymphocytosis (63%) and elevated protein (62%), but CSF-selective oligoclonal bands were rare (3%). Serum ACE levels were elevated in 51% of patients but in only 14% of those with isolated neurosarcoidosis. Elevated CSF ACE was not found in any patient. CONCLUSIONS: Large elevations in total protein, white cell count, and serum ACE occur in neurosarcoidosis but are rare in MS. The diagnostic use of these tests is, however, limited because minimal changes may occur in both. MS clinical mimics in neurosarcoidosis are not common, and intrathecal synthesis of oligoclonal IgG is a powerful discriminator because it is rare in neurosarcoidosis but occurs in 95% to 98% cases of MS. We suggest caution in making a diagnosis of neurosarcoidosis when intrathecal oligoclonal IgG synthesis is found.


Subject(s)
Central Nervous System Diseases/cerebrospinal fluid , Central Nervous System Diseases/diagnosis , Multiple Sclerosis/cerebrospinal fluid , Multiple Sclerosis/diagnosis , Sarcoidosis/cerebrospinal fluid , Sarcoidosis/diagnosis , Adult , Aged , Cerebrospinal Fluid Proteins/analysis , Cohort Studies , Diagnosis, Differential , Female , Humans , Immunoglobulin G/cerebrospinal fluid , Leukocyte Count , Magnetic Resonance Imaging , Male , Middle Aged , Oligoclonal Bands/cerebrospinal fluid , Peptidyl-Dipeptidase A/blood , Peptidyl-Dipeptidase A/cerebrospinal fluid , Positron-Emission Tomography , Spinal Cord/diagnostic imaging , Young Adult
3.
BMJ Case Rep ; 12(11)2019 Nov 19.
Article in English | MEDLINE | ID: mdl-31748369

ABSTRACT

Neurosarcoidosis when encountered by neurologists most commonly presents as cranial neuropathy, peripheral mononeuropathy,polyneuropathy, myopathy, meningitis or myelopathy. There are limited reports in the current literature on the cases of neurosarcoidosis patients presenting with ischaemic stroke. We discuss a 52-year-old patient with a known previous history of cutaneous sarcoidosis presenting with an acute third nerve palsy, facial weakness and ataxia. His magnetic resonance imaging (MRI) brain demonstrated focal signal changes in the midbrain consistent with an acute ischaemic event in the region of his third nucleus, suggesting a partial Claude syndrome presentation. Cerebrospinal fluid (CSF) examination demonstrated an elevated angiotensin-converting enzyme (ACE) level. We discuss the difficulties associated with confirming a diagnosis for his presentation and consider distinctions in stroke in neurosarcoid and its management in comparison to more common causes.


Subject(s)
Ataxia/etiology , Brain Stem Infarctions/diagnostic imaging , Central Nervous System Diseases/drug therapy , Muscle Weakness/etiology , Oculomotor Nerve Diseases/etiology , Sarcoidosis/drug therapy , Administration, Intravenous , Brain Ischemia/diagnostic imaging , Brain Ischemia/pathology , Brain Stem Infarctions/cerebrospinal fluid , Central Nervous System Diseases/complications , Cranial Nerve Diseases/diagnosis , Cranial Nerve Diseases/etiology , Diagnosis, Differential , Facial Muscles/pathology , Humans , Magnetic Resonance Angiography/methods , Male , Mesencephalon/blood supply , Mesencephalon/diagnostic imaging , Mesencephalon/pathology , Methylprednisolone/administration & dosage , Methylprednisolone/therapeutic use , Middle Aged , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/therapeutic use , Peptidyl-Dipeptidase A/cerebrospinal fluid , Sarcoidosis/complications , Treatment Outcome
4.
J Alzheimers Dis ; 72(2): 525-535, 2019.
Article in English | MEDLINE | ID: mdl-31594235

ABSTRACT

Observations in autopsied brain tissue indicate that overactivation of the classical renin-angiotensin system (cRAS) and underactivity within regulatory RAS pathways (rRAS) are associated with pathology in Alzheimer's disease (AD). The primary aim of this study was to investigate whether cerebrospinal fluid (CSF) markers of RAS are altered in AD in relation to established CSF markers of disease pathology (lower Aß42 and elevated tau) and CSF markers of capillary dysfunction. We studied 40 controls and 40 AD cases grouped according to a biomarker profile (i.e., AD cases t-tau>400 pg/mL, pTau >60 pg/mL, and Aß42 <550 pg/mL). Angiotensin-II converting enyme-1 (ACE1) and ACE2 enzyme activity was measured using fluorogenic peptide substrates; sPDGFRß and albumin level by sandwich ELISA; and angiotensin-I (Ang-I), Ang-II, and Ang-(1-7) by direct ELISA. CSF Aß42, total, and phosphorylated tau levels were previously measured by INNOTEST sandwich ELISA. CSF ACE1 activity was significantly elevated in AD (p = 0.008) and positively correlated with ACE2 in AD (r = 0.420, p = 0.007). CSF ACE1 weakly correlated with t-tau (r = 0.294, p = 0.066) and p-tau (r = 0.329, p = 0.038) but not with Aß42 in the controls but not in AD. ACE1 correlated positively with sPDGFRß (r = 0.426, p = 0.007), a marker of pericyte injury, and ACE2 correlated positively with albumin (r = 0.422, p = 0.008), a marker of blood-brain barrier integrity. CSF Ang-I, Ang-II, and Ang-(1-7) levels were unchanged in AD. This cross-sectional CSF study indicates RAS dysfunction in relation to capillary damage in AD.


Subject(s)
Alzheimer Disease/cerebrospinal fluid , Renin-Angiotensin System , Aged , Aged, 80 and over , Amyloid beta-Peptides/cerebrospinal fluid , Angiotensin-Converting Enzyme 2 , Angiotensins/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Blood-Brain Barrier , Capillaries , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Peptide Fragments/cerebrospinal fluid , Peptidyl-Dipeptidase A/cerebrospinal fluid , Receptor, Platelet-Derived Growth Factor beta/cerebrospinal fluid , tau Proteins/cerebrospinal fluid
5.
BMJ Case Rep ; 12(8)2019 Aug 26.
Article in English | MEDLINE | ID: mdl-31451467

ABSTRACT

Neurosarcoidosis (NS) is a rare disease, affecting only 3%-10% of patients with sarcoidosis. The clinical presentation can be protean and often represents a diagnostic challenge. Cerebrospinal fluid (CSF) ACE level has poor sensitivity, but high specificity for establishing a diagnosis of NS. We present a case of NS in a middle-aged African American woman who presented with dysphagia and dysphonia. An extensive radiological workup was negative for structural brain disease. CSF studies demonstrated lymphocyte predominant pleocytosis with an elevated ACE level. A diagnosis of possible neurosarcoidosis was made. She responded to systemic steroid therapy with complete resolution of her symptoms over the next five months. In the appropriate clinical setting, an elevated CSF ACE level could be of paramount importance for making a diagnosis of NS.


Subject(s)
Central Nervous System Diseases , Cerebrospinal Fluid , Deglutition Disorders/diagnosis , Dysphonia/diagnosis , Glucocorticoids/administration & dosage , Leukocytosis , Peptidyl-Dipeptidase A/cerebrospinal fluid , Sarcoidosis , Biomarkers/cerebrospinal fluid , Brain/diagnostic imaging , Central Nervous System Diseases/cerebrospinal fluid , Central Nervous System Diseases/complications , Central Nervous System Diseases/diagnosis , Central Nervous System Diseases/drug therapy , Cerebrospinal Fluid/cytology , Cerebrospinal Fluid/metabolism , Deglutition Disorders/etiology , Diagnosis, Differential , Dysphonia/etiology , Female , Humans , Leukocytosis/cerebrospinal fluid , Leukocytosis/diagnosis , Leukocytosis/etiology , Lymphocytes/pathology , Middle Aged , Sarcoidosis/cerebrospinal fluid , Sarcoidosis/complications , Sarcoidosis/diagnosis , Sarcoidosis/drug therapy , Treatment Outcome
6.
J Neuroimmunol ; 323: 19-27, 2018 10 15.
Article in English | MEDLINE | ID: mdl-30196829

ABSTRACT

We compared cerebrospinal fluid levels of lactate, ß2-microglobulin and angiotensin-converting enzyme (ACE) between 438 untreated patients with multiple sclerosis and 276 patients with non-inflammatory neurological disorders. Age-adjusted ß2-microglobulin and lactate were significantly higher and ACE was significantly lower in MS patients than in controls. ß2-microglobulin and ACE positively correlated with high significance both in MS patients and controls. While disease duration negatively correlated and progression index, defined as EDSS score divided by disease duration in years, positively correlated with age-adjusted lactate levels, both did neither correlate with ß2-microglobulin nor with ACE. Both CSF ß2-microglobulin and ACE deserve further investigation as biomarkers of multiple sclerosis pathophysiology.


Subject(s)
Disease Progression , Lactic Acid/metabolism , Multiple Sclerosis/cerebrospinal fluid , Peptidyl-Dipeptidase A/cerebrospinal fluid , Severity of Illness Index , beta 2-Microglobulin/cerebrospinal fluid , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Biomarkers/cerebrospinal fluid , Cohort Studies , Female , Humans , Male , Middle Aged , Multiple Sclerosis/diagnosis , Retrospective Studies , Young Adult
7.
J Alzheimers Dis ; 64(4): 1085-1090, 2018.
Article in English | MEDLINE | ID: mdl-30040721

ABSTRACT

This study was designed to determine whether the levels of renin-angiotensin system (RAS) components are associated with Alzheimer's disease (AD) pathology. Cerebrospinal fluid levels of Angiotensin (Ang) II, Ang-(1-7), angiotensin-converting enzyme (ACE), ACE2, Amyloid-ß (Aß)40, Aß42, total tau (hTau), and phospho-tau (pTau) were measured in 18 patients with AD and 10 controls. Patients with AD presented decreased levels of ACE when compared with controls. We found a significant positive correlation between ACE and Aß42 levels among patients. Our results strengthen the hypothesis that ACE is associated with Aß pathology in AD.


Subject(s)
Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , Peptidyl-Dipeptidase A/cerebrospinal fluid , Aged , Angiotensin-Converting Enzyme 2 , Female , Humans , Male , Middle Aged , tau Proteins/cerebrospinal fluid
8.
Ann Biol Clin (Paris) ; 75(4): 393-402, 2017 Aug 01.
Article in English | MEDLINE | ID: mdl-28751284

ABSTRACT

Sarcoidosis is a systemic granulomatous disease, which mostly affects lung. Central nervous system can be affected causing a neurosarcoidosis in 5 to 15% of all sarcoidosis patients. The definitive diagnosis is established on histological examination of brain granulomas. Angiotensin converting enzyme is currently the most relevant biomarker to confirm a probable diagnosis; however, it lacks sensitivity and specificity. We aim to find novel biomarkers of neurosarcoidosis in cerebrospinal fluid (CSF) by proteomic analysis, combining two-dimension electrophoresis (2-DE) and mass spectrometry. We performed CSF proteomic profile of both patients (group S) and control subjects (group H). The statistical analysis of 2-D gels highlighted 42 spots significantly different between the two groups. Twenty-five spots were subjected to tryptic digestion; the peptides were analyzed by MALDI-TOF and MALDI-TOF-TOF, giving rise to 10 identifications. Among the identified proteins, low-molecular-mass-kininogen and vitamin-D-binding-protein were increased, while transthyretin was decreased. These proteins have probably an intrathecal source and could be interesting candidates. This study led to the identification of several proteins which can be used for the diagnosis and/or monitoring of neurosarcoidosis. These putative biomarkers have to be confirmed on a larger cohort and assessed for their sensitivity and specificity.


Subject(s)
Biomarkers/cerebrospinal fluid , Central Nervous System Diseases/cerebrospinal fluid , Central Nervous System Diseases/diagnosis , Proteomics/methods , Sarcoidosis/cerebrospinal fluid , Sarcoidosis/diagnosis , Case-Control Studies , Electrophoresis, Gel, Two-Dimensional , Humans , Peptidyl-Dipeptidase A/analysis , Peptidyl-Dipeptidase A/cerebrospinal fluid , Sensitivity and Specificity , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
9.
Methods Mol Biol ; 1527: 117-126, 2017.
Article in English | MEDLINE | ID: mdl-28116711

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is a component of the renin-angiotensin system (RAS) which plays an important role in the regulation of blood pressure and volume homeostasis. Accumulating evidence shows alterations in ACE2 expression and activity in several hypertensive animal models, as well as in patients with hypertension. In order to assess the role of brain ACE2 in hypertension, a specific ACE2 assay is required. Based on a quenched fluorescent substrate, we describe an easy-to-use method for determining ACE2 activity in brain tissue and cerebrospinal fluid. The method can further be adapted for other tissues, plasma, cell extracts, and cell culture supernatants.


Subject(s)
Brain/metabolism , Enzyme Assays/methods , Peptidyl-Dipeptidase A/metabolism , Angiotensin-Converting Enzyme 2 , Animals , Blood Pressure/genetics , Blood Pressure/physiology , Humans , Hypertension/cerebrospinal fluid , Hypertension/metabolism , Peptides , Peptidyl-Dipeptidase A/cerebrospinal fluid , Renin-Angiotensin System/physiology
10.
Transplantation ; 100(10): e96-e100, 2016 Oct.
Article in English | MEDLINE | ID: mdl-26863472

ABSTRACT

BACKGROUND: Sarcoidosis is a presumptive autoimmune disorder characterized by the presence of noncaseating granulomas and is usually treated successfully with immunosuppression. METHODS AND RESULTS: Here, we describe the case of a 63-year-old male renal transplant recipient with a remote history of pulmonary sarcoidosis on chronic immunosuppression who developed recurrent aseptic meningitis and underwent brain biopsy revealing a diagnosis of neurosarcoidosis. CONCLUSIONS: This case highlights the possibility of recurrence of sarcoidosis in the setting of maintenance immunosuppression, the need for heightened awareness of alternative sites of recurrence of autoimmune disease, and future studies to determine the underlying mechanism of recurrence in organ transplant recipients.


Subject(s)
Central Nervous System Diseases/etiology , Kidney Transplantation/adverse effects , Meningitis, Aseptic/etiology , Sarcoidosis/etiology , Activities of Daily Living , Humans , Immunocompromised Host , Male , Middle Aged , Peptidyl-Dipeptidase A/cerebrospinal fluid
11.
J Neuroimmunol ; 285: 1-3, 2015 Aug 15.
Article in English | MEDLINE | ID: mdl-26198911

ABSTRACT

BACKGROUND: Neurosarcoidosis (NS) is a rare condition that may mimic central nervous system (CNS) infection, neoplasia and other inflammatory disorders of the CNS such as multiple sclerosis, encephalitis and vasculitis. Diagnosis is challenging in cases with minimal or absent systemic involvement. Cerebrospinal fluid (CSF) angiotensin-converting enzyme (c-ACE) has been claimed as a valuable diagnostic tool for NS. However, there is little data evaluating its performance in routine clinical practice. FINDINGS: We performed a monocentric, retrospective, chart-based study including all patients investigated with a lumbar puncture and c-ACE dosage for suspected NS between 01/01/2006 and 31/12/2012 at the Geneva University Hospital. Receiver-operating characteristic (ROC) curve and area under the curve (AUC) were performed to calculate the optimal cut-off value of c-ACE and to determine the discriminative ability of c-ACE. Of the 440 patients included in the study, 9 were diagnosed with NS on the basis of tissue biopsy. Mean c-ACE was not significantly different between NS and non-NS patients. With a cut-off value of 2 (0-2 vs ≥3), sensitivity and specificity of c-ACE were 66.7% and 67.3%, respectively. CONCLUSIONS: In our clinical setting, the sensitivity and specificity of c-ACE for NS diagnosis were relatively poor and of little clinical utility.


Subject(s)
Central Nervous System Diseases/cerebrospinal fluid , Central Nervous System Diseases/diagnosis , Peptidyl-Dipeptidase A/cerebrospinal fluid , Sarcoidosis/cerebrospinal fluid , Sarcoidosis/diagnosis , Adult , Aged , Biomarkers/cerebrospinal fluid , Female , Humans , Male , Middle Aged , Retrospective Studies
12.
J Alzheimers Dis ; 44(1): 153-62, 2015.
Article in English | MEDLINE | ID: mdl-25201786

ABSTRACT

BACKGROUND: Higher angiotensin-converting enzyme (ACE) activity might increase the risk of Alzheimer's disease by increasing blood pressure, and subsequent development of cerebral small vessel disease (CSVD). Yet, it may also decrease this risk, as it functions to degrade amyloid-ß, thereby reducing brain atrophy. OBJECTIVE: To examine the cross-sectional associations of serum and cerebrospinal fluid (CSF) ACE protein levels and activity with brain atrophy and CSVD in a memory clinic cohort. METHODS: In 118 subjects from the memory clinic based Amsterdam Dementia Cohort (mean age 66 ± 8 years), ACE protein levels (ng/ml) and activity in CSF and serum were investigated. Poisson regression analyses were used to associate ACE measurements with rated global cortical atrophy, medial temporal lobe atrophy, lacunar infarcts, white matter hyperintensities, and microbleeds on brain MRI. RESULTS: Higher CSF ACE activity was associated with a reduced risk of global brain atrophy. The relative risk (95% CI) of having global cortical atrophy ≥2 per SD increase in CSF ACE activity was 0.67 (0.49; 0.93). ACE levels were not significantly related to measures of CSVD. CONCLUSIONS: These results show that high ACE might have protective effects on the brain. This could suggest that ACE inhibitors, which may lower CSF ACE levels, are not preferred as antihypertensive treatment in patients at risk for Alzheimer's disease.


Subject(s)
Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/pathology , Brain Diseases/cerebrospinal fluid , Brain Diseases/pathology , Brain/pathology , Peptidyl-Dipeptidase A/cerebrospinal fluid , Aged , Aged, 80 and over , Alzheimer Disease/blood , Apolipoproteins E/genetics , Atrophy/cerebrospinal fluid , Atrophy/pathology , Brain Diseases/blood , Cerebral Small Vessel Diseases/enzymology , Female , Humans , Magnetic Resonance Imaging , Male , Memory Disorders/cerebrospinal fluid , Memory Disorders/etiology , Middle Aged , Peptidyl-Dipeptidase A/blood
13.
Med Pregl ; 67(3-4): 97-9, 2014.
Article in English | MEDLINE | ID: mdl-24961051

ABSTRACT

INTRODUCTION: Sarcoidosis can affect any part of the central nervous system presenting with an extremely diverse clinical picture. Clinical presentations actually depend on the localization ofgranulomas in the central nervous system. Making diagnosis according to the localization and the clinical variations is often a clinical challenge. DIAGNOSIS OF NEUROSARCOIDOSIS: Diagnosis is based on the clinical picture, clinical and radiological findings (magnetic resonance imaging with contrast endocranium), laboratory findings (angio-tenzin-converting enzyme and chitotriosidase in cerebrospinal fluid); however, it is necessary first to exclude all other possible causes of granulomatous inflammation. Recent studies in patients with neurosarcoidosis show a high value of at least one marker of the disease. The safest way and the gold standard in diagnosing this disease would be histopathological confirmation, which is rarely performed due to its invasiveness. CONCLUSION: New diagnostic methods will contribute to better methods of bypassing invasive procedures, and they will significantly facilitate the diagnosis of neurosarcoidosis, which is a real challenge even for experienced clinicians who deal with this disease.


Subject(s)
Central Nervous System Diseases/diagnosis , Sarcoidosis/diagnosis , Biomarkers/cerebrospinal fluid , Biopsy , Brain/pathology , Hexosaminidases/cerebrospinal fluid , Humans , Magnetic Resonance Imaging , Peptidyl-Dipeptidase A/cerebrospinal fluid , Spinal Puncture
14.
J Neurochem ; 130(2): 313-23, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24661079

ABSTRACT

Angiotensin-(1-7) [Ang-(1-7)] is an alternative product of the brain renin-angiotensin system that exhibits central actions to lower blood pressure and improve baroreflex sensitivity. We previously identified a peptidase that metabolizes Ang-(1-7) to the inactive metabolite product Ang-(1-4) in CSF of adult sheep. This study purified the peptidase 1445-fold from sheep brain medulla and characterized this activity. The peptidase was sensitive to the chelating agents o-phenanthroline and EDTA, as well as the mercury compound p-chloromercuribenzoic acid (PCMB). Selective inhibitors to angiotensin-converting enzyme, neprilysin, neurolysin, and thimet oligopeptidase did not attenuate activity; however, the metallopeptidase agent JMV-390 was a potent inhibitor of Ang-(1-7) hydrolysis (Ki = 0.8 nM). Kinetic studies using (125) I-labeled Ang-(1-7), Ang II, and Ang I revealed comparable apparent Km values (2.6, 2.8, and 4.3 µM, respectively), but a higher apparent Vmax for Ang-(1-7) (72 vs. 30 and 6 nmol/min/mg, respectively; p < 0.01). HPLC analysis of the activity confirmed the processing of unlabeled Ang-(1-7) to Ang-(1-4) by the peptidase, but revealed < 5% hydrolysis of Ang II or Ang I, and no hydrolysis of neurotensin, bradykinin or apelin-13. The unique characteristics of the purified neuropeptidase may portend a novel pathway to influence actions of Ang-(1-7) within the brain. Angiotensin-(1-7) actions are mediated by the AT7 /Mas receptor and include reduced blood pressure, decreased oxidative stress, enhanced baroreflex sensitivity, and increased nitric oxide (NO). Ang-(1-7) is directly formed from Ang I by neprilysin (NEP). We identify a new pathway for Ang-(1-7) metabolism in the brain distinct from angiotensin-converting enzyme-dependent hydrolysis. The Ang-(1-7) endopeptidase (A7-EP) degrades the peptide to Ang-(1-4) and may influence central Ang-(1-7) tone.


Subject(s)
Angiotensin I/biosynthesis , Angiotensin I/cerebrospinal fluid , Medulla Oblongata/enzymology , Peptide Fragments/biosynthesis , Peptide Fragments/cerebrospinal fluid , Peptidyl-Dipeptidase A/biosynthesis , Peptidyl-Dipeptidase A/cerebrospinal fluid , Animals , Bradykinin/metabolism , Chromatography, Agarose , Chromatography, DEAE-Cellulose , Chromatography, High Pressure Liquid , Electrophoresis, Polyacrylamide Gel , Hydrogen-Ion Concentration , In Vitro Techniques , Intercellular Signaling Peptides and Proteins/metabolism , Kinetics , Mercury Compounds/pharmacology , Neurotensin/metabolism , Oligopeptides/pharmacology , Protease Inhibitors/pharmacology , Sheep , Substrate Specificity
15.
Transl Psychiatry ; 3: e293, 2013 Aug 20.
Article in English | MEDLINE | ID: mdl-23962923

ABSTRACT

ß-amyloid (Aß) plaque accumulation is a hallmark of Alzheimer's disease (AD). It is believed to start many years prior to symptoms and is reflected by reduced cerebrospinal fluid (CSF) levels of the peptide Aß1-42 (Aß42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and Aß metabolism predict the development of Aß plaques, assessed by longitudinal CSF Aß42 decrease in cognitively healthy people. Forty-six healthy people with three to four serial CSF samples were included (mean follow-up 3 years, range 2-4 years). There was an overall reduction in Aß42 from a mean concentration of 211-195 pg ml(-1) after 4 years. Linear mixed-effects models using longitudinal Aß42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for Aß metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal Aß42. The most significant proteins were angiotensin-converting enzyme (ACE, P=0.009), Chromogranin A (CgA, P=0.009) and Axl receptor tyrosine kinase (AXL, P=0.009). Receiver-operating characteristic analysis identified 11 proteins with significant effects on longitudinal Aß42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with Aß42 reduction only in subjects with normal baseline Aß42, and not in subjects with reduced baseline Aß42. We conclude that baseline CSF proteins related to Aß metabolism, microglia activity or synapses predict longitudinal Aß42 reduction in cognitively healthy elders. The finding that some proteins only predict Aß42 reduction in subjects with normal baseline Aß42 suggest that they predict future development of the brain Aß pathology at the earliest stages of AD, prior to widespread development of Aß plaques.


Subject(s)
Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Chromogranin A/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , Peptidyl-Dipeptidase A/cerebrospinal fluid , Plaque, Amyloid/metabolism , Proto-Oncogene Proteins/cerebrospinal fluid , Receptor Protein-Tyrosine Kinases/cerebrospinal fluid , Aged , Aged, 80 and over , Alzheimer Disease/diagnosis , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Biomarkers/cerebrospinal fluid , Female , Humans , Linear Models , Longitudinal Studies , Male , Microglia , Peptide Fragments/metabolism , ROC Curve , Synapses , Axl Receptor Tyrosine Kinase
16.
Am J Physiol Regul Integr Comp Physiol ; 305(7): R679-88, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-23948771

ABSTRACT

Antenatal betamethasone (BM) therapy accelerates lung development in preterm infants but may induce early programming events with long-term cardiovascular consequences. To elucidate these events, we developed a model of programming whereby pregnant ewes are administered BM (2 doses of 0.17 mg/kg) or vehicle at the 80th day of gestation and offspring are delivered at term. BM-exposed (BMX) offspring develop elevated blood pressure; decreased baroreflex sensitivity; and alterations in the circulating, renal, and brain renin-angiotensin systems (RAS) by 6 mo of age. We compared components of the choroid plexus fourth ventricle (ChP4) and cerebral spinal fluid (CSF) RAS between control and BMX male offspring at 6 mo of age. In the choroid plexus, high-molecular-weight renin protein and ANG I-intact angiotensinogen were unchanged between BMX and control animals. Angiotensin-converting enzyme 2 (ACE2) activity was threefold higher than either neprilysin (NEP) or angiotensin 1-converting enzyme (ACE) in control and BMX animals. Moreover, all three enzymes were equally enriched by approximately 2.5-fold in ChP4 brush-border membrane preparations. CSF ANG-(1-7) levels were significantly lower in BMX animals (351.8 ± 76.8 vs. 77.5 ± 29.7 fmol/mg; P < 0.05) and ACE activity was significantly higher (6.6 ± 0.5 vs. 8.9 ± 0.5 fmol·min(-1)·ml(-1); P < 0.05), whereas ACE2 and NEP activities were below measurable limits. A thiol-sensitive peptidase contributed to the majority of ANG-(1-7) metabolism in the CSF, with higher activity in BMX animals. We conclude that in utero BM exposure alters CSF but not ChP RAS components, resulting in lower ANG-(1-7) levels in exposed animals.


Subject(s)
Angiotensin I/cerebrospinal fluid , Betamethasone/toxicity , Choroid Plexus/drug effects , Glucocorticoids/toxicity , Peptide Fragments/cerebrospinal fluid , Peptidyl-Dipeptidase A/cerebrospinal fluid , Prenatal Exposure Delayed Effects , Renin-Angiotensin System/drug effects , Age Factors , Angiotensin-Converting Enzyme 2 , Animals , Baroreflex/drug effects , Betamethasone/administration & dosage , Blood Pressure/drug effects , Choroid Plexus/enzymology , Choroid Plexus/physiopathology , Down-Regulation , Female , Gestational Age , Glucocorticoids/administration & dosage , Hypertension/chemically induced , Hypertension/enzymology , Hypertension/physiopathology , Male , Neprilysin/metabolism , Pregnancy , Sheep , Up-Regulation
17.
J Alzheimers Dis ; 32(1): 147-56, 2012.
Article in English | MEDLINE | ID: mdl-22776970

ABSTRACT

Research shows that certain antihypertensives taken during midlife confer Alzheimer's disease (AD) related benefits in later life. We conducted a clinical trial to evaluate the extent to which the angiotensin converting enzyme inhibitor (ACE-I), ramipril, affects AD biomarkers including cerebrospinal fluid (CSF) amyloid-ß (Aß) levels and ACE activity, arterial function, and cognition in participants with a parental history of AD. This four month randomized, double-blind, placebo-controlled, pilot clinical trial evaluated the effects of ramipril, a blood-brain-barrier crossing ACE-I, in cognitively healthy individuals with mild, or Stage I hypertension. Fourteen participants were stratified by gender and apolipoprotein E ε4 (APOE ε4) status and randomized to receive 5 mg of ramipril or matching placebo daily. Participants were assessed at baseline and month 4 on measures of CSF Aß(1-42) and ACE activity, arterial function, and cognition. Participants were middle-aged (mean 54 y) and highly educated (mean 15.4 y), and included 50% men and 50% APOE ε4 carriers. While results did not show a treatment effect on CSF Aß(1-42) (p = 0.836), data revealed that ramipril can inhibit CSF ACE activity (p = 0.009) and improve blood pressure, however, there were no differences between groups in arterial function or cognition. In this study, ramipril therapy inhibited CSF ACE activity and improved blood pressure, but did not influence CSF Aß1-42. While larger trials are needed to confirm our CSF Aß results, it is possible that prior research reporting benefits of ACE-I during midlife may be attributed to alternative mechanisms including improvements in cerebral blood flow or the prevention of angiotensin II-mediated inhibition of acetylcholine.


Subject(s)
Alzheimer Disease/prevention & control , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Ramipril/therapeutic use , Adult , Aged , Alzheimer Disease/genetics , Amyloid beta-Peptides/cerebrospinal fluid , Ankle Brachial Index , Apolipoproteins E/genetics , Arteries/physiopathology , Biomarkers/cerebrospinal fluid , Blood Pressure/physiology , Brachial Artery/diagnostic imaging , Cognition/physiology , Data Interpretation, Statistical , Double-Blind Method , Family , Female , Humans , Male , Middle Aged , Neuropsychological Tests , Peptidyl-Dipeptidase A/cerebrospinal fluid , Pilot Projects , Ultrasonography , tau Proteins/cerebrospinal fluid
18.
J Neurol ; 258(12): 2163-7, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21553080

ABSTRACT

The diagnosis of neurosarcoidosis is often difficult; the imaging signs of spinal cord sarcoidosis sometimes mimic those of cervical spondylotic myelopathy, which is common in elderly persons. We examined the characteristics of spinal cord sarcoidosis in Japanese patients with neurosarcoidosis. This case series identified patients with neurosarcoidosis at four general hospitals and one university hospital from April 1998 to September 2010. All diagnoses were based on the diagnostic criteria proposed by Zajicek et al. Seventeen patients (nine men and eight women) were involved: six patients with spinal cord lesions accompanied by cervical spondylosis, five with cerebral lesions, three with cranial nerve lesions, two with meningitis, and one with nerve root lesions. Patients with spinal cord sarcoidosis had a higher onset age, longer duration from onset to diagnosis, reduced leukocytosis in the cerebrospinal fluid (CSF), and lower angiotensin-converting enzyme (ACE) levels in the CSF. The results of this study indicate that diagnosis of spinal cord sarcoidosis requires careful evaluation.


Subject(s)
Central Nervous System Diseases/cerebrospinal fluid , Sarcoidosis/cerebrospinal fluid , Spinal Cord Diseases/cerebrospinal fluid , Spinal Cord Diseases/diagnosis , Adrenal Cortex Hormones/therapeutic use , Adult , Age of Onset , Aged , Central Nervous System Diseases/diagnosis , Central Nervous System Diseases/drug therapy , Female , Humans , Immunosuppressive Agents/therapeutic use , Male , Methotrexate/therapeutic use , Middle Aged , Peptidyl-Dipeptidase A/cerebrospinal fluid , Retrospective Studies , Sarcoidosis/diagnosis , Sarcoidosis/drug therapy , Spinal Cord Diseases/drug therapy , Young Adult
19.
J Neurol Sci ; 295(1-2): 41-5, 2010 Aug 15.
Article in English | MEDLINE | ID: mdl-20541774

ABSTRACT

BACKGROUND: Anti-aquaporin-4 (AQP4) antibody targets perivascular astrocyte foot processes, which contain abundant angiotensinogen, a precursor of angiotensin II, angiotensin-converting enzyme (ACE) and ACE2. OBJECTIVE: To disclose any abnormality in the intrathecal angiotensin II metabolic pathway in Japanese patients with neuromyelitis optica (NMO) or NMO spectrum disorders (NMOs) and positive for anti-AQP4 antibody. METHODS: We measured CSF angiotensin II, ACE and ACE2 levels in 15 anti-AQP4 antibody-positive patients with NMO or NMOs, 21 anti-AQP4 antibody-negative multiple sclerosis (MS) patients, 32 patients with other neurological diseases (OND) and 24 non-neurologic controls, using established ELISAs. RESULTS: CSF angiotensin II levels were lower in patients with NMO/NMOs (2.01+/-1.82 pg/ml) and those with MS (3.15+/-1.67 pg/ml) than in the OND (5.41+/-2.34 pg/ml) and control groups (6.71+/-2.65 pg/ml) (P(corr)<0.005). The difference in CSF angiotensin II levels between NMO/NMOs and MS patients was nearly significant (P(uncorr)=0.052). In NMO/NMOs and MS patients, angiotensin II levels were negatively correlated with CSF/serum albumin ratio (P<0.05). ACE levels in CSF were lower in patients with NMO/NMOs (34.3+/-5.61 ng/ml) than in MS patients (42.5+/-8.19 ng/ml, P(corr)=0.035) and controls (44.7+/-4.02 ng/ml, P(corr)<0.0003) while ACE2 levels were lower in NMO/NMOs (1.13+/-0.49 ng/ml) and MS (1.75+/-0.86 ng/ml) patients than in controls (2.76+/-0.23 ng/ml, P(corr)<0.001 for both). CONCLUSION: CSF angiotensin II, ACE, and ACE2 levels are decreased in NMO/NMOs patients with anti-AQP4 antibody, reflecting severe destruction of perivascular astrocytes.


Subject(s)
Angiotensin II/cerebrospinal fluid , Aquaporin 4/immunology , Autoimmunity/physiology , Demyelinating Autoimmune Diseases, CNS/cerebrospinal fluid , Demyelinating Autoimmune Diseases, CNS/immunology , Peptidyl-Dipeptidase A/cerebrospinal fluid , Adult , Cell Line, Transformed , Enzyme-Linked Immunosorbent Assay/methods , Female , Green Fluorescent Proteins/genetics , Humans , Male , Middle Aged , Retrospective Studies , Statistics as Topic , Transfection/methods
20.
J Neurol Sci ; 288(1-2): 194-6, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-19846119

ABSTRACT

Hashimoto's encephalopathy (HE) is a rare, still not well understood, autoimmune disease with neurological and psychiatric manifestations. and elevated titers of antithyroid antibodies in serum and cerebrospinal fluid (CSF) as a hallmark of the disease. Patients are mostly women. Current diagnostic criteria include corticosteroide responsiveness, but it is the case in only 50% of patients with HE. In steroid non-responders other immunomodulatory therapies or plasmapheresis could be applied. Disease course can be acute, subacute, chronic or relapsing-remitting. Two distinct forms emerged from the reported cases: a vasculitic type characterized by multiple relapsing-remitting stroke-like episodes and mild cognitive impairment and a diffuse progressive type characterized by dementia and psychiatric symptoms. Both forms may be accompanied by depressed level of consciousness (stupor or coma), tremor, seizures, or myoclonus. We present two patients with two distinct forms of HE who had different clinical manifestations and response to therapy.


Subject(s)
Encephalitis/diagnosis , Hashimoto Disease/diagnosis , Aged , Anti-Inflammatory Agents/therapeutic use , Azathioprine/therapeutic use , Diagnosis, Differential , Electroencephalography , Encephalitis/drug therapy , Encephalitis/etiology , Female , Hashimoto Disease/complications , Hashimoto Disease/drug therapy , Humans , Immunosuppressive Agents , Magnetic Resonance Imaging , Memory Disorders/etiology , Methylprednisolone/therapeutic use , Middle Aged , Muscle Weakness/etiology , Peptidyl-Dipeptidase A/blood , Peptidyl-Dipeptidase A/cerebrospinal fluid , Stroke/diagnosis , Thyroid Function Tests
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