Biological Markers and Alzheimer Disease: A Canadian Perspective

Decreased β-amyloid1-42 and increased phospho-tau protein levels in the cerebrospinal fluid (CSF) are currently the most accurate chemical neurodiagnostics of sporadic Alzheimer disease (AD). A report (2007) of the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (2006) recommended that biological markers should not be currently requisitioned by primary care physicians in the routine investigation of subjects with memory complaints. Consideration for such testing should prompt patient referral to a specialist engaged in dementia evaluations or a Memory Clinic. The specialist should consider having CSF biomarkers (β-amyloid1-42 and phospho-tau) measured at a reputable facility in restricted cases presenting with atypical features and diagnostic confusion, but not as a routine procedure in all individuals with typical sporadic AD phenotypes. We submit that developments in the field of AD biomarker discovery since publication of the 3rd CCCDTD consensus data do not warrant revision of the 2007 recommendations

MicroRNA: Implications for Alzheimer Disease and other Human CNS Disorders

Understanding complex diseases such as sporadic Alzheimer disease (AD) has been a major challenge. Unlike the familial forms of AD, the genetic and environmental risks factors identified for sporadic AD are extensive. MicroRNAs are one of the major noncoding RNAs that function as negative regulators to silence or suppress gene expression via translational inhibition or message degradation. Their discovery has evoked great excitement in biomedical research for their promise as potential disease biomarkers and therapeutic targets. Key microRNAs have been identified as essential for a variety of cellular events including cell lineage determination, proliferation, apoptosis, DNA repair, and cytoskeletal organization; most, if not all, acting to fine-tune gene expression at the post-transcriptional level in a host of cellular signaling networks. Dysfunctional microRNA-mediated regulation has been implicated in the pathogenesis of many disease states. Here, the current understanding of the role of miRNAs in the central nervous system is reviewed with emphasis on their impact on the etiopathogenesis of sporadic AD

Pathologic effects of estradiol on the hypothalamic arcuate nucleus

The pathologic effects of sex steroids on the hypothalamic arcuate nucleus of adult rats were examined using numbers of reactive microglia and astrocytic granules as quantitative indices of neuropathology.Microglial and astrocytic reactions were observed in adult female rats entering a state of "persistent estrus" following a single injection of 2 mg estradiol valerate (EV) or exposure to continuous illumination. Lower doses of EV failed to elicit both the persistent estrus state and significant glial responses. In EV-treated animals, a hypothalamic lesion could be prevented by prior ovariectomy or by pituitary-ovarian suppression with medroxyprogesterone acetate indicating that an ovarian factor is responsible for the neuropathological changes. This ovarian product is probably estradiol since dose-related enhancement of glial reactivity occurs in male rats treated with multiple injections of EV.Arcuate pathology developed spontaneously in "senile persistent estrus" female and aging male rats. In females, but not in males, early gonadectomy suppressed age-related arcuate glial reactivity. Conceivably, estrogen withdrawal or EV-treatment respectively retards or accelerates histologic aging of the female gonadotropic hypothalamus.Testosterone treatment occasionally elicited mild arcuate glial responses, possibly through prior aromatization to estradiol. In contrast, 5 (alpha)-dihydrotestosterone (a non-aromatizable androgen) appeared to suppress astrocytic granule counts below control values.The EV-induced persistent estrus rat may serve as a useful model for Clover disease of the ewe and the human polycystic ovarian syndrome

Dysregulation of a Heme Oxygenase–Synuclein Axis in Parkinson Disease

α-Synuclein is a key driver of the pathogenesis of Parkinson disease (PD). Heme oxygenase-1 (HO-1), a stress protein that catalyzes the conversion of heme to biliverdin, carbon monoxide and free ferrous iron, is elevated in PD-affected neural tissues and promotes iron deposition and mitochondrial dysfunction in models of the disease, pathways also impacted by α-synuclein. Elevated expression of human HO-1 in astrocytes of GFAP.HMOX1 transgenic mice between 8.5 and 19 months of age elicits a parkinsonian phenotype characterized by nigrostriatal hypodopaminergia, locomotor incoordination and overproduction of neurotoxic native S129-phospho-α-synuclein. Two microRNAs (miRNA) known to regulate α-synuclein, miR-153 and miR-223, are significantly decreased in the basal ganglia of GFAP.HMOX1 mice. Serum concentrations of both miRNAs progressively decline in wild-type (WT) and GFAP.HMOX1 mice between 11 and 18 months of age. Moreover, circulating levels of miR-153 and miR-223 are significantly lower, and erythrocyte α-synuclein concentrations are increased, in GFAP.HMOX1 mice relative to WT values. MiR-153 and miR-223 are similarly decreased in the saliva of PD patients compared to healthy controls. Upregulation of glial HO-1 may promote parkinsonism by suppressing miR-153 and miR-223, which, in turn, enhance production of neurotoxic α-synuclein. The aim of the current review is to explore the link between HO-1, α-synuclein and PD, evaluating evidence derived from our laboratory and others. HO-1, miR-153 and miR-223 and α-synuclein may serve as potential biomarkers and targets for disease-modifying therapy in idiopathic PD

A Heme Oxygenase-1 Transducer Model of Degenerative and Developmental Brain Disorders

Heme oxygenase-1 (HO-1) is a 32 kDa protein which catalyzes the breakdown of heme to free iron, carbon monoxide and biliverdin. The Hmox1 promoter contains numerous consensus sequences that render the gene exquisitely sensitive to induction by diverse pro-oxidant and inflammatory stimuli. In “stressed” astroglia, HO-1 hyperactivity promotes mitochondrial iron sequestration and macroautophagy and may thereby contribute to the pathological iron deposition and bioenergetic failure documented in Alzheimer disease, Parkinson disease and certain neurodevelopmental conditions. Glial HO-1 expression may also impact neuroplasticity and cell survival by modulating brain sterol metabolism and the proteasomal degradation of neurotoxic proteins. The glial HO-1 response may represent a pivotal transducer of noxious environmental and endogenous stressors into patterns of neural damage and repair characteristic of many human degenerative and developmental CNS disorders

Dysregulation of a Heme Oxygenase–Synuclein Axis in Parkinson Disease

α-Synuclein is a key driver of the pathogenesis of Parkinson disease (PD). Heme oxygenase-1 (HO-1), a stress protein that catalyzes the conversion of heme to biliverdin, carbon monoxide and free ferrous iron, is elevated in PD-affected neural tissues and promotes iron deposition and mitochondrial dysfunction in models of the disease, pathways also impacted by α-synuclein. Elevated expression of human HO-1 in astrocytes of GFAP.HMOX1 transgenic mice between 8.5 and 19 months of age elicits a parkinsonian phenotype characterized by nigrostriatal hypodopaminergia, locomotor incoordination and overproduction of neurotoxic native S129-phospho-α-synuclein. Two microRNAs (miRNA) known to regulate α-synuclein, miR-153 and miR-223, are significantly decreased in the basal ganglia of GFAP.HMOX1 mice. Serum concentrations of both miRNAs progressively decline in wild-type (WT) and GFAP.HMOX1 mice between 11 and 18 months of age. Moreover, circulating levels of miR-153 and miR-223 are significantly lower, and erythrocyte α-synuclein concentrations are increased, in GFAP.HMOX1 mice relative to WT values. MiR-153 and miR-223 are similarly decreased in the saliva of PD patients compared to healthy controls. Upregulation of glial HO-1 may promote parkinsonism by suppressing miR-153 and miR-223, which, in turn, enhance production of neurotoxic α-synuclein. The aim of the current review is to explore the link between HO-1, α-synuclein and PD, evaluating evidence derived from our laboratory and others. HO-1, miR-153 and miR-223 and α-synuclein may serve as potential biomarkers and targets for disease-modifying therapy in idiopathic PD

Nausea, Vomiting and Diarrhea: An Unusual Presentation of Multiple Sclerosis

The case of a young woman who presented with nausea, vomiting and diarrhea is outlined; the etiology turned out to be a first attack of multiple sclerosis. Plausible mechanisms are discussed