Biomarker candidates of neurodegeneration in Parkinson’s disease for the evaluation of disease-modifying therapeutics (original) (raw)

Diagnosis and treatment of Parkinson disease: molecules to medicine

Journal of Clinical Investigation, 2006

History Parkinson disease (PD) is a chronic, progressive neurodegenerative disorder that affects at least 1% of people by age 70 (1-3). James Parkinson provided the first detailed description of the disease in his 1817 monograph "An Essay on the Shaking Palsy." In the latter part of the nineteenth century, Charcot further refined the description of this disorder and identified the cardinal clinical features of PD including rest tremor, rigidity, balance impairment, and slowness of movement (reviewed in ref. 4). An early clue to the pathology of the disease came from Brissaud, who speculated that damage in the substantia nigra (SN) might lead to PD (5, 6). Eosinophilic inclusions (Lewy bodies) later were identified in the brains of PD patients (7) and, along with abnormalities in the SN, became a recognized pathologic marker of the disease (8). A major advance in the understanding of PD came when dopamine deficiency was discovered in the corpus striatum and SN of brains taken from patients (9). Later studies demonstrated the connection between the SN and the striatum, thus suggesting that dopaminergic cell loss in the SN directly leads to dopaminergic deficiency in the striatum (10). The determination that PD is a disease of dopamine loss led to the development of rational therapies aimed at correcting this deficiency (11). After some initial uncertainty, the dopamine precursor levodopa proved to be a powerful PD treatment (12). Subsequent advances in therapy included combining levodopa with a peripheral decarboxylase inhibitor, such as carbidopa or benserazide (13, 14). This combination significantly reduced the nausea and vomiting associated with levodopa therapy and allowed a greater proportion of levodopa to enter the brain. Similarly, catechol-O-methyltransferase (COMT) inhibitors, which prolong the half-life of levodopa and dopamine were found to enhance the effect of a given levodopa dose (15-17). In addition to increasing the level of dopamine precursors, the focus of therapeutic design was also on limiting the breakdown of endogenous dopamine. The monoamine oxidase type B (MAO-B) inhibitor selegiline works in this fashion and provides symptomatic benefit (18). Finally, the development of dopamine agonists that directly stimulate postsynaptic dopamine receptors, thus bypassing dopamine synthesis completely, further illustrates how novel therapies can be borne from knowledge of pathology (19, 20). Surgical therapies that reduce tremor and rigidity in PD patients were used prior to the advent of levodopa treatment. Meyers pioneered surgical lesioning procedures that targeted symptoms and spared patients from the hemiparesis that resulted from earlier surgical approaches. These procedures largely were abandoned once levodopa therapy became more common (21). Recent advances in the understanding of basal ganglia physiology and the development of new technologies has led to a reemergence of surgical PD therapies in the form of deep brain stimulation (DBS) (22, 23). DBS has become increasingly common in patients whose disease is difficult to manage with medical therapy alone. Despite these landmark advances in symptomatic PD therapy, the ability of these treatments to facilitate an acceptable quality of life for the patient wanes with time. This is due to the development of motor complications including wearing-off (the

The Development of Treatment for Parkinson’s Disease

Advances in Parkinson's Disease, 2015

Parkinson's disease (PD) is a slowly progressive, age-related, second most common neurodegenerative disorder after Alzheimer's disease of unknown etiology. Dopamine replacement therapies were introduced five decades ago and still remain the mainstay of treatment for Parkinson's disease. However, with long-term treatment with L-dopa, more than 50% of patients were found to develop motor response complications approximately after 4-5 years of initiation of continuous treatment, in 80% of patients treated for 10 years, and in nearly 100% patients with young-onset disease. The complications of long-term treatment with levodopa include-motor fluctuations, dyskinesias, and nonmotor fluctuations are such as mood disturbance, cognitive dysfunction, dysautonomia and pain. Till date, there are various therapeutic approaches having been developed for the treatment of advanced PD comprising Pharmacotherapy, neurotrophic factors, surgical procedures such as DBS, cell-based therapies and gene therapies. The pharmacological and surgical therapies are only aiming to improve the symptoms of PD, but none are proven to have a significant effect on the underlying disease process with respect to either slowing disease progression or restoring the affected dopaminergic neurons. Although there is no cure for PD, Gene based therapy has significant prospective advantages over the conventional treatment modalities for PD, as it could theoretically be used to preserve or restore dopaminergic neurons affected by PD through the action of neurotrophic factors or alternatively increase the availability of enzymes required for dopamine synthesis. All commonly employed PD therapies focus on the amelioration of symptoms and do not cure disease. In this review only we summarize the newer therapeutic strategies for the treatment of PD such as anti-inflammatories, neurotrophic factors, neurosurgical procedures (DBS), cell based therapies and gene therapies.

Biomarkers in Parkinson’s disease (recent update)

Neurochemistry International, 2013

Parkinson's disease (PD) is the second most common neurodegenerative disorder mostly affecting the 29 aging population over sixty. Cardinal symptoms including, tremors, muscle rigidity, drooping posture, 30 drooling, walking difficulty, and autonomic symptoms appear when a significant number of nigrostriatal 31 dopaminergic neurons are already destroyed. Hence we need early, sensitive, specific, and economical 32 peripheral and/or central biomarker(s) for the differential diagnosis, prognosis, and treatment of PD. 33 These can be classified as clinical, biochemical, genetic, proteomic, and neuroimaging biomarkers. Novel 34 discoveries of genetic as well as nongenetic biomarkers may be utilized for the personalized treatment of 35 PD during preclinical (premotor) and clinical (motor) stages. Premotor biomarkers including hyper-ech-36 ogenicity of substantia nigra, olfactory and autonomic dysfunction, depression, hyposmia, deafness, REM 37 sleep disorder, and impulsive behavior may be noticed during preclinical stage. Neuroimaging biomark-38 ers (PET, SPECT, MRI), and neuropsychological deficits can facilitate differential diagnosis. Single-cell pro-39 filing of dopaminergic neurons has identified pyridoxal kinase and lysosomal ATPase as biomarker genes 40 for PD prognosis. Promising biomarkers include: fluid biomarkers, neuromelanin antibodies, pathological 41 forms of a-Syn, DJ-1, amyloid b and tau in the CSF, patterns of gene expression, metabolomics, urate, as 42 well as protein profiling in the blood and CSF samples. Reduced brain regional N-acetyl-aspartate is a bio-43 marker for the in vivo assessment of neuronal loss using magnetic resonance spectroscopy and T 2 relax-44 ation time with MRI. To confirm PD diagnosis, the PET biomarkers include [ 18 F]-DOPA for estimating 45 dopaminergic neurotransmission, [ 18 F]dG for mitochondrial bioenergetics, [ 18 F]BMS for mitochondrial 46 complex-1, [ 11 C](R)-PK11195 for microglial activation, SPECT imaging with 123 Iflupane and bCIT for dopa-47 mine transporter, and urinary salsolinol and 8-hydroxy, 2-deoxyguanosine for neuronal loss. This brief 48 review describes the merits and limitations of recently discovered biomarkers and proposes coenzyme 49 Q 10 , mitochondrial ubiquinone-NADH oxidoreductase, melatonin, a-synculein index, Charnoly body, 50 and metallothioneins as novel biomarkers to confirm PD diagnosis for early and effective treatment of PD.

Current disease modifying approaches to treat Parkinson's disease

Cellular and molecular life sciences : CMLS, 2015

Parkinson's disease (PD is a progressive neurological disorder characterized by the degeneration and death of midbrain dopamine and non-dopamine neurons in the brain leading to motor dysfunctions and other symptoms, which seriously influence the quality of life of PD patients. The drug L-dopa can alleviate the motor symptoms in PD, but so far there are no rational therapies targeting the underlying neurodegenerative processes. Despite intensive research, the molecular mechanisms causing neuronal loss are not fully understood which has hampered the development of new drugs and disease-modifying therapies. Neurotrophic factors are by virtue of their survival promoting activities attract candidates to counteract and possibly halt cell degeneration in PD. In particular, studies employing glial cell line-derived neurotrophic factor (GDNF) and its family member neurturin (NRTN), as well as the recently described cerebral dopamine neurotrophic factor (CDNF) and the mesencephalic astroc...

Strategies for the Treatment of Parkinson’s Disease: Beyond Dopamine

Frontiers in Aging Neuroscience

Parkinson's disease (PD) is the second-leading cause of dementia and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra alongside the presence of intraneuronal α-synuclein-positive inclusions. Therapies to date have been directed to the restoration of the dopaminergic system, and the prevention of dopaminergic neuronal cell death in the midbrain. This review discusses the physiological mechanisms involved in PD as well as new and prospective therapies for the disease. The current data suggest that prevention or early treatment of PD may be the most effective therapeutic strategy. New advances in the understanding of the underlying mechanisms of PD predict the development of more personalized and integral therapies in the years to come. Thus, the development of more reliable biomarkers at asymptomatic stages of the disease, and the use of genetic profiling of patients will surely permit a more effective treatment of PD.