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HIV & HCV & Parkinsons Disease: is there an increased risk - undecided yet with mixed opinions and suggestive data
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[from Jules Levin, NATAP]........studies are mixed with study published below in Jnl of Viral hepatitis in October finding merely an association without confirming causality, this more recent study in Neurology finding similarly, and in HIV discussed below finding similarly, that in HIV pre-Cart they found Parkinsonism in 5-10% of HIV+, which now has fallen to 0.2% and they do not believe there is a causality, but an earlier paper in 2009 from 2 leading HIV neurologists Tisch & Brew found 3 cases of PD in HIV+ with undetectable viral load over a 2-year period which they said is 4-8 times the expected incidence in people 4-59 years old
In recent days a paper published in the journal Neurology whose authors although from China are not the same authors of the paper below also from China publishing earlier this year an epidemiological study finding an association between HCV & Parkinsons with an increased risk of Parkinsons among HCV+ but an epidemiological study does not find causality only an association, followup research is required to confirm causality. Although an association might mean causality it remains uncertain until research can be confuted to confirm causality. Regarding this new study just published in Neurology. ......"Many factors clearly play a role in the development of ParkinsonÕs disease, including environmental factors. This nationwide study suggests that hepatitis caused specifically by the hepatitis C virus may increase the risk of developing the disease. More research is needed to investigate the link,Ó said Dr. Chia-Hung Kao, study author from Taiwan.....After controlling for potentially confounding factors, including participants' age, sex and diagnosis of diabetes or cirrhosis, the researchers found participants with hepatitis C were at 30% greater risk of developing Parkinson's than those who did not have hepatitis......There are some study limitations. The researchers note that hepatitis and Parkinson's were identified through International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes rather than through clinical assessment, neuroimaging or lab data, which may have led to less accurate results. In addition, the researchers point out that the Longitudinal Health Insurance Database - part of the NHIRD - does not hold information on duration of viral hepatitis and risk factors for HCV infection, such as the sharing of needles and tattooing. "These factors for HCV infection might have confounding effects on Parkinson's disease development, but could not be controlled for analysis in the current study," they explain.
from Jules: in this HIV study they concluded although HIV+ individuals may show similar symptoms when viral load is undetectable they so far at this point in time do not find a higher frequency of Parkinsons among HIV+, they say "A higher incidence of medical comorbidities will
probably emerge with the aging of PLH. Although more new PD cases are likely to be diagnosed in PLH, we consider this association to be merely a simultaneous occurrence with no etiopathogenetic link. In 2009 2 well known HIV neurologists published a paper in the journal Neurology saying "We observed 3 new cases of parkinsonism (all <50 viral load in blood) among our cohort of 2,500 HIV-infected patients over a 2-year period, which is 4-8 times higher than the reported incidence of PD among people age 40-59 years....suggests HIV and HAART may preferentially predispose to the development of parkinsonism. But the authors of this later French paper published in JAIDS found "PD prevalence in PLH was similar to that of the general population".
Parkinson Disease in HIV.....Does HIV Infection Alter Parkinson Disease?....."Our results do not support a higher PD frequency in PLH with good HIV-control indices......A higher incidence of medical comorbidities will probably emerge with the aging of PLH. Although more new PD cases are likely to be diagnosed in PLH, we consider this association to be merely a simultaneous occurrence with no etiopathogenetic link"
......http://www.natap.org/2015/HIV/092415_04.htm.......During the pre-cART era (1986-1999), Parkinsonism affected up to 5%-10% of all PLH.3,14 In the post-cART era with better control of HIV infection, that frequency fell to 0.2%, whereas the mean age of these patients rose from 37.2 to 62.5 years.....Our results do not support a higher PD frequency in PLH with good HIV-control indices......A higher incidence of medical comorbidities will probably emerge with the aging of PLH. Although more new PD cases are likely to be diagnosed in PLH, we consider this association to be merely a simultaneous occurrence with no etiopathogenetic link, like the majority of authors who reported PD in association with HIV.......During a 12-year period, we diagnosed only 15 PD among a cohort of 9847 PLH, which is much less than expected based on the study by Tisch and Brew7 who predicted a 4-8 times higher PD incidence in PLH [http://www.natap.org/2010/HIV/091310_04.htm], "We observed 3 new cases of parkinsonism (all <50 viral load in blood) among our cohort of 2,500 HIV-infected patients over a 2-year period, which is 4-8 times higher than the reported incidence of PD among people age 40-59 years....suggests HIV and HAART may preferentially predispose to the development of parkinsonism......The central nervous system (CNS) is highly vulnerable to HIV infection, particularly the dopamine (DA)-rich brain regions. Basal ganglia play a pivotal role because they are a virus-replication hot spot, and the substantia nigra suffered up to 25% neuronal loss in AIDS....Since the identification of increased alpha-synuclein deposition in the substantia nigra of aging PLH,5 the hypothesis that expression and progression of neurodegenerative diseases, for example, Parkinson disease (PD), might be facilitated by HIV was advanced.4 Pathogenetic mechanisms of PD and HIV-associated neurologic complications partially overlap and include chronic neuroinflammation, oxidative stress, lymphocytic infiltration, and impaired mitochondrial function.3,6 Hence,some authors considered a predisposition, even a pathogenetic link, between HIV and long-term cART, with PD development.4,7 However, that notion originated from a few isolated cases or small series (Table 1).7-12......the Parkinsonism seen in patients with AIDS is often atypical in presentation, with symmetrical signs of bradykinesia and rigidity, frequent lack of rest tremor, and early presentation of postural instability and gait difficulty......Evidence from clinical, imaging, biochemical, murine models, and pathological studies underscored a major contribution of bilateral basal ganglia dysfunction in HIVassociated neurologic complications, particularly the pathogenesis of HIV dementia, a subcortical dementia with the core symptoms resembling PD.....However, the dopaminergic transporterÐreduction patterns in PLH were not typical of those seen in PD but showed parallel findings of greater reduction in the putamen than the caudate
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Hepatitis C virus infection: a risk factor for Parkinson's disease.......http://www.natap.org/2015/HCV/092315_02.htm
Journal of Viral Hepatitis Oct 2015
In conclusion, our study demonstrated a significantly positive epidemiological association between HCV infection and PD and corroborated the dopaminergic toxicity of HCV similar to that of MPP+......The study population was derived from a community-based integrated screening programme in Keelung (KCIS), the northernmost area in Taiwan [8].
The crude odds ratios (ORs) for having PD were 0.62 [95% confidence interval (CI), 0.48-0.81] and 1.91 (95% CI, 1.48-2.47) for hepatitis B virus (HBV) and HCV....After controlling for potential confounders, the association between HCV and PD remained statistically significant (adjusted OR = 1.39; 95% CI, 1.07-1.80), but not significantly different between HBV and PD.
The HCV induced 60% dopaminergic neuron death in the midbrain neuron-glia coculture system in rats, similar to that of 1-methyl-4-phenylpyridinium (MPP+) but not caused by HBV. This link was further supported by the finding that HCV infection may release the inflammatory cytokines, which may play a role in the pathogenesis of PD.
Recent studies found that hepatitis C virus (HCV) may invade the central nervous system, and both HCV and Parkinson's disease (PD) have in common the overexpression of inflammatory biomarkers.
We used logistic regression models to investigate association between HCV infection and PD. The neurotoxicity of HCV was evaluated in the midbrain neuron-glia coculture system in rats.
Epidemiologically, we found that anti-HCV(+) patients had statistically significant increased risk of developing PD in the population-based study. This finding was further supported by HCV-induced dopaminergic neuronal toxicity in vitro. The dopaminergic neuronal toxicity induced by HCV was similar to that of MPP+. The levels of chemokines such as sICAM-1, LIX and RANTES were increased, and TIMP-1 was down-regulated in the HCV-infected midbrain culture.
Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra, accompanied by the accumulation of α-synuclein aggregates in Lewy bodies [1]. Although the cause of PD remains unclear, it has been shown that numerous viruses are associated with both acute and chronic parkinsonism including influenza, Coxsackie, Japanese encephalitis (JE), western equine encephalitis, herpes and acquired immunodeficiency disorder (HIV).
These viruses are neurotropic and they may induce a number of encephalopathies that lead to parkinsonism [2]. Hepatitis C virus (HCV) belongs to the flaviviridae family, which includes well-known neurotropic viruses, such as JE, yellow fever, dengue and tick-borne encephalitis viruses [3]. Recent studies suggest that HCV may invade the central nervous system (CNS). Such neuroinvasive harm shows sign of evidence that patients with mild chronic HCV infection had elevated choline/creatine ratios, a biomarker indicating inflammatory and infective conditions, in the basal ganglia and white matter [4]. Moreover, a viral replicative intermediate of HCV RNA has been found in autopsy brain tissue and activation of macrophages/microglial cells has been found in HCV-positive patients [5, 6]. In addition, alteration of striatal dopaminergic neurotransmission has been reported in HCV-infected patients [7]. The evidence that HCV can replicate in the CNS suggests a possible link between PD and HCV.
The association between HCV infection and the pathogenesis of PD is also supported by both HCV infection and PD having in common the overexpression of inflammatory biomarkers that are related to rising concentrations of cytokines in neuronal generation processes, such as abnormal protein handling, oxidative stress, mitochondrial dysfunction, excitotoxicity and apoptotic processes [6]. Despite this speculation, it is rare and difficult to have available information on HCV infection and PD simultaneously in a population- and community-based epidemiological study to assess this hypothesis. Thus, at population and epidemiology level, we attempted to assess whether HCV infection was associated with PD using data from the Keelung community-based integrated screening (KCIS) programme with information on HCV infection, diagnosis of PD and other confounding factors available [8]. At the molecular level, we investigated the dopaminergic toxicity of HCV and compared that of 1-methyl-4-phenylpyridinium (MPP+), the pathognomonic chemical in experimental parkinsonism study.
Furthermore, the differences in the relative amounts of cytokines released from midbrain in the presence and absence of virus were measured by cytokine/chemokine array to investigate the pathogenesis of PD.
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