A study was undertaken to examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson disease (PD).
One hundred forty patients with a clinical diagnosis of PD and either normal cognition or onset of dementia 2 or more years after motor symptoms (PDD) were studied. Patients with a clinical diagnosis of dementia with Lewy bodies were excluded. Autopsy records of genetic data and semiquantitative scores for the burden of neurofibrillary tangles, senile plaques, Lewy bodies (LBs), and Lewy neurites (LNs) and other pathologies were used to develop a multivariate logistic regression model to determine the independent association of these variables with dementia. Correlates of comorbid Alzheimer disease (AD) were also examined.
Niney-two PD patients developed dementia, and 48 remained cognitively normal. Severity of cortical LB (CLB)/LN pathology was positively associated with dementia (p < 0.001), with an odds ratio (OR) of 4.06 (95% confidence interval [CI], 1.87-8.81), as was apolipoprotein E4 (APOE4) genotype (p = 0.018; OR, 4.19; 95% CI, 1.28-13.75). A total of 28.6% of all PD cases had sufficient pathology for comorbid AD, of whom 89.5% were demented. The neuropathological diagnosis of PDD+AD correlated with an older age of PD onset (p = 0.001; OR, 1.12; 95% CI, 1.04-1.21), higher CLB/LN burden (p = 0.037; OR, 2.48; 95% CI, 1.06-5.82), and cerebral amyloid angiopathy severity (p = 0.032; OR, 4.16; 95% CI, 1.13-15.30).
CLB/LN pathology is the most significant correlate of dementia in PD. Additionally, APOE4 genotype may independently influence the risk of dementia in PD. AD pathology was abundant in a subset of patients, and may modify the clinical phenotype. Thus, therapies that target α-synuclein, tau, or amyloid β could potentially improve cognitive performance in PD.
"However, LRRK2 expression or localization in the brain has not yet been described in rats or in transgenic rats. A substantial body of evidence implicates abnormalities in striatonigral circuits in PD in motor behavior (DeLong and Wichmann, 2007), and more recent studies suggest a role for cortical dysfunction in cognitive and executive function decline (Irwin et al., 2012). "
"Reduced Pathological a-syn Spread In Vivo Because Syn303 can reduce pathologic a-syn aggregates in primary neurons and recognizes misfolded a-syn in LBs/LNs in PD brains and various PD mouse models (Giasson et al., 2000b; Irwin et al., 2012; Lim et al., 2011; Luk et al., 2012b), we asked whether Syn303 could reduce a-syn pathology in vivo. We used a previously established mouse model of sporadic PD where we showed that a single intrastriatal injection of mWT a-syn pffs into young WT mice resulted in progressive accumulation of misfolded and hyperphosphorylated a-syn aggregates at neuroanatomically connected areas including the SNpc and amygdala (Luk et al., 2012a). "
[Show abstract][Hide abstract] ABSTRACT: Accumulation of misfolded alpha-synuclein (α-syn) into Lewy bodies (LBs) and Lewy neurites (LNs) is a major hallmark of Parkinson's disease (PD) and dementia with LBs (DLB). Recent studies showed that synthetic preformed fibrils (pffs) recruit endogenous α-syn and induce LB/LN pathology in vitro and in vivo, thereby implicating propagation and cell-to-cell transmission of pathological α-syn as mechanisms for the progressive spread of LBs/LNs. Here, we demonstrate that α-syn monoclonal antibodies (mAbs) reduce α-syn pff-induced LB/LN formation and rescue synapse/neuron loss in primary neuronal cultures by preventing both pff uptake and subsequent cell-to-cell transmission of pathology. Moreover, intraperitoneal (i.p.) administration of mAb specific for misfolded α-syn into nontransgenic mice injected intrastriatally with α-syn pffs reduces LB/LN pathology, ameliorates substantia nigra dopaminergic neuron loss, and improves motor impairments. We conclude that α-syn antibodies could exert therapeutic effects in PD/DLB by blocking entry of pathological α-syn and/or its propagation in neurons.
"Concomitant pathologies (i.e., Alzheimer and Lewy bodies pathologies) resulting from the mutual interaction between Aβ 42 , tau and α-syn during the course of the disease have major role in the neuropathological processes underlying dementia in PD (Tsigelny et al., 2008; Ciaccioli et al., 2013). In PD the spread of fibrillar α-syn pathology from the brainstem to limbic and neocortical structures, and the cortical deposition of β-amyloid plaques, represent major events (Compta et al., 2011; Irwin et al., 2012). Co-occurrence of tau and α-syn pathology has been found in neurons of brains affected by tauopathies and synucleinopathies , including PD (Vekrellis et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: There is a great interest in developing cerebrospinal fluid (CSF) biomarkers for diagnosis and prognosis of Parkinson's disease (PD). CSF alpha synuclein (α-syn) species, namely total and oligomeric α-syn (t-α-syn and o-α-syn), have shown to be of help for PD diagnosis. Preliminary evidences show that the combination of CSF t-α-syn and classical Alzheimer's disease (AD) biomarkers-β-amyloid 1-42 (Aβ42), total tau (t-tau), phosphorylated tau (p-tau)-differentiate PD patients from controls, and that reduced levels of Aβ42 represent a predictive factor for development of cognitive deterioration in PD. In this prospective study carried out in 44 PD patients and 25 neurological controls we wanted to verify whether the combination of CSF α-synuclein species-t-α-syn and o-α-syn-and classical AD biomarkers may help in differentiating PD from neurological controls, and if these biomarkers may predict cognitive decline. The median of follow-up duration was 3 years (range: 2-6 years). Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used for monitoring cognitive changes along time, being administered once a year. Oligo/total α-syn ratio (o/t-α-syn ratio) confirmed its diagnostic value, significantly contributing to the discrimination of PD from neurological controls. A greater diagnostic accuracy was reached when combining o/t-α-syn and Aβ42/tau ratios (Sens = 0.70, Spec = 0.84, AUC = 0.82; PPV = 0.89, NPV = 0.62, LR+ = 4.40, DOR = 12.52). Low CSF Aβ42 level was associated with a higher rate of MMSE and MoCA decline, confirming its role as independent predictive factor for cognitive decline in PD. None of the other biomarkers assessed (t-tau, p-tau, t-α-syn and o-α-syn) showed to have prognostic value. We conclude that combination of CSF o/t-α-syn and Aβ42/tau ratios improve the diagnostic accuracy of PD. PD patients showing low CSF Aβ42 levels at baseline are more prone to develop cognitive decline.
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