Interaction Between Ca<Subscript>v</Subscript>2.1α<Subscript>1</Subscript> and CaMKII in Ca<Subscript>v</Subscript>2.1α<Subscript>1</Subscript> Mutant Mice, <Emphasis Type="Italic">Rolling Nagoya</Emphasis>

It has been reported earlier that interactions between Ca_v2.1α₁ and calcium/calmodulin-dependent protein kinase II (CaMKII) in the presynaptic fraction and between the NMDA receptor subunit NR2B and CaMKII in the postsynaptic density (PSD) fraction are important for neuronal function. Ca_v2.1α₁, CaMKII, and NR2B are predominantly expressed in the hippocampus. To examine the above interactions and CaMKII activity in the hippocampal presynapse and PSD of Rolling Nagoya mice carrying a mutation in Ca_v2.1α₁ subunit, we performed immunoprecipitation and Western blot analyses. In the presynapse, the interaction between Ca_v2.1α₁ and CaMKII and the phosphorylation of CaMKII (at Thr286) and its substrate Synapsin I (at Ser603) were decreased in mutant mice compared to wild-type mice. In the PSD, a similar pattern was observed for the interaction between NR2B and CaMKII and the phosphorylation of CaMKII (at Thr286) and its substrate AMPA receptor subunit glutamate receptor 1 (at Ser831) between mutant and wild-type mice. Our data indicate that disruption of the interaction between Ca_v2.1α₁ and CaMKII may down-regulate presynaptic CaMKII activity and that Rolling Nagoya mice would be a useful model for examining presynaptic function.     

New molecular targets for antiepileptic drugs: α<Subscript>2</Subscript>δ, SV2A,and K<Subscript>v</Subscript>7/KCNQ/M potassium channels

Many currently prescribed antiepileptic drugs (AEDs) act via voltage-gated sodium channels, through effects on γ-aminobutyric acid-mediated inhibition, or via voltage-gated calcium channels. Some newer AEDs do not act via these traditional mechanisms. The molecular targets for several of these nontraditional AEDs have been defined using cellular electrophysiology and molecular approaches. Here, we describe three of these targets: α₂δ, auxiliary subunits of voltage-gated calcium channels through which the gabapentinoids gabapentin and pregabalin exert their anticonvulsant and analgesic actions; SV2A, a ubiquitous synaptic vesicle glycoprotein that may prepare vesicles for fusion and serves as the target for levetiracetam and its analog brivaracetam (which is currently in late-stage clinical development); and K_v7/KCNQ/M potassium channels that mediate the M-current, which acts a brake on repetitive firing and burst generation and serves as the target for the investigational AEDs retigabine and ICA-105665. Functionally, all of the new targets modulate neurotransmitter output at synapses, focusing attention on presynaptic terminals as critical sites of action for AEDs.     

CSF Aβ<Subscript>1–42</Subscript>, but not p-Tau<Subscript>181</Subscript>, Predicted Progression from Amnestic MCI to Alzheimer’s Disease Dementia

The purpose of the study was to determine whether Aβ_1–42 and p-Tau₁₈₁ cerebral spinal fluid (CSF) levels can predict progression from amnestic mild cognitive impairment (aMCI) to Alzheimer’s disease dementia (ADD) in a 3-year follow-up study. All participants were evaluated blindly by a behavioral neurologist and a neuropsychologist, and classified according to the Petersen criteria for aMCI and according to the Clinical Dementia Rating (CDR) scale. Individuals were also submitted to lumbar puncture at baseline. Levels of Aβ_1–42 and p-Tau₁₈₁ were measured by immunoenzymatic assay. Values were adjusted for age and sex. Thirty-one of 33 (93.9%) participants completed follow-up. Approximately 39% of aMCI individuals progressed to ADD. The relative risk of developing ADD in those with Aβ_1–42 CSF levels lower than 618.5 pg/mL was 17.4 times higher than in those whose levels were higher than 618.5 pg/mL (P?=?0.003). p-Tau₁₈₁ alone did not predict progression to ADD (P?=?0.101). The relative risk in those with a p-Tau₁₈₁/Aβ_1–42 ratio higher than 0.135 was 5.7 times greater (P?<?0.001). Aβ_1–42 and p-Tau₁₈₁ explained 40.1% of the verbal memory test subscore of the Consortium to Establish a Registry for Alzheimer’s Disease (ΔCERADs) variance (P?=?0.008). Aβ_1–42 strongly predicted progression from aMCI to ADD. p-Tau₁₈₁ alone, or its relation to Aβ_1–42, was inferior than Aβ_1–42 alone as a predictor of progression to ADD.     

Receptor–receptor interactions involving adenosine A<Subscript>1</Subscript> or dopamine D<Subscript>1</Subscript> receptors and accessory proteins

Summary. The molecular basis for the known intramembrane receptor–receptor interactions among heptahelical receptors (G protein coupled receptors, GPCR) was postulated to be heteromerization based on receptor subtype specific interactions between different types of homomers of GPCR. Adenosine and dopamine receptors in the basal ganglia have been fundamental to demonstrate the existence of receptor heteromers and the functional consequences of such molecular interactions. The heterodimer is only one type of heteromeric complex and the evidence is equally compatible with the existence of higher order heteromeric complexes, where also adapter proteins such as homer proteins and scaffolding proteins can exist, assisting in the process of linking the GPCR and ion channel receptors together in a receptor mosaic that may have special integrative value and may constitute the molecular basis for learning and memory. Heteromerization of D₂ dopamine and A_2A adenosine receptors is reviewed by Fuxe in another article in this special issue. Here, heteromerization between D₁ dopamine and A₁ adenosine receptors is reviewed. Heteromers formed by dopamine D₁ and D₂ receptors and by adenosine A₁ and A_2A receptors also occur in striatal cells and open new perspectives to understand why two receptors with apparently opposite effects are expressed in the same neuron and in the nerve terminals. The role of accessory proteins also capable of interacting with receptor–receptor heteromers in regulating the traffic and the molecular physiology of these receptors is also discussed. Overall, the knowledge of the reason why such complex networks of receptor–receptor and receptor–protein interactions occur in striatal cells is crucial to develop new strategies to combat neurological and neuropsychiatric diseases.     

Can vitamin D<Subscript>3</Subscript> supplementation prevent bone loss in persons with MS? A placebo-controlled trial

Multiple sclerosis (MS) is a possible cause of secondary osteoporosis. In this phase II trial we assessed whether a weekly dose of 20,000 IU vitamin D₃ prevents bone loss in ambulatory persons with MS age 18–50 years. ClinicalTrials.gov ID NCT00785473. All patients managed at the University Hospital of North Norway who fulfilled the main inclusion criteria were invited to participate in this double-blinded trial. Participants were randomised to receive 20,000 IU vitamin D₃ or placebo once a week and 500 mg calcium daily for 96 weeks. The primary outcome was the effect of the intervention on percentage change in bone mineral density (BMD) at the hip, the spine, and the ultradistal radius over the study period. Of 71 participants randomised, 68 completed. Mean serum 25-hydroxyvitamin D [25(OH)D] levels in the intervention group increased from 55 nmol/L at baseline to 123 nmol/L at week 96. After 96 weeks, percentage change in BMD did not differ between groups at any site. BMD decreased at the hip, by 1.4% in the placebo group (95% CI −2.3 to −0.4, SD 2.7, p = 0.006) and by 0.7% in the treatment group (−1.6 to 0.2, 2.7, p = 0.118), difference 0.7% (−1.9 to 0.7, p = 0.332). Findings were not altered by adjustment for sex or serum 25(OH)D. Supplementation with 20,000 IU vitamin D₃ a week did not prevent bone loss in this small population. Larger studies are warranted to assess the effect of vitamin D on bone health in persons with MS.     

Fast Inactivation of Ca<Subscript>V</Subscript>2.2 Channels Is Prevented by the Gβ<Subscript>1</Subscript> Subunit in Rat Sympathetic Neurons

Voltage-dependent regulation of Ca_V2.2 channels by G-proteins is performed by the β (Gβ) subunit. Most studies of regulation by G-proteins have focused on channel activation; however, little is known regarding channel inactivation. This study investigated inactivation of Ca_V2.2 channels in superior cervical ganglion neurons that overexpressed Gβ subunits. Ca_V2.2 currents were recorded by whole-cell patch clamping configuration. We found that the Gβ₁ subunit reduced inactivation, while Gβ₅ subunit did not alter at all inactivation kinetics compared to control recordings. Ca_V2.2 current decay in control neurons consisted of both fast and slow inactivation; however, Gβ₁-overexpressing neurons displayed only the slow inactivation. Fast inactivation was restored by a strong depolarization of Gβ₁-overexpressing neurons, therefore, through a voltage-dependent mechanism. The Gβ₁ subunit shifted the voltage dependence of inactivation to more positive voltages and reduced the fraction of Ca_V2.2 channels resting in the inactivated state. These results support that the Gβ₁ subunit inhibits the fast inactivation of Ca_V2.2 channels in SCG neurons. They explain the long-observed sustained Ca²⁺ current under G-protein modulation.     

IRF-8 is Involved in Amyloid-β<Subscript>1–40</Subscript> (Aβ<Subscript>1–40</Subscript>)-induced Microglial Activation: a New Implication in Alzheimer’s Disease

Using microarray analysis, we detected microRNA-124 (miR-124) to be abundantly expressed in the olfactory bulb (OB). miR-124 regulates adult neurogenesis in the subventricular zone (SVZ). However, much less is known about its role in newborn OB neurons. Here, using both gain-of-function and loss-of-function approaches, we demonstrate that brain-specific miR-124 affects dendritic morphogenesis and spine density in newborn OB neurons. Functional Annotation Clustering of miR-124 targets was enriched in “cell morphogenesis involved in neuron differentiation.”     

mRNA and Protein Levels for GABA<Subscript>A</Subscript>α4, α5, β1 and GABA<Subscript>B</Subscript>R1 Receptors are Altered in Brains from Subjects with Autism

We have shown altered expression of gamma-aminobutyric acid A (GABA_A) and gamma-aminobutyric acid B (GABA_B) receptors in the brains of subjects with autism. In the current study, we sought to verify our western blotting data for GABBR1 via qRT-PCR and to expand our previous work to measure mRNA and protein levels of 3 GABA_A subunits previously associated with autism (GABRα4; GABRα5; GABRβ1). Three GABA receptor subunits demonstrated mRNA and protein level concordance in superior frontal cortex (GABRα4, GABRα5, GABRβ1) and one demonstrated concordance in cerebellum (GABΒR1). These results provide further evidence of impairment of GABAergic signaling in autism.     

Periodic Variation of AAK1 in an Aβ<Subscript>1–42</Subscript>-Induced Mouse Model of Alzheimer’s Disease

Inhibition of endocytosis in an Alzheimer’s disease (AD) model has been shown to be able to prevent amyloid β (Aβ)-induced damage and to exert a beneficial effect in treating AD. Adaptor-associated kinase 1 (AAK1), which binds to the adaptor protein complex 2 (AP-2), regulates the process of clathrin-mediated endocytosis. However, how AAK1 expression varies over the course of AD is unknown. In this study, we investigated AAK1 levels in AD model mice over time. Aβ_1–42 was used to establish a mouse AD model, and the Morris water maze test was used to characterize the time course of Aβ_1–42-induced cognition changes. ELISA was used to determine AAK1 levels in plasma and Aβ_1–42 levels in brain tissues. Subsequently, the protein or gene levels of AAK1, AP-2, and Rab5 (an early endosome marker) were tested in each group. The cognitive function of Aβ_1–42-induced mice was significantly declined compared to control group, and the deficits reached a peak on day 14, but partly recovered on day 30. Moreover, the level of Aβ_1–42 detected with ELISA was highest on day 14, but reduced on day 30, paralleling the cognitive changes in the mice in our study. AAK1, AP-2, and Rab5 expression showed the same periodic variation as the changes in cognition. Thus, periodic variation in AAK1 expression is closely correlated to the decline in cognition, and AAK1 might be a suitable indicator for Alzheimer’s disease.     

Preprothyrotropin-releasing hormone<Subscript>178–199</Subscript> affects tyrosine hydroxylase biosynthesis in hypothalamic neurons

ProThyrotropin-releasing hormone (proTRH) is a prohormone widely distributed in many areas of the brain. After biosynthesis, proTRH is subjected to post-translational processing to generate TRH and seven non-TRH peptides. Among these non-TRH sequences, we found previously that preproTRH_178–199 could regulate the secretion of prolactin in suckled rats by their pups. Dopamine (DA), the main regulator of prolactin secretion, is produced in dopaminergic tyrosine hydroxylase (TH)-positive neurons in the hypothalamic arcuate nucleus (ARC). In this study we investigated whether prolactin release during the estrous sexual cycle is regulated by prepro TRH_178–199 through its effecton DA neurons of the ARC. We observed that biotinylated prepro TRH_178–199 bound to neurons in the ARC; this was higher during proestrus than during diestrus. Binding of preproTRH_178–199 to DA neurons was seen only during proestrus in the ARC. Using primary neuronal hypothalamic cultures we found that preproTRH_178–199peptide decreased TH levels in a dose-responsive manner, whereas intra-ARC administration of preproTRH_178–199 induced a 20-fold increase in plasma prolactin levels. Together, these results suggest a potential role for preproTRH_178–199 in regulating dopaminergic neurons involved in the inhibition of pituitary prolactin release.     

Serum α<Subscript>1</Subscript>-antitrypsin level and phenotype associated with familial moyamoya disease

Background Obstructive vascular lesions at the terminal portion of the internal carotid arteries are thought to be the primary and essential lesions in moyamoya disease. The etiology remains unknown. To detect possible mediators of the thickened intima of moyamoya disease, we measured serum alpha-1-antitrypsin (1-AT) levels and characterized the phenotype of patients with familial moyamoya disease.Patients and methods Fifty-six individuals were examined, including 29 patients with moyamoya disease from 14 families. Serum 1-AT levels were analyzed by electroimmunoassay and genomic phenotype by isoelectric focusing.Results All individuals had a normal 1-AT phenotype. The average serum 1-AT level in moyamoya disease patients was significantly higher than that of normal individuals, although both were within the normal range.Conclusions These findings suggest that serum 1-AT level may be a marker, rather than an etiologic factor, indicating the progression of moyamoya disease.     

Changes in the mRNA Levels of α<Subscript>2A</Subscript> and α<Subscript>2C</Subscript> Adrenergic Receptors in Rat Models of Parkinson’s Disease and <Emphasis Type="SmallCaps">l</Emphasis>-DOPA-Induced Dyskinesia

The changes in the mRNA levels of α_2A and α_2C adrenoceptors were investigated in unilateral 6-OHDA-lesioned rat model of Parkinson’s disease and l-DOPA-induced dyskinesia using in situ hybridization. In the untreated 6-OHDA-lesioned rats, α_2A expression was elevated in the locus coeruleus (160 ± 8% and 142 ± 8% in lesioned and unlesioned sides compared to the comparable side in sham-operated rats). Following long-term (21 days, twice daily) treatment with l-DOPA (25 mg/kg l-DOPA methyl ester plus benserazide 6.25 mg/kg) in 6-OHDA-lesioned rats, levels of α_2A adrenoceptor mRNA in the locus coeruleus were decreased, compared to the 6-OHDA-lesioned rats, returning to the levels of α_2A mRNA in the sham-operated rats. α_2A adrenoceptor expression was not changed in other brain regions in any treatment group. There was no change in α_2C expression in the rostral or caudal striatum in which the highest density of α_2C mRNA is present. In conclusion, the data presented in this study demonstrate an increase in α_2A adrenoceptor mRNA in the locus coeruleus in the 6-OHDA-lesioned rat model of Parkinson’s disease. In addition, the data show that repeated treatment with l-DOPA in 6-OHDA-lesioned rats, which induces dyskinesia, restores α_2A mRNA levels. These changes of α_2A mRNA expression, observed in the locus coeruleus, might be of importance to basal ganglia transmission and motor function.     

GluR2/3, NMDAε1 and GABA<Subscript>A</Subscript> receptors in Creutzfeldt-Jakob disease

The excitatory ionotropic glutamate receptors N-methyl-d-aspartate (NMDA) and -amino-3-hydro-5methyl-4-isoxazole propionic acid (AMPA) receptors, and the inhibitory -aminobutyric acid (GABA) receptors are major regulators of synaptic transmission in the central nervous system. Glutamate receptors AMPA GluR2/3 and NMDA R2A: NR2A (NMDA1), and GABA_A (GABA_A R1) receptors were examined by immunohistochemistry in the cerebral cortex (frontal cortex) entorhinal cortex, hippocampus and cerebellar cortex in nine patients with sporadic Creutzfeldt-Jakob disease (CJD) and eight age-matched controls obtained 3–8 h after death. All patients with CJD showed methionine/methionine in codon 129 of the prion protein gene. Decreased GluR2/3 immunoreactivity was found in the frontal cortex, entorhinal cortex and Purkinje cells; reduced NMDA1 immunoreactivity was found in the frontal cortex, entorhinal cortex, and molecular and granular cell layers of the cerebellum. Decreased GluR2/3 and NMDA1 immunoreactivity was also observed in the molecular layer of the dentate gyrus, but not in the hippocampus proper in cases with hippocampal involvement. GABA_A R1 expression was markedly decreased in the granular cell layer of the cerebellum in CJD. Decreased GluR2/3 and NMDA1 expression correlated with prion protein deposition, neuron loss and spongiform degeneration in the cerebral cortex in every case. However, reduced GluR2/3 immunoreactivity in Purkinje cells was apparently independent of these parameters. In contrast to ionotropic glutamate receptors, GABA_A R1 immunoreactivity was moderately increased in the frontal cortex, entorhinal cortex and molecular layer of the cerebellum in CJD. The present results show marked and selective abnormalities in the expression of crucial neurotransmitter receptors in CJD, ionotropic glutamate receptors being more severely affected than ionotropic GABA receptors. These findings stress selective vulnerability of glutamate receptors versus GABA receptors in CJD.     

Platelet phospholipase A<Subscript>2</Subscript> activity in Alzheimer’s disease and mild cognitive impairment

Summary. Phospholipase A₂ (PLA₂) controls the metabolism of phospholipids in cell membranes. In the brain, PLA₂ influences the processing of the amyloid precursor protein (APP) and thus the production of the amyloid-beta peptides (A), which are the major components of the senile plaques in Alzheimers disease (AD). Reduced PLA₂ activity has been reported in brain and in platelets of AD patients. In the present study we investigated PLA₂ activity in platelets from 21 AD patients as compared to 17 healthy elderly controls and 11 individuals with mild cognitive impairment (MCI). Subjects were cognitively assessed by the Mini-Mental State Examination (MMSE) and the CAMDEX schedule. Platelet PLA₂ activity was determined by radio-enzymatic assay, which mainly detected a calcium-independent form of the enzyme present also in the brain (iPLA₂). PLA₂ activity was significantly lower in AD than in controls (p<0.001). Mean PLA₂ activity in MCI individuals was between the values of AD patients and controls, with a subgroup showing PLA as low as the lowest AD patients, but the differences from MCI were not significant from AD and control groups. Lower PLA₂ activity was significantly correlated with a worse cognitive performance both at the MMSE (p=0.001) and the cognitive sub-scale of the CAMDEX inventory (p=0.002). Our data replicate previous findings of reduced platelet PLA₂ activity in AD. Both reduced PLA₂ activity and the correlation with impaired cognition were also reported in brain tissue of AD patients, suggesting thus that the present determinations in platelets may be related to a reduction in the brain. In the brain the inhibition of PLA₂ inhibits the physiological secretion of the APP, a mechanism that increases A formation. Further longitudinal studies should investigate whether those MCI individuals with the lowest PLA₂ values in platelets would be at a higher risk to develop AD during a longitudinal follow up.     

Involvement of the α<Subscript>1D</Subscript>-adrenergic Receptor in Methamphetamine-Induced Hyperthermia and Neurotoxicity in Rats

Methamphetamine (METH) is a psychostimulant that damages nigrostriatal dopaminergic terminals, primarily by enhancing dopamine and glutamate release. α₁-adrenergic receptor (AR) subtype involved in METH-induced neurotoxicity in rats was investigated using selective α₁-AR antagonists. METH neurotoxicity was evaluated by (1) measuring body temperature; (2) determining tyrosine hydroxylase (TH) immunoreactivity levels; (3) examining levels of dopamine and its metabolites; and (4) assessing glial fibrillary acidic protein (GFAP) and microglial immunoreactivity in the striatum. METH caused a decrease in dopamine and TH levels and induced hyperthermia which is an exacerbating factor of METH neurotoxicity. Concurrently, METH increased GFAP expression and the number of activated microglia. Pretreatment with prazosin, a nonselective α₁-AR antagonist, completely abolished METH-induced decrease in both dopamine and TH and caused a partial reduction in hyperthermia. Prazosin also prevented METH-induced increase in both GFAP expression and the number of activated microglia. In vivo microdialysis analysis revealed that prazosin, however, does not alter the METH-induced dopamine release in the striatum. The neuroprotective effects of prazosin could be mimicked by a selective α_1D antagonist, BMY 7378, but not by selective α_1A or α_1B antagonists. These results suggest that the α_1D-AR is involved in METH-induced hyperthermia and neurotoxicity in rats.     

Role of dopamine D<Subscript>3</Subscript> and serotonin 5-HT<Subscript>1A</Subscript> receptors in <Emphasis Type="SmallCaps">l</Emphasis>-DOPA-induced dyskinesias and effects of sarizotan in the 6-hydroxydopamine-lesioned rat model of Parkinson’s disease

Sarizotan, a 5-HT_1A agonist with additional affinity for D₃ and D₄ receptors, has been demonstrated to have anti-dyskinetic effects. The mechanism by which these effects occur is not clear. Using unilateral 6-hydroxydopamine-lesioned rats that received chronic intraperitoneal (ip) administration of l-3,4-dihydroxyphenylalanine (l-DOPA) we investigated the involvement of D₃ and 5-HT_1A receptors in the effects of sarizotan on contraversive circling and abnormal involuntary movements (AIMs). Before sensitization by chronic l-DOPA treatment (12.5 with 3.25 mg/kg benserazide ip, twice daily for 21 days), no effect of the selective D₃ agonist, PD128907 (1 or 3 mg/kg ip), or the selective D₃ antagonist, GR103691 (0.5 or 1.5 mg/kg ip), was observed. Treatment with sarizotan (1 or 5 mg/kg ip) dose-dependently inhibited the l-DOPA-induced contraversive turning and AIMs. In co-treatment with the 5-HT_1A antagonist, WAY100635 (1 mg/kg ip), sarizotan failed to affect this behaviour, confirming the prominent 5-HT_1A receptor-mediated mechanism of action. In the presence of PD128907 (3 mg/kg ip), the effects of sarizotan on contraversive turning, locomotive dyskinesia and axial dystonia, but not on orolingual and forelimb dyskinesia, were blocked. On its own, PD128907 had no effect on the behavioural effects of l-DOPA except that it tended to reduce orolingual and forelimb dyskinesia. GR103691 had no effect on its own or in combination with sarizotan. These data identify an involvement of D₃ receptors in the action of sarizotan on some, but not all l-DOPA-induced motor side effects. This selective involvement is in contrast to the more general involvement of 5-HT_1A receptors in the anti-dyskinetic effects of sarizotan.     

A Lipoxin A<Subscript>4</Subscript> Analog Ameliorates Blood–Brain Barrier Dysfunction and Reduces MMP-9 Expression in a Rat Model of Focal Cerebral Ischemia–Reperfusion Injury

LXA₄ methyl ester (LXA₄ME), a lipoxin A₄ analog, reduces ischemic insult in the rat models of transient or permanent cerebral ischemic injury. We investigated whether LXA₄ME could ameliorate blood–brain barrier (BBB) dysfunction after stroke by reducing matrix metalloproteinase (MMP)-9 expression. Adult male rats were subjected to 2-h middle cerebral artery occlusion (MCAO) followed by 24-h reperfusion. Brain infarctions were detected by triphenyltetrazolium chloride (TTC) staining. BBB dysfunction was determined by examining brain edema and Evans Blue extravasation. Temporal expression of MMP-9 was determined by zymography and Western blot. The presence of tissue inhibitors of metalloproteinase-1 (TIMP-1) was also determined by Western blot in tissue protein sample. Brain edema and Evans Blue leakage were significantly reduced after stroke in the LXA₄ME group and were associated with reduced brain infarct volumes. MMP-9 activity and expression were inhibited by LXA₄ME after stroke. In addition, LXA₄ME significantly increased TIMP-1 protein levels. Our results indicate that LXA₄ME reduces brain injury by improving BBB function in a rat model of MCAO, and that a relationship exists between BBB permeability and MMP-9 expression following ischemic insult. Furthermore, these results suggest that LXA₄ME-mediated reduction of MMP-9 following stroke are attributed to increased TIMP-1 expression.     

Tau protein and beta-amyloid<Subscript>1-42</Subscript> CSF levels in different phenotypes of Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder with highly heterogeneous clinical manifestations. This fact has prompted many attempts to divide PD patients into clinical subgroups. This could lead to a better recognition of pathogenesis, improving targeted treatment and the prognosis of PD patients. The aim of the present study was to obtain cerebrospinal fluid (CSF) samples in PD patients and to search for a relationship between neurodegenerative CSF markers (tau protein, beta-amyloid_1-42 and index tau protein/beta-amyloid_1-42) and the clinical subtypes. PD patients were divided into three subgroups: early disease onset (EDO), tremor-dominant PD (TD-PD), and non-tremor dominant PD (NT-PD) according to the previously published classification. Neurodegenerative markers in the CSF were assessed in these three groups of patients suffering from PD (EDO-17, TD-15, NT-16 patients) and in a control group (CG) of 19 patients suffering from non-degenerative neurological diseases and 18 patients with Alzheimer’s disease (AD). The NT-PD patients were found to have significantly higher levels of CSF tau protein and index tau/beta than the control subjects and other Parkinsonian subgroups, but no significant differences in these markers were found between AD and NT-PD patients. In the context of more rapid clinical progression and more pronounced neuropathological changes in the NT-PD patient group, our results corroborate the opinion that CSF level of tau protein may be regarded as a potential laboratory marker of the presence and severity of neurodegeneration.