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.     

Genetic Analysis of <Emphasis Type="Italic">FBXO2</Emphasis>, <Emphasis Type="Italic">FBXO6</Emphasis>, <Emphasis Type="Italic">FBXO12</Emphasis>, and <Emphasis Type="Italic">FBXO41</Emphasis> Variants in Han Chinese Patients with Sporadic Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and has an elusive etiology. It is likely multifactorial, and genetic defects contribute to its pathogenesis. At least 25 genetic loci and 20 monogenic genes have been identified in monogenic PD. Recessive F-box protein 7 gene (FBXO7) mutations reportedly cause hereditary parkinsonism. To explore the roles of four paralogs (FBXO2, FBXO6, FBXO12, and FBXO41) in PD development, their variants (rs9614, rs28924120, rs6442117, and rs61733550, respectively) were analyzed in 502 Han Chinese patients with PD and 556 age, gender, and ethnicity-matched normal participants in mainland China. Statistically significant differences in genotypic and allelic frequencies were detected only in the FBXO2 variant rs9614 (P = 0.001 and 0.023, respectively; odds ratio 0.819, 95% confidence interval 0.690–0.973) between patients and controls. These results suggest that the FBXO2 variant rs9614 C allele may decrease the PD risk in mainland Han Chinese and may be a biomarker for PD.     

Increased infections with β-blocker use in ischemic stroke,a β<Subscript>2</Subscript>-receptor mediated process?

Strokes promote immunosuppression, partially from increased sympathetic activity. Altering sympathetic drive with β-blockers has variably been shown to improve stroke outcomes. This study adds to this literature using propensity score matching to limit confounding and by examining the effects of selective and non-selective β-blockers. Prospective data from acute ischemic stroke admissions at a single center from July 2010–June 2015 were analyzed. Outcomes included infection (urinary tract infection [UTI], pneumonia, or bacteremia), discharge modified Rankin Score (mRS), and in-hospital death. Any selective and non-selective β-blocker use during the first 3 days of admission were investigated with propensity score matching. A sensitivity analysis was also performed. This study included 1431 admissions. Any β-blocker use was associated with increased infections (16.4 vs. 10.7%, p = 0.030). Non-selective β-blocker use was associated with increased infections (18.9 vs. 9.7%, p = 0.005) and UTIs (13.0 vs. 5.5%, p = 0.009). Selective β-blocker use was not associated with infection. There were no associations between β-blocker use and in-hospital death or discharge mRS. In the sensitivity analysis, the association between non-selective β-blocker use and urinary tract infections persisted (12.5 vs. 4.2%, p = 0.044). No associations with death or mRS were found. Early β-blocker use after ischemic stroke may increase the risk of infection but did not change disability or mortality risk. The mechanism may be mediated by β₂-adrenergic receptor antagonism given the different effects seen with selective versus non-selective β-blocker use.     

No Association of <Emphasis Type="Italic">LOXL1</Emphasis> Gene Polymorphisms with Alzheimer’s Disease

Aggregation of amyloid-beta is one of the major characteristics in brains of patients with Alzheimer’s disease (AD). Although several mechanisms behind the formation of such aggregates have been suggested the regulatory factors are still unknown. The present study aimed at investigating the association of lysyl oxidase-like 1 (LOXL1) polymorphisms with AD diagnosis and cerebrospinal fluid biomarkers (CSF) for the disease. Proteins of the lysyl oxidase (LOX) family are involved in cross-linking extracellular matrix proteins to insoluble fibers and have been associated with neurodegenerative diseases including AD. Genetic polymorphisms in LOXL1 (rs1048661, rs3825942, and rs2165241) have been linked to exfoliation syndrome and exfoliation glaucoma, conditions that have shown association with AD. The polymorphisms were genotyped by Taqman allelic discrimination in a study sample including AD patients (n = 318) and controls (n = 575). In a subgroup of the population, the polymorphisms were analyzed in relation to APOE ε4 genotype and to CSF (T-tau, P-tau, and Aβ_1–42). No evidence for associations of these polymorphisms with risk for AD or any of the studied CSF biomarkers measured was found. These results do not support LOXL1 as being a major risk gene for AD.     

Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α<Subscript>2</Subscript>δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity

The α₂δ-1 subunit of the voltage-gated Ca²⁺ channel (VGCC) is a molecular target of gabapentin (GBP), which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive effects by disrupting trafficking of the α₂δ-1 subunit to the presynaptic membrane, resulting in decreased neurotransmitter release. We previously showed that GBP has an anti-allodynic effect in the first two weeks; but this is followed by insensitivity in the later stage after repeated administration in a rat model of central post-stroke pain (CPSP) hypersensitivity induced by intra-thalamic hemorrhage. To explore the mechanisms underlying GBP insensitivity, the cellular localization and time-course of expression of the α₂δ-1 subunit in both the thalamus and spinal dorsal horn were studied in the same model. We found that the α₂δ-1 subunit was mostly localized in neurons, but not astrocytes and microglia. The level of α₂δ-1 protein increased in the first two weeks after injury but then decreased in the third week, when GBP insensitivity occurred. Furthermore, the α₂δ-1 down-regulation was likely caused by later neuronal loss in the injured thalamus through a mechanism other than apoptosis. In summary, the present results suggest that the GBP receptor α₂δ-1 is mainly expressed in thalamic neurons in which it is up-regulated in the early stage of CPSP but this is followed by dramatic down-regulation, which is likely associated with GBP insensitivity after long-term use.     

<Emphasis Type="Italic">N</Emphasis><Superscript>ε</Superscript>-Carboxymethyllysine in diabetic and non-diabetic polyneuropathies

Increased oxidative stress and advanced glycosylation are important factors in the development of diabetic neuropathy. In non-diabetic neuropathies their influence has not been investigated in detail so far. We studied the localisation of N(epsilon)-carboxymethyllysine (CML) - a biomarker for oxidative stress - by immunohistochemistry in sural nerve biopsies of 31 patients with different polyneuropathies [diabetic polyneuropathy (n=5), alcohol-associated polyneuropathy (n=4), vitamin B12-deficient polyneuropathy (n=6), chronic inflammatory demyelinating polyneuropathy (CIDP) (n=6), vasculitic neuropathy (n=6), Charcot-Marie-Tooth disease type I (CMT I) (n=4)] and 4 normal controls. CML was detected in the perineurium of patients with diabetic, alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathies. Epineurial, perineurial and endoneurial vessels were CML positive in diabetic, vitamin B12-deficient and vasculitic polyneuropathies. CML was also found in mononuclear inflammatory cells in vasculitic neuropathy. In CIDP and normal controls there was only marginal perineurial CML deposition in 2/6 and 1/4 cases. In CMT I no CML was detected. Immunohistochemical results were confirmed by immunoblot. Our data suggest a role of oxidative stress in the pathogenesis not only of diabetic but also of alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathies. It may be a minor pathogenetic factor in CIDP and may not be involved in CMT I. Underlying causes for increased oxidative stress may be an elevated production of reactive oxygen species and an impairment of antioxidative defences. Therefore, an antioxidative treatment should be considered in alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathy.     

An antihypokinesic action of <Emphasis Type="Bold">α</Emphasis><Subscript>2</Subscript>-adrenoceptors upon MPTP-induced behaviour deficits in mice

The effects of co-administration of either the dopamine precursor, L-Dopa, or the directly-acting, mixed dopamine (DA) agonist, apomorphine, with the alpha-adrenoceptor agonists, clonidine and guanfacine, upon the motor activity of hypoactive L-Dopa-tolerant MPTP-treated C57 BL/6 mice were measured in four experiments. In each case, MPTP (2 x 40 mg/kg, s.c., separated by a 24-hr interval) was administered eight-to-ten weeks before behavioural testing. It was found that clonidine co-administered with L-Dopa (20 mg/kg) restored motor activity in a dose- and parameter-related manner: locomotion and total activity were restored by the 1 mg/kg dose, rearing behaviour by the 0.3 and 1 mg/kg doses. The restorative effects of clonidine (1 mg/kg), co-administered with L-Dopa, were antagonised completely by pretreatment with yohimbine (1 mg/kg), but not by prazosin (1 mg/kg). Guanfacine (1 mg/kg) co-administered with L-Dopa (20 mg/kg) restored locomotor, but not rearing, behaviour in L-Dopa-tolerant MPTP-treated mice. The antikinesic action of guanfacine was antagonised completely by yohimbine (1 mg/kg), but not prazosin (1 mg/kg). Clonidine (1 or 3 mg/kg) co-administered with apomorphine (0.1, 0.3, 1.0 or 3.0 mg/kg), directly-acting DA agonist, did not restore motor behaviour in the hypokinesic L-Dopa-tolerant MPTP-treated mice. Nor did apomorphine, by itself, affect the motor activity of these animals. Neurochemical analysis indicated marked DA, DOPAC and HVA depletions in the striatum, and to a much lesser extent in the frontal cortex, of MPTP-treated mice. The synergistic antiparkinsonian action of clonidine with L-Dopa, but not apomorphine, in hypokinetic MPTP mice for the restoration of responding to a suprathreshold dose of L-Dopa, to which "wearing-off" had been induced previously, is discussed.     

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.     

Pharmacological Effects on Ceroid Lipofuscin and Neuronal Structure in <Emphasis Type="Italic">Cln3</Emphasis><Superscript><Emphasis Type="Italic">∆ex7/8</Emphasis></Superscript> Mouse Brain Cultures

Juvenile Batten disease (JBD) is an inherited disorder that is characterized by the development of blindness, seizures, and progressive motor, psychiatric, and cognitive impairment. A model of JBD expressing the predominant human mutation (Cln3 ^?ex7/8 ) has been explored. Dissociated brain cultures from Cln3 ^?ex7/8 knock-in mice were compared to wild type (WT) for effects on granules of ceroid lipofuscin (CL) and neuronal structure. Utilizing high content image analysis of CL granules identified with antibodies to mitochondrial ATP synthase subunit c or tripeptidyl peptidase-1, significant increases in the areas for both immunoreactive granules were observed in Cln3 ^?ex7/8 cultures in comparison to WT. CL granules also exhibit autofluorescence at 488 and 560 nm, and the areas of these autofluorescent spots were found to be significantly increased in Cln3 ^?ex7/8 cultures in comparison to WT. Progressive increases in CL granule area in Cln3 ^?ex7/8 cultures were observed during culture development. Because current therapies for JBD provide only symptomatic support, a therapeutic strategy has been explored based on the observations that JBD-related tissues are deficient in β-galactosyl ceramide. Treatment of cultures for 40 h with a potent analog of β-galactosyl ceramide (SNB-4050) produced significant decreases in CL granule area in the Cln3 ^?ex7/8 cultures; whereas identical studies on WT cultures produced no detectible changes. Significant decreases in average neurite length and neurite branch point number were also observed in the Cln3 ^?ex7/8 cultures that were attenuated by treatment with 1 nM SNB-4050. These studies indicate Cln3 ^?ex7/8 brain cultures may be useful to screen therapeutic agents for treatment of JBD.     

Characterization of brain tumours with spin–spin relaxation: pilot case study reveals unique <Emphasis Type="Italic">T</Emphasis><Subscript>2</Subscript> distribution profiles of glioblastoma,oligodendroglioma and meningioma

Prolonged spin–spin relaxation times in tumour tissue have been observed since some of the earliest nuclear magnetic resonance investigations of the brain. Over the last three decades, numerous studies have sought to characterize tumour morphology and malignancy using quantitative assessment of T ₂ relaxation times, although attempts to categorize and differentiate tumours have had limited success. However, previous work must be interpreted with caution as relaxation data were typically acquired using a variety of multiple echo sequences with a range of echoes and T ₂ decay curves and were frequently fit with monoexponential analysis. We defined the distribution of T ₂ components in three different human brain tumours (glioblastoma, oligodendroglioma, meningioma) using a multi-echo sequence with a greater number of echoes and a longer acquisition window than previously used (48 echoes, data collection out to 1120 ms) with no a priori assumptions about the number of exponential components contributing to the T ₂ decay. T ₂ relaxation times were increased in tumour tissue and each tumour showed a distinct T ₂ distribution profile. Tumours have complex and unique compartmentalization characteristics. Quantitative assessment of T ₂ relaxation in brain cancer may be useful in evaluating different grades of brain tumours on the basis of their T ₂ distribution profile, and has the potential to be a non-invasive diagnostic tool which may also be useful in monitoring therapy. Further study with a larger sample size and varying grades of tumours is warranted.     

<Superscript>123</Superscript>I-β-CIT binding and recovery from depression

Abstract. Eighteen depressive outpatients were investigated using single-photon emission computerized tomography (SPECT) with a high-affinity dopamine (DA) and serotonin transporter (SERT) specific radioligand, ¹²³I-labeled -CIT (2-carbomethoxy-3-(4-iodophenyl)-tropane). The patients were tested at the beginning of the study and on follow-up after six months. The severity of depression was evaluated using the 17-item Hamilton Rating Scale of Depression (HRSD). Eight of the eighteen patients had an HRSD score below the median (12 points) on follow-up, and they had a significantly greater increase in ¹²³I--CIT binding in the midbrain region compared with those patients who did not recover (ANCOVA: F = 8.12; df = 1, 14; p = 0.013). These results indicate that recovery from depression is associated with an increase in ¹²³I--CIT binding in the midbrain.     

Lower functional connectivity of default mode network in cognitively normal young adults with mutation of <Emphasis Type="Italic">APP</Emphasis>, <Emphasis Type="Italic">presenilins</Emphasis> and <Emphasis Type="Italic">APOE ε4</Emphasis>

In this study, we used resting-state functional magnetic resonance imaging to explore the genetic effects of amyloid precursor protein (APP) or presenilins mutation and apolipoprotein E (APOE) ε4 on the default-mode network (DMN) in cognitively intact young adults (24.1 ± 2.5 years). Both the APP or presenilin-1/2 group and the APOE ε4 group had significantly lower DMN functional connectivity (FC) in the some brain regions like precuneus/middle cingulate cortices (PCu/MCC) than controls (AlphaSim corrected, P < 0.05). Only a lower FC tendency was demonstrated (control < APOE ε4 < APP or presenilin-1/2 group). Moreover, lower FC in PCu/MCC is correlated with some neuropsychological assessments such as similarity test in APOE ε4 group. These findings indicate that DMN FC alteration in APP or presenilin-1/2 or APOE ε4 subjects is prior to the occurrence of neurological alterations and clinical symptoms, and DMN FC might be a valuable biomarker to detect genetic risk in the preclinical stage.     

Olfactory Dysfunction in Parkinson’s Disease Patients with the <Emphasis Type="Italic">LRRK2</Emphasis> G2385R Variant

Olfactory dysfunction has been reported in Parkinson’s disease (PD) patients carrying the LRRK2 G2019S variant in Caucasians but rarely in those with the LRRK2 G2385R variant. In this study, we performed genotyping for the LRRK2 G2385R variant in PD patients recruited from the Movement Disorder Clinic of Xuanwu Hospital in Beijing and in healthy controls randomly selected from the Beijing Longitudinal Study on Aging cohort. The “five-odor olfactory detection array”, an olfactory threshold test, was used to assess olfactory function. One hundred and eighty-six participants were enrolled, comprising 43 PD patients without (iPD) and 25 with (LRRK2-PD) the LRRK2 G2385R variant, and 118 healthy controls. Our results showed that the threshold of olfactory identification was significantly worse in PD patients than in controls, but not significantly different between the iPD and LRRK2-PD groups. These findings suggested that although olfactory function in LRRK2-PD patients is impaired, it is similar to that in iPD patients.     

Amyloid-Positronenemissionstomographie mit [<Superscript>18</Superscript> F]-Florbetaben in der Demenzdiagnostik

Background

To this day the definite diagnosis of Alzheimer’s disease still relies on post-mortem histopathological detection of neurofibrillary tangles and beta-amyloid deposits. Amyloid positron emission tomography (PET) is a new diagnostic tool that enables the in vivo quantification of pathological beta-amyloid deposits. The aim of the current study was to evaluate to what extent ¹⁸F-florbetaben-PET (FBB-PET) influences the diagnosis of patients with dementia.

Material and methods

Imaging with FBB-PET was performed on 33 patients from our outpatient department for cognitive neurology. Beforehand all patients underwent a comprehensive clinical, neuropsychiatric and laboratory examination as well as imaging by means of magnetic resonance imaging (MRI) and fluorodeoxyglucose-PET. The working diagnoses before and after FBB-PET imaging were compared.

Results

17 out of 33 patients were scored as FBB-PET positive. In four cases the initial diagnosis had to be changed to Alzheimer’s disease (three cases) and cerebral amyloid angiopathy (one case) due to the positive FBB-PET scan. 16 patients showed a negative FBB-PET scan. In three patients the initial diagnosis of Alzheimer’s disease could be ruled out due to the negative FBB-PET scan. Overall, in 7 out of 33 examined patients the initial diagnosis had to be changed because of the findings of the FBB-PET scan. In 24 patients the initial diagnosis was confirmed by the results of the FBB-PET scan.

Conclusion

Amyloid-PET is currently no standard procedure in the diagnosis of dementia; however, it can be a helpful additional diagnostic tool when used according to the “Appropriate Use Criteria” and the S3 guidelines on dementia in cases of unclear clinical presentation, atypically early age of onset as well as in patients with persistent or progressive unexplained mild cognitive impairment. By facilitating early diagnosis amyloid-PET imaging allows patient selection for therapeutic drug trials.

     

Phenotype analysis in patients with early onset Parkinson’s disease with and without <Emphasis Type="Italic">parkin</Emphasis> mutations

The data regarding whether parkin genotype attributes phenotypic variation are conflicting. Since the incidence of parkin mutations is very low in patients with an age at onset (AAO) of >40 years, previous studies have unfairly compared phenotypes of two early onset Parkinson’s disease (EOPD) groups with different AAOs. Thus, we compared the clinical features between patients with and without parkin mutations in EOPD with an AAO of ≤40 years. Of the 124 patients with EOPD with an AAO of ≤40 years who were recruited and screened for parkin mutations, 84 completed assessments for comparison of the phenotype according to parkin genotype. Fourteen of the 84 subjects carried two parkin mutations; 6, a single mutation; and 64, no mutations. Patients with two mutations had significantly younger AAOs, longer duration of PD, and more common family history than patients without parkin mutations. Otherwise, motor and nonmotor symptoms did not differ between them. Subgroup analysis of EOPD with an AAO of ≤35 years revealed similar results. Phenotype of EOPD may depend on early AAOs rather than presence of parkin mutations.     

<Emphasis Type="Italic">TOX3</Emphasis> Variants Are Involved in Restless Legs Syndrome and Parkinson’s Disease with Opposite Effects

Parkinson’s disease (PD) and restless legs syndrome (RLS) may be clinically and/or etiologically related, yet this association is under debate. Single-nucleotide polymorphisms (SNPs) in the TOX3 gene locus were implicated in both RLS and PD genome-wide association studies (GWASs), suggesting a potential pleiotropy. Two case-control cohorts including 644 PD patients, 457 RLS patients, and 945 controls were genotyped for one known RLS-related SNP (rs3104767) and one PD-related SNP (rs4784226) in the TOX3 locus. The associations between genotype and PD and RLS risk were tested using multivariate regression models. The allele frequencies of RLS-related SNP rs3104767 in RLS patients and controls were 0.35 and 0.43, respectively (OR 0.70, p?=?0.0007). Regression model suggested that this association is derived by homozygous carriage of rs3104767 (adjusted p?=?0.008). A nominal association was observed for homozygous carriers of the rs3104767 SNP in PD (OR 1.62, 95% CI 1.05–2.54, p?=?0.034), i.e., with an opposite direction of effect on RLS and PD, but this was not significant after Bonferroni correction. However, data from published GWASs of RLS and PD, and from the PDgene database, further supported these inverse associations. Our results confirm the association between the TOX3 SNP rs3104767 and RLS and suggest that TOX3 variants are involved in both RLS and PD, but with different or even opposite effects. Studies in larger populations of different ethnicities are required to further refine the TOX3 locus is involved in RLS and PD.     

Sleep microstructure and neurodegeneration as measured by [<Superscript>123</Superscript>I]β-CIT SPECT in treated patients with Parkinson’s disease

Abstract Objectives Along with spindles, K-complexes are well known hallmarks of stage 2 (S2) sleep. However, little is known about their quantity in S2 sleep of patients with Parkinsons disease (PD). Setting Sleep laboratory, Department of Neurology, University of Vienna, Austria. Patients and methods Whole-night polysomnography (PSG) was performed in twelve treated PD patients and ten healthy controls without history of sleep complaints. The quantity of spontaneous K-complexes, K-alpha-complexes, and sleep spindles in one hour S2 sleep, distributed in four epochs of 15 minutes all through the night, were visually selected and analysed. The quantity and the temporal course of these phasic events were compared with the quantity in age-matched healthy controls. Nine of the twelve PD patients underwent [¹²³I]-CIT SPECT for calculating dopamine transporter binding in the striatum and serotonin transporter density in the thalamus-hypothalamus region. Results There was no difference between the quantity of K-complexes, K-alpha-complexes, and sleep spindles in PD patients and in the healthy control group. K-complexes but not sleep spindles decreased over the night in both groups. The number of sleep spindles did not correlate with the dopamine transporter binding in the striatum or the serotonin binding in the thalamic/hypothalamic region. Conclusion K-complexes and sleep spindles are not reduced and do not seem to be related to the degree of dopaminergic degeneration in treated PD patients.This research was supported in part by the European Commission, DG XII (Project Biomed-2 BMH4-CT97–2040 SIESTA) and by the Austrian National Bank (Project 7870). Svenja Happe, MD, was recipient for a fellowship stipend of the European Neurological Society (ENS).     

Brain aging and Aβ<Subscript>1–42</Subscript> neurotoxicity converge via deterioration in autophagy–lysosomal system: a conditional <Emphasis Type="Italic">Drosophila</Emphasis> model linking Alzheimer’s neurodegeneration with aging

Aging is known to be the most prominent risk factor for Alzheimer’s disease (AD); however, the underlying mechanism linking brain aging with AD pathogenesis remains unknown. The expression of human amyloid beta 42 peptide (Aβ_1–42), but not Aβ_1–40 in Drosophila brain induces an early onset and progressive autophagy–lysosomal neuropathology. Here we show that the natural process of brain aging also accompanies a chronic and late-onset deterioration of neuronal autophagy–lysosomal system. This process is characterized by accumulation of dysfunctional autophagy–lysosomal vesicles, a compromise of these vesicles leading to damage of intracellular membranes and organelles, necrotic-like intraneuronal destruction and neurodegeneration. In addition, conditional activation of neuronal autophagy in young animals is protective while late activation is deleterious for survival. Intriguingly, conditional Aβ_1–42 expression limited to young animals exacerbates the aging process to a greater extent than Aβ_1–42 expression in old animals. These data suggest that the neuronal autophagy–lysosomal system may shift from a functional and protective state to a pathological and deleterious state either during brain aging or via Aβ_1–42 neurotoxicity. A chronic deterioration of the neuronal autophagy–lysosomal system is likely to be a key event in transitioning from normal brain aging to pathological aging leading to Alzheimer’s neurodegeneration.     

The murine <Emphasis Type="Italic">Bis1</Emphasis> seizure gene and the <Emphasis Type="Italic">Kcnab2</Emphasis> gene encoding the β2-subunit of the K<Superscript>+</Superscript> channel are different

Received: April 22, 1999 / Accepted: August 30, 1999 / Published online: January 10, 2000     

Changes of cerebrospinal fluid Aβ<Subscript>42</Subscript>, t-tau,and p-tau in Parkinson’s disease patients with cognitive impairment relative to those with normal cognition: a meta-analysis

The cerebrospinal fluid (CSF) signature of reduced amyloid beta 1–42 (Aβ₄₂), elevated total tau (t-tau), and phosphorylated tau181 (p-tau) is important for the early diagnosis of Alzheimer’s disease (AD). Aβ₄₂, t-tau, and p-tau have been reported in numerous studies to contribute to predicting cognitive impairment in Parkinson’s disease (PDCI). However, no consistent conclusion can be drawn so far. Literatures regarding Aβ₄₂, t-tau, and p-tau in CSF were systematically reviewed, and a meta-analysis was thus performed to evaluate the changes of these biomarkers in PDCI patients, including PD with mild cognitive impairment (PDMCI) and PD dementia (PDD) patients, relative to PD with normal cognition (PDNC) patients. Databases of “PubMed,” “EBSCO,” and “Springer” were retrieved for articles concerning Aβ₄₂, t-tau, and p-tau in PDCI patients relative to those in PDNC patients published from January 1, 2000 to February 1, 2017. The following keywords were set, namely, “dementia” or “cognitive impairment” or “mild cognitive impairment” and “cerebrospinal fluid” and “Parkinson*.” Sixteen articles comprising 590 PDCI patients and 1182 PDNC patients were included. The results showed that CSF Aβ₄₂ level in PDCI cohort was lower than that in PDNC cohort (pooled Std.MD = ?0.44, 95% CI [?0.61, ?0.26], p < 0.00001). Reduced Aβ₄₂ (pooled Std.MD = ?0.60, 95% CI [?0.75, ?0.45], p < 0.00001) as well as elevated t-tau (pooled Std.MD = 0.21, 95% CI [0.06, 0.35], p = 0.006) and p-tau (pooled Std.MD = 0.36, 95% CI [0.02, 0.69], p = 0.04) could be observed in PDD cohort compared with PDNC cohort. Therefore, amyloid pathology and tauopathy may participate in the development of PDD, which is similar to AD.