Cerebrospinal Fluid Biomarkers of Synaptic Dysfunction are Altered in Parkinson's Disease and Related Disorders

Background

Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects.

Objective

To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders.

Methods

Mass spectrometry was used to quantify 15 synaptic proteins in two clinical cerebrospinal fluid (CSF) cohorts, including PD (n₁ = 51, n₂ = 101), corticobasal degeneration (CBD) (n₁ = 11, n₂ = 3), progressive supranuclear palsy (PSP) (n₁ = 22, n₂ = 21), multiple system atrophy (MSA) (n₁ = 31, n₂ = 26), and healthy control (HC) (n₁ = 48, n₂ = 30) participants, as well as Alzheimer's disease (AD) (n₂ = 23) patients in the second cohort.

Results

Across both cohorts, lower levels of the neuronal pentraxins (NPTX; 1, 2, and receptor) were found in PD, MSA, and PSP, compared with HC. In MSA and PSP, lower neurogranin, AP2B1, and complexin-2 levels compared with HC were observed. In AD, levels of 14-3-3 zeta/delta, beta- and gamma-synuclein were higher compared with the parkinsonian disorders. Lower pentraxin levels in PD correlated with Mini-Mental State Exam scores and specific cognitive deficits (NPTX2; rho = 0.25–0.32, P < 0.05) and reduced dopaminergic pre-synaptic integrity as measured by DaTSCAN (NPTX2; rho = 0.29, P = 0.023). Additionally, lower levels were associated with the progression of postural imbalance and gait difficulty symptoms (All NPTX; β-estimate = −0.025 to −0.038, P < 0.05) and cognitive decline (NPTX2; β-estimate = 0.32, P = 0.021).

Conclusions

These novel findings show different alterations of synaptic proteins in parkinsonian disorders compared with AD and HC. The neuronal pentraxins may serve as prognostic CSF biomarkers for both cognitive and motor symptom progression in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges

No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer''s disease (AD) and Parkinson''s disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era.     

Definite Behavioral Variant of Frontotemporal Dementia with C9ORF72 Expansions Despite Positive Alzheimer's Disease Cerebrospinal Fluid Biomarkers

Hexanucleotide expansion repeats in the C9ORF72 gene are a major cause of familial and, to a lesser extent, sporadic frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and FTLD-ALS. To examine whether C9ORF72 expansions could be involved in early-onset Alzheimer's disease (EOAD), we genotyped the hexanucleotide repeat region in a large cohort of 114 EOAD patients who all had positive AD cerebrospinal fluid (CSF) biomarkers. We found hexanucleotide expansion repeats of the C9ORF72 gene in 3 out of 114 patients (2.6%). We raise several hypotheses to explain our results and discuss the current status of AD CSF biomarkers in the dementia diagnostic algorithm.     

Increased Cortisol Levels in Aging and Alzheimer's Disease in Postmortem Cerebrospinal Fluid

The hypothalamo-pituitary-adrenal (HPA) axis is activated during aging and even more so in dementia. Increased levels of corticosteroids may be neurotoxic. Therefore we have investigated cortisol levels in cerebrospinal fluid (CSF) of Alzheimer patients and controls. Ventricular postmortem CSF was collected from clinically and neuropathologically well-defined Alzheimer patients (n = 26) and control subjects (n = 21). In the group of Alzheimer patients the mean CSF total cortisol level was 83% higher than that in the controls. In presenile Alzheimer patients (< 65 years of age; n = 13) the CSF-cortisol level was 5 times higher than that of presenile controls (n = 7). In contrast, senile Alzheimer patients (n = 13) and controls of over 65 years of age (n = 14) did not show a significant difference in CSF-cortisol levels. The presence or absence of a difference in the cortisol-CSF levels in, respectively, presenile or senile Alzheimer patients as compared to controls was due to the 3.5-fold rise of CSF-cortisol in control subjects over 65 years of age as compared with controls under 65 years of age. The CSF-cortisol levels in presenile and senile Alzheimer patients were similar. No significant correlation was observed in the Alzheimer patients between age of onset of the dementia and CSF cortisol levels or duration of Alzheimer's disease and CSF cortisol levels. The finding that in senile Alzheimer patients cortisol levels were similar to those of unaffected age-matched controls does not seem to support the cortisol neurotoxicity hypothesis. On the other hand, it should be noted that postmortem ventricular CSF cortisol levels were found to be 13–16 times higher than lumbar puncture CSF cortisol levels of ambulatory patients. This means that the ventricular CSF levels probably reflect the reaction of the HPA-axis to the process of dying rather than the basal levels of this system. The exact consequences of elevated HPA-axis activity for the human brain should be studied in more detail.     

阿尔茨海默病患者脑脊液中Tau蛋白的含量及意义

目的：Ａｌｚｈｅｉｍｅｒ病（ＡＤ）实验室诊断指标测定。方法：ＥＬＩＳＡ测定４０例ＡＤ患者,２６例梗塞性痴呆（ＭＩＤ）患者,５８例正常人脑脊液Ｔａｕ含量。结果ＡＤ患者、ＭＩＤ患者脑脊液Ｔａｕ 蛋白含量均明显高于正常对照组（Ｐ＜０．００１）,而ＡＤ组与ＭＩＤ组差别无统计意义（Ｐ＞０．０５）。ＡＤ组Ｔａｕ蛋白含量与病程呈正相关关系（Ｐ＜０．０１,ｒ＝０．４４）,ＭＩＤ组未发现此相关关系（Ｐ＞０．ｌ）．三组测定值与年龄均无相关关系。结论：Ｔａｕ蛋白含量在 ＡＤ患者脑脊液中明显升高,在 ＭＩＤ组亦增高,故单纯测定Ｔａｕ蛋白难以鉴别ＡＤ和ＭＩＤ。作者单位：卫生部课题资助基金（批准编号：９４－１－２４６,卫生部九五攻关课题）     

A Consensus in Korea Regarding a Protocol to Reduce Preanalytical Sources of Variability in the Measurement of the Cerebrospinal Fluid Biomarkers of Alzheimer's Disease

Cerebrospinal fluid (CSF) can provide vital informative about pathological processes occurring in the brain. In particular, the CSF concentrations of Aβ42, tTau, and pTau181 are useful for the early diagnosis of Alzheimer''s disease (AD). However, many studies have demonstrated that confounding factors related to the preanalytical processing of CSF can seriously influence measurements of these AD biomarkers. It is therefore important to develop a standardized protocol for the acquisition and handling of CSF, particularly with regard to the types of tube used for collection and storage, the proper aliquot volume, blood contamination, and the number of tube transfers and freeze-thaw cycles, because these aspects of the procedure have been shown to affect AD biomarker measurements. A survey of the impact of several individual preanalytical procedures on the measurement of AD biomarkers in CSF was conducted for this review article, and the implications of the differences among them are discussed. Furthermore, following a review of the procedures used in Korean and international biomarker laboratories, a consensus was reached among a cooperative Korean multicenter research group regarding a standardized protocol for the analysis of AD biomarkers in CSF. All efforts were made to be stringent regarding the controversial issues associated with this protocol, thus minimizing the confounding influence of various factors on current investigations using established AD biomarkers and on future studies using novel biomarkers of AD and other neurodegenerative disorders.     

LRRK2 Quantification in Cerebrospinal Fluid of Patients with Parkinson's Disease and Atypical Parkinsonian Syndromes

Background

The alteration of leucine-rich repeat kinase 2 (LRRK2) kinase activity is thought to be involved in Parkinson's disease (PD) pathogenesis beyond familiar cases, and LRRK2 inhibitors are currently under investigation. Preliminary data suggest a relationship between LRRK2 alteration and cognitive impairment in PD.

Objective

To investigate cerebrospinal fluid (CSF) LRRK2 levels in PD and other parkinsonian disorders, also correlating them with cognitive impairment.

Methods

In this study, we retrospectively investigated by means of a novel highly sensitive immunoassay the levels of total and phosphorylated (pS1292) LRRK2 in CSF of cognitively unimpaired PD (n = 55), PD with mild cognitive impairment (n = 49), PD with dementia (n = 18), dementia with Lewy bodies (n = 12), atypical parkinsonian syndromes (n = 35), and neurological controls (n = 30).

Results

Total and pS1292 LRRK2 levels were significantly higher in PD with dementia with respect to PD with mild cognitive impairment and PD, and also showed a correlation with cognitive performances.

Conclusions

The tested immunoassay may represent a reliable method for assessing CSF LRRK2 levels. The results appear to confirm an association of LRRK2 alteration with cognitive impairment in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Concentration of Neural Thread Protein in Cerebrospinal Fluid from Progressive Supranuclear Palsy and Parkinson's Disease

Abstract: We measured the concentration of neural thread protein (NTP) in cerebrospinal fluid (CSF) by an automatized microparticle enzyme immunoassay from 11 progressive supranuclear palsy (PSP) patients and 11 Parkinson's disease (PD) patients and 7 patients with cervical spondylosis as controls. The mean levels did not differ significantly among the groups. In the PSP group, however, the levels correlated significantly with the severity of motor symptoms, signs and functional disability but not with dementia, while the opposite was true in the PD group. The elevated levels in PSP cases may reflect an increase with progression of the disease in such pathological structures as neurofibrillary tangles or neuropil threads, while in PD such levels may indicate associated Alzheimer-type pathology.