A study protocol for identifying aging trajectories toward chronic neurodegenerative diseases by means of Marche regional administrative databases - TREND project.

Background: People are living longer but an increasing number of older people experience chronicity and disability in the latest years of their life. The Marche region is one of the Italian regions where people live the longest lives; therefore, the number of people with age-related chronic diseases is expected to be at least similar, if not higher, compared to the rest of Italy. The identification of the aging trajectories is of huge interest in the arena of public health. Administrative healthcare databases represent valuable reservoirs for reconstructing the trajectories of aging. Here, we present the protocol for a study (TREND project) aimed to integrate existing administrative databases into a Marche regional dataset in order to estimate the prevalence and incidence rates of age-related neurodegenerative diseases (ND), with a specific focus on Parkinsonism and Dementia. Methods: The TREND Project is a retrospective cross-sectional study. The source population includes permanent residents in the Marche region aged 40 years and older. A minimal dataset has been built up linking data on drug prescriptions, outpatient services, and diagnosis for hospital admission, from 2014 to 2021 in the Marche Region. Data on clinical outcomes (re-hospitalization, mortality, comorbidities), and therapeutic approaches (drugs and medicines) have been integrated with state-of-the-art statistical methods to define patients into different risk clusters and to analyze the aging trend by assessing the Comorbidity Index (CI) as a proxy for chronicity. Discussion: Our research contributes to the integration of existing administrative databases on ND to create a Marche regional ND database, support regional health policy, and better understand patients' needs and their aging trajectories. This approach could be implemented also at the National level. Moreover, by linking different administrative data sources, this study sheds light on important issues related to ND, such as early-onset dementia; ethical aspects such as anticipated wills; problems of dementia in patients still in the job market, etc. The results of this study will contribute to the successful implementation of integrated care for patients affected by ND at regional or national levels.

Circulating biomarkers of inflammaging and Alzheimer's disease to track age-related trajectories of dementia: Can we develop a clinically relevant composite combination?

Alzheimer's disease (AD) is a rapidly growing global concern due to a consistent rise of the prevalence of dementia which is mainly caused by the aging population worldwide. An early diagnosis of AD remains important as interventions are plausibly more effective when started at the earliest stages. Recent developments in clinical research have focused on the use of blood-based biomarkers for improve diagnosis/prognosis of neurodegenerative diseases, particularly AD. Unlike invasive cerebrospinal fluid tests, circulating biomarkers are less invasive and will become increasingly cheaper and simple to use in larger number of patients with mild symptoms or at risk of dementia. In addition to AD-specific markers, there is growing interest in biomarkers of inflammaging/neuro-inflammaging, an age-related chronic low-grade inflammatory condition increasingly recognized as one of the main risk factor for almost all age-related diseases, including AD. Several inflammatory markers have been associated with cognitive performance and AD development and progression. The presence of senescent cells, a key driver of inflammaging, has also been linked to AD pathogenesis, and senolytic therapy is emerging as a potential treatment strategy. Here, we describe blood-based biomarkers clinically relevant for AD diagnosis/prognosis and biomarkers of inflammaging associated with AD. Through a systematic review approach, we propose that a combination of circulating neurodegeneration and inflammatory biomarkers may contribute to improving early diagnosis and prognosis, as well as providing valuable insights into the trajectory of cognitive decline and dementia in the aging population.

Neuroinflammaging: A Tight Line Between Normal Aging and Age-Related Neurodegenerative Disorders.

Aging in the healthy brain is characterized by a low-grade, chronic, and sterile inflammatory process known as neuroinflammaging. This condition, mainly consisting in an up-regulation of the inflammatory response at the brain level, contributes to the pathogenesis of age-related neurodegenerative disorders. Development of this proinflammatory state involves the interaction between genetic and environmental factors, able to induce age-related epigenetic modifications. Indeed, the exposure to environmental compounds, drugs, and infections, can contribute to epigenetic modifications of DNA methylome, histone fold proteins, and nucleosome positioning, leading to epigenetic modulation of neuroinflammatory responses. Furthermore, some epigenetic modifiers, which combine and interact during the life course, can contribute to modeling of epigenome dynamics to sustain, or dampen the neuroinflammatory phenotype. The aim of this review is to summarize current knowledge about neuroinflammaging with a particular focus on epigenetic mechanisms underlying the onset and progression of neuroinflammatory cascades in the central nervous system; furthermore, we describe some diagnostic biomarkers that may contribute to increase diagnostic accuracy and help tailor therapeutic strategies in patients with neurodegenerative diseases.

Dementia, stroke, age, use of medical devices and antipsychotic drugs may increase the risk of nosocomial infections among elderly patients hospitalized at Neurology Clinics.

Healthcare-acquired infections (HCAI) represent a major health problem worldwide. Stroke and dementia are considered risk factors for HCAI. Preliminary data suggest that use of antipsychotic drugs also increase the risk for HCAI. Here, we performed a retrospective study aimed at investigating the major risk and protective factors for HCAI in a cohort of elderly subjects hospitalized at an Italian tertiary Neurology Clinics. We included all patients with age ≥ 65 years hospitalized at Neurology Clinics of National Institute on Ageing, Ancona, Italy from 1st January 2018 to 31st December 2021. For each patient, the following data were collected: age, sex, use of medical devices, comorbidities, use of antipsychotic medications, development of HCAI. We included 1543 patients (41.4% males; median age 85 years [80-89]). According to multivariable analysis, age, stroke, duration of urinary catheter placement (for all p < 0.001) and midline placement (p = 0.035) resulted to be risk factors for HCAI, Diabetes resulted to be a protective factor for pneumonia (p = 0.041), while dementia and nasogastric tube were risks factor for this condition (p = 0.022 and p < 0.001, respectively). Urinary catheter was a risk factor for urinary tract infections (p < 0.001). Duration of placement of vascular catheters and use of antipsychotic drugs resulted to significantly increase the risk for bloodstream infections. Stroke, age and use of medical devices were confirmed to be risk factors for HCAI. Antipsychotic drugs resulted to increase risk for bloodstream infections. Further prospective studies will be needed to confirm these findings.

Radiomics and Artificial Intelligence for the Diagnosis and Monitoring of Alzheimer's Disease: A Systematic Review of Studies in the Field.

The use of radiomics and artificial intelligence applied for the diagnosis and monitoring of Alzheimer's disease has developed in recent years. However, this approach is not yet completely applicable in clinical practice. The aim of this paper is to provide a systematic analysis of the studies that have included the use of radiomics from different imaging techniques and artificial intelligence for the diagnosis and monitoring of Alzheimer's disease in order to improve the clinical outcomes and quality of life of older patients. A systematic review of the literature was conducted in February 2023, analyzing manuscripts and articles of the last 5 years from the PubMed, Scopus and Embase databases. All studies concerning discrimination among Alzheimer's disease, Mild Cognitive Impairment and healthy older people performing radiomics analysis through machine and deep learning were included. A total of 15 papers were included. The results showed a very good performance of this approach in the differentiating Alzheimer's disease patients-both at the dementia and pre-dementia phases of the disease-from healthy older people. In summary, radiomics and AI can be valuable tools for diagnosing and monitoring the progression of Alzheimer's disease, potentially leading to earlier and more accurate diagnosis and treatment. However, the results reported by this review should be read with great caution, keeping in mind that imaging alone is not enough to identify dementia due to Alzheimer's.

The putative role of neuroinflammation in the complex pathophysiology of migraine: From bench to bedside.

The implications of neurogenic inflammation and neuroinflammation in the pathophysiology of migraine have been clearly demonstrated in preclinical migraine models involving several sites relevant in the trigemino-vascular system, including dural vessels and trigeminal endings, the trigeminal ganglion, the trigeminal nucleus caudalis as well as central trigeminal pain processing structures. In this context, a relevant role has been attributed over the years to some sensory and parasympathetic neuropeptides, in particular calcitonin gene neuropeptide, vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Several preclinical and clinical lines of evidence also support the implication of the potent vasodilator and messenger molecule nitric oxide in migraine pathophysiology. All these molecules are involved in vasodilation of the intracranial vasculature, as well as in the peripheral and central sensitization of the trigeminal system. At meningeal level, the engagement of some immune cells of innate immunity, including mast-cells and dendritic cells, and their mediators, has been observed in preclinical migraine models of neurogenic inflammation in response to sensory neuropeptides release due to trigemino-vascular system activation. In the context of neuroinflammatory events implicated in migraine pathogenesis, also activated glial cells in the peripheral and central structures processing trigeminal nociceptive signals seem to play a relevant role. Finally, cortical spreading depression, the pathophysiological substrate of migraine aura, has been reported to be associated with inflammatory mechanisms such as pro-inflammatory cytokine upregulation and intracellular signalling. Reactive astrocytosis consequent to cortical spreading depression is linked to an upregulation of these inflammatory markers. The present review summarizes current findings on the roles of immune cells and inflammatory responses in the pathophysiology of migraine and their possible exploitation in the view of innovative disease-modifying strategies.

Toll-like receptors and NLRP3 inflammasome-dependent pathways in Parkinson's disease: mechanisms and therapeutic implications.

Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder characterized by motor and non-motor disturbances as a result of a complex and not fully understood pathogenesis, probably including neuroinflammation, oxidative stress, and formation of alpha-synuclein (α-syn) aggregates. As age is the main risk factor for several neurodegenerative disorders including PD, progressive aging of the immune system leading to inflammaging and immunosenescence may contribute to neuroinflammation leading to PD onset and progression; abnormal α-syn aggregation in the context of immune dysfunction may favor activation of nucleotide-binding oligomerization domain-like receptor (NOD) family pyrin domain containing 3 (NLRP3) inflammasome within microglial cells through interaction with toll-like receptors (TLRs). This process would further lead to activation of Caspase (Cas)-1, and increased production of pro-inflammatory cytokines (PC), with subsequent impairment of mitochondria and damage to dopaminergic neurons. All these phenomena are mediated by the translocation of nuclear factor kappa-B (NF-κB) and enhanced by reactive oxygen species (ROS). To date, drugs to treat PD are mainly aimed at relieving clinical symptoms and there are no disease-modifying options to reverse or stop disease progression. This review outlines the role of the TLR/NLRP3/Cas-1 pathway in PD-related immune dysfunction, also focusing on specific therapeutic options that might be used since the early stages of the disease to counteract neuroinflammation and immune dysfunction.

Immunological findings in patients with migraine and other primary headaches: a narrative review.

Experimental findings suggest an involvement of neuroinflammatory mechanisms in the pathophysiology of migraine. Specifically, preclinical models of migraine have emphasized the role of neuroinflammation following the activation of the trigeminal pathway at several peripheral and central sites including dural vessels, the trigeminal ganglion, and the trigeminal nucleus caudalis. The evidence of an induction of inflammatory events in migraine pathophysiological mechanisms has prompted researchers to investigate the human leukocyte antigen (HLA) phenotypes as well as cytokine genetic polymorphisms in order to verify their potential relationship with migraine risk and severity. Furthermore, the role of neuroinflammation in migraine seems to be supported by evidence of an increase in pro-inflammatory cytokines, both ictally and interictally, together with the prevalence of Th1 lymphocytes and a reduction in regulatory lymphocyte subsets in peripheral blood of migraineurs. Cytokine profiles of cluster headache (CH) patients and those of tension-type headache patients further suggest an immunological dysregulation in the pathophysiology of these primary headaches, although evidence is weaker than for migraine. The present review summarizes available findings to date from genetic and biomarker studies that have explored the role of inflammation in primary headaches.

Headache and immunological/autoimmune disorders: a comprehensive review of available epidemiological evidence with insights on potential underlying mechanisms.

Several lines of evidence support a role of the immune system in headache pathogenesis, with particular regard to migraine. Firstly, alterations in cytokine profile and in lymphocyte subsets have been reported in headache patients. Secondly, several genetic and environmental pathogenic factors seem to be frequently shared by headache and immunological/autoimmune diseases. Accordingly, immunological alterations in primary headaches, in particular in migraine, have been suggested to predispose some patients to the development of immunological and autoimmune diseases. On the other hand, pathogenic mechanisms underlying autoimmune disorders, in some cases, seem to favour the onset of headache. Therefore, an association between headache and immunological/autoimmune disorders has been thoroughly investigated in the last years. The knowledge of this possible association may have relevant implications in the clinical practice when deciding diagnostic and therapeutic approaches. The present review summarizes findings to date regarding the plausible relationship between headache and immunological/autoimmune disorders, starting from a description of immunological alteration of primary headaches, and moving onward to the evidence supporting a potential link between headache and each specific autoimmune/immunological disease.

Novel noninvasive biomarkers of prodromal Alzheimer disease: The role of optical coherence tomography and optical coherence tomography-angiography.

BACKGROUND AND PURPOSE: A reduction of retinal thickness and an alteration of retinal perfusion have been found in Alzheimer disease (AD). Nowadays, retinal layers and retinal perfusion can be evaluated by means of noninvasive imaging techniques, namely, optical coherence tomography (OCT) and OCT-angiography (OCT-A). Here, we have compared the retinal thickness and the perfusion index, measured by means of OCT and OCT-A, in patients with mild cognitive impairment due to AD (MCI-AD) and in age- and sex-matched cognitively healthy controls. METHODS: Twenty-four MCI-AD patients and 13 control subjects were enrolled. MCI-AD patients underwent lumbar puncture; all of them showed a cerebrospinal fluid (CSF) profile compatible with AD. OCT was used for evaluating retinal volumes and thicknesses, whereas with OCT-A we measured fractal dimension (FD), vascular perfusion density (VPD), and vessel length density (VLD) of superficial capillary plexus (SCP), intermediate capillary plexus (ICP), deep capillary plexus (DCP), and choriocapillaris. The comparisons between groups were made after adjustment for age, diabetes, and hypertension. RESULTS: A significant reduction of SCP-VLD (p = 0.012), ICP-VPD (p = 0.015), ICP-VLD (p = 0.004), DCP-VPD (p = 0.012), and DCP-VLD (p = 0.009) was found in MCI-AD patients compared to controls. Conversely, FD was higher in MCI-AD than in controls (p = 0.044). CSF Aß42/total tau negatively correlated with FD (r = -0.51, p = 0.010). CONCLUSIONS: OCT-A might have a potential role in detecting new noninvasive biomarkers for early AD detection. Retinal VPD might identify amyloid angiopathy-related chronic injury, and FD could show early vessel recruitment as a compensative mechanism at disease onset. Further studies will be needed to confirm these findings.

Fingerprinting Alzheimer's Disease by 1H Nuclear Magnetic Resonance Spectroscopy of Cerebrospinal Fluid.

In this study, we sought for a cerebrospinal fluid (CSF) metabolomic fingerprint in Alzheimer's disease (AD) patients characterized, according to the clinical picture and CSF AD core biomarkers (Aß42, p-tau, and t-tau), both at pre-dementia (mild cognitive impairment due to AD, MCI-AD) and dementia stages (ADdem) and in a group of patients with a normal CSF biomarker profile (non-AD) using untargeted 1H nuclear magnetic resonance (NMR) spectroscopy-based metabolomics. This is a retrospective study based on two independent cohorts: a Dutch cohort, which comprises 20 ADdem, 20 MCI-AD, and 20 non-AD patients, and an Italian cohort, constituted by 14 ADdem and 12 non-AD patients. 1H NMR CSF spectra were analyzed using OPLS-DA. Metabolomic fingerprinting in the Dutch cohort provides a significant discrimination (86.1% accuracy) between ADdem and non-AD. MCI-AD patients show a good discrimination with respect to ADdem (70.0% accuracy) but only slight differences when compared with non-AD (59.6% accuracy). Acetate, valine, and 3-hydroxyisovalerate result to be altered in ADdem patients. Valine correlates with cognitive decline at follow-up (R = 0.53, P = 0.0011). The discrimination between ADdem and non-AD was confirmed in the Italian cohort. The CSF metabolomic fingerprinting shows a signature characteristic of ADdem patients with respect to MCI-AD and non-AD patients.

The Italian version of Cognitive Function Instrument (CFI) for tracking changes in healthy elderly: results at 1-year follow-up.

Cognitive Function Instrument (CFI) is a questionnaire aimed at detecting very early changes in cognitive and functional abilities and useful for monitoring cognitive decline in individuals without clinical impairment. The Italian version has been recently validated. The aim of the present study was to investigate the utility of the Italian version of CFI in tracking early cognitive changes in a cohort of healthy elderly subjects. A consecutive series of 257 cognitively healthy and functionally independent subjects, recruited either among relatives of patients attending our Memory Clinic or as volunteers after advertisement, underwent a baseline neuropsychological assessment. Of them, 157 subjects performed a 1-year follow-up assessment. All subjects completed the CFI, a short questionnaire composed of 14 items administered to both the subject and the referent (study-partner). Cognitive performance was assessed by Mini-Mental State Examination (MMSE) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). At 1-year follow-up, Cronbach's α was 0.79 (95% CI, 0.74-0.84) in self-report and 0.83 (95% CI, 0.79-0.87) for partner-report. CFI self-report correlated with MMSE (rS = - 0.22, p = 0.006) and RBANS (rS = - 0.23, p = 0.004). CFI partner-report showed negative correlation with MMSE (rS = - 0.17, p = 0.037) and RBANS (rS = - 0.20, p = 0.014). CFI 1-year follow-up score correlated with baseline both in self-report (rS = 0.56, p < 0.001) and partner-report (rS = 0.66, p < 0.001). Baseline CFI partner-report (p = 0.014) and CFI self+partner report (p = 0.023) were associated with RBANS total score less than 85 at 1-year follow-up, while only a trend was found considering baseline CFI self-report. Our results support the suitability of the Italian version of CFI for tracking cognitive changes along aging.

The added value of Aß42/Aß40 in the CSF signature for routine diagnostics of Alzheimer's disease.

The cerebrospinal fluid (CSF) signature of Alzheimer's disease (AD) includes abnormal levels of amyloid-ß 1-42 (Aß42), total tau (t-Tau) and phosphorylated tau (p-Tau). Several studies have reported that the CSF Aß42/Aß40 ratio could outperform CSF Aß42 as a more accurate marker of brain amyloidosis, since it normalizes the CSF Aß42 levels according to the total production of Aß in the brain. In the present study, we wanted to assess the diagnostic utility of adding the Aß42/Aß40 ratio within the core AD CSF biomarkers for the classification of patients, according to NIA-AA criteria and Erlangen score. We consecutively recruited 168 patients (62 with AD and 106 with other neurological diseases) who referred to our Memory Clinic for diagnostic work- up from 2003 to 2016. The use of CSF Aß42/Aß40 ratio increased the percentage of correctly diagnosed AD patients from 72.0% to 82.8%. The high gain in sensitivity (from 75.8% to 85.5%) was obtained in face of loss of specificity (from 95.3% to 82.5%). Our study showed that the use of CSF Aß42/Aß40 could significantly improve the routine diagnostic work up of AD.

Case of posterior cortical atrophy (PCA) evolved to PCA-CBS.

A 68-year-old lawyer developed insidious disturbances in topographic orientation and apraxia. He underwent a geriatric evaluation, only documenting slight cognitive disturbances, and a 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), showing mild right-lateralised frontoparietal hypometabolism. After 1 year, because of worsening in spatial orientation and the onset of dressing apraxia, he was referred to our memory clinic. The neuropsychological evaluation documented proeminent visuospatial, praxis deficits and dysgraphia. Cerebrospinal fluid biomarker analysis showed mild increase of total-τ, with normal Aß1-42, ruling out Alzheimer's disease. Progression of the right parietal hypometabolism at FDG-PET and right superior longitudinal fasciculus damage at high-field MRI revealed a probable neurodegenerative aetiology. The neurological examination disclosed then Gerstmann's and Balint's syndromes, and extrapyramidal signs later appeared, suggesting the diagnosis of posterior cortical atrophy associated with corticobasal syndrome. Genetic analysis for mutations inmicrotubule-associated protein tau (MAPT), C9orf72 and GRN genes was negative. A 1-year follow-up documented significant worsening of the cognitive and functional impairment, revealing a frank dementia.

Diagnostic utility of cerebrospinal fluid α-synuclein in Parkinson's disease: A systematic review and meta-analysis.

BACKGROUND: The accumulation of misfolded α-synuclein aggregates is associated with PD. However, the diagnostic value of the α-synuclein levels in CSF is still under investigation. METHODS: A comprehensive search of the literature was performed, yielding 34 studies eligible for meta-analysis. We included studies that reported data on CSF total, oligomeric and phosphorylated α-synuclein in patients with PD and healthy participants, neurological controls, or other parkinsonisms. Standardized mean differences were pooled using random-effects models, and heterogeneity was reported as I2 . Bivariate random effects meta-analysis was also performed on diagnostic data. Methodological quality of the selected studies was assessed using the QUADAS-2 tool. RESULTS: Concentrations of α-synuclein species in PD did not show significant differences with respect to the levels found in other parkinsonisms. Total α-synuclein was significantly reduced in PD when compared with controls (standardized mean differences -0.48; P < .001, I2 = 60%). Oligomeric (standardized mean differences 0.57; P < .001, I2 = 44%) and phosphorylated α-synuclein (standardized mean differences 0.86; P < .001) were significantly increased in PD when compared with controls. Sensitivity and specificity for distinguishing PD and controls were 0.72 and 0.65, respectively, for total α-synuclein, and 0.71 and 0.64, respectively, for oligomeric α-syn. CONCLUSION: Most of the studies were at high risk of bias and have concerns regarding applicability. Diagnostic performance of CSF α-synuclein species is still below what would be considered acceptable for their introduction in clinical practice. Future research should focus on combining α-synuclein species with other biochemical markers as well on improving the standardization of current assays. © 2017 International Parkinson and Movement Disorder Society.

Differential role of CSF fatty acid binding protein 3, α-synuclein, and Alzheimer's disease core biomarkers in Lewy body disorders and Alzheimer's dementia.

BACKGROUND: Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB) share clinical and molecular features. Cerebrospinal fluid (CSF) biomarkers may help the characterization of these diseases, improving the differential diagnosis. We evaluated the diagnostic performance of five CSF biomarkers across a well-characterized cohort of patients diagnosed with AD, DLB, PDD, and Parkinson's disease (PD). METHODS: A total of 208 patients were enrolled in 3 European centers. The diagnostic groups (AD, n = 48; DLB, n = 40; PDD, n = 20; PD, n = 54) were compared with cognitively healthy neurological control subjects (patients with other neurological diseases [OND], n = 46). CSF levels of fatty acid binding protein 3, heart type (FABP3), α-synuclein (α-syn), amyloid-ß peptide 1-42, total tau (t-tau), and phosphorylated tau 181 (p-tau) were assessed with immunoassays. Univariate and multivariate statistical analyses were applied to calculate the diagnostic value of the biomarkers as well as their association with clinical scores. RESULTS: FABP3 levels were significantly increased in patients with AD and DLB compared with those with PD and OND (p < 0.001). CSF t-tau, p-tau, and α-syn were significantly higher in patients with AD than in patients with PDD, DLB, PD, and OND. Combination of FABP3 with p-tau showed high accuracy for the differential diagnosis between AD and DLB (AUC 0.92), whereas patients with AD were separated from those with PDD using a combination of p-tau, FABP3, and α-syn (AUC 0.96). CSF FABP3 was inversely associated with Mini Mental State Examination score in the whole cohort (r = -0.42, p < 0.001). CONCLUSIONS: The combination of CSF biomarkers linked to different aspects of neurodegeneration, such as FABP3, α-syn, and AD biomarkers, improves the biochemical characterization of AD and Lewy body disorders.

Associations of Alzheimer's disease with macular degeneration.

There is growing evidence of epidemiological, genetic, molecular and clinical links between Alzheimer's disease (AD) and age-related macular degeneration (AMD). Major interest in the relationship between AD and AMD has derived from the evidence that beta-amyloid, the main component of senile plaques, the hallmark of AD, is also an important component of drusen, the hallmark of AMD. This finding has a great potential in the present era of anti-amyloid agents for the treatment of AD. The connection between AD and AMD is also supported by the evidence that the two diseases share other pathophysiological factors, such as oxidative stress and neuroinflammation. Accordingly, a few clinical trials have evaluated the efficacy of antioxidants on visual and cognitive performance in patients presenting both disorders. In this review, we summarize the pathophysiological and clinical evidence of the relationship between these two age-related disorders. Considering the increasing prevalence of both conditions along with the aging of the population, further investigations of this important issue are highly needed.

Performance Evaluation of an Automated ELISA System for Alzheimer's Disease Detection in Clinical Routine.

The variability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers undermines their full-fledged introduction into routine diagnostics and clinical trials. Automation may help to increase precision and decrease operator errors, eventually improving the diagnostic performance. Here we evaluated three new CSF immunoassays, EUROIMMUNtrademark amyloid-ß 1-40 (Aß1-40), amyloid-ß 1-42 (Aß1-42), and total tau (t-tau), in combination with automated analysis of the samples. The CSF biomarkers were measured in a cohort consisting of AD patients (n = 28), mild cognitive impairment (MCI, n = 77), and neurological controls (OND, n = 35). MCI patients were evaluated yearly and cognitive functions were assessed by Mini-Mental State Examination. The patients clinically diagnosed with AD and MCI were classified according to the CSF biomarkers profile following NIA-AA criteria and the Erlangen score. Technical evaluation of the immunoassays was performed together with the calculation of their diagnostic performance. Furthermore, the results for EUROIMMUN Aß1-42 and t-tau were compared to standard immunoassay methods (INNOTESTtrademark). EUROIMMUN assays for Aß1-42 and t-tau correlated with INNOTEST (r = 0.83, p < 0.001 for both) and allowed a similar interpretation of the CSF profiles. The Aß1-42/Aß1-40 ratio measured with EUROIMMUN was the best parameter for AD detection and improved the diagnostic accuracy of Aß1-42 (area under the curve = 0.93). In MCI patients, the Aß1-42/Aß1-40 ratio was associated with cognitive decline and clinical progression to AD.The diagnostic performance of the EUROIMMUN assays with automation is comparable to other currently used methods. The variability of the method and the value of the Aß1-42/Aß1-40 ratio in AD diagnosis need to be validated in large multi-center studies.

Diagnostic utility of CSF α-synuclein species in Parkinson's disease: protocol for a systematic review and meta-analysis.

INTRODUCTION: The diagnostic criteria currently used for Parkinson's disease (PD) are mainly based on clinical motor symptoms. For these reasons many biomarkers are under investigation to support the diagnosis at the early stage. The neuropathological hallmark of PD is represented by Lewy bodies (LBs), which are intracytoplasmic inclusions in substantia nigra neurons. The major component of LBs, α-synuclein (α-syn), has been implicated in the pathogenesis of PD and in other 'synucleinopathies' such as multisystem atrophy (MSA) and dementia with LBs (DLBs). Several studies have investigated this presynaptic protein as a potential biomarker of PD. The aim of our meta-analysis is to determine the ability of cerebrospinal fluid (CSF) concentrations of total α-syn, oligomeric α-syn and phosphorylated α-syn to discriminate patients with PD from healthy participants, non-degenerative neurological controls and patients suffering from parkinsonism and or synucleinopathies. METHODS AND ANALYSIS: This systematic review protocol has been developed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocol (PRISMA-P) 2015 statement and was registered on PROSPERO (CRD42016013217). We will search Cochrane Library, Web of Science, MEDLINE (via PubMed) and EMBASE from inception, using appropriate search strategies. Two independent reviewers will screen titles, abstracts and full-text articles, and will complete data abstraction. We will include studies that involved patients with PD, DLB, MSA, progressive supranuclear palsy, corticobasal disease and vascular PD, and in which at least one between total α-syn, oligomeric α-syn and phosphorylated α-syn was measured in CSF. To evaluate the risk of bias and applicability of primary diagnostic accuracy studies, we will use QUADAS-2. ETHICS AND DISSEMINATION: Our study will not include confidential data, and no intervention will be involved, so ethical approval is not required. The results of the study will be reported in international peer-reviewed journals.