BackgroundMild Cognitive Impairment (MCI) and Mild Behavioral Impairment (MBI) can be prodromal stages of neurodegenerative disease associated with plasma biomarkers of tau pathology and neuroaxonal damage. However, in psychiatric populations, the relationship between MCI, MBI and these plasma biomarkers remains unclear.ObjectiveThis study examined the association of MCI with plasma biomarkers of neurodegeneration (phosphorylated tau217 [p-tau217] and neurofilament light chain [NfL]), metabolic alterations, psychiatric disorder features, and MBI in older adults receiving psychiatric treatment.MethodsFifty-one non-demented patients ≥60 years, referred for mood or anxiety disorders, were enrolled and classified based on cognitive performance as MCI (n = 20) or non-MCI (n = 31). Assessments included psychiatric, cognitive, functional, and plasma biomarker measures.ResultsMCI patients exhibited higher p-tau217 (P = .003) and NfL (P = .042) levels, lower cognitive scores (P < .001), and a trend toward reduced functioning (P = .074). MCI was also associated with later onset of psychiatric symptoms (P = .033) and greater prevalence of MBI (P < .001). Logistic regression identified plasma NfL as a marker of MCI (P < .05) in this sample.ConclusionOur findings suggest that integrating cognitive, psychiatric, and biomarker assessments may improve early detection of dementia risk.

Dependent older patients show high risk of adverse health outcomes when admitted to the emergency department (ED). The prompt identification of ED use risk factors in such population is hence needed. While frailty and cognitive impairment are a known clinical risk factors, biomarkers of most prevalent dementias have been scarcely investigated as possible ED use predictors. Within this framework, this prospective study explored whether plasma phospho-tau181 (ptau181) and cerebrovascular burden provide additional predictive value for 6-month ED use in elderly dependent patients, beyond frailty and age. We collected baseline clinical and laboratory data to validate a 32-item frailty index, while assessing cognitive impairment through the Mini-Mental State Examination. Biomarkers of cognitive impairment included plasma ptau181 and cerebrovascular burden, i.e., the Fazekas Scale. Binomial and Cox regression models tested the biomarkers of cognitive impairment as predictors of ED use, adjusting for frailty and age. The interaction between cognitive impairment biomarkers was explored. Of the 102 recruited patients, 38 visited the ED. In the binomial models, the frailty index (OR = 1.69, p = 0.011) and the Fazekas Scale (OR = 3.57, p = 0.007) predicted ED use. At lower p-tau181 levels, ED admission risk increased only with higher cerebrovascular burden. Conversely, higher p-tau181 levels predicted ED use (OR = 4.90, p = 0.037) irrespective of cerebrovascular burden. No significant predictors of time to ED use emerged. Beyond measures of clinical frailty, the routinary employment of cognitive impairment biomarkers may contribute identifying dependent older patients at short-term high risk of ED use, possibly reducing adverse health outcomes in such population. ● Plasma phosho-tau181 and cerebrovascular burden predict emergency department use in dependent older patients. ● Cognitive impairment biomarkers predict emergency department use irrespective of multidimensional frailty. ● The assessment of cognitive impairment biomarkers may reduce adverse health outcomes in dependent older patients.

BackgroundMild Behavioral Impairment (MBI) has been increasingly recognized as a potential early clinical marker of neurodegenerative disease, while blood-based biomarkers such as phosphorylated tau 217 (p-tau217) and neurofilament light chain (NfL) are associated with Alzheimer's disease and axonal damage, respectively.ObjectiveTo investigate the role of MBI and blood-based biomarkers of neurodegeneration in the early detection of dementia.MethodsFifty-one individuals without dementia aged 60 or older with mood or anxiety disorders underwent psychiatric, neuropsychiatric, and cognitive evaluations, as well as assessment of plasma p-tau217 and NfL at baseline and at one-year follow-up.ResultsA higher proportion of males was observed in the MBI group compared to the non-MBI group (P = 0.076). MBI was significantly associated with a higher risk of conversion to dementia (P = 0.006). MBI patients showed a trend toward higher baseline p-tau217 (P = 0.096) and significantly higher NfL at follow-up (P = 0.025), suggesting active neurodegeneration. Individuals who converted to dementia had marginally higher baseline p-tau217 (P = 0.053) and NfL (P = 0.091).ConclusionMBI and blood-based biomarkers of neurodegeneration appear to be promising clinical tools for identifying dementia risk in its early stages.

We analyzed peripheral blood mononuclear cells (PBMCs) and serum inflammatory biomarkers in patients with mesial temporal lobe epilepsy (drug-resistant - DR, vs. drug-sensitive - DS). Patients with epilepsy showed higher levels of serum CCL2, CCL3, IL-8 and AOPP, and lower levels of FRAP and thiols compared to healthy controls (HC). Although none of the serum biomarkers distinguished DR from DS patients, when analysing intracellular cytokines after in vitro stimulation, DR patients presented higher percentages of IL-1β and IL-6 positive monocytes compared to DS patients and HC. Circulating innate immune cells might be implicated in DR epilepsy and constitute potential new targets for treatments.

Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the SMN1 gene resulting in reduced levels of the SMN protein. Nusinersen, the first antisense oligonucleotide (ASO) approved for SMA treatment, binds to the SMN2 gene, paralogue to SMN1 , and mediates the translation of a functional SMN protein. Here, we used longitudinal high-resolution mass spectrometry (MS) to assess both global proteome and metabolome in cerebrospinal fluid (CSF) from ten SMA type 3 patients, with the aim of identifying novel readouts of pharmacodynamic/response to treatment and predictive markers of treatment response. Patients had a median age of 33.5 [29.5; 38.25] years, and 80% of them were ambulant at time of the enrolment, with a median HFMSE score of 37.5 [25.75; 50.75]. Untargeted CSF proteome and metabolome were measured using high-resolution MS (nLC-HRMS) on CSF samples obtained before treatment (T0) and after 2 years of follow-up (T22). A total of 26 proteins were found to be differentially expressed between T0 and T22 upon VSN normalization and LIMMA differential analysis, accounting for paired replica. Notably, key markers of the insulin-growth factor signaling pathway were upregulated after treatment together with selective modulation of key transcription regulators. Using CombiROC multimarker signature analysis, we suggest that detecting a reduction of SEMA6A and an increase of COL1A2 and GRIA4 might reflect therapeutic efficacy of nusinersen. Longitudinal metabolome profiling, analyzed with paired t -Test, showed a significant shift for some aminoacid utilization induced by treatment, whereas other metabolites were largely unchanged. Together, these data suggest perturbation upon nusinersen treatment still sustained after 22 months of follow-up and confirm the utility of CSF multi-omic profiling as pharmacodynamic biomarker for SMA type 3. Nonetheless, validation studies are needed to confirm this evidence in a larger sample size and to further dissect combined markers of response to treatment.

Converging translational and clinical research strongly indicates that altered immune and inflammatory homeostasis (neuroinflammation) plays a critical pathophysiological role in Alzheimer's disease (AD), across the clinical continuum. A dualistic role of neuroinflammation may account for a complex biological phenomenon, representing a potential pharmacological target. Emerging blood-based pathophysiological biomarkers, such as cytokines (Cyt) and interleukins (ILs), have been studied as indicators of neuroinflammation in AD. However, inconsistent results have been reported probably due to a lack of standardization of assays with methodological and analytical differences. We used machine-learning and a cross-validation-based statical workflow to explore and analyze the potential impact of key biological factors, such as age, sex, and apolipoprotein-E (APOE) genotype (the major genetic risk factor for late-onset AD) on Cyt. A set of Cyt was selected based on previous literature, and we investigated any potential association in a pooled cohort of cognitively healthy, mild cognitive impairment (MCI), and AD-like dementia patients. We also performed explorative analyses to extrapolate preliminary clinical insights. We found a robust sex effect on IL12 and an APOE-related difference in IL10, with the latter being also related to the presence of advanced cognitive decline. IL1 beta was the variable most significantly associated with MCI-to-dementia conversion over a 2.5 year-clinical follow-up. Although preliminary, our data support further clinical research to understand whether plasma Cyt may represent reliable and noninvasive tools serving the investigation of neuroimmune and inflammatory dynamics in AD and to foster biomarker-guided pathway-based therapeutic approaches, within the precision medicine development framework.

We investigated a panel of plasma interleukins (ILs) levels hypothesized to play a role in aging and AD pathophysiology, in a pooled cohort of clinically characterized (according to NIA-AA core clinical criteria) cognitively unimpaired (HC), Mild Cognitive Impairment (MCI), and Alzheimer's Disease Dementia (ADD) individuals.

BACKGROUND:Red blood cells (RBCs) contain the majority of α-synuclein (α-syn) in blood, representing an interesting model for studying the peripheral pathological alterations proved in neurodegeneration.OBJECTIVE:The current study aimed to investigate the diagnostic value of total α-syn, amyloid-β (Aβ1-42), tau, and their heteroaggregates in RBCs of Lewy body dementia (LBD) and Alzheimer's disease (AD) patients compared to healthy controls (HC).METHODS:By the use of enzyme-linked immunosorbent assays, RBCs concentrations of total α-syn, Aβ1-42, tau, and their heteroaggregates (α-syn/Aβ1-42 and α-syn/tau) were measured in 27 individuals with LBD (Parkinson's disease dementia, n = 17; dementia with Lewy bodies, n = 10), 51 individuals with AD (AD dementia, n = 37; prodromal AD, n = 14), and HC (n = 60).RESULTS:The total α-syn and tau concentrations as well as α-syn/tau heterodimers were significantly lower in the LBD group and the AD group compared with HC, whereas α-syn/Aβ1-42 concentrations were significantly lower in the AD dementia group only. RBC α-syn/tau heterodimers had a higher diagnostic accuracy for differentiating patients with LBD versus HC (AUROC = 0.80).CONCLUSION:RBC α-syn heteromers may be useful for differentiating between neurodegenerative dementias (LBD and AD) and HC. In particular, RBC α-syn/tau heterodimers have demonstrated good diagnostic accuracy for differentiating LBD from HC. However, they are not consistently different between LBD and AD. Our findings also suggest that α-syn, Aβ1-42, and tau interact in vivo to promote the aggregation and accumulation of each other.

Abstract Background Red blood cells (RBC) account for more than 99% of α-syn concentrations in blood representing an interesting in vivo model for studying peripheral pathological alterations proved in neurodegeneration. The aim of the current study was to investigate the diagnostic value of total α-syn, Aβ 1-42 , tau and their heteroaggregates in RBCs of Lewy Body Dementias (LBDs) and Alzheimer’s disease (AD) patients compared to and healthy controls (HCs). Methods With a “home-made” sandwich enzyme-linked immunosorbent assay (ELISA) system, RBCs levels of total α-syn, Aβ 1-42 , tau and their heteroaggregates (α-syn/Aβ 1-42 and α-syn/tau) were measured in 27 subjects with LBDs (PDD, n = 17; DLB, n = 10), 51 subjects with AD (AD dementia, n = 37, prodromal AD, n = 14), and HC (n = 60). Results Compared with HC, total α-syn and tau concentrations as well as α-syn/tau heterodimers were significantly lower in LBDs group (p = 0.009, p = 0.009, and p < 0.001, respectively) and in AD group (p = 0.011, p = 0.003, and p < 0.001, respectively), whereas the heteroaggregates α-syn/Aβ 1-42 were significantly lower in AD dementia group (p < 0.001) only. RBC α-syn/tau heterodimers had the higher diagnostic accuracy for differentiating patients with LBD vs controls (AUROC = 0.80). Conclusion RBC α-syn heteroaggregates may be useful for differentiating between neurodegenerative dementias (LBD and AD) and healthy control. In particular, RBC α-syn/tau heterodimers have demonstrated good diagnostic accuracy for differentiating LBDs from HC. However, they are not consistently different between LBD and AD. Our findings also go beyond the clinical setting, suggesting that α-syn, Aβ 1-42 , and tau interact in vivo to promote the aggregation and accumulation of each other presumably accelerating cognitive dysfunction.

α‐synuclein’s (α‐syn) pathological accumulation is involved in the development of Lewy body dementias (LBDs), namely Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). Several autoptic series have nonetheless documented pathologic α‐syn deposits up to 30% cases of otherwise confirmed Alzheimers’s disease (AD) brains. A considerable body of evidence supports the mutual pathological interaction between α‐syn and AD’s hallmark altered proteins, namely beta‐amyloid and tau, both in AD and LBDs. Aim of this study was to explore the diagnostic potential of red blood cells (RBCs) levels of α‐syn, beta‐amyloid 1‐42 (Aβ1‐42), total‐tau (t‐tau), and their heteromers in subjects with LBDs, AD, and healthy controls (HCs).

A growing interest is recently focused on sex‐related differences in Alzheimer’s Disease (AD) pathology to optimize patients stratification and to personalize treatment. Among markers that are expression of this neurodegenerative disease, red blood cells (RBCs) levels of α‐synuclein (α‐syn) and its heterocomplexes with amyloid‐β (Aβ) and tau have been proposed as peripheral biomarker of AD. The aim of our study was to explore sex differences in RBC levels of α‐syn and its heterocomplexes in a group of AD/ mild cognitive impairment due to AD (MCI‐AD) patients and of Healthy Controls (HC).

The antisense oligonucleotide Nusinersen has been recently licensed to treat spinal muscular atrophy (SMA). Since SMA type 3 is characterized by variable phenotype and milder progression, biomarkers of early treatment response are urgently needed. We investigated the cerebrospinal fluid (CSF) concentration of neurofilaments in SMA type 3 patients treated with Nusinersen as a potential biomarker of treatment efficacy. The concentration of phosphorylated neurofilaments heavy chain (pNfH) and light chain (NfL) in the CSF of SMA type 3 patients was evaluated before and after six months since the first Nusinersen administration, performed with commercially available enzyme-linked immunosorbent assay (ELISA) kits. Clinical evaluation of SMA patients was performed with standardized motor function scales. Baseline neurofilament levels in patients were comparable to controls, but significantly decreased after six months of treatment, while motor functions were only marginally ameliorated. No significant correlation was observed between the change in motor functions and that of neurofilaments over time. The reduction of neurofilament levels suggests a possible early biochemical effect of treatment on axonal degeneration, which may precede changes in motor performance. Our study mandates further investigations to assess neurofilaments as a marker of treatment response.

A plethora of complex misfolded protein combinations have been found in Alzheimer disease (AD) brains besides the classical pathological hallmarks. Recently, α-synuclein (α-syn) and its heterocomplexes with amyloid-β (Aβ) and tau have been suggested to be involved in the pathophysiological processes of neurodegenerative diseases. These pathological features are not limited to the brain, but can be also found in peripheral fluids. In this respect, red blood cells (RBCs) have been suggested as a good model to investigate the biochemical alterations of neurodegeneration. Our aim is to find whether RBC concentrations of α-syn and its heterocomplexes (i.e., α-syn/Aβ and α-syn/tau) were different in AD patients compared with healthy controls (HC). The levels of homo- and heteroaggregates of α-syn, Aβ and tau, were analyzed in a cohort of AD patients at early stage either with dementia or prodromal symptoms (N = 39) and age-matched healthy controls (N = 39). All AD patients received a biomarker-based diagnosis (low cerebrospinal fluid levels of Aβ peptide combined with high cerebrospinal fluid concentrations of total tau and/or phospho-tau proteins; alternatively, a positivity to cerebral amyloid-PET scan). Our results showed lower concentrations of α-syn and its heterocomplexes (i.e., α-syn/Aβ and α-syn/tau) in RBCs of AD patients with respect to HC. RBC α-syn/Aβ as well as RBC α-syn/tau heterodimers discriminated AD participants from HC with fair accuracy, whereas RBC α-syn concentrations differentiated poorly the two groups. Although additional investigations are required, these data suggest α-syn heteroaggregates in RBCs as potential tool in the diagnostic work-up of early AD diagnosis.

Aim: The apathetic syndrome is a common clinical feature in patients with Alzheimer diseases (AD), from preclinical phases to late stages of dementia, and it is strongly related to major disease outcomes. Unfortunately, no specific pharmacological treatments for apathy have been accomplished so far. Translational evidences have previously shown that a link between apathy and hallmarks of AD-related pathophysiology, that is, β-amyloid (Aβ) plaques and neurofibrillary tangles, exists. However, only few studies investigated the association between core biomarkers of AD and apathy scores, finding conflicting results. Methods: Thirty-seven patients were identified as having AD dementia according to National Institute on Aging–Alzheimer Association 2011 criteria. All participants underwent an extensive diagnostic workup including cerebrospinal fluid (CSF) assessment to measure the concentrations of Aβ42, t-tau, and pTau181. To follow, they were stratified as: apathy absence, apathy mild, and apathy severe according to the Neuro Psychiatric Inventory-apathy item scores. We investigated for potential associations between apathy scores and CSF biomarkers concentrations as well as for differences in terms of clinical and CSF biomarkers data across the 3 apathy groups. Results: The CSF Aβ42 concentrations were negatively correlated with apathy scores. In addition, patients with severe apathy had significantly lower Aβ42 levels compared to nonapathetic ones. Conclusion: Based on our results, we encourage further studies to untangle the potential association between the complex pathophysiological dynamics of AD and apathy which may represent an innovative reliable clinical outcome measure to use in clinical trials, investigating treatments with either a symptomatic or a disease-modifying effect.

OBJECTIVE:To investigate the efficacy of curcumin oral supplementation (600 mg/day, Brainoil), a natural antioxidant compound, in Amyotrophic Lateral Sclerosis (ALS). METHODS:Patients were randomized into two groups: Group A received placebo for 3 months, then Brainoil for the following 3 months, Group B took Brainoil for 6 months. The evaluations were conducted at basal (T0), after 3 months of double blinded Brainoil or placebo treatment (T1), and after the 3 month open-label phase (T2). Clinical evaluations and oxidative stress biomarkers, including oxidative protein products (AOPPs), ferric reducing ability (FRAP), total thiols (T-SH) and lactate, were evaluated, compared to a control group, during an incremental forearm exercise test. RESULTS:Over the entire study Group B showed a stable score of the ALS-FRS-r which decreased in Group A (p<0.01), in parallel with a reduction of AOPPs (p<0.01) which was not detected into Group A. Also FRAP exercise values remained stable in Group B, while in Group A they were reduced without treatment at T1 (0.05T0 exercise lactate was lower compared to Group A (p<0.01). Compared to controls, the whole ALS population showed a greater oxidative stress (p<0.001), those treated with curcumin (Group B) exhibiting decreased exercise AOPPs at T2 with values approaching those of controls. CONCLUSION:Although further studies are needed to confirm these data, treatment with curcumin shows encouraging results indicating a slight slowdown in disease progression, improving aerobic metabolism and oxidative damage, this also contributing to deepen knowledge into the pathogenic mechanisms of ALS.

The loss of protein homeostasis that has been associated with aging leads to altered levels and conformational instability of proteins, which tend to form toxic aggregates. In particular, brain aging presents characteristic patterns of misfolded oligomers, primarily constituted of β-amyloid (Aβ), tau, and α-synuclein (α-syn), which can accumulate in neuronal membranes or extracellular compartments. Such aging-related proteins can also reach peripheral compartments, thus suggesting the possibility to monitor their accumulation in more accessible fluids. In this respect, we have demonstrated that α-syn forms detectable hetero-aggregates with Aβ or tau in red blood cells (RBCs) of healthy subjects. In particular, α-syn levels and its heteromeric interactions are modulated by plasma antioxidant capability (AOC), which increases in turn with physical activity. In order to understand if a specific distribution of misfolded proteins can occur in other blood cells, a cohort of human subjects was enrolled to establish a correlation among AOC, the level of physical exercise and the concentrations of aging-related proteins in platelets. The healthy subjects were divided depending on their level of physical exercise (i.e., athletes and sedentary subjects) and their age (young and older subjects). Herein, aging-related proteins (i.e., α-syn, tau and Aβ) were confirmed to be present in human platelets. Among such proteins, platelet tau concentration was demonstrated to decrease in athletes, while α-syn and Aβ did not correlate with physical exercise. For the first time, α-syn was shown to directly interact with Aβ and tau in platelets, forming detectable hetero-complexes. Interestingly, α-syn interaction with tau was inversely related to plasma AOC and to the level of physical activity. These results suggested that α-syn heterocomplexes, particularly with tau, could represent novel indicators to monitor aging-related proteins in platelets.

Neurodegenerative disorders (NDs) are characterized by abnormal accumulation/misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid1–42 (Aβ1–42) and tau, in both brain and peripheral tissues. In addition to oligomers, the role of the interactions of α-syn with Aβ or tau has gradually emerged. Nevertheless, despite intensive research, NDs have no accepted peripheral markers for biochemical diagnosis. In this respect, Red Blood Cells (RBCs) are emerging as a valid peripheral model for the study of aging-related pathologies. Herein, a small cohort (N = 28) of patients affected by Parkinson’s disease (PD) and age-matched controls were enrolled to detect the content of α-syn (total and oligomeric), Aβ1–42 and tau (total and phosphorylated) in RBCs. Moreover, the presence of α-syn association with tau and Aβ1–42 was explored by co-immunoprecipitation/western blotting in the same cells, and quantitatively confirmed by immunoenzymatic assays. For the first time, PD patients were demonstrated to exhibit α-syn heterocomplexes with Aβ1–42 and tau in peripheral tissues; interestingly, α-syn-Aβ1–42 concentrations were increased in PD subjects with respect to healthy controls (HC), and directly correlated with disease severity and motor deficits. Moreover, total-α-syn levels were decreased in PD subjects and inversely related to their motor deficits. Finally, an increase of oligomeric-α-syn and phosphorylated-tau was observed in RBCs of the enrolled patients. The combination of three parameters (total-α-syn, phosphorylated-tau and α-syn-Aβ1–42 concentrations) provided the best fitting predictive index for discriminating PD patients from controls. Nevertheless further investigations should be required, overall, these data suggest α-syn hetero-aggregates in RBCs as a putative tool for the diagnosis of PD.