Phytotherapeutic alternatives for neurodegenerative dementias: Scientific review, discussion and therapeutic proposal.

The incidence and prevalence of age-related neurodegenerative dementias have been increasing. There is no curative therapy and conventional drug treatment can cause problems for patients. Medicinal plants traditionally used for problems associated with ageing are emerging as a therapeutic resource. The main aim is to give a proposal for use and future research based on scientific knowledge and tradition. A literature search was conducted in several searchable databases. The keywords used were related to neurodegenerative dementias, ageing and medicinal plants. Boolean operators and filters were used to focus the search. As a result, there is current clinical and preclinical scientific information on 49 species used in traditional medicine for ageing-related problems, including neurodegenerative dementias. There are preclinical and clinical scientific evidences on their properties against protein aggregates in the central nervous system and their effects on neuroinflammation, apoptosis dysregulation, mitochondrial dysfunction, gabaergic, glutamatergic and dopaminergic systems alterations, monoamine oxidase alterations, serotonin depletion and oestrogenic protection. In conclusion, the potential therapeutic effect of the different medicinal plants depends on the type of neurodegenerative dementia and its stage of development, but more clinical and preclinical research is needed to find better, safer and more effective treatments.

Plasma total prion protein as a potential biomarker for neurodegenerative dementia: diagnostic accuracy in the spectrum of prion diseases.

AIMS: In the search for blood-based biomarkers of neurodegenerative diseases, we characterized the concentration of total prion protein (t-PrP) in the plasma of neurodegenerative dementias. We aimed to assess its accuracy in this differential diagnostic context. METHODS: Plasma t-PrP was measured in 520 individuals including healthy controls (HC) and patients diagnosed with neurological disease control (ND), Alzheimer's disease (AD), sporadic Creutzfeldt-Jakob disease (sCJD), frontotemporal dementia (FTD), Lewy body dementia (LBD) and vascular dementia (VaD). Additionally, t-PrP was quantified in genetic prion diseases and iatrogenic CJD. The accuracy of t-PrP discriminating the diagnostic groups was evaluated and correlated with demographic, genetic and clinical data in prion diseases. Markers of blood-brain barrier impairment were investigated in sCJD brains. RESULTS: Compared to HC and ND, elevated plasma t-PrP concentrations were detected in sCJD, followed by FTD, AD, VaD and LBD. In sCJD, t-PrP was associated neither with age nor sex, but with codon 129 PRNP genotype. Plasma t-PrP concentrations correlated with cerebrospinal fluid (CSF) markers of neuro-axonal damage, but not with CSF t-PrP. In genetic prion diseases, plasma t-PrP was elevated in all type of mutations investigated. In sCJD brain tissue, extravasation of immunoglobulin G and the presence of swollen astrocytic end-feet around the vessels suggested leakage of blood-brain barrier as a potential source of increased plasma t-PrP. CONCLUSIONS: Plasma t-PrP is elevated in prion diseases regardless of aetiology. This pilot study opens the possibility to consider plasma t-PrP as a promising blood-based biomarker in the diagnostic of prion disease.

ZTE MR-based attenuation correction in brain FDG-PET/MR: performance in patients with cognitive impairment.

OBJECTIVE: One of the main challenges of integrated PET/MR is to achieve an accurate PET attenuation correction (AC), especially in brain acquisition. Here, we evaluated an AC method based on zero echo time (ZTE) MRI, comparing it with the single-atlas AC method and CT-based AC, set as reference. METHODS: Fifty patients (70 ± 11 years old, 28 men) underwent FDG-PET/MR examination (SIGNA PET/MR 3.0 T, GE Healthcare) as part of the investigation of suspected dementia. They all had brain computed tomography (CT), 2-point LAVA-flex MRI (for atlas-based AC), and ZTE-MRI. Two AC methods were compared with CT-based AC (CTAC): one based on a single atlas, one based on ZTE segmentation. Impact on brain metabolism was evaluated using voxel and volumes of interest-based analyses. The impact of AC was also evaluated through comparisons between two subgroups of patients extracted from the whole population: 15 patients with mild cognitive impairment and normal metabolic pattern, and 22 others with metabolic pattern suggestive of Alzheimer disease, using SPM12 software. RESULTS: ZTE-AC yielded a lower bias (3.6 ± 3.2%) than the atlas method (4.5 ± 6.1%) and lowest interindividual (4.6% versus 6.8%) and inter-regional (1.4% versus 2.6%) variabilities. Atlas-AC resulted in metabolism overestimation in cortical regions near the vertex and cerebellum underestimation. ZTE-AC yielded a moderate metabolic underestimation mainly in the occipital cortex and cerebellum. Voxel-wise comparison between the two subgroups of patients showed that significant difference clusters had a slightly smaller size but similar locations with PET images corrected with ZTE-AC compared with those corrected with CT, whereas atlas-AC images showed a notable reduction of significant voxels. CONCLUSION: ZTE-AC performed better than atlas-AC in detecting pathologic areas in suspected neurodegenerative dementia. KEY POINTS: • The ZTE-based AC improved the accuracy of the metabolism quantification in PET compared with the atlas-AC method. • The overall uptake bias was 21% lower when using ZTE-based AC compared with the atlas-AC method. • ZTE-AC performed better than atlas-AC in detecting pathologic areas in suspected neurodegenerative dementia.

Incidence of frontotemporal disorders in Olmsted County: A population-based study.

INTRODUCTION: Frontotemporal dementia disorders (FTDs) are heterogeneous phenotypical behavioral and language disorders usually associated with frontal and/or temporal lobe degeneration. We investigated their incidence in a population-based cohort. METHODS: Using a records-linkage system, we identified all patients with a diagnostic code for dementia in Olmsted County, MN, 1995-2010, and confirmed the diagnosis of FTD. A behavioral neurologist verified the clinical diagnosis and determined phenotypes. RESULTS: We identified 35 FTDs cases. Overall, the incidence of FTDs was 4.3/100,000/year (95% CI: 2.9, 5.7). Incidence was higher in men (6.3/100,000, 95% CI 3.6, 9.0) than women (2.9/100,000; 95% CI: 1.3, 4.5); we observed an increased trend over time (B = 0.83, 95% CI: 0.54, 1.11, P < .001). At autopsy, clinical diagnosis was confirmed in eight (72.7%) cases. DISCUSSION: We observed an increased incidence and trends of FTDs over time. This may reflect a better recognition by clinicians and improvement of clinical criteria and diagnostic tools.

Plasma YKL-40 in the spectrum of neurodegenerative dementia.

BACKGROUND: Increased plasma YKL-40 has been reported in Alzheimer's disease (AD), but its levels in other neurodegenerative diseases are unknown. Here, we aimed to investigate plasma YKL-40 in the spectrum of neurodegenerative dementias. METHODS: YKL-40 was quantified in the plasma of 315 cases, including healthy controls (HC), neurological disease controls (ND), AD, vascular dementia (VaD), frontotemporal dementia (FTD), sporadic Creutzfeldt-Jakob disease (CJD) and Lewy body dementia (LBD). Diagnostic accuracy in the differential diagnostic context and influence of age and gender was assessed. RESULTS: Highest YKL-40 levels were detected in CJD, followed by LBD, VaD, AD, FTD, ND and HC. YKL-40 was associated to age but not to sex. After controlling for age, YKL-40 was significantly elevated in CJD compared to HC (p < 0.001), ND, AD and VaD (p < 0.01) and in LBD compared to HC (p < 0.05). In CJD, YKL-40 concentrations were significantly higher at late disease stages. CONCLUSIONS: Plasma YKL-40 is significantly elevated in CJD regardless of clinical and genetic parameters, with moderate diagnostic accuracy in the discrimination from control cases. Our study discards a potential use of this biomarker in the differential diagnostic context but opens the possibility to be explored as a marker for CJD monitoring.

Regional pattern of microgliosis in sporadic Creutzfeldt-Jakob disease in relation to phenotypic variants and disease progression.

AIMS: The aim of this study was to describe the regional profiles of microglial activation in sporadic Creutzfeldt-Jakob disease (sCJD) subtypes and analyse the influence of prion strain, disease duration and codon 129 genotype. METHODS: We studied the amount/severity and distribution of activated microglia, protease-resistant prion protein (PrPSc ) spongiform change, and astrogliosis in eight regions of 57 brains, representative of the entire spectrum of sCJD subtypes. RESULTS: In each individual subtype, the regional extent and distribution of microgliosis significantly correlated with PrPSc deposition and spongiform change, leading to subtype-specific 'lesion profiles'. However, large differences in the ratio between PrPSc load or the score of spongiform change and microglial activation were seen among disease subtypes. Most significantly, atypical sCJD subtypes such as VV1 and MM2T showed a degree of microglial activation comparable to other disease variants despite the relatively low PrPSc deposition and the less severe spongiform change. Moreover, the mean microglial total load was significantly higher in subtype MM1 than in MM2C, whereas the opposite was true for the PrPSc and spongiform change total loads. Finally, some sCJD subtypes showed distinctive regional cerebellar profiles of microgliosis characterized by a high granular/molecular layer ratio (MV2K) and/or a predominant involvement of white matter (MVK and MM2T). CONCLUSIONS: Microglial activation is an early event in sCJD pathogenesis and is strongly influenced by prion strain, PRNP codon 129 genotype and disease duration. Microglial lesion profiling, by highlighting strain-specific properties of prions, contributes to prion strain characterization and classification of human prion diseases, and represents a valid support to molecular and histopathologic typing.

7T MRI for neurodegenerative dementias in vivo: a systematic review of the literature.

The spatial resolution of 7T MRI approaches the scale of pathologies of interest in degenerative brain diseases, such as amyloid plaques and changes in cortical layers and subcortical nuclei. It may reveal new information about neurodegenerative dementias, although challenges may include increased artefact production and more adverse effects. We performed a systematic review of papers investigating Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and Huntington's disease (HD) in vivo using 7T MRI. Of 19 studies identified, 15 investigated AD (the majority of which examined hippocampal subfield changes), and 4 investigated HD. Ultrahigh resolution revealed changes not visible using lower field strengths, such as hippocampal subfield atrophy in mild cognitive impairment. Increased sensitivity to susceptibility-enhanced iron imaging, facilitating amyloid and microbleed examination; for example, higher microbleed prevalence was found in AD than previously recognised. Theoretical difficulties regarding image acquisition and scan tolerance were not reported as problematic. Study limitations included small subject groups, a lack of studies investigating LBD and FTD and an absence of longitudinal data. In vivo 7T MRI may illuminate disease processes and reveal new biomarkers and therapeutic targets. Evidence from AD and HD studies suggest that other neurodegenerative dementias would also benefit from imaging at ultrahigh resolution.

Cerebrovascular Lesions in Mixed Neurodegenerative Dementia: A Neuropathological and Magnetic Resonance Study.

BACKGROUND: In elderly brains of demented patients, Alzheimer and Lewy body pathology (LBP) are frequently associated. Cortical microinfarcts (CoMIs) are more observed in Lewy body disease, even in the absence of cerebral amyloid angiopathy (CAA). The present neuropathological and 7.0-tesla MRI studies investigate whether CoMIs are also more frequent in mixed neurodegenerative dementia syndromes. SUMMARY: Both examinations revealed that CoMIs are increased to different degrees in mixed dementia syndromes according to the severity of the LBP. They were mainly associated with a trend of older age and arterial hypertension in the patients with the most severe LBP. Messages: The increased number of CoMIs in mixed dementia syndromes with LBP is mainly due to the associated cerebrovascular pathology, even in the absence of CAA.

Dementia after Three Months and One Year from Stroke: New Onset or Previous Cognitive Impairment?

OBJECTIVE: Stroke is an important risk factor for dementia, but the exact mechanism involved in cognitive decline remains unclear. METHODS: Patients were divided into 2 groups: poststroke dementia group (PSD) and poststroke nondementia group (PSND). Variables and neuroradiological hallmarks were compared between 2 groups at 3 months (114 subjects) and 1 year (105 subjects) after stroke. RESULTS: Older age (OR 1.11, 95% CI 1.0-1.2; P < .05), education (OR .6, 95% CI .4-.8; P < .05), prestroke IQCODE (Informant Questionnaire on Cognitive Decline in the Elderly; OR .78, 95% CI .1-5.9; P < .05), premorbid apathy (OR 2.03, 95% CI 1.1-3.7; P < .05), and medial temporal lobe atrophy (MTLA) (OR 6.14, 95% CI 1.4-26.2; P < .05) were independently associated with PSD at 3 months after a cerebrovascular event, whereas at 1-year follow-up older age (OR 1.1, 95% CI 1.0-1.2; P < .05), prestroke IQCODE (OR .05, 95% CI .0-.9; P < .05), MTLA (OR 1.3, 95% CI 1.0-1.6; P < .05), and APACHE II (Acute Physiology and Chronic Health Evaluation; OR .6, 95% CI .4-.9; P < .05) were independently associated with PSD. CONCLUSIONS: Acute cerebrovascular disease could not be the only one mechanism explaining PSD. Neurodegenerative pathology must be taken into account.

Brain-targeting autoantibodies in patients with dementia.

Autoantibodies against proteins in the brain are increasingly considered as a potential cause of cognitive decline, not only in subacute autoimmune encephalopathies but also in slowly progressing impairment of memory in patients with classical neurodegenerative dementias. In this retrospective cohort study of 161 well-characterized patients with different forms of dementia and 34 controls, we determined the prevalence of immunoglobulin (Ig) G and IgA autoantibodies to brain proteins using unbiased immunofluorescence staining of unfixed murine brain sections. Autoantibodies were detected in 21.1% of dementia patients and in 2.9% of gender-matched controls, with higher frequencies in vascular dementia (42%), Alzheimer's disease (30%), dementia of unknown cause (25%), and subjective cognitive impairment (16.7%). Underlying antigens involved glial fibrillary acidic protein (GFAP), glycine receptor, and Rho GTPase activating protein 26 (ARHGAP26), but also a range of yet undetermined epitopes on neurons, myelinated fiber tracts, choroid plexus, glial cells, and blood vessels. Antibody-positive patients were younger than antibody-negative patients but did not differ in the extent of cognitive impairment, epidemiological and clinical factors, or comorbidities. Further research is needed to understand the potential contribution to disease progression and symptomatology, and to determine the antigenic targets of dementia-associated autoantibodies.

Clinical Value of Hybrid PET/MR Imaging: Brain Imaging Using PET/MR Imaging.

Hybrid PET/MR imaging offers a unique opportunity to acquire MR imaging and PET information during a single imaging session. PET/MR imaging has numerous advantages, including enhanced diagnostic accuracy, improved disease characterization, and better treatment planning and monitoring. It enables the immediate integration of anatomic, functional, and metabolic imaging information, allowing for personalized characterization and monitoring of neurologic diseases. This review presents recent advances in PET/MR imaging and highlights advantages in clinical practice for neuro-oncology, epilepsy, and neurodegenerative disorders. PET/MR imaging provides valuable information about brain tumor metabolism, perfusion, and anatomic features, aiding in accurate delineation, treatment response assessment, and prognostication.

Dementia-Specific Nursing Care Competencies for Nursing Education and Long-Term Care Practice.

Enhanced dementia-specific nursing care is needed to incorporate the rapid changes in dementia science for an expanding population of persons living with dementia (PLWD) in long-term care. Dementia-specific nursing care competencies should be incorporated into current curricula for undergraduate and graduate nursing programs as well as nurse professional practice. This article proposes a set of dementia nursing care competencies that reflect current scientific findings on neurodegenerative dementia diseases, communication and shared decision-making, supportive care management for symptoms of distress and deficits in activities of daily living, risk assessments for adverse outcomes, palliative care and advance directives, and caregiver issues.

Targets and mechanisms of Alpinia oxyphylla Miquel fruits in treating neurodegenerative dementia.

The dried and ripe fruits of Alpinia oxyphylla and ripe fruits of Alpinia oxyphylla Miquel (AO) have the effects of tonifying kidney-essence and nourishing intelligence and thus have been widely used in treating dementia. Alzheimer's disease (AD) is a typical form of neurodegenerative dementia with kidney-essence deficiency in Traditional Chinese Medicine (TCM). So far, there is a lack of systematic studies on the biological basis of tonifying kidney-essence and nourishing intelligence and the corresponding phytochemicals. In this study, we investigated the targets of AO in tonifying kidney-essence and nourishing intelligence based on the key pathophysiological processes of neurodegenerative dementia. According to ultra-high-performance liquid chromatography with triple quadrupole mass spectrometry data and Lipinski's rule of five, 49 bioactive phytochemicals from AO were identified, and 26 of them were found to target 168 key molecules in the treatment of neurodegenerative dementia. Nine phytochemicals of AO were shown to target acetylcholinesterase (ACHE), and 19 phytochemicals were shown to target butyrylcholinesterase (BCHE). A database of neurodegenerative dementia with kidney-essence deficiency involving 731 genes was constructed. Furthermore, yakuchinone B, 5-hydroxy-1,7-bis (4-hydroxy-3-methoxyphenyl) heptan-3-one (5-HYD), oxyhylladiketone, oxyphyllacinol, butyl-ß-D-fructopyranoside, dibutyl phthalate, chrysin, yakuchinone A, rhamnetin, and rhamnocitrin were identified as the key phytochemicals from AO that regulate the pathogenesis of neurodegenerative dementia in a multitargeted manner. The approach of studying the pharmacological mechanism underlying the effects of medicinal plants and the biological basis of TCM syndrome may be helpful in studying the translation of TCM.

FAM69C, a kinase critical for synaptic function and memory, is defective in neurodegenerative dementia.

Synapse loss and memory decline are the primary features of neurodegenerative dementia. However, the molecular underpinnings that drive memory loss remain largely unknown. Here, we report that FAM69C is a kinase critically involved in neurodegenerative dementia. Biochemical analyses uncover that FAM69C is a serine/threonine kinase. We generate the Fam69c knockout mice and show by single-cell RNA sequencing that FAM69C deficiency drives cell-type-specific transcriptional changes relevant to synapse dysfunction. Electrophysiological, morphological, and behavioral experiments demonstrate impairments in synaptic plasticity, dendritic spine density, and memory in Fam69c knockout mice, as well as stress-induced neuronal death. Phosphoproteomic characterizations reveal that FAM69C substrates are involved in synaptic structure and function. Finally, reduced levels of FAM69C are found in postmortem brains of Alzheimer's disease patients. Our study demonstrates that FAM69C is a protective regulator of memory and suggests FAM69C as a potential therapeutic target for memory loss in neurodegenerative dementia.

History in perspective: How Alzheimer's Disease came to be where it is?

Treatment of Alzheimer's Disease (AD) remains an unsolved issue despite the pronounced global attention it has received from researchers over the last four decades. Determining the primary cause of the disease is challenging due to its long prodromal phase and multifactorial etiology. Regardless, academic disagreements amongst the scientific community have helped in making significant advancements in underpinning the molecular basis of disease pathogenesis. Substantial development in fluid and imaging biomarkers for AD led to a sharp turn in defining the disease as a molecular construct, dispensing its clinical definition. With conceptual progress, revisions in the diagnostic criteria of AD were made, culminating into the research framework proposed by National Institute on Aging and Alzheimer's Association in 2018 which unified different stages of the disease continuum, giving a common language of AT(N)1 classification to researchers. With realization that dementia is the final stage of AD spectrum, its early diagnosis by means of cerebrospinal fluid biomarkers, Positron Emission Tomography and Magnetic Resonance Imaging of the brain holds crucial importance in discovering ways of halting the disease progression. This article maps the insights into the pathogenesis as well as the diagnostic criteria and tests for AD as these have evolved over time. A contextualized timeline of how the understanding of AD has matured with advancing knowledge allows future research to be directed and unexplored avenues to be prioritized.

Association between Previous Statin Use and Alzheimer's Disease: A Nested Case-Control Study Using a National Health Screening Cohort.

A number of studies report the incidence of Alzheimer's disease (AD) in patients taking statins, but the results are inconsistent. (1) Background: The present study investigated the cross-sectional association between previous statin use and the risk of AD development in Korean residents. (2) Methods: We used the Korean National Health Insurance Service-National Sample Cohort; 17,172 AD patients were matched by age, gender, income, and region of residence with 68,688 control participants at a ratio of 1:4. We used a multiple conditional logistic regression model to analyse the association between the number of days of statin use and AD occurrence. Further analyses were performed to identify whether this association is maintained for different ages, genders, socioeconomic status groups, and covariates. (3) Results: The odds ratio, which was adjusted for potential confounders, for the days of statin use per year in the AD group compared to the control group was 0.95 (95% confidence interval = 0.92-0.98; p = 0.003). The number of days of statin use in the AD group was significantly smaller in the subgroups of non-smokers and individuals with normal weight, alcohol consumption less than once a week, total cholesterol level below 200 mg/dL, systolic blood pressure below 140, diastolic blood pressure below 90, and fasting blood glucose below 100 mg/dL. (4) Conclusions: Our results suggest that statin use prevents the occurrence of AD. The effects of statin use in preventing AD may be greater in individuals at relatively low risk.

Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration.

Mounting evidence shows a link between mitochondrial dysfunction and neurodegenerative disorders, including Alzheimer Disease. Increased oxidative stress, defective mitodynamics, and impaired oxidative phosphorylation leading to decreased ATP production, can determine synaptic dysfunction, apoptosis, and neurodegeneration. Furthermore, mitochondrial proteostasis and the protease-mediated quality control system, carrying out degradation of potentially toxic peptides and misfolded or damaged proteins inside mitochondria, are emerging as potential pathogenetic mechanisms. The enzyme pitrilysin metallopeptidase 1 (PITRM1) is a key player in these processes; it is responsible for degrading mitochondrial targeting sequences that are cleaved off from the imported precursor proteins and for digesting a mitochondrial fraction of amyloid beta (Aß). In this review, we present current evidence obtained from patients with PITRM1 mutations, as well as the different cellular and animal models of PITRM1 deficiency, which points toward PITRM1 as a possible driving factor of several neurodegenerative conditions. Finally, we point out the prospect of new diagnostic and therapeutic approaches.

POINT/COUNTER-POINT-Beyond the headlines: the actual evidence that traumatic brain injury is a risk factor for later-in-life dementia.

Traumatic brain injury (TBI) as a risk factor for developing dementia later in life has been a subject of debate and controversy. TBI has been found to be associated with an increased likelihood for developing dementia 10-30 years later in several retrospective studies using population records. However, understanding the link between TBI and dementia requires looking beyond calculated risk estimates and delving into the association TBI has with pathological changes seen in Alzheimer's disease and related conditions, as well as those seen in normal aging. Some individuals with TBI, notably those with more serious injuries, show evidence of AD-related pathological changes, such as tau aggregates, at a much earlier age than healthy older individuals without a history of TBI. This would suggest that some people may be more susceptible to the effects of TBI, accumulating additional pathological changes seen in Alzheimer disease and related conditions, which may synergistically and/or cumulatively interact with factors associated with aging. The strongest support to date suggests that TBI may confer an increased risk for earlier onset of neurodegenerative changes in some individuals, possibly as a function of an accumulation of additional pathological changes. While there appears to be a link between TBI and the development of dementia in group studies, the evidence to date does not suggest an association between TBI and progressive cognitive decline during normal aging nor a greater rate of decline in those with dementia. Thus, there remains much to be learned about the pathophysiology of this apparent relationship.

Identification of expanded repeats in NOTCH2NLC in neurodegenerative dementias.

Recently, the (GGC)n repeat expansion in the NOTCH2NLC gene has been identified to be associated with neuronal intranuclear inclusion disease (NIID). Given the clinical overlap of dementia-dominant NIID with neurodegenerative dementia, we therefore hypothesized that the NOTCH2NLC repeat expansion might also contribute to these diseases. In the present study, repeat primed polymerase chain reaction (RP-PCR) and GC-rich PCR were conducted to detect the repeats of NOTCH2NLC in a cohort of 1004 patients with neurodegenerative dementias from mainland China. As a result, 4 sporadic patients were found to carry the NOTCH2NLC repeats expansion, totally accounting for 0.4% of all dementia individuals, and the accurate repeated sizes were 110, 133,120 and 76 respectively. Of 4 mutation carriers, three and one were clinically diagnosed Alzheimer's disease (AD) and frontotemporal dementia (FTD) respectively. In addition, 3 out of them revealed leukoencephalopathy in T2-Flair imaging. This study revealed that although rare, the NOTCH2NLC repeat expansions may be associated with AD or FTD-like phenotype as well as leukoencephalopathy.

A new tetra-plex fluorimetric assay for the quantification of cerebrospinal fluid ß-amyloid42, total-tau, phospho-tau and α-synuclein in the differential diagnosis of neurodegenerative dementia.

BACKGROUND: Differential diagnosis of neurodegenerative dementia is currently supported by biomarkers including cerebrospinal fluid (CSF) tests. Among them, CSF total-tau (t-tau), phosphorylated tau (p-tau) and ß-amyloid42 (Aß42) are considered core biomarkers of neurodegeneration. In the present work, we hypothesize that simultaneous assessment of these biomarkers together with CSF α-synuclein (α-syn) will significantly improve the differential diagnostic of Alzheimer's disease and other dementias. To that aim, we characterized the analytical and clinical performance of a new tetra-plex immunoassay that simultaneously quantifies CSF Aß42, t-tau, p-tau and α-syn in the differential diagnosis of neurodegenerative dementia. METHODS: Biomarkers' concentrations were measured in neurological controls (n = 38), Alzheimer's disease (n = 35), Creutzfeldt-Jakob disease (n = 37), vascular dementia (n = 28), dementia with Lewy bodies/Parkinson's disease dementia (n = 27) and frontotemporal dementia (n = 34) using the new tetra-plex assay and established single-plex assays. Biomarker's performance was evaluated and diagnostic accuracy in the discrimination of diagnostic groups was determined using partial least squares discriminant analysis. RESULTS: The tetra-plex assay presented accuracies similar to individual single-plex assays with acceptable analytical performance. Significant correlations were observed between tetra-plex and single-plex assays. Using partial least squares discriminant analysis, Alzheimer's disease and Creutzfeldt-Jakob disease were well differentiated, reaching high accuracies in the discrimination from the rest of diagnostic groups. CONCLUSIONS: The new tetra-plex assay coupled with multivariate analytical approaches becomes a valuable asset for the differential diagnosis of neurodegenerative dementia and related applications.