A case of corticobasal syndrome possibly associated with anti-Yo antibodies.

INTRODUCTION: Corticobasal syndrome (CBS) is a rare form of atypical parkinsonism, most commonly caused by neurodegenerative disorders. Autoimmune underlying conditions are extremely rare, and anti-Yo antibody-associated CBS has not been reported yet. CASE REPORT: Herein, we describe a case of a 68-year-old woman presenting with progressive dysarthria, gait instability and difficulty using her left hand with subacute deterioration during the last three months. Neurological examination revealed asymmetrical parkinsonism and pyramidal syndrome, reflex myoclonus and dystonia of her left upper limb, accompanied by apraxia of her left lower limb, fulfilling the criteria for possible CBS. Neuroimaging showed asymmetric frontoparietal atrophy, while cerebrospinal fluid and dopamine transporter imaging were normal. Prior to our evaluation, antineuronal autoantibody testing indicated positive anti-Yo antibodies. There was mild improvement after second IVIG cycle, and further investigation revealed no tumor. CONCLUSION: Although autoimmune etiology of this case cannot be certain, it highlights the potential expansion of the clinical spectrum of anti-Yo-associated paraneoplastic syndrome.

Precision Dopaminergic Treatment in a Cohort of Parkinson's Disease Patients Carrying Autosomal Recessive Gene Variants: Clinical Cohort Data and a Mini Review.

INTRODUCTION: Parkinson's disease (PD) patients harboring recessive gene variants exhibit a distinct clinical phenotype with an early disease onset and relatively mild symptoms. Data concerning individualized therapy for autosomal recessive PD forms are still scarce. METHODS: Demographic and treatment data of a cohort of PD carriers of recessive genes (nine homozygous or compound heterozygous PRKN carriers, four heterozygous PRKN carriers, and three biallelic PINK1 carriers) were evaluated. RESULTS: The average levodopa equivalent daily dose (LEDD) was 806.8 ± 453.5 (range 152-1810) in PRKN carriers and 765 ± 96.6 (range 660-850) in PINK1 carriers. The majority responded to low/moderate doses of levodopa. The response to dopamine agonists (DAs) was often favorable both as initial and longitudinal therapy. In total, 8/13 PRKN and 1/3 PINK1 carriers were treated with amantadine successfully, and this also applied to patients who could not tolerate levodopa or DAs. CONCLUSIONS: In the era of personalized treatment, the therapeutic approach in recessive PD gene carriers might differ as compared to idiopathic PD. Lower LEDD doses were efficient even in patients with a very long disease duration, while a few patients were doing well without any levodopa treatment decades after disease initiation. DAs or amantadine could be used as a first and main line treatment regimen if well tolerated. Literature data on therapeutic strategies in carriers of pathogenic mutations in recessive PD genes, including device-aided treatments, will be further discussed.

Cerebrospinal Fluid Total and Phosphorylated Tau Protein in Behavioral Variant Frontotemporal Dementia, Progressive Supranuclear Palsy, Corticobasal Syndrome and Non-Fluent Agrammatic Primary Progressive Aphasia: A Systematic Review and Meta-Analysis.

(1) Background: Frontotemporal lobar degeneration (FTLD) is a generic term which refers to multiple pathologies, including FTLD-tau. The most common FTLD-tau diseases are Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). These diseases share four major syndromes: behavioral variant frontotemporal dementia (bvFD), Richardson syndrome (RS), corticobasal syndrome (CBS) and non-fluent agrammatic primary progressive aphasia (nfa-PPA). The primary aim of this meta-analysis was to examine the diagnostic performance of CSF total (t-tau) and phosphorylated (p-tau) protein in bvFTD, RS, CBS, nfa-PPA and pathologically or genetically defined tauopathy. (2) Methods: A systematic review and meta-analysis was performed on all studies with >10 subjects in a bvFTD/RS/CBS/nfa-PPA group and control group and available data on CSF t-tau or p-tau (mean, SD). Cohen's d was used to quantify the effect size of each study (3) Results: The PSP/tauopathy patients exhibited decreased levels of CSF p-tau compared to the control subjects. The CBS/bvFTD/nfa-PPA cohorts exhibited an increase in t-tau compared to the control groups. (4) Conclusions: Tauopathies may exhibit an inherent decrease in CSF p-tau. The admixture of AD patients in FTD cohorts and high heterogeneity among studies on rare diseases are significant confounding factors in FTLD studies.

In Vivo Prevalence of Beta-Amyloid Pathology and Alzheimer's Disease Co-Pathology in Idiopathic Normal-Pressure Hydrocephalus-Association with Neuropsychological Features.

Idiopathic normal-pressure hydrocephalus (iNPH) is a clinic-radiological neurological syndrome presenting with cognitive deficits, gait disturbances and urinary incontinence. It often coexists with Alzheimer's disease (AD). Due to the reversible nature of iNPH when promptly treated, a lot of studies have focused on possible biomarkers, among which are cerebrospinal fluid (CSF) biomarkers. The aim of the present study was to determine the rate of beta-amyloid pathology and AD co-pathology by measuring AD CSF biomarkers, namely, amyloid beta with 42 and 40 amino acids (Aß42), the Aß42/Aß40 ratio, total Tau protein (t-Tau) and phosphorylated Tau protein at threonine 181 (p-Tau), in a cohort of iNPH patients, as well as to investigate the possible associations among CSF biomarkers and iNPH neuropsychological profiles. Fifty-three patients with iNPH were included in the present study. CSF Aß42, Aß40, t-Tau and p-Tau were measured in duplicate with double-sandwich ELISA assays. The neuropsychological evaluation consisted of the Mini-Mental State Examination, Frontal Assessment Battery, Five-Word Test and CLOX drawing tests 1 and 2. After statistical analysis, we found that amyloid pathology and AD co-pathology are rather common in iNPH patients and that higher values of t-Tau and p-Tau CSF levels, as well as the existence of the AD CSF profile, are associated with more severe memory impairment in the study patients. In conclusion, our study has confirmed that amyloid pathology and AD-co-pathology are rather common in iNPH patients and that CSF markers of AD pathology and t-Tau are associated with a worse memory decline in these patients.

Objective Sleep Function is Associated with Hippocampal Subfield Volumes in Community-Dwelling Adults.

BACKGROUND: Sleep patterns often shift as people age, a phenomenon frequently associated with the onset of neurodegenerative conditions. Additionally, distinct alterations occur in brain structure as individuals grow older, particularly within the hippocampus, a region known for its role in cognition and sleep regulation. Yet, how exactly do changes in sleep relate to specific subfields within the hippocampus is still unclear. METHODS: We conducted a study involving non-demented healthy adults from the Aiginition Longitudinal Biomarker Investigation Of Neurodegeneration (ALBION) cohort. Participants underwent objective sleep measurements using wrist Actiwatch and WatchPAT devices. Further, all participants underwent the same Magnetic Resonance Imaging (MRI) protocol, including a 3D high resolution T1-weighted sequence, on the same 3.0 Tesla MRI scanner using an eight-channel head coil. The study aimed to examine the relationship between objectively measured sleep metrics and the morphology of twenty-two distinct hippocampal subregions. RESULTS: In total, 75 non-demented participants with 63 mean years of age were included in the study. Results indicated that a higher frequency of awakenings during sleep was associated with increased volume in the right presubiculum body (beta = 0.630, p False Discovery Rate (FDR) <0.036). Longer sleep duration showed a tendency to be associated with smaller volumes of the right presubiculum body, hinting at a possible negative impact of prolonged sleep on this brain region. Similar trends were observed regarding sleep apnea and the presubiculum body volume. Further analysis based on age stratification revealed that in younger participants, longer sleep duration was linked to decreased volume of the presubiculum body, while a greater number of awakenings was correlated with increased volume of the same region. Among older participants, higher frequencies of awakenings were associated with larger volumes in various hippocampal subfields. CONCLUSIONS: These findings shed light on the complex relationship between sleep characteristics and brain structure, highlighting potential age-related differences. The study provides valuable insights into how sleep disruptions may impact hippocampal morphology and cognitive function of cognitively healthy adults. Further research is warranted to elucidate the underlying mechanisms and implications for neurodegenerative diseases.

SIMOA Diagnostics on Alzheimer's Disease and Frontotemporal Dementia.

BACKGROUND: Accurate diagnosis of Alzheimer's disease (AD) and frontotemporal dementia (FTD) represents a health issue due to the absence of disease traits. We assessed the performance of a SIMOA panel in cerebrospinal fluid (CSF) from 43 AD and 33 FTD patients with 60 matching Control subjects in combination with demographic-clinical characteristics. METHODS: 136 subjects (AD: n = 43, FTD: n = 33, Controls: n = 60) participated. Single-molecule array (SIMOA), glial fibrillary acidic protein (GFAP), neurofilament light (NfL), TAU, and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) in CSF were analyzed with a multiplex neuro 4plex kit. Receiver operating characteristic (ROC) curve analysis compared area under the curve (AUC), while the principal of the sparse partial least squares discriminant analysis (sPLS-DA) was used with the intent to strengthen the identification of confident disease clusters. RESULTS: CSF exhibited increased levels of all SIMOA biomarkers in AD compared to Controls (AUCs: 0.71, 0.86, 0.92, and 0.94, respectively). Similar patterns were observed in FTD with NfL, TAU, and UCH-L1 (AUCs: 0.85, 0.72, and 0.91). sPLS-DA revealed two components explaining 19% and 9% of dataset variation. CONCLUSIONS: CSF data provide high diagnostic accuracy among AD, FTD, and Control discrimination. Subgroups of demographic-clinical characteristics and biomarker concentration highlighted the potential of combining different kinds of data for successful and more efficient cohort clustering.

Localizing apraxia in corticobasal syndrome: a morphometric MRI study.

Apraxia localization has relied on voxel-based, lesion-symptom mapping studies in left hemisphere stroke patients. Studies on the neural substrates of different manifestations of apraxia in neurodegenerative disorders are scarce. The primary aim of this study was to look into the neural substrates of different manifestations of apraxia in a cohort of corticobasal syndrome patients (CBS) by use of cortical thickness. Twenty-six CBS patients were included in this cross-sectional study. The Goldenberg apraxia test (GAT) was applied. 3D-T1-weighted images were analyzed via the automated recon-all Freesurfer version 6.0 pipeline. Vertex-based multivariate General Linear Model analysis was applied to correlate GAT scores with cortical thickness. Deficits in imitation of meaningless gestures correlated with bilateral superior parietal atrophy, extending to the angular and supramarginal gyri, particularly on the left. Finger imitation relied predominantly on superior parietal lobes, whereas the left angular and supramarginal gyri, in addition to superior parietal lobes, were critical for hand imitation. The widespread bilateral clusters of atrophy in CBS related to apraxia indicate different pathophysiological mechanisms mediating praxis in neurodegenerative disorders compared to vascular lesions, with implications both for our understanding of praxis and for the rehabilitation approaches of patients with apraxia.

Genetic risk for Alzheimer's disease and adherence to the Mediterranean diet: results from the HELIAD study.

Obejctives: The aim of the current study was to investigate whether genetic risk factors may moderate the association between adherence to the Mediterranean diet and AD incidence.Mehtods: The sample was drawn from the HELIAD study, a longitudinal study with a follow-up interval of 3 years. In total 537 older adults without dementia or AD at baseline were included. Adherence to the Mediterranean diet was assessed at baseline and AD diagnosis was determined at both visits. A Polygenic Index for late onset AD (PGI-AD) was constructed. Cox proportional hazard models adjusted for age, sex, education, baseline Global cognition score and APOE e-4 genotype were employed to evaluate the association between PGI-AD and Mediterranean diet with AD incidence. Next, we examined the association between adherence to the Mediterranean diet and AD risk over time across participants stratified by low and high PGI-AD.Results: Twenty-eight participants developed AD at follow-up. In fully adjusted models both the PGI-AD and the adherence to the Mediterranean diet were associated with AD risk (p < 0.05 for both). In the low PGI-AD group, those with a low adherence had a 10-fold higher risk of developing AD per year of follow-up, than did the participants with a high adherence to the Mediterranean diet (p = 0.011), whereas no such association was found for participants in the high PGI-AD group.Discussion: The association of Mediterranean diet with AD risk is more prominent in the group of older adults with a low polygenic risk for developing AD. Our findings suggest that genetic risk factors should be taken into account when planning interventions aiming to improve cognitive health.

Alzheimer's Disease CSF Biomarkers as Possible Indicators of Tap-Test Response in Idiopathic Normal Pressure Hydrocephalus.

The aim of the present study is the evaluation of established Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in patients with idiopathic normal-pressure hydrocephalus (iNPH), both individually and as a total profile, and the investigation of their use as potential predictors of Tap-test responsiveness. Fifty-three patients with iNPH participated in the study. Aß42, Aß40, total Tau and phospho-Tau proteins were measured in duplicate with double-sandwich ELISA assays. Clinical evaluation involved a 10 m timed walk test before an evacuative lumbar puncture (LP) and every 24 h for three consecutive days afterwards. Neuropsychological assessment involved a mini-mental state examination, frontal assessment battery, 5-word test and CLOX drawing test 1 and 2, which were also performed before and 48 h after LP. Response in the Tap-test was defined as a 20% improvement in gait and/or a 10% improvement in neuropsychological tests. The Aß42/Aß40 ratio was found to be significantly higher in Tap-test responders than non-responders. Total Tau and phospho-Tau CSF levels also differed significantly between these two groups, with Tap-test responders presenting with lower levels compared to non-responders. Regarding the AD CSF biomarker profile (decreased amyloid and increased Tau proteins levels), patients with a non-AD profile were more likely to have a positive response in the Tap-test than patients with an AD profile.

Imaging Markers for Normal Pressure Hydrocephalus: An Overview.

Idiopathic bormal pressure hydrocephalus (iNPH) is a neurological syndrome that clinically presents with Hakim's triad, namely cognitive impairment, gait disturbances, and urinary incontinence. The fact that iNPH is potentially reversible makes its accurate and early diagnosis of paramount importance. Its main imaging characteristic is the dilation of the brain's ventricular system and the imaging parameters are also included in its diagnostic criteria along with clinical data. There is a variety of different modalities used and a great number of imaging markers that have been described while assessing iNPH patients. The present literature review attempts to describe the most important of these imaging markers and to shed some light on their role in diagnosis, differential diagnosis, and possibly prognosis of this potentially reversible neurological syndrome.

CSF Aß42 and Aß42/Aß40 Ratio in Alzheimer's Disease and Frontotemporal Dementias.

BACKGROUND: Alzheimer's disease dementia (ADD) may manifest with atypical phenotypes, resembling behavioral variant frontotemporal dementia (bvFTD) and corticobasal syndrome (CBS), phenotypes which typically have an underlying frontotemporal lobar degeneration with tau proteinopathy (FTLD-tau), such as Pick's disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or FTLD with TDP-43 proteinopathy (FTLD-TDP). CSF biomarkers total and phosphorylated tau (τT and τP-181), and amyloid beta with 42 and 40 amino acids (Aß42 and Aß40) are biomarkers of AD pathology. The primary aim of this study was to compare the diagnostic accuracy of Aß42 to Aß42/Aß40 ratio in: (a) differentiating ADD vs. frontotemporal dementias; (b) patients with AD pathology vs. non-AD pathologies; (c) compare biomarker ratios and composite markers to single CSF biomarkers in the differentiation of AD from FTD; Methods: In total, 263 subjects were included (ADD: n = 98; bvFTD: n = 49; PSP: n = 50; CBD: n = 45; controls: n = 21). CSF biomarkers were measured by commercially available ELISAs (EUROIMMUN). Multiple biomarker ratios (Aß42/Aß40; τT/τP-181; τT/Aß42; τP-181/Aß42) and composite markers (t-tau: τT/(Aß42/Aß40); p-tau: τP-181/(Aß42/Aß40) were calculated. ROC curve analysis was performed to compare AUCs of Aß42 and Aß42/Aß40 ratio and relevant composite markers between ADD and FTD, as defined clinically. BIOMARKAPD/ABSI criteria (abnormal τT, τP-181 Aß42, and Aß42/Aß40 ratio) were used to re-classify all patients into AD pathology vs. non-AD pathologies, and ROC curve analysis was repeated to compare Aß42 and Aß42/Aß40; Results: Aß42 did not differ from Aß42/Aß40 ratio in the differentiation of ADD from FTD (AUCs 0.752 and 0.788 respectively; p = 0.212). The τT/Aß42 ratio provided maximal discrimination between ADD and FTD (AUC:0.893; sensitivity 88.8%, specificity 80%). BIOMARKAPD/ABSI criteria classified 60 patients as having AD pathology and 211 as non-AD. A total of 22 had discrepant results and were excluded. Aß42/Aß40 ratio was superior to Aß42 in the differentiation of AD pathology from non-AD pathology (AUCs: 0.939 and 0.831, respectively; p < 0.001). In general, biomarker ratios and composite markers were superior to single CSF biomarkers in both analyses. CONCLUSIONS: Aß42/Aß40 ratio is superior to Aß42 in identifying AD pathology, irrespective of the clinical phenotype. CSF biomarker ratios and composite markers provide higher diagnostic accuracy compared to single CSF biomarkers.

Application of the AT(N) and Other CSF Classification Systems in Behavioral Variant Frontotemporal Dementia.

BACKGROUND: Patients with a frontotemporal lobar degeneration (FTLD) usually manifest with behavioral variant frontotemporal dementia (bvFTD). Alzheimer's disease (AD) may also manifest with a predominant behavioral-dysexecutive syndrome, similar to bvFTD. Cerebrospinal fluid (CSF) biomarkers, such as total tau (τT), phosphorylated tau (τP-181) and amyloid beta with 42 amino-acids (Aß42), can predict AD pathology in vivo. The aim of this study was to compare the τT/Aß42 and τP-181/Aß42 ratios, the BIOMARKAPD/ABSI criteria and the AT(N) classification system in a cohort of bvFTD patients. METHODS: A total of 105 bvFTD patients (21 possible bvFTD; 20%) with CSF data, examined from 2008 to 2022, were included. Seventy-eight AD patients and 62 control subjects were included. The CSF biomarkers were measured with Innotest (2008-2017 subcohort) and EUROIMMUN (2017-2022 subcohort) ELISAs. RESULTS: Depending on the classification system, 7.6 to 28.6% of bvFTD had an AD biochemical profile. The τT/Aß42 and τP-181/Aß42 ratios classified more patients as AD compared to the BIOMARKAPD/ABSI and AT(N) systems. The patients with possible bvFTD had higher frequencies of AD compared to the probable bvFTD patients. CONCLUSIONS: The four classification criteria of CSF AD biomarkers resulted in differences in AD allocation in this bvFTD cohort. A consensus on the optimal classification criteria of CSF AD biomarkers is pivotal.

Dopamine transporter SPECT imaging in Parkinson's disease and atypical Parkinsonism: a study of 137 patients.

INTRODUCTION: Differential diagnosis between Parkinson's disease (PD) and multiple system atrophy-parkinsonian type (MSA-P), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), collectively termed atypical Parkinsonism (AP), is challenging. Dopamine transporter density imaging with Ioflupane I123 (DaTscan) is a marker of presynaptic nigrostriatal dysfunction. The primary aim of this study was to investigate the utility of DaTscan in the differential diagnosis of MSA-P, CBD, and PSP. METHODS: Patients examined at Eginition Hospital (2011-2021), with available DaTscan data and a diagnosis of probable AP, clinically established PD, as well as a neurological control (NC) group were included. Mean binding specific index (BSI), BSI of the most affected side, asymmetry index, laterality, and caudate/putamen ratio were recorded. Analyses were performed by Kruskal-Wallis and ANCOVA. RESULTS: 137 patients were included (CBD: [Formula: see text]; MSA-P: [Formula: see text]; PSP: [Formula: see text]; PD: [Formula: see text]; NC: [Formula: see text]). There were significant differences when comparing CBS, PSP, and NC vs. all other groups combined. Pairwise between-group comparisons revealed significant differences between PSP and CBD (mean striatum BSI>1.95; sensitivity 74.1%; specificity 85.0%), CBD and MSA-P (mean striatum BSI>2.04; sensitivity 70.4%; specificity 86.7%), and CBD and PD (mean striatum BSI>2.11; sensitivity 66.7%; specificity 100.0%). There were no differences between PSP, MSA-P, and PD. PSP, MSA-P, and PD differed from NC subjects, with 100% specificity and high sensitivity. Differentiation of NC from CBD was suboptimal. DISCUSSION: CBD patients exhibit relatively mild DaTscan abnormalities. DaTscan may assist in the differentiation of CBD from PSP. DaTscan does not differentiate among PD, MSA-P, and PSP.

Hippocampal subfield volumetry in corticobasal syndrome of diverse underlying pathologies.

INTRODUCTION: Multiple pathologies may underlie corticobasal syndrome (CBS), including Alzheimer's disease (AD). Typical amnestic AD is characterized by early selective hippocampal atrophy. The profile of hippocampal atrophy in AD patients presenting as CBS (CBS-AD), compared to CBS patients of non-AD pathologies (CBS-nAD) and amnestic AD patients, has not been studied. OBJECTIVES: To compare hippocampal subfield atrophy patterns between CBS-AD, CBS-nAD, typical amnestic AD patients, and control subjects. METHODS: Automated hippocampal subfield volumetry was performed via the hippocampal subfield segmentation pipeline of Freesurfer 6.0 on 3D T1-weighted images. CBS patients were classified as CBS-AD or CBS-nAD based on CSF AD biomarkers by applying the AT(N) classification system. Mean volumes of nine hippocampal subfields, head-body-tail segments, total hippocampus, and entorhinal and parahippocampal gyrus cortical thickness were measured. RESULTS: Eighty-three subjects were included (CBS-AD: n = 14; CBS-nAD: n = 17; amnestic AD: n = 29; controls: n = 23). CBS-AD patients had greater whole hippocampal and hippocampal subfield atrophy compared to CBS-nAD. CBS-AD and amnestic AD patients did not differ in subfield volumes. CBS-nAD did not exhibit hippocampal atrophy compared to controls, with the exception of fimbria. (Cohen's d = 1.27; p = 0.038). Presubiculum (Cohen's d = 1.00; p = 0.002) and hippocampal body (Cohen's d = 0.95; p = 0.001) volumes exhibited the greatest differences between CBS-AD and CBS-nAD. Hippocampal subfield volume provided combined sensitivity and specificity < 80% for the discrimination of CBS-AD from CBS-nAD. CONCLUSION: CBS-AD and amnestic AD patients exhibit comparable, and significantly greater hippocampal atrophy compared to CBS-nAD patients. Hippocampal subfield volumetry in CBS is indicative of an AD underlying pathology.

Planimetric and Volumetric Brainstem MRI Markers in Progressive Supranuclear Palsy, Multiple System Atrophy, and Corticobasal Syndrome. A Systematic Review and Meta-Analysis.

BACKGROUND: Various MRI markers-including midbrain and pons areas (Marea, Parea) and volumes (Mvol, Pvol), ratios (M/Parea, M/Pvol), and composite markers (magnetic resonance imaging Parkinsonism Indices 1,2; MRPI 1,2)-have been proposed as imaging markers of Richardson's syndrome (RS) and multiple system atrophy-Parkinsonism (MSA-P). A systematic review/meta-analysis of relevant studies aiming to compare the diagnostic accuracy of these imaging markers is lacking. METHODS: Pubmed and Scopus were searched for studies with >10 patients (RS, MSA-P or CBS) and >10 controls with data on Marea, Parea, Mvol, Pvol, M/Parea, M/Pvol, MRPI 1, and MRPI 2. Cohen's d, as a measure of effect size, was calculated for all markers in RS, MSA-P, and CBS. RESULTS: Twenty-five studies on RS, five studies on MSA-P, and four studies on CBS were included. Midbrain area provided the greatest effect size for differentiating RS from controls (Cohen's d = -3.10; p < 0.001), followed by M/Parea and MRPI 1. MSA-P had decreased midbrain and pontine areas. Included studies exhibited high heterogeneity, whereas publication bias was low. CONCLUSIONS: Midbrain area is the optimal MRI marker for RS, and pons area is optimal for MSA-P. M/Parea and MRPIs produce smaller effect sizes for differentiating RS from controls.

Cerebrospinal Fluid Biomarkers in iNPH: A Narrative Review.

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological syndrome characterized by the clinical triad of gait disorder, cognitive impairment and urinary incontinence. It has attracted interest because of the possible reversibility of symptoms, especially with timely treatment. The main pathophysiological theory is based on a vicious circle of disruption in circulation of cerebrospinal fluid (CSF) that leads to the deceleration of its absorption. Data regarding CSF biomarkers in iNPH are contradictory and no definite CSF biomarker profile has been recognized as in Alzheimer's disease (AD), which often co-exists with iNPH. In this narrative review, we investigated the literature regarding CSF biomarkers in iNPH, both the established biomarkers total tau protein (t-tau), phosphorylated tau protein (p-tau) and amyloid peptide with 42 amino acids (Aß42), and other molecules, which are being investigated as emerging biomarkers. The majority of studies demonstrate differences in CSF concentrations of Aß42 and tau-proteins (t-tau and p-tau) among iNPH patients, healthy individuals and patients with AD and vascular dementia. iNPH patients present with lower CSF Aß42 and p-tau concentrations than healthy individuals and lower t-tau and p-tau concentrations than AD patients. This could prove helpful for improving diagnosis, differential diagnosis and possibly prognosis of iNPH patients.

Recognizing Atypical Presentations of Alzheimer's Disease: The Importance of CSF Biomarkers in Clinical Practice.

Besides the typical amnestic presentation, neuropathological studies indicate that Alzheimer's disease (AD) may present with atypical clinical pictures. The relative frequencies of typical and atypical or mixed presentations within the entire spectrum of AD remain unclear, while some mixed or atypical presentations may have not received adequate attention for them to be included in diagnostic criteria. We investigated the spectrum of clinical presentations in patients with the AD CSF biomarker profile (high tau and phospho-tau, low Aß42 levels), hospitalized in a tertiary academic center. Among 98 patients with the CSF AD profile, 46% of patients had the typical presentation of "hippocampal" amnestic dementia. Additionally, 23.5% and 15.3% fulfilled the criteria of mixed or atypical presentations, respectively, as described in the IWG-2 criteria. The remaining 15.3% had unusual presentations, including non-logopenic (semantic and non-fluent agrammatic) primary progressive aphasia, corticobasal syndrome, and Richardson syndrome, or could be diagnosed with normal pressure hydrocephalus. Despite selection bias (academic center), atypical clinical presentations of AD may be more common than previously thought. CSF biomarkers seem to be a useful tool for antemortem identification of such patients, which is likely to affect therapeutic decisions. Some of the unusual presentations described above should be incorporated in diagnostic criteria.

Cerebrospinal Fluid Biomarker Profile in TDP-43-Related Genetic Frontotemporal Dementia.

Cerebrospinal fluid (CSF) biomarkers, namely total tau, phospho-tau and amyloid beta peptides, have received much attention specifically regarding Alzheimer's disease (AD), since they can detect the biochemical fingerprint of AD and serve as a diagnostic tool for accurate and early diagnosis during life. In the same way, biomarkers for other neurodegenerative disease pathologies are also needed. We present a case series of six patients with genetic frontotemporal dementia (FTD), with TDP-43 underlying proteinopathy, in an attempt to assess TDP-43 as a novel biomarker alone and in combination with established AD biomarkers for this specific patient group, based on the principles of personalized and precision medicine. Our results indicate that genetic TDP-43-FTD is characterized by increased CSF TPD-43 and increased TDP-43 × τΤ/τP-181 combination. Hence, TDP-43 combined with tau proteins could be a useful tool for the diagnosis of genetic FTD with TDP-43 underling histopathology, supplementing clinical, neuropsychological and imaging data.

Silent Pauses and Speech Indices as Biomarkers for Primary Progressive Aphasia.

Background and Objectives: Recent studies highlight the importance of investigating biomarkers for diagnosing and classifying patients with primary progressive aphasia (PPA). Even though there is ongoing research on pathophysiological indices in this field, the use of behavioral variables, and especially speech-derived factors, has drawn little attention in the relevant literature. The present study aims to investigate the possible utility of speech-derived indices, particularly silent pauses, as biomarkers for primary progressive aphasia (PPA). Materials and Methods: We recruited 22 PPA patients and 17 healthy controls, from whom we obtained speech samples based on two elicitation tasks, i.e., cookie theft picture description (CTP) and the patients' personal narration of the disease onset and course. Results: Four main indices were derived from these speech samples: speech rate, articulation rate, pause frequency, and pause duration. In order to investigate whether these indices could be used to discriminate between the four groups of participants (healthy individuals and the three patient subgroups corresponding to the three variants of PPA), we conducted three sets of analyses: a series of ANOVAs, two principal component analyses (PCAs), and two hierarchical cluster analyses (HCAs). The ANOVAs revealed significant differences between the four subgroups for all four variables, with the CTP results being more robust. The subsequent PCAs and HCAs were in accordance with the initial statistical comparisons, revealing that the speech-derived indices for CTP provided a clearer classification and were especially useful for distinguishing the non-fluent variant from healthy participants as well as from the two other PPA taxonomic categories. Conclusions: In sum, we argue that speech-derived indices, and especially silent pauses, could be used as complementary biomarkers to efficiently discriminate between PPA and healthy speakers, as well as between the three variants of the disease.

Expanding the spectrum of C9ORF72-related neurodegenerative disorders in the Greek population.

The C9ORF72 hexanucleotide repeat expansion is an established cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and has also been associated with Huntington disease (HD)-like syndromes and rarely with Parkinson's disease (PD) and Alzheimer's disease (AD). In the present study we aimed to investigate the genotypic and phenotypic profile of C9ORF72-related disorders in Greece. For this reason, 957 patients (467 with ALS, 53 with HD-like syndromes, 247 with dementia, 175 with PD and 15 with hereditary spastic paraplegia, HSP) and 321 controls were tested for the C9ORF72 repeat expansion. Forty-nine patients with ALS (10.5%), 2 with HD-like syndromes (3.8%), 13 with FTD (11.5%), 1 with AD (1.6%), and 2 with PD (1.1%) were expansion-positive. The expansion was not detected in the HSP or control groups. The results of this study provide an update on the spectrum of C9ORF72-related neurodegenerative diseases, emphasizing the importance of C9ORF72 genetic testing in Greek patients with familial and sporadic ALS and/or FTD and HD-like syndromes.