Sulcal Morphometry Predicts Mild Cognitive Impairment Conversion to Alzheimer's Disease.

Background: Being able to differentiate mild cognitive impairment (MCI) patients who would eventually convert (MCIc) to Alzheimer's disease (AD) from those who would not (MCInc) is a key challenge for prognosis. Objective: This study aimed to investigate the ability of sulcal morphometry to predict MCI progression to AD, dedicating special attention to an accurate identification of sulci. Methods: Twenty-five AD patients, thirty-seven MCI and twenty-five healthy controls (HC) underwent a brain-MR protocol (1.5T scanner) including a high-resolution T1-weighted sequence. MCI patients underwent a neuropsychological assessment at baseline and were clinically re-evaluated after a mean of 2.3 years. At follow-up, 12 MCI were classified as MCInc and 25 as MCIc. Sulcal morphometry was investigated using the BrainVISA framework. Consistency of sulci across subjects was ensured by visual inspection and manual correction of the automatic labelling in each subject. Sulcal surface, depth, length, and width were retrieved from 106 sulci. Features were compared across groups and their classification accuracy in predicting MCI conversion was tested. Potential relationships between sulcal features and cognitive scores were explored using Spearman's correlation. Results: The width of sulci in the temporo-occipital region strongly differentiated between each pair of groups. Comparing MCIc and MCInc, the width of several sulci in the bilateral temporo-occipital and left frontal areas was significantly altered. Higher width of frontal sulci was associated with worse performances in short-term verbal memory and phonemic fluency. Conclusions: Sulcal morphometry emerged as a strong tool for differentiating HC, MCI, and AD, demonstrating its potential prognostic value for the MCI population.

Multimodal investigation of melanopsin retinal ganglion cells in Alzheimer's disease.

OBJECTIVE: In Alzheimer's disease (AD), the presence of circadian dysfunction is well-known and may occur early in the disease course. The melanopsin retinal ganglion cell (mRGC) system may play a relevant role in contributing to circadian dysfunction. In this study, we aimed at evaluating, through a multimodal approach, the mRGC system in AD at an early stage of disease. METHODS: We included 29 mild-moderate AD (70.9 ± 11 years) and 26 (70.5 ± 8 years) control subjects. We performed an extensive neurophtalmological evaluation including optical coherence tomography with ganglion cell layer segmentation, actigraphic evaluation of the rest-activity rhythm, chromatic pupillometry analyzed with a new data-fitting approach, and brain functional MRI combined with light stimuli assessing the mRGC system. RESULTS: We demonstrated a significant thinning of the infero-temporal sector of the ganglion cell layer in AD compared to controls. Moreover, we documented by actigraphy the presence of a circadian-impaired AD subgroup. Overall, circadian measurements worsened by age. Chromatic pupillometry evaluation highlighted the presence of a pupil-light response reduction in the rod condition pointing to mRGC dendropathy. Finally, brain fMRI showed a reduced occipital cortex activation with blue light particularly for the sustained responses. INTERPRETATION: Overall, the results of this multimodal innovative approach clearly document a dysfunctional mRGC system at early stages of disease as a relevant contributing factor for circadian impairment in AD providing also support to the use of light therapy in AD.

The Tree Drawing Test in Evolution: An Explorative Longitudinal Study in Alzheimer's Disease.

OBJECTIVE: To study the evolution of the Tree Drawing Test (TDT) in a group of Alzheimer's disease (AD) patients. METHODS: A total of 33 AD patients were consecutively evaluated by Mini Mental State Evaluation (MMSE) and TDT. The evolution of the TDT parameters, trunk-to-crown (TC) and space occupation (SO) index, were analyzed. RESULTS: The median age at first visit was 79 years. Globally, trees drawn by patients showed an evolution characterized by a progressive reduction of the crown compared to the trunk. TC index showed a significant linear growth change (2.52 points per year) while SO index did not significantly increase. No significant associations were found examining the relations between MMSE and TC and SO index. CONCLUSIONS: TDT could represent a complementary technique to the main neuropsychological screening tests for orienting cognitive impairment diagnosis and an aid in following the evolution of cognitive impairment over time in AD patients.

Diagnostic value of plasma p-tau181, NfL, and GFAP in a clinical setting cohort of prevalent neurodegenerative dementias.

BACKGROUND: Increasing evidence supports the use of plasma biomarkers of neurodegeneration and neuroinflammation to screen and diagnose patients with dementia. However, confirmatory studies are required to demonstrate their usefulness in the clinical setting. METHODS: We evaluated plasma and cerebrospinal fluid (CSF) samples from consecutive patients with frontotemporal dementia (FTD) (n = 59), progressive supranuclear palsy (PSP) (n = 31), corticobasal syndrome (CBS) (n = 29), dementia with Lewy bodies (DLB) (n = 49), Alzheimer disease (AD) (n = 97), and suspected non-AD physiopathology (n = 51), as well as plasma samples from 60 healthy controls (HC). We measured neurofilament light chain (NfL), phospho-tau181 (p-tau181), and glial fibrillary acid protein (GFAP) using Simoa (all plasma biomarkers and CSF GFAP), CLEIA (CSF p-tau181), and ELISA (CSF NfL) assays. Additionally, we stratified patients according to the A/T/N classification scheme and the CSF α-synuclein real-time quaking-induced conversion assay (RT-QuIC) results. RESULTS: We found good correlations between CSF and plasma biomarkers for NfL (rho = 0.668, p < 0.001) and p-tau181 (rho = 0.619, p < 0.001). Plasma NfL was significantly higher in disease groups than in HC and showed a greater increase in FTD than in AD [44.9 (28.1-68.6) vs. 21.9 (17.0-27.9) pg/ml, p < 0.001]. Conversely, plasma p-tau181 and GFAP levels were significantly higher in AD than in FTD [3.2 (2.4-4.3) vs. 1.1 (0.7-1.6) pg/ml, p < 0.001; 404.7 (279.7-503.0) vs. 198.2 (143.9-316.8) pg/ml, p < 0.001]. GFAP also allowed discriminating disease groups from HC. In the distinction between FTD and AD, plasma p-tau181 showed better accuracy (AUC 0.964) than NfL (AUC 0.791) and GFAP (AUC 0.818). In DLB and CBS, CSF amyloid positive (A+) subjects had higher plasma p-tau181 and GFAP levels than A- individuals. CSF RT-QuIC showed positive α-synuclein seeding activity in 96% DLB and 15% AD patients with no differences in plasma biomarker levels in those stratified by RT-QuIC result. CONCLUSIONS: In a single-center clinical cohort, we confirm the high diagnostic value of plasma p-tau181 for distinguishing FTD from AD and plasma NfL for discriminating degenerative dementias from HC. Plasma GFAP alone differentiates AD from FTD and neurodegenerative dementias from HC but with lower accuracy than p-tau181 and NfL. In CBS and DLB, plasma p-tau181 and GFAP levels are significantly influenced by beta-amyloid pathology.

Dementia-related genetic variants in an Italian population of early-onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) is the most common form of early-onset dementia. Although three major genes have been identified as causative, the genetic contribution to the disease remains unsolved in many patients. Recent studies have identified pathogenic variants in genes representing a risk factor for developing Alzheimer's disease (AD) and in causative genes for other degenerative dementias as responsible for EOAD. To study them further, we investigated a panel of candidate genes in 102 Italian EOAD patients, 45.10% of whom had a positive family history and 21.74% with a strong family history of dementia. We found that 10.78% of patients carried pathogenic or likely pathogenic variants, including a novel variant, in PSEN1, PSEN2, or APP, and 7.84% showed homozygosity for the ε4 APOE allele. Additionally, 7.84% of patients had a moderate risk allele in PSEN1, PSEN2, or TREM2 genes. Besides, we observed that 12.75% of our patients carried only a variant in genes associated with other neurodegenerative diseases. The combination of these variants contributes to explain 46% of cases with a definite familiarity and 32% of sporadic forms. Our results confirm the importance of extensive genetic screening in EOAD for clinical purposes, to select patients for future treatments and to contribute to the definition of overlapping pathogenic mechanisms between AD and other forms of dementia.

Italian adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB 1.0): development and normative data.

BACKGROUND: Neuropsychological testing plays a cardinal role in the diagnosis and monitoring of Alzheimer's disease. A major concern is represented by the heterogeneity of the neuropsychological batteries currently adopted in memory clinics and healthcare centers. The current study aimed to solve this issue. METHODS: Following the initiative of the University of Washington's National Alzheimer's Coordinating Center (NACC), we presented the Italian adaptation of the Neuropsychological Test Battery of the Uniform Data Set (I-UDSNB). We collected data from 433 healthy Italian individuals and employed regression models to evaluate the impact of demographic variables on the performance, deriving the reference norms. RESULTS: Higher education and lower age were associated with a better performance in the majority of tests, while sex affected only fluency tests and Digit Span Forward. CONCLUSIONS: The I-UDSNB offers a valuable and harmonized tool for neuropsychological testing in Italy, to be used in clinical and research settings.

Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer's disease and longevity in an Italian population.

Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant "zeitgeber" able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.

Diagnostic Value of the CSF α-Synuclein Real-Time Quaking-Induced Conversion Assay at the Prodromal MCI Stage of Dementia With Lewy Bodies.

OBJECTIVE: To investigate whether the CSF α-synuclein (α-syn) real-time quaking-induced conversion (RT-QuIC) assay accurately identifies patients with mild cognitive impairment (MCI) due to probable Lewy body (LB) disease. METHODS: We applied α-syn RT-QuIC to 289 CSF samples obtained from 2 independent cohorts, including 81 patients with probable MCI-LB (age 70.7 ± 6.6 years, 13.6% female, Mini-Mental State Examination [MMSE] score 26.1 ± 2.4), 120 with probable MCI due to Alzheimer disease (AD) (age 68.6 ± 7.4 years, 45.8% female, MMSE score 25.5 ± 2.8), and 30 with unspecified MCI (age 65.4 ± 9.3 years, 30.0% female, MMSE score 27.0 ± 3.0). Fifty-eight individuals with no cognitive decline or evidence of neurodegenerative disease and 121 individuals lacking brain α-syn deposits at the neuropathologic examination were used as controls. RESULTS: RT-QuIC identified patients with MCI-LB against cognitively unimpaired controls with 95% sensitivity, 97% specificity, and 96% accuracy and showed 98% specificity in neuropathologic controls. The accuracy of the test for MCI-LB was consistent between the 2 cohorts (97.3% vs 93.7%). Thirteen percent of patients with MCI-AD also had a positive test; of note, 44% of them developed 1 core or supportive clinical feature of dementia with Lewy bodies (DLB) at follow-up, suggesting an underlying LB copathology. CONCLUSIONS: These findings indicate that CSF α-syn RT-QuIC is a robust biomarker for prodromal DLB. Further studies are needed to fully explore the added value of the assay to the current research criteria for MCI-LB. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CSF α-syn RT-QuIC accurately identifies patients with MCI-LB.

The Combination of Metabolic Posterior Cingulate Cortical Abnormalities and Structural Asymmetries Improves the Differential Diagnosis Between Primary Progressive Aphasia and Alzheimer's Disease.

Differential diagnosis between primary progressive aphasia (PPA) and Alzheimer's disease (AD) could be difficult if based on clinical grounds alone. We evaluated the combination of proton MR spectroscopy of posterior cingulate cortex (PCC) and quantitative structural imaging asymmetries to differentiate PPA from AD patients. A greater left-lateralized temporo-parietal atrophy (higher accuracy for the PCC, 81.4%) and metabolic neurodegenerative changes in PCC (accuracy 76.8%) was demonstrated in PPA versus AD. The combined multiparametric approach increased the accuracy to 94%in the differential diagnosis between these two neurodegenerative diseases.

In Vivo Diagnosis of Synucleinopathies: A Comparative Study of Skin Biopsy and RT-QuIC.

OBJECTIVE: To determine whether (1) immunofluorescence is a reproducible technique in detecting misfolded α-synuclein in skin nerves and subsequently whether (2) immunofluorescence and real-time quaking-induced conversion (RT-QuIC) (both in skin and CSF) show a comparable in vivo diagnostic accuracy in distinguishing synucleinopathies from non-synucleinopathies in a large cohort of patients. METHODS: We prospectively recruited 90 patients fulfilling clinical and instrumental diagnostic criteria for all synucleinopathies variants and non-synucleinopathies (mainly including Alzheimer disease, tauopathies, and vascular parkinsonism or dementia). Twenty-four patients with mainly peripheral neuropathies were used as controls. Patients underwent skin biopsy for immunofluorescence and RT-QuIC; CSF was examined in patients who underwent lumbar puncture for diagnostic purposes. Immunofluorescence and RT-QuIC analysis were made blinded to the clinical diagnosis. RESULTS: Immunofluorescence showed reproducible results between 2 pairs of neighboring skin samples. Both immunofluorescence and RT-QuIC showed high sensitivity and specificity in discriminating synucleinopathies from non-synucleinopathies and controls but immunofluorescence presented higher diagnostic accuracy. Immunofluorescence presented a good level of agreement with RT-QuIC in both skin and CSF in synucleinopathies. CONCLUSIONS: Both immunofluorescence and RT-QuIC showed high diagnostic accuracy, although immunofluorescence displayed the better value as well as optimal reproducibility; they presented a good level of agreement in synucleinopathies, supporting the use of less invasive tests such as skin immunofluorescence or RT-QuIC instead of CSF RT-QuIC as a diagnostic tool for synucleinopathies. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that immunofluorescence or RT-QuIC accurately distinguish synucleinopathies from non-synucleinopathies.

Cognitive Profile and Its Evolution in a Cohort of Multiple System Atrophy Patients.

Introduction: Cognitive decline is not a characteristic feature of multiple system atrophy (MSA), but recent evidence suggests cognitive impairment as an integral part of the disease. We aim to describe the cognitive profile and its progression in a cohort of patients with MSA. Methods: We retrospectively selected patients referred to our department with a clinical diagnosis of MSA who were evaluated at least once a year during the course of the disease and underwent a comprehensive neuropsychological evaluation. Results: At the first evaluation (T0), 37 out of 60 patients (62%) were cognitively impaired, mainly (76%) in attention and executive functioning. Thirteen patients were impaired in one cognitive domain and 24 in more than one cognitive domain. Six out of the 24 had dementia. Twenty patients underwent a follow-up evaluation (T1) after a mean of 16.6 ± 9.3 months from the first evaluation (T0). Eight out of 20 patients were cognitively normal at both T0 and T1. Seven out of 12 patients presented with stable cognitive impairment at T1, while cognitive decline progressed in five patients. Patients with progression in cognitive decline performed significantly worse at T0 than cognitively stable patients. Education was significantly different between patients with and without cognitive impairment. No other differences in demographic and clinical variables and autonomic or sleep disturbances were found. Patients with dementia were older at disease onset and at T0 and had lower education and disease duration at T0 compared to those in other groups. Conclusions: In patients with MSA, we observed three different cognitive profiles: normal cognition, stable selective attention-executive deficits, and progressive cognitive deficits evolving to dementia. The detection of cognitive impairment in patients with suspected MSA suggests the need for comprehensive and longitudinal neuropsychological evaluation.

Chromatic Pupillometry Findings in Alzheimer's Disease.

Intrinsically photosensitive melanopsin retinal ganglion cells (mRGCs) are crucial for non-image forming functions of the eye, including the photoentrainment of circadian rhythms and the regulation of the pupillary light reflex (PLR). Chromatic pupillometry, using light stimuli at different wavelengths, makes possible the isolation of the contribution of rods, cones, and mRGCs to the PLR. In particular, post-illumination pupil response (PIPR) is the most reliable pupil metric of mRGC function. We have previously described, in post-mortem investigations of AD retinas, a loss of mRGCs, and in the remaining mRGCs, we demonstrated extensive morphological abnormalities. We noted dendrite varicosities, patchy distribution of melanopsin, and reduced dendrite arborization. In this study, we evaluated, with chromatic pupillometry, the PLR in a cohort of mild-moderate AD patients compared to controls. AD and controls also underwent an extensive ophthalmological evaluation. In our AD cohort, PIPR did not significantly differ from controls, even though we observed a higher variability in the AD group and 5/26 showed PIPR values outside the 2 SD from the control mean values. Moreover, we found a significant difference between AD and controls in terms of rod-mediated transient PLR amplitude. These results suggest that in the early stage of AD there are PLR abnormalities that may reflect a pathology affecting mRGC dendrites before involving the mRGC cell body. Further studies, including AD cases with more severe and longer disease duration, are needed to further explore this hypothesis.

Anterior Callosal Angle: A New Marker of Idiopathic Normal Pressure Hydrocephalus?

OBJECTIVE: Diagnosing idiopathic normal pressure hydrocephalus (iNPH) still remains a clinical challenge. The callosal angle (CA) is a widely used neuroradiologic marker for iNPH. However, the relationship of the CA to clinical features has not been well investigated. We hypothesize that iNPH symptoms might better correlate with a variant of the CA (anterior callosal angle [ACA]). We aim to establish the validity of the ACA measurement for the diagnosis of iNPH and compare it with current radiologic parameters. METHODS: The multidisciplinary BOLOGNA PRO-HYDRO Study Group performed a retrospective review of consecutive iNPH patients. Magnetic resonance imaging studies for these patients were collected, as well as magnetic resonance imaging studies from Alzheimer disease and healthy control patients. The CA, ACA, and Evans Index were measured by 2 blinded members of the study team based on magnetic resonance images for each of these populations. RESULTS: The ACA shows high accuracy, sensitivity, and specificity in distinguishing iNPH patients from healthy control and Alzheimer disease patients. The optimal pathologic diagnostic cut-off value for the ACA is 119 degrees. The diagnostic accuracy of the ACA is not significantly different from the CA. CONCLUSIONS: The ACA could be a valid radiologic parameter in the diagnostic armamentarium for iNPH.

Color Choice Preference in Cognitively Impaired Patients: A Look Inside Alzheimer's Disease Through the Use of Lüscher Color Diagnostic.

OBJECTIVE: To study the emotional state of cognitively impaired patients through the color choice preference in a group of Alzheimer's disease (AD) patients and compare it with a group of Mild Cognitive Impairment (MCI) patients and a matched control group. METHODS: A total of 71 AD, 50 MCI and 68 controls were consecutively evaluated. All patients and controls underwent the Mini Mental State Evaluation (MMSE) and the Lüscher color test. RESULTS: Cognitively impaired patients mainly chose auxiliary colors, in particular violet and brown, and rejected black and gray. AD patients predominantly chose forms corresponding to auxiliary colors. The auxiliary color choice negatively correlated with the MMSE score. MCI patients and controls had a higher presence of anxiety on gray table and controls had higher frustration and ambivalence, i.e., psychic complexity, on basic color tables.Data globally suggest that AD patients live with a feeling of personal change due to instability and emotional insecurity, experiencing physical discomfort and a bodily need of being welcomed in a favorable environment. They aspire to a sensitive understanding by someone with whom they can be identified. Differently, MCI patients have less of these needs; however, they feel more anxious. CONCLUSION: The comprehension of the inner emotional state of cognitively impaired patients allows us to better communicate with them and effectively approach their behavioral disorders. Like other projective techniques, such as the tree-drawing test and the human figure-drawing test, Lüscher color test is proposed as a simple and unconventional approach to understand the emotional life of AD patients. The awareness of clinicians about the existential fragility and insecurity of such type of patients allows us not only to better manage their behavioral disturbances but also to improve their quality of life and that of their caregivers.

Effects on cognition of 20-day anodal transcranial direct current stimulation over the left dorsolateral prefrontal cortex in patients affected by mild cognitive impairment: a case-control study.

BACKGROUND: Mild cognitive impairment (MCI) is a common disorder affecting as much as 15% of the elderly population. Transcranial direct current stimulation (tDCS) is a non-invasive technique of neuromodulation that has proven to influence performance in different cognitive domains. OBJECTIVE/HYPOTHESIS: We investigated the effects on cognition of 20-day anodal tDCS in 17 MCI patients compared with 17 matched MCI patients. METHODS: Patients underwent neuropsychological evaluation at baseline and then were randomly assigned to the anodal or sham group. The tDCS protocol consisted in 20 min, 5 days per week (up to a total of 20 days), of 2-mA anodal stimulation over the left dorsolateral prefrontal cortex (DLPFC). The location of anodal electrode was chosen in accordance with previous reports which relate anodal stimulation of this site with cognitive enhancement. At the end of the last day of stimulation, a second neuropsychological evaluation was performed. We compared baseline and post-stimulation neuropsychological results in the anodal vs sham group using repeated measures ANOVA as a statistical analysis test. RESULTS: At follow-up, patients exposed to anodal stimulation showed improvement in episodic verbal memory (p < 0.001) and figure naming test (p < 0.01), in a general index of cognitive function (Brief Mental Deterioration Battery) (p < 0.0001) and in a mood measurement test (Beck Depression Inventory) (p < 0.01). CONCLUSION: Anodal tDCS could be a useful tool to improve cognitive symptoms in MCI although more evidence is needed to understand the exact underlying mechanisms. Confirmation of its potential benefits in MCI would be significant.

Predicting conversion from mild cognitive impairment to Alzheimer's disease using brain 1H-MRS and volumetric changes: A two- year retrospective follow-up study.

This study investigated the ability of magnetic resonance spectroscopy (1H-MRS) of posterior cingulate cortex (PCC) and brain volumetry to predict the progression from mild cognitive impairment (MCI) to Alzheimer's Disease (AD) on the basis of clinical classification at 2 years follow-up. Thirty-eight MCI patients, eighteen healthy older adults and twenty-three AD patients were included in this study. All participants underwent a brain-MR protocol (1.5 T GE scanner) including high-resolution T1-weighted volumetric sequence (isotropic 1mm3). Voxel-wise differences in brain volumetry were evaluated using FreeSurfer software and all volumes were normalized by the total intracranial volume (TIV). Careful localization of 1H-MRS volume of PCC was performed and data were processed with the LCModel program. MCI patients underwent a complete neuropsychological assessment at baseline and were clinically re-evaluated after a mean of 28 months; twenty-six MCI patients (68.4%) converted to AD and twelve remained stable. At baseline these two MCI subgroups did not differ in the global cognitive level (Mini Mental State Examination, MMSE) or in any of the other cognitive domains; the NAA/ mI ratio in the PCC was able to differentiate MCI converters from those MCI that did not develop AD (p = 0.022) with a level of accuracy (AUC area) of 0.779. A significantly reduced volume of parahippocampal gyrus (p = 0.010) and fusiform gyrus (p = 0.026) were found in the converter MCI subgroup compared to the stable MCI subgroup. The combined use of both N- acetyl-aspartate (NAA)/myo-Inositol (mI) ratio and volume of parahippocampal gyrus, increases the overall accuracy (AUC = 0.910) in predicting the conversion to AD two years before the development of clinical symptoms. Additional longitudinal studies with a broader representative sample of MCI patients and longer follow-up might be helpful to confirm these results and to elucidate the role of each parameter in predicting the possible progression to AD, and also to all the other non-AD dementia subtypes.

Revisiting the Cerebrospinal Fluid Biomarker Profile in Idiopathic Normal Pressure Hydrocephalus: The Bologna Pro-Hydro Study.

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in idiopathic normal pressure hydrocephalus (iNPH) with the aim of a better differential diagnosis, but the pathophysiological mechanisms underlying CSF biomarker changes and the relationship between biomarker levels and clinical variables are still a matter of debate. We evaluated CSF amyloid-ß (Aß)42 and Aß40, total (t)-tau, phosphorylated (p)-tau, total prion protein (t-PrP), and neurofilament light chain protein (NfL) in healthy controls (n = 50) and subjects with iNPH (n = 71), Alzheimer's disease (AD) (n = 60), and several other subtypes of dementia (n = 145). Patients with iNPH showed significantly lower levels of Aß42, Aß40, t-tau, and p-tau compared to controls. Similarly, t-PrP values showed a trend toward lower levels in iNPH patients than in controls. At variance, NfL levels were increased in iNPH as in all other neurodegenerative dementias, with no significant difference between "pure" iNPH cases and those with vascular or AD comorbidities. The Aß42/Aß40 ratio showed higher diagnostic value than Aß42 alone in the differential diagnosis between iNPH and AD. There were no clinically relevant associations between neuroimaging markers, scores at clinical and cognitive scales/tests, or rates of response at tap test and CSF biomarker results. In summary, the CSF biomarker signature in patients with iNPH is mainly characterized by reduced CSF concentrations of Aß- and tau-related proteins. The assessment of CSF neurodegenerative biomarker profile in iNPH, including the Aß42/Aß40 ratio, contributes to the differential diagnosis with AD and other dementias but shows poor associations with clinical variables.

Cerebrospinal Fluid Biomarkers in Patients with Frontotemporal Dementia Spectrum: A Single-Center Study.

Cerebrospinal fluid (CSF) neurofilament light chain protein (NfL) and Alzheimer's disease (AD) core biomarker levels have been evaluated in cohorts of patients with frontotemporal dementia spectrum (FTD), but the distribution of values across the different clinical syndromes and underlying proteinopathies, and the relative diagnostic accuracy appear discordant among studies. We measured CSF NfL, total (t)-tau, phosphorylated (p)-tau, and amyloid-ß (Aß)42 in healthy controls (n = 38) and subjects with a clinical, genetic, CSF biomarker-based, and/or neuropathological diagnosis of FTD (n = 141) or AD (n = 60). Sub-analyses were conducted in a proportion of subjects with definite and/or probable frontotemporal lobar degeneration with tau (FTLD-TAU) (n = 42) or TDP43 pathology (FTLD-TDP) (n = 36). Both FTD and AD groups showed significantly increased CSF NfL levels in comparison to controls (p < 0.001). CSF NfL levels were significantly higher in FTD patients than in AD (p < 0.001), reaching the highest values in amyotrophic lateral sclerosis associated with FTD. Patients with probable and definite FTLD-TDP had significantly higher NfL levels (p < 0.001) and lower p-tau/t-tau values (p < 0.001) in comparison with probable and definite FTLD-TAU cases. NfL showed good diagnostic accuracy in the distinction between FTD and controls (AUC 0.862±0.027) and yielded an accuracy (AUC 0.861±0.045) comparable to that of the p-tau/t-tau ratio (AUC 0.814±0.050), with 80.0% sensitivity and 81.0% specificity, in the discrimination between probable/definite FTLD-TAU and FTLD-TDP. Our data further validate CSF NfL as a surrogate biomarker of neurodegeneration and disease severity in patients with FTD spectrum. Moreover, they demonstrate a good diagnostic value for NfL and p-tau/t-tau ratio in the discrimination between FTLD-TAU and FTLD-TDP.