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

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

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

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

The expression of interictal, preictal, and postictal facial-wiping behavior in temporal lobe epilepsy: a neuro-ethological analysis and interpretation.

By videotape recordings analysis we investigated the frequencies of interictal, preictal, and postictal wiping or rubbing movements targeting the face region (face wiping, FW) in 17 right and 13 left mesial temporal lobe epilepsy (MTLE) patients. Patients' data were compared with FW frequencies obtained in 22 healthy controls listening to a presentation. Results showed that: (1) FW movements were present in both controls and patients; however, the patient groups showed lower interictal and preictal FW rates relative than controls; (2) right and left temporal lobe seizures were followed by a marked increase in the expression of wiping activities directed to the nose as well as to other face regions with respect to the interictal-preictal period; (3) during the first 5min postictal FW was performed preferentially with the hand ipsilateral to the seizure focus; (4) postictal examination of the patient by an observer, especially if of the opposite sex, resulted in a higher incidence of FW acts. After temporal lobe seizures there is an exaggerated expression of movements targeting the face region, and not exclusively directed to the nose. According to an ethological interpretation of the FW behavior as a motor behavior present throughout the phylogenetic scale, from rodents to primates, we suggest the postictal emergence of an innate action pattern modulated by external emotional-cognitive stimuli

The expression of interictal, preictal, and postictal facial-wiping behavior in temporal lobe epilepsy: a neuro-ethological analysis and interpretation

By videotape recordings analysis we investigated the frequencies of interictal, preictal, and postictal wiping or rubbing movementstargeting the face region (face wiping, FW) in 17 right and 13 left mesial temporal lobe epilepsy (MTLE) patients. Patientsdata were compared with FW frequencies obtained in 22 healthy controls listening to a presentation. Results showed that: (1) FWmovements were present in both controls and patients; however, the patient groups showed lower interictal and preictal FW ratesrelative than controls; (2) right and left temporal lobe seizures were followed by a marked increase in the expression of wipingactivities directed to the nose as well as to other face regions with respect to the interictal–preictal period; (3) during the first 5 minpostictal FW was performed preferentially with the hand ipsilateral to the seizure focus; (4) postictal examination of the patient byan observer, especially if of the opposite sex, resulted in a higher incidence of FW acts. After temporal lobe seizures there is anexaggerated expression of movements targeting the face region, and not exclusively directed to the nose. According to an ethological interpretation of the FW behavior as a motor behavior present throughout the phylogenetic scale, from rodents to primates, we suggest the postictal emergence of an innate action pattern modulated by external emotional–cognitive stimuli

"Hand to face": A behaviour modulated by epileptic seizures | ["La mano al viso": Un comportamento modulato dalle crisi epilettiche]

Postictal nosewiping is commonly observed in temporal lobe epilepsy and is highly predictive of seizure onset ipsilateral to the hand used. Our aim was to quantify by videotape analysis all hand movements directed toward either the nose or mouth, eye, ear, front and scalp in the preictal, postictal, and interictal periods. We found that these movements represent a unique pattern of behaviour, facilitated in the postictal period, and not necessarily reflex movements triggered by ictal-related vegetative modifications

\uc9mergence de comportements moteurs inn\ue9s communs aux crises frontales nocturnes et aux parasomnies:approche \ue9thologique et r\uf4le des \uabcentral pattern generators\ubb

Certaines crises \ue9pileptiques pr\ue9sentent, au cours de leur d\ue9roulement, des s\ue9quences motrices st\ue9r\ue9otyp\ue9es qui correspondent \ue0 des comportements moteurs inn\ue9s que l'on retrouve \ue0 l'identique au cors de l'\ue9volution, des premiers vert\ue9br\ue9s jusqu'\ue0 l'homme. Par ailleurs, on d\ue9crit des comportements moteur analogues, sinon identiques, qui surviennent au cors du sommeil chez des sujets non \ue9pileptiques, sous le nom de \uabparasomnies\ubb