Clinical and neuroradiological spectrum of biallelic variants in NOTCH3.

BACKGROUND: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised. METHODS: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants. FINDINGS: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches. INTERPRETATION: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD. FUNDING: The Wellcome Trust, the MRC.

Expanding the Neurological Phenotype of Anderson-Fabry Disease: Proof of Concept for an Extrapyramidal Neurodegenerative Pattern and Comparison with Monogenic Vascular Parkinsonism.

Anderson-Fabry disease (AFD) is a genetic sphingolipidosis involving virtually the entire body. Among its manifestation, the involvement of the central and peripheral nervous system is frequent. In recent decades, it has become evident that, besides cerebrovascular damage, a pure neuronal phenotype of AFD exists in the central nervous system, which is supported by clinical, pathological, and neuroimaging data. This neurodegenerative phenotype is often clinically characterized by an extrapyramidal component similar to the one seen in prodromal Parkinson's disease (PD). We analyzed the biological, clinical pathological, and neuroimaging data supporting this phenotype recently proposed in the literature. Moreover, we compared the neurodegenerative PD phenotype of AFD with a classical monogenic vascular disease responsible for vascular parkinsonism and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). A substantial difference in the clinical and neuroimaging features of neurodegenerative and vascular parkinsonism phenotypes emerged, with AFD being potentially responsible for both forms of the extrapyramidal involvement, and CADASIL mainly associated with the vascular subtype. The available studies share some limitations regarding both patients' information and neurological and genetic investigations. Further studies are needed to clarify the potential association between AFD and extrapyramidal manifestations.

The False Recognition Test, a new tool for the assessment of false memories, with normative data from an Italian sample.

INTRODUCTION: False memory can be defined as remembering something that did not happen. To a certain extent it is a normal phenomenon, but its occurrence seems to increase in healthy and pathological aging, possibly providing relevant clues on some clinical conditions in the spectrum of dementia. We adapted a well-established Deed-Roediger-McDermott paradigm, frequently used in experimental contexts, to devise a new neuropsychological assessment tool, the False Recognition Test (FRT), that can investigate classical facets of episodic memory performance (i.e. free recall and recognition), and assess proneness to produce semantically related and non-semantic false memories. Here we describe the FRT and provide normative data and correction grids to consider the possible effects of age, gender, and education on the FRT scores. METHOD: Two-hundred and thirty-two Italian healthy individuals (99 male) aged 18-91 years, with different educational levels (from primary to university) underwent the FRT, together with validated tests for cognitive screening and episodic memory assessment and one scale for depression. RESULTS: Multiple linear regression analysis revealed that age and education significantly influenced performance on FRT. From the derived linear equations, we provide correction grids for the raw scores of the FRT, and equivalent scores estimated using a nonparametric method. Correlational analysis showed significant associations between FRT subscores and cognitive, executive and memory functions, and depression. CONCLUSION: The FRT may constitute a useful instrument for both clinical and research purposes.

The involvement of rTPJ in intention attribution during social decision making: A TMS study.

The mini-Ultimatum Game (mini-UG) is a bargaining game used to assess the reactions of a responder to unfair offers made by a proposer under different intentionality conditions. Previous studies employing this task showed the activation of responders' right temporoparietal junction (rTPJ), which could be related to its involvement in judgments of intentionality. To verify this hypothesis, in the present study we applied online transcranial magnetic stimulation (TMS) over the rTPJ in responders during the mini-UG, in which we manipulated intention attribution implicitly. A cover story was employed to induce participants to believe they were interacting with another agent. We expected that interfering with the rTPJ could affect the ability of responders to assume proposers' perspective, producing higher rates of rejections of unfair offers when offers are perceived as independent from responders' intentionality to inequality. Twenty-six healthy women voluntarily participated in the study. In the mini-UG, an unfair distribution of the proposer (8/2 offer) was pitted against one of three alternative offers: fair-alternative (5/5), no-alternative (8/2), hyperfair-alternative (2/8). During the task, a train of TMS pulses was delivered at proposers' offer presentation in blocks of active (rTPJ) or control (Vertex) stimulation according to an ABAB design. As expected, findings showed that rejection of the no-alternative offers was higher under TMS stimulation of the rTPJ compared with the control TMS. This effect was modulated by the degree of trustworthiness in the cover story. These data contribute defining the mechanisms and brain areas underpinning social decision making as assessed by bargaining tasks.

A digital teleneuropsychology platform for the diagnosis of mild cognitive impairment: from concept to certification as a medical device.

BACKGROUND: Innovative digital solutions are shaping a new concept of dementia care, opening additional venues for prevention, diagnosis, monitoring and treatment. Hereby, we report the development of a tablet-based teleneuropsychology platform (Tenèpsia®), from concept to certification as Medical Device (MD) Class IIA, as per new MD regulation 745/2017. METHODS: The platform was designed for the remote cognitive evaluation and created thanks to the effort of a collaborative working group including experts from three Italian scientific societies and Biogen Italia S.r.l. (hereafter "Biogen"), and developers from Xenia Reply and Inside AI. The development strategy was guided by converting traditional paper-and-pencil tests into digital versions while maintaining comparable neuropsychological features and optimizing patient accessibility and user experience. The experts focused on the choice and adaptation of traditional neuropsychology measures for a 45-min teleneuropsychology assessment. RESULTS: The developers created a web and a mobile interface, respectively, for the professional (neuropsychologist) and non-professional (patient and caregiver) use. Recording of voice, drawing and typing information was enabled. Instant dashboards provide a quick overview of the patient's condition. Simulation activities were performed to obtain MD certification, valid across Europe. CONCLUSION: Neuropsychology services will benefit from the implementation in clinics of harmonized digital tools with adequate scientific and technological standards. The use of digital cognitive testing for the diagnosis of mild cognitive impairment is expected to enhance patient and clinician outcomes through simplified, digital objective data collection, sparing of time and resources, with a positive impact on healthcare costs and access to treatments, reducing inequalities and delays in diagnosis and cure.

Measuring mindreading in preschoolers: The perspective battery (PERBAT).

OBJECTIVE: The capacity to take another person's visual perspective is pivotal for solving mindreading tests, such as Theory of Mind (ToM) tasks, but most of them heavily rely on domain-general abilities (e.g., language, executive functions). Here we present a novel battery of visual perspective-taking tests for child neuropsychological assessment, the Perspective Battery (PERBAT), which poses a limited load on domain-general abilities. METHODS: The battery includes four tests: i) Block Building; ii) Hide and Seek; iii) Deceptive Figures; iv) Double-Sided Shelf. We administered the PERBAT to 126 typically developing preschoolers (65 males; 3-6-year-old); the participants also performed classical tests of social cognition, language, and nonverbal abstract reasoning. RESULTS: The scores of all the PERBAT tests were significantly and positively related with age and scores of the classical social cognition tests, but not with scores of the language and nonverbal abstract reasoning tests. CONCLUSIONS: The PERBAT could represent a useful neuropsychological tool providing a comprehensive assessment of visual perspective-taking skills in preschool children. Future investigation is needed to examine the validity of the PERBAT with neurotypical samples across countries, race, ethnicity, and language as well as with clinical populations. Longitudinal studies are also encouraged to examine whether early visual perspective-taking weaknesses are associated with later development of mindreading skills.

Spontaneous eye blinking during an auditory, an interoceptive and a visual task: The role of the sensory modality and the attentional focus.

Previous evidence suggested that spontaneous eye blinking changes as a function of the attentional focus. In particular, eye blink rate (EBR) tends to increase when attention is directed to internal versus environmental processing. Most studies on this issue compared eye blinking during visual and mental imagery tasks, and interpreted the increase in EBR as a mechanism to focus cognitive resources on internal processing by disengaging attention from interfering information. However, since eye blinking also depends on the sensory modality of the task, the findings might be influenced by a modality-specific effect. In the present Registered Report we aim at investigating whether the environmental versus internal attentional focus can affect spontaneous blinking behaviour in non-visual tasks as well, in conditions where visual stimuli are not relevant. In a within-subject design, healthy participants performed an interoceptive task (i.e., heartbeat counting) and an auditory task in which pre-recorded heartbeats were presented aurally; during both tasks irrelevant visual stimuli were also presented. In a further control condition with the same auditory and visual stimuli, the participants were required to focus their attention on visual stimuli. Participants' EBR was recorded during each task by means of an eye-tracking system. We found that, although the interoceptive task was more difficult than the auditory and visual tasks, participants' EBR decreased by a comparable level in all tasks with respect to a rest condition, with no differences between internal versus environmental conditions. The present findings do not support the idea that EBR is modulated by an internal versus external focus of attention, at least in presence of controlled visual stimulation.

Memory Phenotypes In Early, De Novo Parkinson's Disease Patients with Mild Cognitive Impairment.

BACKGROUND: Memory deficits in mild cognitive impairment related to Parkinson's disease (PD-MCI) are quite heterogeneous, and there is no general agreement on their genesis. OBJECTIVES: To define memory phenotypes in de novo PD-MCI and their associations with motor and non-motor features and patients' quality of life. METHODS: From a sample of 183 early de novo patients with PD, cluster analysis was applied to neuropsychological measures of memory function of 82 patients with PD-MCI (44.8%). The remaining patients free of cognitive impairment were considered as a comparison group (n = 101). Cognitive measures and structural magnetic resonance imaging-based neural correlates of memory function were used to substantiate the results. RESULTS: A three-cluster model produced the best solution. Cluster A (65.85%) included memory unimpaired patients; Cluster B (23.17%) included patients with mild episodic memory disorder related to a "prefrontal executive-dependent phenotype"; Cluster C (10.97%) included patients with severe episodic memory disorder related to a "hybrid phenotype," where hippocampal-dependent deficits co-occurred with prefrontal executive-dependent memory dysfunctions. Cognitive and brain structural imaging correlates substantiated the findings. The three phenotypes did not differ in terms of motor and non-motor features, but the attention/executive deficits progressively increased from Cluster A, through Cluster B, to Cluster C. This last cluster had worse quality of life compared to others. CONCLUSIONS: Our results demonstrated the memory heterogeneity of de novo PD-MCI, suggesting existence of three distinct memory-related phenotypes. Identification of such phenotypes can be fruitful in understanding the pathophysiological mechanisms underlying PD-MCI and its subtypes and in guiding appropriate treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Memory biases in Alzheimer's disease and mild cognitive impairment. A systematic review and metanalysis.

Several studies demonstrated that individuals are more likely to remember emotional than neutral information; this phenomenon is known as emotional enhancement of memory (EEM). Adults generally tend to remember negative information more efficiently than neutral or positive items. In contrast, healthy elders seem to show an opposite bias for positive information, but results are inconsistent, also because during aging, elaboration of emotional information could change as a consequence of cognitive impairment. In this systematic review and meta-analysis, we conducted literature search of studies investigating emotion memory biases in mild cognitive impairment (MCI) and Alzheimer's disease (AD) on PubMed, Scopus and PsycINFO databases following PRISMA guidelines. The findings showed that emotional memory biases are still present despite the presence of cognitive impairment, both in MCI and at least in early stages of AD. However, the direction of emotion memory biases is not consistent across studies. These results suggest that patients with cognitive impairment might still benefit from EEM and help to define targets of intervention for cognitive rehabilitation in pathological aging.

Cognitive impairment is associated with gait variability and fall risk in amyotrophic lateral sclerosis.

BACKGROUND: In amyotrophic lateral sclerosis (ALS), gait abnormalities contribute to poor mobility and represent a relevant risk for falls. To date, gait studies in ALS patients have focused on the motor dimension of the disease, underestimating the cognitive aspects. METHODS: Using a wearable gait analysis device, we compared gait patterns in ambulatory ALS patients with mild cognitive impairment (ALS MCI+; n = 18), and without MCI (ALS MCI-; n = 24), and healthy subjects (HS; n = 16) under two conditions: (1) normal gait (single task) and (2) walking while counting backward (dual task). Finally, we examined if the occurrence and number of falls in the 3 months following the baseline test were related to cognition. RESULTS: In the single task condition, ALS patients, regardless of cognition, displayed higher gait variability than HS, especially for stance and swing time (p < 0.001). The dual task condition revealed additional differences in gait variability parameters between ALS MCI+ and ALS MCI- for cadence (p = 0.005), stance time (p = 0.04), swing time (p = 0.04) and stability index (p = 0.02). Moreover, ALS MCI+ showed a higher occurrence (p = 0.001) and number of falls (p < 0.001) at the follow-up. Regression analyses demonstrated that MCI condition predicted the occurrence of future falls (ß = 3.649; p = 0.01) and, together with executive dysfunction, was associated with the number of falls (cognitive impairment: ß = 0.63; p < 0.001; executive dysfunction: ß = 0.39; p = 0.03), regardless of motor impairment at clinical examination. CONCLUSION: In ALS, MCI is associated with exaggerated gait variability and predicts the occurrence and number of short-term falls.

Long-term clinical evolution of patients with prolonged disorders of consciousness due to severe anoxic brain injury: A meta-analytic study.

BACKGROUND AND PURPOSE: The prognosis of prolonged (28 days to 3 months post-onset) disorders of consciousness (pDoC) due to anoxic brain injury is uncertain. The present study aimed to evaluate the long-term outcome of post-anoxic pDoC and identify the possible predictive value of demographic and clinical information. METHOD: This is a systematic review and meta-analysis. The rates of mortality, any improvement in clinical diagnosis, and recovery of full consciousness at least 6 months after severe anoxic brain injury were evaluated. A cross-sectional approach searched for differences in baseline demographic and clinical characteristics between survivors and non-survivors, patients improved versus not improved, and patients who recovered full consciousness versus not recovered. RESULTS: Twenty-seven studies were identified. The pooled rates of mortality, any clinical improvement and recovery of full consciousness were 26%, 26% and 17%, respectively. Younger age, baseline diagnosis of minimally conscious state versus vegetative state/unresponsive wakefulness syndrome, higher Coma Recovery Scale Revised total score, and earlier admission to intensive rehabilitation units were associated with a significantly higher likelihood of survival and clinical improvement. These same variables, except time of admission to rehabilitation, were also associated with recovery of full consciousness. CONCLUSIONS: Patients with anoxic pDoC might improve over time up to full recovery of consciousness and some clinical characteristics can help predict clinical improvement. These new insights could support clinicians and caregivers in the decision-making on patient management.

Gait asymmetry in stroke patients with unilateral spatial neglect.

The recovery of independent gait represents one of the main functional goals of the rehabilitative interventions after stroke but it can be hindered by the presence of unilateral spatial neglect (USN). The aim of the paper is to study if the presence of USN in stroke patients affects lower limb gait parameters between the two body sides, differently from what could be expected by the motor impairment alone, and to explore whether USN is associated to specific gait asymmetry. Thirty-five stroke patients (right or left lesion and ischemic or hemorrhagic etiology) who regained independent gait were assessed for global cognitive functioning and USN. All patients underwent a gait analysis session by using a wearable inertial system, kinematic parameters were computed. Enrolled patients presented altered motion parameters. Stroke patients with USN showed specific asymmetries in the following parameters: stance phase, swing phase, and knee range of motion. No differences in the clinical scores were found as the presence of USN. The presence of USN was associated with a specific form of altered gait symmetry. These findings may help clinicians to develop more tailored rehabilitative training to enhance gait efficacy of patients with motor defects complicated by the presence of selected cognitive impairments. Overview of the experiment setup. The workflow shows: diagnosis of unilateral spatial neglect by the neuropsychologist, sensors placement, gait analysis protocol and evaluation of the gait asymmetry together with the statistically significant features.

The Cognitive Profile of Atypical Parkinsonism: A Meta-Analysis.

Atypical Parkinsonism (AP) syndromes are characterized by a wide spectrum of non-motor symptoms including prominent attentional and executive deficits. However, the cognitive profile of AP and its differences and similarities with that of Parkinson's Disease (PD) are still a matter of debate. The present meta-analysis aimed at identifying patterns of cognitive impairment in AP by comparing global cognitive functioning, memory, executive functions, visuospatial abilities, language, non-verbal reasoning, and processing speed test performances of patients with AP relative to healthy controls and patients with PD. All investigated cognitive domains showed a substantial impairment in patients with AP compared to healthy controls. When AP syndromes were considered separately, their cognitive functioning was distributed along a continuum from Multiple Systemic Atrophy at one extreme, with the least impaired cognitive profile (similar to that observed in PD) to Progressive Supranuclear Palsy, with the greatest decline in global cognitive and executive functioning (similar to Corticobasal Syndrome). These findings indicate that widespread cognitive impairment could represent an important clinical indicator to distinguish AP from other movement disorders.

Constructional Impairments and Their Neural Correlates in Nondemented Adults With Cerebral Autosomal-dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

BACKGROUND: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small-vessel disease that is characterized by a wide range of neurologic and neuropsychological impairments. Constructional impairments have been reported in some cases but have never been assessed systematically. OBJECTIVE: To evaluate constructional abilities and their cognitive and neural correlates in nondemented individuals with CADASIL. METHOD: Thirty individuals with CADASIL who were not affected by clinically relevant cognitive deterioration and 30 healthy controls (HC) underwent an extensive cognitive assessment and paper-and-pencil visuoconstructional tasks in order to detect constructional impairments. Performance on the visuoconstructional tasks was correlated with the cognitive assessment scores and with quantitative indices of regional gray matter atrophy (obtained via FreeSurfer image analysis) and white matter involvement. RESULTS: The individuals with CADASIL achieved significantly lower scores on the cognitive assessment compared with the HC. Poor visuoconstructional abilities were observed in seven (23.3%) of the individuals with CADASIL when performing the copy drawing task and in nine (30%) when performing the Rey Complex Figure Test. Logistic regression revealed that visuoconstructional impairments were significantly associated with scores on the Frontal Assessment Battery and the Attentional Matrices Test. Morphometric results revealed that scores on the visuoconstructional tasks were related to gray matter atrophy of the left frontal lobe and right parietal lobe. CONCLUSION: Impairments on visuoconstructional tasks are quite common in individuals with CADASIL, even in the lack of clinically relevant cognitive deterioration, and are critically related to frontal and parietal atrophy.

Relationship between apathy and cognitive dysfunctions in multiple sclerosis: A 4-year prospective longitudinal study.

BACKGROUND: Cognitive dysfunctions are highly prevalent in multiple sclerosis (MS) and negatively impact occupational and social functioning. OBJECTIVE: In the present longitudinal study, we aimed at modeling cognitive changes and at assessing whether apathy could be a predictor of cognitive decline in MS. METHODS: We assessed 67 people with MS at two-time points (baseline, T0; 4-year follow-up, T1), by means of several clinical, behavioural, and cognitive measures. We used a delta approach to measure cognitive decline during the follow-up period. We applied a mixed factorial design and a linear regression model to explore factors associated with cognitive changes over time. RESULTS: A higher level of apathy at baseline predicted the progressive cognitive decline at follow-up, whereas a higher level of depression did not. Among demographic and clinical characteristics, only low education level was significantly associated with cognitive decline over time. Interestingly, participants with persistent apathy (diagnosis of apathy at T0 and T1, A+A+) and those who developed apathy (A-A+) showed poorer inhibitory control and a larger decline in executive functioning during the 4-year follow-up than participants who had never received the diagnosis of apathy (A-A-). CONCLUSION: Apathy represents an early marker of cognitive decline in MS. These findings have important clinical and prognostic implications.