The Network Structure of Cognitive Impairment: From Subjective Cognitive Decline to Alzheimer's Disease.

It was proposed that a reorganization of the relationships between cognitive functions occurs in dementia, a vision that surpasses the idea of a mere decline of specific domains. The complexity of cognitive structure, as assessed by neuropsychological tests, can be captured by exploratory graph analysis (EGA). EGA was applied to the neuropsychological assessment of people (humans) with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's disease (AD; total N = 638). Both sexes were included. In AD, memory scores detach from the other cognitive functions, and memory subdomains reduce their reciprocal relation. SCD showed a pattern of segregated neuropsychological domains, and MCI showed a noisy and less stable pattern. Results suggest that AD drives a reorganization of cognitive functions toward a less-fractionated architecture compared with preclinical conditions. Cognitive functions show a reorganization that goes beyond the performance decline. Results also have clinical implications in test interpretations and usage.

Irisin Levels in Cerebrospinal Fluid Correlate with Biomarkers and Clinical Dementia Scores in Alzheimer Disease.

OBJECTIVE: Irisin, released by muscles during exercise, was recently identified as a neuroprotective factor in mouse models of Alzheimer disease (AD). In a cohort of AD patients, we studied cerebrospinal fluid (CSF) and plasma irisin levels, sex interactions, and correlations with disease biomarkers. METHODS: Correlations between CSF and plasma irisin levels and AD biomarkers (amyloid ß 1-42, hyperphosphorylated tau, and total tau [t-tau]) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) were analyzed in a cohort of patients with Alzheimer dementia (n = 82), mild cognitive impairment (n = 44), and subjective memory complaint (n = 20) biologically characterized according to the recent amyloid/tau/neurodegeneration classification. RESULTS: CSF irisin was reduced in Alzheimer dementia patients (p < 0.0001), with lower levels in female patients. Moreover, CSF irisin correlated positively with Aß42 in both female (r = 0.379, p < 0.001) and male (r = 0.262, p < 0.05) patients, and negatively with CDR-SOB (r = -0.234, p < 0.05) only in female patients. A negative trend was also observed between CSF irisin and t-tau levels in all patients (r = -0.144, p = 0.082) and in the female subgroup (r = -0.189, p = 0.084). INTERPRETATION: The results highlight the relationship between irisin and biomarkers of AD pathology, especially in females. Our findings also offer perspectives toward the use of irisin as a marker of the AD continuum. ANN NEUROL 2024;96:61-73.

Sarcopenia in subjects with Alzheimer's disease: prevalence and comparison of agreement between EGWSOP1, EGWSOP2, and FNIH criteria.

BACKGROUND: Sarcopenia is an age-related clinical syndrome characterized by the progressive loss of muscle mass and muscle strength. It appears to be closely linked to dementia, particularly Alzheimer's disease (AD); however, its prevalence among AD patients remains unclear. In this study, we assessed differences in sarcopenia prevalence between non-demented individuals and AD patients. Moreover, we assessed sex-specific differences in sarcopenia prevalence and explored the diagnostic value of the Muscle Quality Index (MQI) for diagnosing sarcopenia among AD patients. METHOD: Cross-sectional study including 145 patients with probable AD and 51 older adults with normal cognition. Sarcopenia was diagnosed according to the criteria of the European Working Group on Sarcopenia in Older People (EWGSOP1 and EWGSOP2) and of the Foundation for the National Institutes of Health (FNIH). The MQI was computed as the ratio of handgrip strength to skeletal muscle mass. RESULTS: No significant difference in sarcopenia prevalence was observed between AD patients and controls. Prevalence ranged from 3.4 to 23.4% in AD patients and from 2 to 11.8% in controls, depending on diagnostic criteria. Prevalence was higher using EWGSOP1 and decreased using EWGSOP2 and FNIH. Prevalence was higher in males than in females with AD. The MQI was lower in AD patients than in controls (95%CI: - 0.23, - 0.05, p < 0.001), but displayed poor diagnostic accuracy in identifying sarcopenia cases. CONCLUSIONS: AD patients and controls show comparable sarcopenia prevalence. Sarcopenia prevalence is higher in males than females among AD patients and higher when using EWGSOP1 compared to FNIH and EWGSOP2 criteria.

Sleep and circadian rhythm disruptions in behavioral variant frontotemporal dementia.

INTRODUCTION: Sleep and rest-activity rhythm alterations are common in neurodegenerative diseases. However, their characterization in patients with behavioral variant frontotemporal dementia (bvFTD) has proven elusive. We investigated rest-activity rhythm alterations, sleep disturbances, and their neural correlates in bvFTD. METHODS: Twenty-seven bvFTD patients and 25 healthy controls completed sleep questionnaires and underwent 7 days of actigraphy while concurrently maintaining a sleep diary. Cortical complexity and thickness were calculated from T1-weighted magnetic resonance (MR) images. RESULTS: Compared to controls, bvFTD patients showed longer time in bed (95% confidence interval [CI]: 79.31, 321.83) and total sleep time (95% CI: 24.38, 321.88), lower sleep efficiency (95% CI: -12.58, -95.54), and rest-activity rhythm alterations in the morning and early afternoon. Increased sleep duration was associated with reduced cortical thickness in frontal regions. DISCUSSION: Patients with bvFTD showed longer sleep duration, lower sleep quality, and rest-activity rhythm alterations. Actigraphy could serve as a cost-effective and accessible tool for ecologically monitoring changes in sleep duration in bvFTD patients. HIGHLIGHTS: We assessed sleep and circadian rhythms in behavioral variant frontotemporal dementia (bvFTD) using actigraphy. Patients with bvFTD show increased sleep duration and reduced sleep quality. Patients with bvFTD show rest-activity alterations in the morning and early afternoon. Sleep duration is associated with reduced cortical thickness in frontal regions. These alterations may represent an early sign of neurodegeneration.

Nocturnal visual hallucinations in patients with disorders of arousal: a novel behavioral and EEG pattern.

AIM: To investigate clinical and video-polysomnography (VPSG) findings of hallucinatory experiences in patients suffering from disorders of arousal (DOA) in the absence of other pathologies. METHODS: The authors retrospectively reviewed the records of 370 adults with DOA. Thirty (8.1%) patients concomitantly reported complex nocturnal visual hallucinations. VPSG recordings were scrutinized, and motor behavioral and electroencephalogram (EEG) patterns were classified according to previous descriptions of DOA. RESULTS: Thirty DOA patients reported seeing images of objects, people, and animals; either distorted, static, or mobile. The images disappeared with increased illumination in 80% of patients, and 23.3% reported preceding dream imagery. In addition to the classical DOA patterns on VPSG, a distinct pattern of behavioral and EEG manifestation associated with complex hallucinatory episodes was identified in 16 (53.3%) DOA patients. This consisted of low-voltage mixed-frequency EEG activity before eye opening that persisted while patients were observed staring or visually tracking before the onset of motor behavior. CONCLUSION: A novel, distinct behavioral and EEG pattern in patients with DOA and history of reported complex nocturnal visual hallucinations was identified. This may represent a unique phenotype of dissociation between sleep states that merits further investigation.

Cyclic alternating pattern in obstructive sleep apnea: A preliminary study.

Obstructive sleep apnea is linked to cardiovascular disease, metabolic disorders and dementia. The precise nature of the association between respiratory events in obstructive sleep apnea, cortical or subcortical arousals, and cognitive, autonomic and oxidative stress consequences remains incompletely elucidated. Previous studies have aimed to understand the relationship between obstructive sleep apnea and arousal patterns, as defined by the cyclic alternating pattern, but results have been inconsistent, in part likely due to the presence of associated comorbidities. To better define this relationship, we analysed cyclic alternating patterns in patients with obstructive sleep apnea without any additional comorbidities. We identified 18 adult male, non-obese subjects with obstructive sleep apnea and no other comorbidities or medication history, who underwent whole-night electroencephalography and polysomnography. Cyclic alternating pattern analysis was performed and verified by certified somnologists. Pairwise linear regression analysis demonstrated an inverse relationship between obstructive sleep apnea severity and cyclic alternating pattern subtype A1, and a direct correlation with cyclic alternating pattern subtype A3. Cyclic alternating pattern subtypes A1 prevail in milder obstructive sleep apnea phenotype, whilst cyclic alternating pattern subtypes A2 and A3 overcome among moderate-to-severe obstructive sleep apnea patients. The milder obstructive sleep apnea group also presented higher sleep efficiency, and increased percentages of non-rapid eye movement stage 3 and rapid eye movement sleep, as well as longer cyclic alternating pattern sequences in N3, while severe obstructive sleep apnea patients spent more time in lighter sleep stages. These results imply/suggest a balance between cyclic alternating pattern's adaptive and maladaptive arousal processes in obstructive sleep apnea of differing severities. In milder obstructive sleep apnea (apnea-hypopnea index < 20), sleep continuity may be reinforced by cyclic alternating pattern subtype A1, whereas in more severe obstructive sleep apnea, decompensation of these sleep-stabilizing mechanisms may occur and more intrusive cyclic alternating pattern fluctuations disrupt sleep circuitry.

Video polysomnographic findings in non-rapid eye movement parasomnia.

Although video polysomnography (vPSG) is not routinely recommended for the evaluation of typical cases of non-rapid eye movement (NREM) parasomnias, it can aid diagnosis of unusual cases, other sleep disorders and complicated cases with REM behaviour disorder (RBD), and in differentiating parasomnias from epilepsy. In this study, we aimed to assess vPSG findings in consecutive patients with a clinical diagnosis of NREM-parasomnia covering the whole phenotypic spectrum. Five hundred and twelve patients with a final diagnosis of NREM parasomnia who had undergone vPSG were retrospectively identified. vPSGs were analysed for features of NREM parasomnia and for the presence of other sleep disorders. Two hundred and six (40.0%) patients were clinically diagnosed with sleepwalking, 72 (14.1%) with sleep terrors, 39 (7.6%) with confusional arousals, 15 (2.9%) with sexsomnia, seven (1.4%) with sleep-related eating disorder, 122 (23.8%) with mixed phenotype, and 51 (10.0%) with parasomnia overlap disorder (POD). The vPSG supported the diagnosis of NREM parasomnia in 64.4% of the patients and of POD in 98%. In 28.9% of the patients, obstructive sleep apnea (OSA) or/and periodic limb movements during sleep (PLMS) were identified, most commonly in older, male, sleepy and obese patients. vPSG has a high diagnostic yield in patients with NREM parasomnia and should be routinely performed when there is diagnostic doubt, or in patients where there is a suspicion of OSA and PLMS.

Upper airway surgery of obstructive sleep apnea in pycnodysostosis: case report and literature review.

Pycnodysostosis is an autosomal recessive disorder due to a mutation in the cathepsin K gene, which causes a decrease of the bone turnover; a review of the literature suggests that pycnodysostosis is frequently associated with severe respiratory obstruction, which needs surgical treatment. The aim of this paper is to describe the surgical treatment of a 3½-year-old girl affected by Pycnodysostosis complicated by a severe sleep-related respiratory disorder. The surgical treatment, consisting of adenotonsillectomy and palatoplasty, resulted in a striking amelioration of respiratory parameters and increased posterior airway space, and allowed the patient to avoid tracheotomy while awaiting for maxillo-mandibular surgery.

Memories of attachment hamper EEG cortical connectivity in dissociative patients.

In this study, we evaluated cortical connectivity modifications by electroencephalography (EEG) lagged coherence analysis, in subjects with dissociative disorders and in controls, after retrieval of attachment memories. We asked thirteen patients with dissociative disorders and thirteen age- and sex-matched healthy controls to retrieve personal attachment-related autobiographical memories through adult attachment interviews (AAI). EEG was recorded in the closed eyes resting state before and after the AAI. EEG lagged coherence before and after AAI was compared in all subjects. In the control group, memories of attachment promoted a widespread increase in EEG connectivity, in particular in the high-frequency EEG bands. Compared to controls, dissociative patients did not show an increase in EEG connectivity after the AAI. Conclusions: These results shed light on the neurophysiology of the disintegrative effect of retrieval of traumatic attachment memories in dissociative patients.

Heart rate and heart rate variability modification in chronic insomnia patients.

Chronic insomnia is highly prevalent in the general population, provoking personal distress and increased risk for psychiatric and medical disorders. Autonomic hyper-arousal could be a pathogenic mechanism of chronic primary insomnia. The aim of this study was to investigate autonomic activity in patients with chronic primary insomnia by means of heart rate variability (HRV) analysis. Eighty-five consecutive patients affected by chronic primary insomnia were enrolled (38 men and 47 women; mean age: 53.2 ± 13.6). Patients were compared with a control group composed of 55 healthy participants matched for age and gender (23 men and 32 women; mean age: 54.2 ± 13.9). Patients underwent an insomnia study protocol that included subjective sleep evaluation, psychometric measures, and home-based polysomnography with evaluation of HRV in wake before sleep, in all sleep stages, and in wake after final awakening. Patients showed modifications of heart rate and HRV parameters, consistent with increased sympathetic activity, while awake before sleep and during Stage-2 non-REM sleep. No significant differences between insomniacs and controls could be detected during slow-wave sleep, REM sleep, and post-sleep wake. These results are consistent with the hypothesis that autonomic hyper-arousal is a major pathogenic mechanism in primary insomnia, and confirm that this condition is associated with an increased cardiovascular risk.

Deep Learning-based Approach for Brainstem and Ventricular MR Planimetry: Application in Patients with Progressive Supranuclear Palsy.

Purpose To develop a fast and fully automated deep learning (DL)-based method for the MRI planimetric segmentation and measurement of the brainstem and ventricular structures most affected in patients with progressive supranuclear palsy (PSP). Materials and Methods In this retrospective study, T1-weighted MR images in healthy controls (n = 84) were used to train DL models for segmenting the midbrain, pons, middle cerebellar peduncle (MCP), superior cerebellar peduncle (SCP), third ventricle, and frontal horns (FHs). Internal, external, and clinical test datasets (n = 305) were used to assess segmentation model reliability. DL masks from test datasets were used to automatically extract midbrain and pons areas and the width of MCP, SCP, third ventricle, and FHs. Automated measurements were compared with those manually performed by an expert radiologist. Finally, these measures were combined to calculate the midbrain to pons area ratio, MR parkinsonism index (MRPI), and MRPI 2.0, which were used to differentiate patients with PSP (n = 71) from those with Parkinson disease (PD) (n = 129). Results Dice coefficients above 0.85 were found for all brain regions when comparing manual and DL-based segmentations. A strong correlation was observed between automated and manual measurements (Spearman ρ > 0.80, P < .001). DL-based measurements showed excellent performance in differentiating patients with PSP from those with PD, with an area under the receiver operating characteristic curve above 0.92. Conclusion The automated approach successfully segmented and measured the brainstem and ventricular structures. DL-based models may represent a useful approach to support the diagnosis of PSP and potentially other conditions associated with brainstem and ventricular alterations. Keywords: MR Imaging, Brain/Brain Stem, Segmentation, Quantification, Diagnosis, Convolutional Neural Network Supplemental material is available for this article. © RSNA, 2024 See also the commentary by Mohajer in this issue.

Mapping lower-limbs muscle vulnerability in patients with ALS: The role of upper and lower motor neurons.

BACKGROUND: Several studies have reported disproportionate wasting of the flexor muscles of the lower limbs (LL) compared to the extensors in patients with amyotrophic lateral sclerosis (ALS). However, these studies have involved small sample sizes (n ã€ˆ100), and their findings have been inconsistent. Thus, it remains uncertain whether a distinct pattern of LL muscle weakness is specific to ALS. AIMS: To investigate the muscle weakness pattern in the LL at the knee, ankle, and toes in a large cohort of ALS patients and evaluate the relationship between the pattern of muscle strength and the extent of upper (UMN) and lower (LMN) motoneuron impairment. MATERIAL AND METHODS: The strength of flexor and extensor muscle was evaluated in 1250 legs of newly diagnosed ALS patients at the knee, ankle, and foot toes. UMN and LMN burden were assessed using validated scores. Within-subjects ANOVA considering the type of muscle (flexor/extensor) and anatomical sites (knee/ankle/toes) and mixed-factorial ANOVA were conducted to explore the impact of UMN and LMN impairments on the muscle weakness pattern. RESULTS: Muscle strength showed a significant decline from proximal to distal regions. Indeed both flexor and extensor muscles at the knee outperformed those at the ankle and toes. Within each site, extensor muscles exhibited less strength than flexor, except at the knee. Patients with heightened UMN impairment showed a more marked difference between flexors and extensors within each site, with extensor muscles being more compromised at the ankle and toes. Higher LMN impairment corresponded to a more pronounced weakness in flexor muscles at the ankle and toes compared to those at the knee. CONCLUSIONS: The extensor muscle at the knee and the flexors at the foot and toes displayed relative resistance to ALS disease. UMN impairment amplified the differences between flexor and extensor muscles within each site, while LMN impairment demonstrated a clear distal-to-proximal vulnerability.

Narcissistic Personality Disorder as Prodromal Feature of Early-Onset, GRN-Positive bvFTD: A Case Report.

Background: Behavioral variant frontotemporal dementia (bvFTD) typically involves subtle changes in personality that can delay a timely diagnosis. Objective: Here, we report the case of a patient diagnosed of GRN-positive bvFTD at the age of 52 presenting with a 7-year history of narcissistic personality disorder, accordingly to DSM-5 criteria. Methods: The patient was referred to neurological and neuropsychological examination. She underwent 3 Tesla magnetic resonance imaging (MRI) and genetic studies. Results: The neuropsychological examination revealed profound deficits in all cognitive domains and 3T brain MRI showed marked fronto-temporal atrophy. A mutation in the GRN gene further confirmed the diagnosis. Conclusions: The present case documents an unusual onset of bvFTD and highlights the problematic nature of the differential diagnosis between prodromal psychiatric features of the disease and primary psychiatric disorders. Early recognition and diagnosis of bvFTD can lead to appropriate management and support for patients and their families. This case highlights the importance of considering neurodegenerative diseases, such as bvFTD, in the differential diagnosis of psychiatric disorders, especially when exacerbations of behavioral traits manifest in adults.

Dreaming Characteristics in Non-Rapid Eye Movement Parasomnia and Idiopathic Rapid Eye Movement Sleep Behaviour Disorder: Similarities and Differences.

Background: Speech graph analysis (SGA) of dreams has recently shown promise as an objective and language-invariant diagnostic tool that can aid neuropsychiatric diagnosis. Whilst the notion that dreaming mentations reflect distinct physiologic processes is not new, such studies in patients with sleep disorders remain exceptionally scarce. Here, using SGA and other dream content analyses, we set to investigate structural and thematic differences in morning dream recalls of patients diagnosed with Non-Rapid Eye Movement Parasomnia (NREMP) and Idiopathic REM Sleep Behavior Disorder (iRBD). Methods: A retrospective cross-sectional study of morning dream recalls of iRBD and NREMP patients was undertaken. Traditional dream content analyses, such as Orlinsky and Hall and Van de Castle analyses, were initially conducted. Subsequently, SGA was performed in order to objectively quantify structural speech differences between the dream recalls of the two patient groups. Results: Comparable rate of morning recall of dreams in the sleep laboratory was recorded; 25% of iRBD and 18.35% of NREMP patients. Aggression in dreams was recorded by 28.57% iRBD versus 20.00% in NREMP group. iRBD patients were more likely to recall dreams (iRBD vs NREMP; P = 0.007), but they also had more white dreams, ie having a feeling of having dreamt, but with no memory of it. Visual and quantitative graph speech analyses of iRBD dreams suggested stable sequential structure, reflecting the linearity of the chronological narrative. Conversely, NREMP dream reports displayed more recursive, less stable systems, with significantly higher scores of graph connectivity measures. Conclusion: The findings of our exploratory study suggest that iRBD and NREMP patients may not only differ on what is recalled in their dreams but also, perhaps more strikingly, on how dreams are recalled. It is hoped that future SGA-led dream investigations of larger groups of patients will help discern distinct mechanistic underpinnings and any associated clinical implications.

Pain and the alpha-sleep anomaly: a mechanism of sleep disruption in facioscapulohumeral muscular dystrophy.

OBJECTIVE: To measure the presence of the alpha-sleep anomaly in facioscapulohumeral muscular dystrophy (FSHD) and to evaluate the association between the sleep electroencephalogram (EEG) pattern and the presence of musculoskeletal pain. DESIGN: Cross-sectional study. SETTING: Sleep laboratory. SUBJECTS: Fifty-five consecutive adult FSHD patients, 26 women and 29 men, age 49.6 ± 15.1 years (range 18-76). INTERVENTIONS: Questionnaires and polysomnography. OUTCOME MEASURES: Patients were asked to indicate if in the 3 months before the sleep study they presented persisting or recurring musculoskeletal pain. Patients who reported pain were asked to fill in the Italian version of the Brief Pain Inventory and the McGill Pain questionnaire, and a 101-point visual analog scale (VAS) for pain intensity. Polysomnographic recordings were performed. EEG was analyzed by means of Fast Fourier Transform. Four power spectra bands (δ 0-4 Hz, θ 4-8 Hz, α 8-14 Hz, ß 14-32 Hz) were computed. Sleep macrostructure parameters and alpha/delta EEG power ratio during non rapid eye movement (NREM) sleep were compared between patients with and without pain. RESULTS: Forty-two patients in our sample reported chronic pain. VAS mean score was 55.2 ± 23.8 (range 10-100), pain rating index score was 13.8 ± 10.2, and present pain intensity was 2.5 ± 0.8. The statistical analysis documented an increased occurrence of the alpha and beta rhythms during NREM sleep in FSHD patients with pain. Significant correlations were observed between the alpha/delta power ratio during NREM sleep and pain measures. CONCLUSIONS: Chronic musculoskeletal pain is frequent in FSHD patients, and it represents a major mechanism of sleep disruption.

Prevalence and utility of overnight pulse oximetry as a screening tool for obstructive sleep apnoea in newly diagnosed idiopathic intracranial hypertension.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a condition of raised intracranial pressure (ICP). Obstructive sleep apnoea (OSA) has been shown to cause episodic rises in ICP and is frequently reported in patients with IIH. The aim of this study is to identify the prevalence of OSA in a cohort of IIH patients. METHODS: We conducted a retrospective case notes review as part of a service evaluation of newly diagnosed IIH patients who were all referred for OSA screening with overnight pulse oximetry. The 3% oxygen desaturation index (3% ODI) was used to evaluate the presence and severity of OSA. The clinical outcomes of patients who received continuous positive airway pressure (CPAP) therapy as treatment for OSA were reviewed. RESULTS: In our cohort of newly diagnosed IIH patients, the yield of overnight pulse oximetry as a screening tool was 48.6% for OSA and 15.3% for moderate to severe OSA. We found that age (p = 0.0008), BMI (p < 0.0001), vitamin B12 (p = 0.0183), and a higher Epworth Sleep Score (p = 0.0269) correlated with more severe OSA. Eleven (10%) patients had CPAP therapy and those with good adherence alongside weight loss or medical therapy found improvements in symptoms of raised ICP. CONCLUSION: We report the largest series of consecutive IIH patients screened for OSA using overnight pulse oximetry. The high rate of OSA highlights a potential role for the recognition and management of OSA in the IIH patient cohort. Further studies on the potential contribution of OSA as a cause of raised ICP in the IIH cohort is warranted.

Hypothalamus and amyotrophic lateral sclerosis: potential implications in sleep disorders.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects both motor and non-motor functions, including sleep regulation. Emerging evidence suggests that the hypothalamus, a brain region that plays a critical role in sleep-wake regulation, may be involved in the pathogenesis of ALS-related sleep disturbances. In this review, we have summarized results of studies on sleep disorders in ALS published between 2000 and 2023. Thereafter, we examined possible mechanisms by which hypothalamic dysfunctions may contribute to ALS-related sleep disturbances. Achieving a deeper understanding of the relationship between hypothalamic dysfunction and sleep disturbances in ALS can help improve the overall management of ALS and reduce the burden on patients and their families.

Different patterns of spreading direction and motor neurons involvement in a cohort of limb-onset amyotrophic lateral sclerosis patients from Southern Italy: Potential implication on disease course or progression?

BACKGROUND: Currently, there is a lack of knowledge concerning where the pathological process starts and how the neurodegeneration spreads during the course of amyotrophic lateral sclerosis (ALS). AIMS: This study aims to evaluate the spreading direction of the disease and the corresponding clinical characteristics in a cohort of patients with limb-onset ALS. PATIENTS AND METHODS: Consecutive incident ALS patients referring to an ALS tertiary center from Southern Italy, between 2015 and 2021, were recruited in the study. According to the initial directions of spread, patients were dichotomized into horizontal spreading pattern (HSP) or vertical spreading pattern (VSP) groups. RESULTS: Among 137 newly diagnosed ALS, 87 presented a spinal onset. Ten patients with pure LMN were not included in the study. All cases reported a clear spread direction. The frequency of HSP and VSP spreading was similar overall (47 vs. 30). The prevalence of HSP was higher (74% vs. 50%) in patients with upper limb-onset (UL-ALS), compared to patients with lower limb-onset (LL-ALS; p < .05). Conversely, the occurrence of VSP spread was threefold higher in patients with LL-ALS, compared to UL-ALS (p < .05). Patients with VSP showed a wider upper motor neuron impairment, whereas the involvement of LMN resulted greater in patients with HSP. Patients with HSP exhibited a greater drop of ALSFRS-r sub-score in the region of onset, while VSP showed a slighter but more diffuse reduction of ASLFRS-r subscore in more body districts beyond the site of onset. Patients with VSP were also characterized by a higher median progression rate and an earlier median bulbar involvement, compared to HSP. CONCLUSIONS: Our findings suggested investigating the spreading direction of ALS among patients with spinal onset, to better delineate the clinical profiles of patients with ALS, and predict an earlier impairment of bulbar muscle and a more rapid progression of the disease.

Asymmetry of radiomics features in the white matter of patients with primary progressive aphasia.

Introduction: Primary Progressive Aphasia (PPA) is a neurological disease characterized by linguistic deficits. Semantic (svPPA) and non-fluent/agrammatic (nfvPPA) variants are the two main clinical subtypes. We applied a novel analytical framework, based on radiomic analysis, to investigate White Matter (WM) asymmetry and to examine whether asymmetry is associated with verbal fluency performance. Methods: Analyses were performed on T1-weighted images including 56 patients with PPA (31 svPPA and 25 nfvPPA) and 53 age- and sex-matched controls. Asymmetry Index (AI) was computed for 86 radiomics features in 34 white matter regions. The relationships between AI, verbal fluency performance (semantic and phonemic) and Boston Naming Test score (BNT) were explored through Spearman correlation analysis. Results: Relative to controls, WM asymmetry in svPPA patients involved regions adjacent to middle temporal cortex as part of the inferior longitudinal (ILF), fronto-occipital (IFOF) and superior longitudinal fasciculi. Conversely, nfvPPA patients showed an asymmetry of WM in lateral occipital regions (ILF/IFOF). A higher lateralization involving IFOF, cingulum and forceps minor was found in nfvPPA compared to svPPA patients. In nfvPPA patients, semantic fluency was positively correlated to asymmetry in ILF/IFOF tracts. Performances at BNT were associated with AI values of the middle temporal (ILF/SLF) and parahippocampal (ILF/IFOF) gyri in svPPA patients. Discussion: Radiomics features depicted distinct pathways of asymmetry in svPPA and nfvPPA involving damage of principal fiber tracts associated with speech and language. Assessing asymmetry of radiomics in PPA allows achieving a deeper insight into the neuroanatomical damage and may represent a candidate severity marker for language impairments in PPA patients.