Search

BackgroundPoor affect recognition is an early sign of frontotemporal dementia (FTD). Here, we applied the abbreviated version of the Comprehensive Affect Testing System (CATS-A) battery to Italian FTD cases and healthy controls (HC) to provide cut-offs of emotional dysfunction in the whole group and in different FTD clinical syndromes.MethodsOne hundred thirty-nine FTD patients (60 behavioural variant [bvFTD],13 semantic behavioural variant of FTD [sbvFTD], 28 progressive supranuclear palsy [PSP], 21 semantic [svPPA] and 17 nonfluent [nfvPPA] variants of primary progressive aphasia) and 116 HC were administered the CATS-A, yielding an Affective Recognition Quotient (ARQ), which was used as outcome measure. Age- and education-adjusted, regression-based norms were derived in HC. In patients, the ARQ was assessed for its internal reliability, factorial validity and construct validity by testing its association with another social cognition paradigm, the Story-Based Empath Task (SET). The diagnostic accuracy of the ARQ in discriminating patients from HC, genetic cases from HC and patient groups among each other was tested via ROC analyses.ResultsIn the whole FTD cohort, CATS-A proved to be underpinned by a mono-component factor (51.1%) and was internally consistent (McDonalds ω = 0.76). Moreover, the ARQ converged with the SET (r(122) = 0.50; p

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Background: This study aimed to assess whether quantitative susceptibility imaging (QSM)-based measures of iron accumulation in the cerebellum predict cognitive and behavioral features in non-demented amyotrophic lateral sclerosis (ALS) patients. Methods: A total of ALS patients underwent 3-T MRI and a clinical assessment using the ALS Functional Rating Scale-Revised (ALSFRS-R) and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Regression models were applied to each subscale of the cognitive section of the ECAS and the ECASCarer Interview to examine the effect of QSM-based measures in white and gray matter (WM; GM) of the cerebellum, separately for right, left, and bilateral cerebellar regions of interest (ROIs). These effects were compared to those of cerebellar volumetrics in WM/GM, right and left hemispheres while controlling for demographics, disease status, and total intracranial volume. Results: Higher QSM measures of the cerebellar GM on the left, right, and bilateral sides significantly predicted (ps = 0.003) a greater number of errors on the executive functioning (EF) subscale of the ECAS (ECAS-EF). Moreover, higher GM-related, QSM measures of the cerebellum were associated with an increased probability of a below-cut-off performance on the ECAS-EF (ps = 0.024). No significant effects were observed for QSM measures of the cerebellar WM or for volumetric measures on the ECAS-EF. Other ECAS measures showed no significant effects. Bilateral QSM measures of the cerebellar GM also selectively predicted performance on backward digit span and social cognition tasks. Discussion: Iron accumulation within the cerebellar GM, particularly in the cerebellar cortices, may be associated with executive functioning deficits in nondemented ALS patients. Therefore, QSM-based measures could be useful for identifying the neural correlates of extra-motor cognitive deficits in ALS patients. [ABSTRACT FROM AUTHOR]

Background: Beyond memory deterioration, spatial disorientation may occur along the continuum of normal aging—dementia of Alzheimer's type. The present study aims at detecting behavioral disorders of spatial cognition in prodromal Alzheimer's disease (AD) and verifying the association between Apolipoprotein E-ε4 (ApoE-ε4) genotype and gait patterns during a real-world naturalistic task. Methods: A sample of 58 elderly participants, of which 20 patients with mild cognitive impairment with CFS biomarker evidence of AD, 23 individuals with subjective cognitive decline (SCD), and 15 healthy controls (HCs), was tested by a modified version of the Detour Navigation Test (DNT-mv). Generalized linear models were run to explore the association between group belonging and wrong turns (WTs)/moments of hesitation (MsH) as behavioral disorientation scores of the DNT-mv as well as the effect of ApoE-ε4 genotype on time and walking speed registered by a smartphone app providing GPS tracking of body movement around urban environments. Results: Patients with MCI due to AD reported more WTs than individuals with SCD and HCs. Further, the ApoE-ε4 genotype determined a lower capacity in spatial information processing, influencing gait during naturalistic spatial navigation tasks. Conclusions: Behavior alterations of spatial cognition can be detected ecologically in prodromal AD. The use of technological solutions supporting gait analysis may help in corroborating the experimental observation. [ABSTRACT FROM AUTHOR]

Objective: Little is known about amyotrophic lateral sclerosis (ALS)‐nonspecific cognitive deficits – most notably memory disturbance – and their biological underpinnings. We investigated the associations of the Alzheimer's disease (AD) genetic risk factor APOE and cerebrospinal fluid (CSF) biomarkers Aβ and tau proteins with cognitive and motor phenotype in ALS. Methods: APOE haplotype was determined in 281 ALS patients; for 105 of these, CSF levels of Aβ42, Aβ40, total tau (T‐tau), and phosphorylated tau (P‐tau181) were quantified by chemiluminescence enzyme immunoassay (CLEIA). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was employed to evaluate the neuropsychological phenotype. Results: APOE‐E4 allele was associated with worse ECAS memory score (median, 14.0 in carriers vs. 16.0 in non‐carriers) and lower CSF Aβ42 (−0.8 vs. 0.1, log‐transformed values) and Aβ42/40 ratio (−0.1 vs. 0.3). Some 37.1% of ALS patients showed low Aβ42 levels, possibly reflecting cerebral Aβ deposition. While lower Aβ42/40 correlated with lower memory score (β = 0.20), Aβ42 positively correlated with both ALS‐specific (β = 0.24) and ALS‐nonspecific (β = 0.24) scores. Although Aβ42/40 negatively correlated with T‐tau (β = −0.29) and P‐tau181 (β = −0.33), we found an unexpected positive association of Aβ42 and Aβ40 with both tau proteins. Regarding motor phenotype, lower levels of Aβ species were associated with lower motor neuron (LMN) signs (Aβ40: β = 0.34; Aβ42: β = 0.22). Conclusions: APOE haplotype and CSF Aβ biomarkers are associated with cognitive deficits in ALS and particularly with memory impairment. This might partly reflect AD‐like pathophysiological processes, but additional ALS‐specific mechanisms could be involved. [ABSTRACT FROM AUTHOR]

Background and purpose: Neurofilament light chain (NFL) has been shown to be increased in amyotrophic lateral sclerosis (ALS) and, to a lesser extent, in frontotemporal dementia (FTD). A meta‐analysis of NFL in ALS and FTD was performed. Methods: Available studies comparing cerebrospinal fluid and blood NFL levels in ALS versus neurologically healthy controls (NHCs), other neurological diseases (ONDs) and ALS mimics, as well as in FTD and related entities (behavioural variant of FTD and frontotemporal lobar degeneration syndromes) versus NHCs, ONDs and other dementias were evaluated. Results: In ALS, both cerebrospinal fluid and blood levels of NFL were higher compared to other categories. In FTD, behavioural variant of FTD and frontotemporal lobar degeneration syndromes, NFL levels were consistently higher compared to NHCs; however, several comparisons with ONDs and other dementias did not demonstrate significant differences. Discussion: Amyotrophic lateral sclerosis is characterized by higher NFL levels compared to most other conditions. In contrast, NFL is not as good at discriminating FTD from other dementias. [ABSTRACT FROM AUTHOR]

Background: Spatial navigation deficits are reported as early symptoms of Alzheimer's disease (AD) alongside episodic memory ones. The aim of the present study was to ascertain whether neuropsychological deficits of visuospatial long-term memory can predict behavioral alterations during the navigation of older adults in novel urban environments along the normal aging–dementia continuum of the Alzheimer's type. Methods: A total of 24 community-dwelling patients with Mild Cognitive Impairment (MCI) due to AD, 27 individuals with subjective cognitive decline (SCD), and 21 healthy controls were assessed in terms of their sequential egocentric and allocentric navigation abilities by using a modified version of the Detour Navigation Test, and neuropsychologically tested by the Corsi learning suvra-span (CLSS) test. Generalized linear models were adopted to verify whether the scores obtained by the three groups in the CLSS test predicted wrong turns and moments of hesitation during the navigation task, with the results presented as topographical disorientation scores. Results: Higher scores in the CLSS test predicted fewer wrong turns (b = −0.05; z = −2.91; p = 0.004; net of between-groups differences) and moments of hesitation for patients with MCI due to AD (b = −0.14; z = −2.43; p = 0.015), and individuals with SCD (b = −0.17; z = −3.85; p < 0.001). Conclusions: Since the CLSS test has been reported to be a reliable measure of ecological navigational abilities in the progression towards AD dementia, we recommend its use in clinical practice and highlight implications for future research. [ABSTRACT FROM AUTHOR]

Background: This study aimed at: (1) assessing, in an Italian cohort of non-demented Parkinson's disease (PD) patients, the construct validity of the Montreal Cognitive Assessment (MoCA) against both first- and second-level cognitive measures; (2) delivering an exhaustive and updated evaluation of its diagnostic properties. Methods: A retrospective cohort of N = 237 non-demented PD patients having been administered the MoCA was addressed, of whom N = 169 further underwent the Mini-Mental State Examination (MMSE) and N = 68 the Parkinson's Disease Cognitive Rating Scale (PD-CRS). A subsample (N = 60) also underwent a second-level cognitive battery encompassing measures of attention/executive functioning, language, memory, praxis and visuo-spatial abilities. Construct validity was assessed against both the PD-CRS and the second-level cognitive battery. Diagnostics were tested via receiver-operating characteristics analyses against a below-cut-off MMSE score. Results: The MoCA was associated with both PD-CRS scores (p <.001) and the vast majority of second-level cognitive measures (ps <.003). Both raw and adjusted MoCA scores proved to be highly accurate to the aim of identifying patients with MMSE-confirmed cognitive dysfunctions. A MoCA score adjusted for age and education according to the most recent normative dataset and < 19.015 is herewith suggested as indexing cognitive impairment in this population (AUC =.92; sensitivity =.92; specificity =.80). Discussion: The Italian MoCA is a valid and diagnostically sound screener for global cognitive inefficiency in non-demented PD patients. Further studies are nevertheless needed that confirm its diagnostic values against a measure other than the MMSE. [ABSTRACT FROM AUTHOR]

Objective: To compare serum levels of the astrocyte biomarker glial fibrillary acidic protein (GFAP) in patients with amyotrophic lateral sclerosis (ALS) and neurologically healthy controls and to analyze the relations between serum GFAP (sGFAP) and phenotype in ALS. Methods: We studied 114 ALS patients and 38 controls. sGFAP was quantified with single molecule array (Simoa) technology. Results: In both ALS patients and controls, sGFAP moderately correlated with age. ALS patients had higher sGFAP levels compared to controls, but this yielded a weak discriminative performance (AUC = 0.6198). In ALS, sGFAP was not associated with most of the motor phenotypic features, including site of onset, functional status, disease progression rate, disease stage, and indices of upper (UMN) and lower motor neuron (LMN) impairment. However, sGFAP negatively correlated with cognitive scores regarding ALS‐nonspecific functions, particularly memory (r = −0.2082) and tended to be higher in ALS patients with eye movement abnormalities (p = 0.0628). sGFAP also correlated with polysomnographic indices of oxygen desaturation (ODI; r = 0.2639) and apnea‐hypopnea (AHI; r = 0.2858). In a multivariate analysis, sGFAP was negatively associated with survival (HR = 1.005). Relevantly, we found a negative correlation between sGFAP and estimated glomerular filtration rate (eGFR; r = −0.3500). Interpretation: Our work provides neurochemical evidence of astrocyte involvement in ALS pathophysiology and particularly in the development of extra‐motor manifestations (namely, cognitive – memory – impairment) and respiratory dysfunction. The negative correlation between sGFAP and eGFR has practical relevance and should not be disregarded in future investigations. [ABSTRACT FROM AUTHOR]