BACKGROUND:This study aimed at identifying neuropsychological sub-phenotypes in amyotrophic lateral sclerosis (ALS) within the mild cognitive impairment (MCI) and mild behavioral impairment (MBI) frameworks. METHODS:We used individual task-/item-level data from the cognitive and behavioral sections of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) from 901 non-demented ALS to derive neuropsychological sub-phenotypes pursuant to classical MCI and MBI frameworks and in accordance with an expanded version of Strong's criteria, which also addressed memory and visuo-spatial measures. RESULTS:The prevalence of MCI and MBI was 39% and 37%, respectively in this retrospective review. The following MCI sub-phenotypes were identified: dysexecutive MCI-single- and multiple-domain (dMCI-sd: 63%; dMCI-md: 24%, respectively); non-dysexecutive MCI-single- and multiple-domain (ndMCI-sd: 12%; ndMCI-md: 1%, respectively). MBI was classified as follows: apathetic MBI-single- and multiple-domain (aMBI-sd: 40%; aMBI-md: 20%, respectively); apathetic-disinihibited/perseverative MBI-multiple domain (ad/pMBI-md: 21%); disinihibited/perseverative MBI-multiple domain (d/pMBI-md: 7%); psychotic MBI-single- and multiple-domain (psyMBI-sd: 2%; psyMBI-md: 3%, respectively); unclassifiable MBI-multiple domain (uMBI-md: 1%). 143 (16%) of patients exhibited mild cognitive and behavioral impairment (MCBI). CONCLUSIONS:This study delivers a provisional, ECAS-based classification for the neuropsychological sub-phenotyping of non-demented ALS patients, which, with further validation, might be useful for both research and clinical purposes.

This study aimed to provide preliminary information on the clinical usability of a set of Italian telephone-based cognitive screening (TBCS) tests in patients with neurodegenerative MCI and dementia. Eighty-one patients with MCI (N = 32) and dementia (N = 49) due to Alzheimer’s disease, frontotemporal lobar degeneration and Lewy body disease and 100 healthy controls (HCs) were administered a battery of TBCS tests assessing global cognition (Telephone Interview for Cognitive Status), executive functioning (Telephone-based Frontal Assessment Battery), verbal fluency (Telephone-based Phonemic and Semantic Verbal Fluency), working memory (Telephone-based Backward Digit Span) and language (Telephone Language Screener). For each test, we assessed their (1) applicability, (2) construct validity against in-person first- and second-level cognitive measures, (3) ecological validity against the Amsterdam IADL Questionnaire-Short Version (A-IADL-Q-SV), (4) capability to discriminate MCI and dementia patients from HCs and (5) to discriminate MCI from dementia. TBCS tests could be completed by the majority of patients (75–96

This study aimed to compare different algorithms based on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) to classify patients with amyotrophic lateral sclerosis (ALS) according to their neuropsychological phenotype to identify possible discrepancies among these systems. ECAS-Cognitive and -Carer Interview (ECAS-C/-CI) scores of N = 901 patients with ALS without a formal diagnosis of dementia were retrospectively retrieved. Patients were classified, pursuant to Strong et al.’s criteria, as cognitively and behaviourally normal (ALScbn), cognitively and/or behaviourally impaired (ALSci/bi/cbi), or Possible ALS-FTD, according the following ECAS-based algorithms: (1) Abrahams’, solely addressing ECAS-C total and ALS-Specific subtotals; (2) Poletti et al.’s, addressing single task-level ECAS-C scores; (3) “Subscale”, addressing ECAS-C subscales (i.e., Language, Executive, Fluency, Memory and Visuospatial). All algorithms relied on single-item-level ECAS-CI scores for behavioural classifications. Whilst agreement rates among these classifications were moderate to high (84–86

BackgroundThe yes-no reversal (YNR) phenomenon consists in a patient saying "yes" when meaning "no", or vice-versa.ObjectiveTo investigate the prevalence of the YNR phenomenon in mild cognitive impairment (MCI) and dementia across different neurodegenerative, chronic cerebrovascular, or mixed etiologies, and to explore its demographic and clinical correlates.MethodsInformants of N = 267 patients with MCI or dementia due to possible/probable Alzheimer's disease (AD; N = 164), frontotemporal lobar degeneration (N = 25), Lewy body disease (N = 18), mixed-i.e., AD and chronic cerebrovascular-etiologies (N = 37), Aβ-negative degenerative etiologies (N = 6), and chronic cerebrovascular disease (N = 17) were inquired on the occurrence of YNRs in everyday-life conversations. YNR+ and YNR- patients were compared on demographics (i.e., age, sex, education), disease duration (in months), disease severity (i.e., MCI versus dementia), etiology and total and subscale-/item-level Mini-Mental State Examination (MMSE) scores. A multiple logistic model was also run on the presence/absence of YNRs by addressing, as predictors, variables that yielded significance at an univariable level.ResultsThe YNR phenomenon was recorded in 23 patients (8.61%), all of them being demented (i.e., no MCI patient showed YNRs). YNR+ patients were younger and scored lower on Immediate recall and Language subscores of the MMSE. The prevalence of YNRs was higher in non-AD- (∼18%) versus AD-related (∼5%) etiologies. The effects of disease severity and etiology were confirmed by the multiple logistic model, while the others were not.ConclusionsThe YNR phenomenon is a clinical sign possibly associated with dementia due to non-AD etiologies.

Chronic activation of glial cells leads to the dysfunction and degeneration of motor and cortical neurons in amyotrophic lateral sclerosis and frontotemporal dementia with an unknown mechanism. To shed light on the molecular pathogenetic processes underlying the exordium and contribution of gliosis to disease onset and progression, we used cells, mice and patient-derived cells modelling TDP-43, SOD1 and C9ORF72-linked and sporadic ALS. Our data reveal a sequential disease progression, starting with enhanced glial reactivity and proliferation, and transitioning into inflammation with upregulation of pro-inflammatory genes. Using mouse genetics, we show that expression of mutant TDP-43 in astrocytes is necessary to cause gliosis and behavioural abnormalities. Mechanistically, we show that glial MYC gain-of-function drives neurodegeneration by promoting the release of astrocyte-derived extracellular vesicles that nonetheless fail to provide trophic support to surrounding neurons. Our research reveals a novel functional role for MYC in glia-to-neuron miscommunication in ALS.

Neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and Amyotrophic Lateral Sclerosis, are characterized by multifactorial pathologies that extend beyond neuronal loss to include neuroinflammation, oxidative stress, mitochondrial dysfunction, and glial dysregulation. Despite extensive research, disease-modifying therapies remain elusive, hindered by late diagnosis, limited availability of specific biomarkers, and the persistent dominance of reductionist, single-target strategies. This comprehensive and informative review provides a critical synthesis of integrated neuroprotective strategies, with particular focus on glial mechanisms and biomarker-guided interventions. Therapeutic emphasis is placed on coordinated mechanisms targeting both neurons and non-neuronal cells, such as astrocytes, microglia, and oligodendrocytes. Emerging strategies are reported to include modulation of synaptic plasticity and neurotransmission, delivery of neurotrophic factors, activation of intrinsic cytoprotective pathways (e.g., Nrf2 signaling), restoration of proteostasis, and induction of regeneration via cellular reprogramming. Glial cells are discussed as therapeutic targets involved in inflammation, metabolism, myelination, and neuronal survival. Advances in predictive, preventive, personalized, and participatory (P4) medicine, supported by genomics, multi-omics, imaging, and real-world data, are presented as accelerating biomarker discovery and enabling earlier and more precise stage-specific interventions. Future success in combating neurodegeneration will depend on integrated approaches that combine protective, supportive, and regenerative strategies, appropriate for disease stage and patient profile. By reframing neuroprotection as a systemic, multicellular endeavor, this review highlights the potential to not only extend life expectancy, but also preserve meaningful quality of life in individuals affected by neurodegenerative diseases.

We explored the comparability of the “Serial 7s” (S7) and Spelling Backwards (SB) tasks from MMSE in 313 patients with MCI ( N =54) and dementia ( N =259) due to Alzheimer’s disease (AD), frontotemporal lobar degeneration, Lewy body disease, non-AD degenerative (NADD), chronic cerebrovascular disease (CVD) or mixed (AD+CVD) etiologies. Although the two tasks were significantly associated with each other ( r =.54), a two one-sided test revealed that they were not statistically equivalent. Consistently, a linear mixed model testing the effect of task Type (S7 vs. SB) net of demographics, disease duration, disease severity and etiology revealed that the S7 condition was more difficult to be performed ( M =1.69) than the SB one ( M =3.03). Hence, in MCI and dementia due to chronic-degenerative etiologies, the S7 and the SB tasks from the MMSE are not comparable. Users should exert caution when qualitatively interpreting examinees’ attentional levels based on these tasks.

Background Clinically relevant anxiety can be detected in patients with amyotrophic lateral sclerosis (ALS), but its prevalence and determinants have not yet been fully assessed. Aims This study aimed at assessing the prevalence and clinical underpinnings of anxiety in ALS. Method Non-demented ALS patients (N = 433) and healthy controls (N = 313) were administered the State- and Trait-Anxiety Inventory – Form Y (STAI-Y1 for state-anxiety and STAI-Y2 for trait-anxiety) and the Beck Depression Inventory (BDI). Patients were further assessed for cognition (Edinburgh Cognitive and Behavioural ALS Screen), behaviour (Frontal Behavioural Inventory) and motor status (disease duration, ALS Functional Rating Scale-Revised and progression rate). The prevalence of clinically significant state- and trait-anxiety were estimated by applying age-stratified cut-offs to STAI-Y1/-Y2 t-scores. Linear and logistic regressions were run to test the determinants of STAI-Y1/-Y2 scores. Results STAI-Y1 and -Y2 scores above cut-off were detected in 18.2 and 13.9% of patients, respectively – with proportions being higher in cases versus controls (ps < 0.001). BDI, but neither cognitive/behavioural nor motor variables, was identified as a significant predictor of STAI-Y1/-Y2 scores (ps < 0.003). The cognitive–affective subscale of BDI was the sole predictor of scores above cut-off on both STAI-Y1 and STAI-Y2 (ps < 0.001). Conclusions Clinically significant levels of state- and trait-anxiety occur in ∼18 and ∼14% of non-demented ALS patients, respectively, mostly driven by cognitive and affective facets of depression, and are independent of motor and cognitive/behavioural features.

BackgroundIn clinical settings, the head turning sign (HTS) occurs when patients with cognitive complaints turn their head toward the accompanying person seeking assistance. Due to its nature, and unlike other non-canonical neurological signs of cognitive impairment, the HTS is likely to occur in ecological, daily-life scenarios too. However, this hypothesis has not been tested yet.ObjectiveTo assess the prevalence and clinical correlates of the "ecological HTS" (eHTS) in MCI and dementia due to chronic-degenerative etiologies.MethodsThis retrospective cohort included 112 patients with MCI/dementia due to Alzheimer's disease (AD; N = 71), frontotemporal lobar degeneration (N = 6), Lewy body disease (N = 6), chronic cerebrovascular diseases (CVD; N = 11), mixed (i.e., AD + CVD; N = 15) unspecified non-AD neurodegenerative etiologies (N = 3). We recorded the number of HTSs displayed by patients during the MMSE and inquired accompanying persons whether the HTS occurred in daily life too.ResultsThe overall prevalence of the eHTS in the cohort was 50%; its distribution was independent of demographics, disease severity (i.e., MCI versus dementia), and etiology. Within multiple logistic models, the presence of the eHTS + proved to be predicted both by lower scores on the Spatial Orientation subtest of the MMSE and by a higher number of HTSs during the execution of the MMSE. Moreover, a trend towards longer disease duration and the occurrence of the eHTS was found.ConclusionsIn MCI and dementia, the HTS is an ecologically valid non-canonical sign, frequently occurs in daily life too, associated with longer disease duration and spatial disorientation.

This study aimed to assess the ability of the frontal assessment battery (FAB) to differentiate Alzheimer’s disease (AD) from behavioral variant frontotemporal dementia (bvFTD), as well as to test whether its discriminatory accuracy varies as a function of disease stage. The present retrospective cohort included N = 595 participants—153 with biomarker-supported AD, 96 with probable bvFTD, and 346 healthy controls (HCs). All HCs scored within the normal range on the Montreal Cognitive Assessment. In patients, disease severity was staged according to Clinical Dementia Rating scores, retrospectively derived from the Mini-Mental State Examination. Receiver operating characteristic (ROC) analyses were performed to assess the ability of demographically adjusted FAB scores to differentiate both patient groups from HCs and AD from bvFTD patients, including severity-stratified analyses. Binary logistic regression models adjusted for age and sex examined the contribution of individual FAB subtests to diagnostic classification. The FAB showed excellent accuracy in distinguishing patients from HCs. In contrast, its ability to differentiate AD from bvFTD was modest overall and depended on disease severity, with adequate discrimination emerging solely at moderate-to-severe stages. At the subtest level, Lexical fluency was the only subtests that significantly differentiated bvFTD from AD, particularly in patients at the MCI/questionable dementia and moderate-to-severe dementia stage. No significant differences emerged for the remaining subtests. The FAB is an excellent screening test for executive dysfunction in both bvFTD and AD, but its contribution to the differential diagnosis between these two conditions emerges only at moderate-to-severe stages.

Theory of mind (ToM), the ability to infer others' beliefs (cognitive ToM) and emotions (affective ToM), is compromised in behavioural variant frontotemporal dementia (bvFTD). However, its diagnostic and prognostic value in other frontotemporal dementia (FTD) variants remains underexplored due to limited understanding of the underlying neural mechanisms. This study investigated whether ToM deficits are shared across the frontotemporal dementia spectrum and explored the functional connectivity alterations underlying these disturbances using resting-state functional magnetic resonance imaging. Sixty-seven FTD patients [14 non-fluent variant primary progressive aphasia (nfvPPA), 17 semantic variant primary progressive aphasia (svPPA), 23 bvFTD, 13 right temporal variant frontotemporal dementia (rtvFTD); 34 women; mean age 66.5 ± 7.7 years] and two control groups (48 age-matched healthy controls; 50 young healthy controls) underwent clinical, neuropsychological and brain magnetic resonance imaging assessments. ToM was evaluated in patients using the Story-Based Empathy Task (SET), which includes the Story-Based Empathy Task affective subtest (SET-EA) and the Story-Based Empathy Task cognitive subtest (SET-IA). Resting-state functional connectivity networks were obtained in young healthy controls using seed-based analysis centred on the left medial prefrontal cortex for affective ToM and the right supramarginal gyrus for cognitive ToM. In addition, four large-scale functional networks were reconstructed to reflect disease-specific vulnerability. Functional brain connectivity within all networks was quantified using graph analysis and connectomics, and between-group comparisons were performed on both global and seed-based regional metrics. All patient groups showed similar impairments in affective and cognitive ToM performance. Network analyses revealed two dissociable but interconnected ToM systems. Global metrics of network topology indicated increased path length and reduced nodal strength in both ToM networks, particularly in bvFTD and nfvPPA patients (P < 0.05). Direct seed-based connectivity analyses confirmed widespread functional connectivity reductions from key nodes (e.g. left inferior frontal gyrus, anterior cingulate cortex) in these groups. In contrast, svPPA and rtvFTD cases exhibited relatively preserved functional connectivity within ToM circuits. Correlation analyses revealed associations between cognitive ToM network metrics and global ToM performance, and between functional connectivity in the salience network and behavioural dysfunction. Affective and cognitive ToM abilities are comparably impaired across FTD variants, suggesting that socio-cognitive impairments may represent a core and early feature across the FTD spectrum. Such deficits are mirrored by patterns of functional disconnection within dedicated large-scale networks, with bvFTD and nfvPPA showing the most pronounced disruptions. This study underscores the diagnostic relevance of socio-cognitive markers and highlights their potential as clinical and biomarker targets in future therapeutic interventions.

Serum neurofilament light and heavy chains (sNfL and sNfH) have been assessed as neuronal markers for amyotrophic lateral sclerosis (ALS) and dementias. Whereas sNfL has robust literature, systematic studies on sNfH are lacking. Here, we aimed to assess the diagnostic value of sNfH in comparison to sNfL in a broad range of neurodegenerative disorders. We measured with immunoassays sNfH and sNfL in patients recruited in the multicenter German Frontotemporal Lobar Degeneration (FTLD) Consortium (n = 340) and in a single-center German cohort (n = 290). We assessed the diagnostic accuracy of serum biomarkers for ALS and dementia subtypes and their relationship with cognitive impairment. sNfH and sNfL were significantly increased in ALS (n = 90) vs. controls (n = 109) and ALS mimics (n = 56, p < 0.001), with sNfL showing higher discriminative accuracy (AUC = 0.94–0.95) than sNfH (AUC = 0.87–0.88). sNfH/sNfL ratio did not improve the diagnostic performance. Both markers were elevated in patients with dementia (n = 289) vs. controls (p < 0.001). sNfL was higher in behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA) and Creutzfeldt-Jakob disease (CJD) than in Alzheimer’s disease (AD), whereas sNfH was similar in AD, PPA and bvFTD. sNfL, but not sNfH, was correlated with cognitive impairment at baseline and cognitive decline at follow-up in AD and bvFTD. sNfH and sNfL are elevated in motoneuron and dementia disorders. sNfH showed good discriminative accuracy for ALS, which was slightly lower than that of sNfL. sNfL, but not sNfH, showed prognostic value for assessing cognitive decline in dementia.

Timely and accurate diagnosis of Alzheimer’s disease (AD) in clinical practice is a great challenge, especially during early disease stages with subtle or mild symptoms of cognitive decline. Moreover, robust and more accessible blood-based screening tests for early diagnosis are needed. In this study, we investigated the core AD blood biomarkers — amyloid beta 42 (Aβ42) and 40 (Aβ40) peptides, phosphorylated tau 181 (p-Tau181), neurofilament light chain (NfL), and total tau (t-Tau) — and extracellular vesicle (EVs) size and concentration in individuals characterized by different stages of cognitive decline to identify biochemical markers of dementia for early diagnosis. A total of n = 800 human plasma samples were analyzed. Plasma levels of NfL, t-Tau, p-Tau181, Aβ42, Aβ40 and plasma EVs were evaluated in n = 217 elderly healthy subjects (CTRL), in individuals with subjective cognitive complaints (SCC, n = 48), pre-mild cognitive impairment (pre-MCI, n = 58) and mild cognitive impairment (MCI, n = 426), and in n = 51 probable AD dementia patients (AD-dem), using ultrasensitive Single Molecule Array technology (Simoa®) and nanoparticle tracking analysis (NTA). Logistic regression and Receiver Operating Characteristic (ROC) analyses were employed. Plasma NfL displayed increased levels in AD-dem and MCI patients, while p-Tau181, Aβ42/Aβ40 ratio, Aβ42/p-Tau181 ratio, and EVs plasma levels were altered since the early stages of the pathology: in particular, p-Tau181 levels increased as cognitive symptoms worsened, already in the SCC and pre-MCI groups compared to CTRL, while the ratio of EVs concentration and size (EVs ratio) was decreased in all groups compared to CTRL. Plasma p-Tau181 best classified AD-dem patients from CTRL with an area under the curve (AUC) equal to 0.87, while EVs ratio best differentiated SCC from CTRL (AUC = 0.78). Combining p-Tau181 and EVs ratio with Aβ42/Aβ40 ratio and NfL, respectively, significantly improved the classification of pre-MCI and MCI from CTRL (AUCcomb = 0.79 and AUCcomb = 0.85). Combining biomarkers did not improve accuracy in discriminating MCI from SCC, pre-MCI and AD-dem. p-Tau181 and EVs ratio are promising biomarkers for the identification of individuals at risk of degenerative dementia. Combining the core AD plasma biomarkers with EVs ratio can aid in diagnosing the early stages of AD dementia.

This study validated the Italian version of the In-Person Telephone Interview for Cognitive Status (IP-TICS). 468 healthy Italian individuals (176 males; age: 57.5 ± 15.4, education: 13.2 ± 3.7) completed the TICS, IP-TICS, MMSE and MoCA. Correlational analyses explored the construct validity of the IP-TICS against the TICS, MMSE and MoCA. Hierarchical Confirmatory Factor Analyses tested the configural, metric and scalar invariance between the TICS and IP-TICS. Statistical equivalence was assessed via a two one-sided test (TOST) procedure. Equating norms were derived via log-linear smoothing equipercentile equating (LSEE) analyses, with TOST procedures assessing equivalence between empirical and LSEE-derived scores. The IP-TICS converged with the TICS, MMSE and MoCA, showing configural and metric invariance and equivalence with the TICS. Empirical and LSEE-derived scores were statistically equivalent. Findings support the convergence, equivalence and invariance between the TICS and the IP-TICS. The IP-TICS converges with established in-person screeners.

OBJECTIVE:This study aimed at reviewing currently available evidence on cognitive and behavioral involvement in spinal and bulbar muscular atrophy (SBMA). METHODS:This review was performed in accordance with the 2020 PRISMA guidelines. We included case reports/series and group studies reporting data on the neuropsychological features of SBMA patients. RESULTS:Out of 123 unique records identified, 11 studies were included (N = 5 case reports/series; N = 6 group studies), comprising 151 SBMA patients. Among case reports and series, 6 out of 10 patients were reported to exhibit some degree of neuropsychological involvement, with two being diagnosed with a dementia condition resembling the characteristics of behavioral variant-frontotemporal dementia. Three of the 6 case-control studies found no cognitive differences between SBMA patients and healthy controls. Cognitive deficits reported in group studies mostly involved the executive, attentional, memory and visuo-spatial/-constructive domains. CONCLUSIONS:The available evidence on cognitive and behavioral involvement in SBMA is scarce and conflicting. However, it is conceivable that at least some patients may exhibit dysexecutive-type changes, possibly reflecting a frontal system involvement.

BACKGROUND:This study aimed to determine whether educational attainment-a common proxy of cognitive reserve (CR)-influences the association between motor and cognitive/behavioural outcomes in a large cohort of ALS patients without dementia. METHODS:N = 726 ALS patients without FTD were assessed for motor (ALSFRS-R), cognitive (Edinburgh Cognitive and Behavioural ALS Screen, ECAS) and behavioural outcomes (ECAS-Carer Interview, ECAS-CI). CR was operationalized via educational attainment (in years). Moderation models were run on each subscale of the cognitive section of the ECAS and on the ECAS-CI by addressing ALSFRS-R as the predictor and education as the moderator. RESULTS:Education was associated with both the ALSFRS-R and all the cognitive subscales of the ECAS, while not with the ECAS-CI. As to moderation models, a significant Education*ALSFRS-R interaction was detected solely with regard to the ECAS-Executive-with its simple slope-based decomposition revealing that higher ALSFRS-R scores were associated with higher scores on the ECAS-Executive for patients with low (p < 0.001) and average (p = 0.007), while not high, levels of education. DISCUSSION:Education seems to moderate the association between motor involvement and executive status in ALS patients without dementia, thus possibly exerting a protective role towards both motor function and cognition in this population.

Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease involving loss of motor neurons, typically results in death within 3–5 years of disease onset. Although roughly 10

This study aimed to assess the screening properties of Foderaro et al.s’ updated normative framework for the Italian MMSE in detecting mild cognitive impairment (MCI) and dementia due to neurodegenerative, chronic cerebrovascular, and mixed etiologies, as well as in differentiating between these two syndromes. Data on 234 patients with either MCI (N = 83) or dementia (N = 151) due to Alzheimer’s disease (N = 112), Lewy body disease (N = 11), frontotemporal lobar degeneration (N = 20), chronic cerebrovascular disease (N = 39), or mixed (N = 47) etiologies having been administered Foderaro et al.’s version of the MMSE were retrospectively recruited. Moreover, N = 247 healthy controls (HCs) with a normal Montreal Cognitive Assessment performance were prospectively recruited. Receiver-operating characteristics analyses were run to test the capability of both raw and demographically adjusted MMSE scores to discriminate both HCs from MCI/dementia and MCI from dementia. For these comparisons, screening metrics were also computed at Foderaro et al.’s cut-off (<26.02). The capability of demographically adjusted MMSE scores to discriminate both HCs from dementia and MCI from dementia was excellent (AUC = 0.91 and 0.93, respectively), whilst good for MCI case-finding (AUC = 0.85). Consistently, the screening metrics associated with the cut-off at hand were optimal-to-excellent for dementia case-finding (sensitivity = 0.95; specificity = 0.99) and for the differentiation between MCI and dementia (sensitivity = 0.95; specificity = 0.64), whilst imbalanced for detecting MCI (sensitivity = 0.35; specificity = 0.99). Foderaro et al.’s updated normative framework for the Italian MMSE has optimal screening properties for both dementia case-finding and the discrimination between MCI and dementia, being at variance unbalanced towards specificity when it comes to detecting MCI.

Apathy and depression are the most prevalent neuropsychiatric symptoms in amyotrophic lateral sclerosis (ALS). Although insufficiently investigated, their distinction holds important clinical relevance for accurate diagnosis of ALS with behavioural impairment and for patients’ prognosis and management. In the present study, we aimed to assess both apathy and depressive symptoms in patients with ALS and whether they have similar or different functional neural correlates. Using graph analysis and connectomics, global and lobar nodal properties and regional functional brain connectivity were assessed in ALS patients without apathy/depression (ALSn, n = 42), with apathy without depression (ALSa, n = 14), with depressive symptoms without apathy (ALSd, n = 20), and with apathy and depressive symptoms (ALSad, n = 6), and 46 healthy controls. Correlations between brain functional properties, apathy and depressive symptoms were performed in all patients. Depressive symptoms were related with reduced path length within bilateral basal ganglia (BG) network, and apathy was related with increased path length, decreased nodal strength and local efficiency within left BG network. ALSa patients showed altered functional nodal properties within BG network compared to ALSn and ALSd. Compared to healthy controls and all non-apathetic patients (ALSn and ALSd), all apathetic patients (ALSa and ALSad) exhibited altered functional nodal properties within parietal, occipital and frontal networks. Non-apathetic patients, compared to apathetic patients, showed relatively preserved functional nodal properties in the BG network. Our findings indicate differences in brain functional neural organization associated with apathy and depression, underscoring the importance of distinguishing these symptoms in ALS and highlighting the need for targeted interventions.