Plasma neurofilament light chain predicts Alzheimer's disease in patients with subjective cognitive decline and mild cognitive impairment: A cross-sectional and longitudinal study.

BACKGROUND AND PURPOSE: We aimed to evaluate the accuracy of plasma neurofilament light chain (NfL) in predicting Alzheimer's disease (AD) and the progression of cognitive decline in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). METHODS: This longitudinal cohort study involved 140 patients (45 with SCD, 73 with MCI, and 22 with AD dementia [AD-D]) who underwent plasma NfL and AD biomarker assessments (cerebrospinal fluid, amyloid positron emission tomography [PET], and 18 F-fluorodeoxyglucose-PET) at baseline. The patients were rated according to the amyloid/tau/neurodegeneration (A/T/N) system and followed up for a mean time of 2.72 ± 0.95 years to detect progression from SCD to MCI and from MCI to AD. Forty-eight patients (19 SCD, 29 MCI) also underwent plasma NfL measurements 2 years after baseline. RESULTS: At baseline, plasma NfL detected patients with biomarker profiles consistent with AD (A+/T+/N+ or A+/T+/N-) with high accuracy (area under the curve [AUC] 0.82). We identified cut-off values of 19.45 pg/mL for SCD and 20.45 pg/mL for MCI. During follow-up, nine SCD patients progressed to MCI (progressive SCD [p-SCD]), and 14 MCI patients developed AD dementia (progressive MCI [p-MCI]). The previously identified cut-off values provided good accuracy in identifying p-SCD (80% [95% confidence interval 65.69: 94.31]). The rate of NfL change was higher in p-MCI (3.52 ± 4.06 pg/mL) compared to non-progressive SCD (0.81 ± 1.25 pg/mL) and non-progressive MCI (-0.13 ± 3.24 pg/mL) patients. A rate of change lower than 1.64 pg/mL per year accurately excluded progression from MCI to AD (AUC 0.954). CONCLUSION: Plasma NfL concentration and change over time may be a reliable, non-invasive tool to detect AD and the progression of cognitive decline at the earliest stages of the disease.

The role of plasma neurofilament light chain and glial fibrillary acidic protein in subjective cognitive decline and mild cognitive impairment.

INTRODUCTION AND AIM: NfL and GFAP are promising blood-based biomarkers for Alzheimer's disease. However, few studies have explored plasma GFAP in the prodromal and preclinical stages of AD. In our cross-sectional study, our aim is to investigate the role of these biomarkers in the earliest stages of AD. MATERIALS AND METHODS: We enrolled 40 patients (11 SCD, 21 MCI, 8 AD dementia). All patients underwent neurological and neuropsychological examinations, analysis of CSF biomarkers (Aß42, Aß42/Aß40, p-tau, t-tau), Apolipoprotein E (APOE) genotype analysis and measurement of plasma GFAP and NfL concentrations. Patients were categorized according to the ATN system as follows: normal AD biomarkers (NB), carriers of non-Alzheimer's pathology (non-AD), prodromal AD, or AD with dementia (AD-D). RESULTS: GFAP was lower in NB compared to prodromal AD (p = 0.003, d = 1.463) and AD-D (p = 0.002, d = 1.695). NfL was lower in NB patients than in AD-D (p = 0.011, d = 1.474). NfL demonstrated fair accuracy (AUC = 0.718) in differentiating between NB and prodromal AD, with a cut-off value of 11.65 pg/mL. GFAP showed excellent accuracy in differentiating NB from prodromal AD (AUC = 0.901) with a cut-off level of 198.13 pg/mL. CONCLUSIONS: GFAP exhibited excellent accuracy in distinguishing patients with normal CSF biomarkers from those with prodromal AD. Our results support the use of this peripheral biomarker for detecting AD in patients with subjective and objective cognitive decline.

The Frequency of Intermediate Alleles in Patients with Cerebellar Phenotypes.

Cerebellar syndromes are clinically and etiologically heterogeneous and can be classified as hereditary, neurodegenerative non-hereditary, or acquired. Few data are available on the frequency of each form in the clinical setting. Growing interest is emerging regarding the genetic forms caused by triplet repeat expansions. Alleles with repeat expansion lower than the pathological threshold, termed intermediate alleles (IAs), have been found to be associated with disease manifestation. In order to assess the relevance of IAs as a cause of cerebellar syndromes, we enrolled 66 unrelated Italian ataxic patients and described the distribution of the different etiology of their syndromes and the frequency of IAs. Each patient underwent complete clinical, hematological, and neurophysiological assessments, neuroimaging evaluations, and genetic tests for autosomal dominant cerebellar ataxia (SCA) and fragile X-associated tremor/ataxia syndrome (FXTAS). We identified the following diagnostic categories: 28% sporadic adult-onset ataxia, 18% cerebellar variant of multiple system atrophy, 9% acquired forms, 9% genetic forms with full-range expansion, and 12% cases with intermediate-range expansion. The IAs were six in the FMR1 gene, two in the gene responsible for SCA8, and one in the ATXN2 gene. The clinical phenotype of patients carrying the IAs resembles, in most of the cases, the one associated with full-range expansion. Our study provides an exhaustive description of the causes of cerebellar ataxia, estimating for the first time the frequency of IAs in SCAs- and FXTAS-associated genes. The high percentage of cases with IAs supports further screening among patients with cerebellar syndromes.

FDG PET in the differential diagnosis of degenerative parkinsonian disorders: usefulness of voxel-based analysis in clinical practice.

BACKGROUND: The early differential diagnosis among neurodegenerative parkinsonian disorders becomes essential to set up the correct clinical-therapeutic approach. The increased utilization of [18F] fluoro-deoxy-glucose positron emission tomography (FDG PET) and the pressure for cost-effectiveness request a systematic evaluation and a validation of its utility in clinical practice. This retrospective study aims to consider the contribution, in terms of increasing accuracy and increasing diagnostic confidence, of voxel-based FDG PET analyses in the differential diagnosis of these disorders, including Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and cortico-basal syndrome. METHOD: Eighty-three subjects with a clinically confirmed diagnosis of degenerative parkinsonian disorders who underwent FDG brain PET/CT were selected. A voxel-based analysis was set up using statistical parametric mapping (SPM) on MATLAB to produce maps of brain hypometabolism and relative hypermetabolism. Four nuclear physicians (two expert and two not expert), blinded to the patients' symptoms, other physicians' evaluations, and final clinical diagnosis, independently evaluated all data by visual assessment and by adopting metabolic maps. RESULTS: In not-expert evaluators, the support of both hypometabolism and hypermetabolism maps results in a significant increase in diagnostic accuracy as well as clinical confidence. In expert evaluators, the increase in accuracy and in diagnostic confidence is mainly supported by hypometabolism maps alone. CONCLUSIONS: In this study, we demonstrated the additional value of combining voxel-based analyses with qualitative assessment of brain PET images. Moreover, maps of relative hypermetabolism can also make their contribution in clinical practice, particularly for less experienced evaluators.

Cerebral amyloid load determination in a clinical setting: interpretation of amyloid biomarker discordances aided by tau and neurodegeneration measurements.

BACKGROUND: Alzheimer's disease (AD) diagnosis can be hindered by amyloid biomarkers discordances. OBJECTIVE: We aim to interpret discordances between amyloid positron emission tomography (Amy-PET) and cerebrospinal fluid (CSF) (Aß42 and Aß42/40), using Amy-PET semiquantitative analysis, [18F]fluorodeoxyglucose (FDG)-PET pattern, and CSF assays. METHOD: Thirty-six subjects with dementia or mild cognitive impairment, assessed by neuropsychological tests, structural and functional imaging, and CSF assays (Aß42, Aß42/40, p-tau, t-tau), were retrospectively examined. Amy-PET and FDG-PET scans were analyzed by visual assessment and voxel-based analysis. SUVR were calculated on Amy-PET scans. RESULTS: Groups were defined basing on the agreement among CSF Aß42 (A), CSF Aß42/40 Ratio (R), and Amy-PET (P) dichotomic results ( ±). In discordant groups, CSF assays, Amy-PET semiquantification, and FDG-PET patterns supported the diagnosis suggested by any two agreeing amyloid biomarkers. In groups with discordant CSF Aß42, the ratio always agrees with Amy-PET results, solving both false-negative and false-positive Aß42 results, with Aß42 levels close to the cut-off in A + R-P- subjects. The A + R + P- group presented high amyloid deposition in relevant areas, such as precuneus, posterior cingulate cortex (PCC) and dorsolateral frontal inferior cortex at semiquantitative analysis. CONCLUSION: The amyloid discordant cases could be overcome by combining CSF Aß42, CSF ratio, and Amy-PET results. The concordance of any 2 out of the 3 biomarkers seems to reveal the remaining one as a false result. A cut-off point review could avoid CSF Aß42 false-negative results. The regional semiquantitative Amy-PET analysis in AD areas, such as precuneus and PCC, could increase the accuracy in AD diagnosis.

Behavioural disorders in Alzheimer's disease: the descriptive and predictive role of brain 18 F-fluorodesoxyglucose-positron emission tomography.

BACKGROUND: Alzheimer's disease (AD) has a high incidence in the elderly. Besides cognitive disorders, patients may also develop behavioural and psychological symptoms of dementia (BPSD), which can be particularly disabling for patients and families. BPSD encompass a wide range of symptoms, among which psychotic symptoms and disruptive behaviours often prompt the first related hospitalization and request for family support. The aetiological mechanism of BPSD has not yet been clarified, and no predictive or risk factors have been identified. The main objectives of our study are to describe the frequency of aggression/agitation and psychotic symptoms, defined 'positive BPSD', in a cohort of 60 AD patients, identify areas of the brain involved in behavioural symptomatology through brain 18 F-fluorodesoxyglucose-positron emission tomography (FDG-PET), and investigate a potential predictive role of brain FDG-PET in BPSD development. METHODS: A cohort of 60 AD patients was retrospectively enrolled and regularly followed for at least 3 years. Each subject underwent brain FDG-PET at the time of diagnosis. Patients were divided into three groups based on the presence of behavioural disturbances: present, absent, and developed later. RESULTS: Of the 60 AD patients in the cohort, 52% had positive BPSD: 17 at baseline and 14 during the 3-year follow-up. FDG-PET identified an association between hypometabolism in the bilateral temporal lobes and the presence of BPSD, and showed initial hypometabolism in the postero-temporal lobes 3 years before symptom onset. CONCLUSIONS: Positive BPSD are frequently manifested in AD. Our study identified the temporal lobes as the neurobiological substrate of positive BPSD and FDG-PET as a potential instument to predict their developement. Temporal lobes are involved in processing facial expression and recognizing emotions; an impairment of these functions could cause delusions and agitated/aggressive behaviour. To confirm the potential predictive role of FDG-PET in the onset of BPSD in AD, further studies are needed.

Primary Progressive Aphasia: Natural History in an Italian Cohort.

BACKGROUND/AIMS: Few longitudinal studies have explored the progression of cognitive and functional impairment of patients with primary progressive aphasia (PPA). The aims of the study were to describe the clinical, neuroimaging, and genetic features of a cohort of 68 PPA patients, and to outline the natural history of the disease. MATERIALS AND METHODS: A sample of 23 patients with the logopenic variant, 26 with the nonfluent/agrammatic variant, and 19 with the semantic variant was retrospectively collected and followed-up for a maximum of 6 years. Clinical-neuropsychological assessment, fluorodeoxyglucose positron emission tomographic imaging, and genetic analyses were acquired at baseline. Disease progression was evaluated in terms of language impairment, global cognitive decline, and functional dependency. RESULTS: During follow-up, one third of subjects presented total language loss, and 20% severe functional dependency. Global cognitive decline after the first year (hazard ratio, 5.93; confidence interval, 1.63-21.56) and high schooling (hazard ratio, 0.07; confidence interval, 0.008-0.74) represented risk factors for functional impairment. The apolipoprotein E status was associated with the progression of cognitive decline. Positive family history for dementia was frequent and 3 genetic autosomal dominant mutations were identified. CONCLUSIONS: There were no differences in the progression of PPA subtypes. Genetics plays an important role in disease onset and progression.

Screening for Aphasia in NeuroDegeneration for the Diagnosis of Patients with Primary Progressive Aphasia: Clinical Validity and Psychometric Properties.

BACKGROUND: We evaluated the psychometric proprieties of the Screening for Aphasia in NeuroDegeneration (SAND) battery in Italian primary progressive aphasia (PPA) and movement disorder (MD) patients. METHODS: The sample included 30 consecutive PPA and 45 MD patients who completed the SAND battery together with a clinical interview and a neurological/neuropsychological examination and 130 healthy controls (HC). RESULTS: The SAND battery showed good internal consistency and good convergent and divergent validity. receiver operating characteristic analysis revealed an area under the curve of 0.978 for PPA versus HC and of 0.786 for PPA versus MD. A cutoff ≥3 gave a sensitivity of 0.933% and a specificity of 0.946% for discriminating PPA versus HC, whereas a cutoff ≥5 gave a sensitivity of 0.767% and a specificity of 0.667% for discriminating PPA versus MD. CONCLUSION: These results indicate that the SAND battery is an adequate, reliable, and valid diagnostic tool for PPA.

Biomarkers study in atypical dementia: proof of a diagnostic work-up.

BACKGROUND: An early differentiation between Alzheimer's Disease (AD) and other dementias is crucial for an adequate patients' management, albeit it may result difficult for the occurrence of "atypical presentations." Current diagnostic criteria recognize the importance of biomarkers for AD diagnosis, but still an optimal diagnostic work-up isn't available. OBJECTIVE: Evaluate the utility and reproducibility of biomarkers and propose an "optimal" diagnostic work-up in atypical dementia. METHODS: (1) a retrospective selection of "atypical dementia cases"; (2) a repetition of diagnostic assessment by two neurologists following two different diagnostic work-ups, each consisting of multiple steps; (3) a comparison between diagnostic accuracy and confidence reached at each step by both neurologists and evaluation of the inter-rater agreement. RESULTS: In AD, regardless of the undertaken diagnostic work-up, a significant gain in accuracy was reached by both neurologists after the second step, whereas in frontotemporal dementia (FTD), adding subsequent steps was not always sufficient to increase significantly the baseline accuracy. A relevant increment in diagnostic confidence was detectable after studying pathophysiological markers in AD, and after assessing brain metabolism in FTD. The inter-rater agreement was higher at the second step for the AD group when the pathophysiological markers were available and for the FTD group when the results of FDG-PET were accessible. CONCLUSIONS: In atypical cases of dementia, biomarkers significantly raise diagnostic accuracy, confidence, and agreement. This study introduces a proof of diagnostic work-up that combines imaging and CSF biomarkers and suggests distinct ways to proceed on the basis of a greater diagnostic likelihood.

SAND: a Screening for Aphasia in NeuroDegeneration. Development and normative data.

Language assessment has a critical role in the clinical diagnosis of neurodegenerative diseases, in particular, in the case of Primary Progressive Aphasia (PPA). The current diagnostic criteria (Gorno-Tempini et al., 2011) identify three main variants on the basis of clinical features and patterns of brain atrophy. Widely accepted tools to diagnose, clinically classify, and follow up the heterogeneous language profiles of PPA are still lacking. In this study, we develop a screening battery, composed of nine tests (picture naming, word and sentence comprehension, word and sentence repetition, reading, semantic association, writing and picture description), following the recommendations of current diagnostic guidelines and taking into account recent research on the topic. All tasks were developed with consideration of the psycholinguistic factors that can affect performance, with the aim of achieving sensitivity to the language deficit to which each task was relevant, and to allow identification of the selective characteristic impairments of each PPA variant. Normative data on 134 Italian subjects pooled across homogeneous subgroups for age, sex, and education are reported. Although further work is still needed, this battery represents a first step towards a concise multilingual standard language examination, a fast and simple tool to help clinicians and researchers in the diagnosis of PPA.

Rethinking on the concept of biomarkers in preclinical Alzheimer's disease.

The neuropathological processes eventually leading to Alzheimer's disease (AD) are thought to start decades before the appearance of clinical symptoms and the clinical diagnosis of AD dementia. The term "preclinical AD" has been recently introduced to identify this "silent stage" of AD, when the disease is already present, but symptoms are not yet clinically evident. Advances in AD biomarkers have dramatically improved the ability to detect AD pathological processes in vivo in cognitively intact subjects, thus demonstrating the presence of AD pathology in the preclinical phase. This review focuses on the recent advances in the field of neuroimaging and CSF AD biomarkers specifically in the preclinical phase of AD, and aims to discuss the significance that such biomarkers could have in cognitively intact subjects. Even though the use of such biomarkers in AD preclinical phase has contributed to improve our understanding of AD early pathological processes, it raised also a number of new challenges that still remain to be overcome, such as a better definition of the clinical and individual significance of currently known biomarkers in preclinical stages and the development of novel biomarkers of different early AD-related events.

Heterogeneity and overlap in the continuum of linguistic profile of logopenic and semantic variants of primary progressive aphasia: a Profile Analysis based on Multidimensional Scaling study.

BACKGROUND: Primary progressive aphasia (PPA) diagnostic criteria underestimate the complex presentation of semantic (sv) and logopenic (lv) variants, in which symptoms partially overlap, and mixed clinical presentation (mixed-PPA) and heterogenous profile (lvPPA +) are frequent. Conceptualization of similarities and differences of these clinical conditions is still scarce. METHODS: Lexical, semantic, phonological, and working memory errors from nine language tasks of sixty-seven PPA were analyzed using Profile Analysis based on Multidimensional Scaling, which allowed us to create a distributed representation of patients' linguistic performance in a shared space. Patients had been studied with [18F] FDG-PET. Correlations were performed between metabolic and behavioral data. RESULTS: Patients' profiles were distributed across a continuum. All PPA, but two, presented a lexical retrieval impairment, in terms of reduced production of verbs and nouns. svPPA patients occupied a fairly clumped space along the continuum, showing a preponderant semantic deficit, which correlated to fusiform gyrus hypometabolism, while only few presented working memory deficits. Adjacently, lvPPA + presented a semantic impairment combined with phonological deficits, which correlated with metabolism in the anterior fusiform gyrus and posterior middle temporal gyrus. Starting from the shared phonological deficit side, a large portion of the space was occupied by all lvPPA, showing a combination of phonological, lexical, and working memory deficits, with the latter correlating with posterior temporo-parietal hypometabolism. Mixed PPA did not show unique profile, distributing across the space. DISCUSSION: Different clinical PPA entities exist but overlaps are frequent. Identifying shared and unique clinical markers is critical for research and clinical practice. Further research is needed to identify the role of genetic and pathological factors in such distribution, including also higher sample size of less represented groups.

Data-driven subtypes of mixed semantic-logopenic primary progressive aphasia: Linguistic features, biomarker profiles and brain metabolic patterns.

Mixed primary progressive aphasia (mPPA) accounts for a substantial proportion of primary progressive aphasia (PPA) cases. However, the lack of a standardised definition of this condition has resulted in misclassification of PPA cases. In this study, we enrolled 55 patients diagnosed with PPA, comprising 12 semantic variant (svPPA), 23 logopenic variant (lvPPA), and 20 mPPA cases with linguistic characteristics consistent with both svPPA and lvPPA (s/lvPPA). All patients underwent language assessments, evaluation of Alzheimer's disease biomarkers (via cerebrospinal fluid analysis or Amyloid-PET), and 18F-FDG-PET brain scans. An agglomerative hierarchical clustering (AHC) analysis based on linguistic characteristics revealed two distinct clusters within the s/lvPPA group: cluster k1 (n = 10) displayed an AD-like biomarker profile, with lower levels of Aß42 and Aß42/Aß40 ratio, along with higher levels of t-tau and p-tau compared to cluster k2 (n = 10). Interestingly, k1 exhibited linguistic features that were similar to those of svPPA. Both clusters exhibited extensive temporoparietal hypometabolism. These findings support the hypothesis that a subgroup of s/lvPPA may represent a clinical manifestation of AD-related PPA.

Disentangling empathy impairment along Alzheimer's disease continuum: From subjective cognitive decline to Alzheimer's dementia.

Little is known about empathy changes from the early stages of Alzheimer's Disease (AD) continuum. The aim of this study is to investigate empathy across AD spectrum from Subjective Cognitive Decline (SCD) to Mild Cognitive Impairment (MCI) and AD dementia (AD-d). Forty-five SCD, 83 MCI and 80 AD-d patients were included. Empathy was assessed by Interpersonal Reactivity Index (IRI) (Perspective Taking - PT, Fantasy - FT, Empathic Concern - EC, and Personal Distress - PD), rated by caregivers before (T0) and after (T1) cognitive symptoms' onset. IRI was also administered to SCD patients to have a self-reported empathy evaluation. Facial emotion recognition was assessed by Ekman-60 Faces Test. Twenty-two SCD, 54 MCI and 62 AD-d patients underwent CSF biomarkers analysis and were classified as carriers of AD pathology (AP+) when they were A+/T+ (regardless of N), or non-carriers (AP-) when they were A- (regardless of T and N), or A+/T-/N-, or A+/T-/N+ according to the A/T(N) system. Cerebral FDG-PET SPM analysis was used to explore neural correlates underlying empathy deficits. PD scores significantly increased from T0 to T1 in SCD, MCI and AD-d (p < .001), while PT scores decreased in MCI and in AD-d (p < .001). SCD AP+ showed a greater increase in PD scores over time (ΔPD T0 - T1) than SCD AP- (p < .001). SCD self-reported PT scores were lower than those of general Italian population (14.94 ± 3.94, 95% C.I. [13.68-16.20] vs 17.70 ± 4.36, 95% C.I. [17.30-18.10]). In AD continuum (SCD AP+, MCI AP+, AD-d), a positive correlation was detected between PT-T1 and brain metabolism in left posterior cingulate gyrus, precuneus and right frontal gyri; a negative correlation was found between ΔPT and brain metabolism in bilateral posterior cingulate gyri. PT may be subtly involved since the preclinical phase of AD. Changes over time of PD are influenced by the underlying Alzheimer's pathology and could potentially serve as an early AD neuropsychological marker.

MoCA Domain-Specific Pattern of Cognitive Impairment in Stroke Patients Attending Intensive Inpatient Rehabilitation: A Prospective Study.

A domain-specific perspective to cognitive functioning in stroke patients may predict their cognitive recovery over time and target stroke rehabilitation intervention. However, data about domain-specific cognitive impairment after stroke are still scarce. This study prospectively investigated the domain-specific pattern of cognitive impairments, using the classification proposed by the Montreal Cognitive Assessment (MoCA), in a cohort of 49 stroke patients at admission (T0), discharge (T1), and six-month follow-up (T2) from subacute intensive rehabilitation. The predictive value of T0 cognitive domains cognitive impairment at T1 and T2 was also investigated. Patients' cognitive functioning at T0, T1, and T2 was assessed through the MoCA domains for executive functioning, attention, language, visuospatial, orientation, and memory. Different evolutionary trends of cognitive domain impairments emerged across time-points. Patients' impairments in all domains decreased from T0 to T1. Attention and executive impairments decreased from T0 to T2 (42.9% and 26.5% to 10.2% and 18.4%, respectively). Conversely, altered visuospatial, language, and orientation increased between T1 and T2 (16.3%, 36.7%, and 40.8%, respectively). Additionally, patients' global cognitive functioning at T1 was predicted by the language and executive domains in a subacute phase (p = 0.031 and p = 0.001, respectively), while in the long term, only attention (p = 0.043) and executive (p = 0.019) domains intervened. Overall, these results confirm the importance of a domain-specific approach to target cognitive recovery across time in stroke patients.

Comparing the effects of augmented virtual reality treadmill training versus conventional treadmill training in patients with stage II-III Parkinson's disease: the VIRTREAD-PD randomized controlled trial protocol.

Background: Intensive treadmill training (TT) has been documented to improve gait parameters and functional independence in Parkinson's Disease (PD), but the optimal intervention protocol and the criteria for tailoring the intervention to patients' performances are lacking. TT may be integrated with augmented virtual reality (AVR), however, evidence of the effectiveness of this combined treatment is still limited. Moreover, prognostic biomarkers of rehabilitation, potentially useful to customize the treatment, are currently missing. The primary aim of this study is to compare the effects on gait performances of TT + AVR versus TT alone in II-III stage PD patients with gait disturbance. Secondary aims are to assess the effects on balance, gait parameters and other motor and non-motor symptoms, and patient's satisfaction and adherence to the treatment. As an exploratory aim, the study attempts to identify biomarkers of neuroplasticity detecting changes in Neurofilament Light Chain concentration T0-T1 and to identify prognostic biomarkers associated to blood-derived Extracellular Vesicles. Methods: Single-center, randomized controlled single-blind trial comparing TT + AVR vs. TT in II-III stage PD patients with gait disturbances. Assessment will be performed at baseline (T0), end of training (T1), 3 (T2) and 6 months (T3, phone interview) from T1. The primary outcome is difference in gait performance assessed with the Tinetti Performance-Oriented Mobility Assessment gait scale at T1. Secondary outcomes are differences in gait performance at T2, in balance and spatial-temporal gait parameters at T1 and T2, patients' satisfaction and adherence. Changes in falls, functional mobility, functional autonomy, cognition, mood, and quality of life will be also assessed at different timepoints. The G*Power software was used to estimate a sample size of 20 subjects per group (power 0.95, α < 0.05), raised to 24 per group to compensate for potential drop-outs. Both interventions will be customized and progressive, based on the participant's performance, according to a predefined protocol. Conclusion: This study will provide data on the possible superiority of AVR-associated TT over conventional TT in improving gait and other motor and non-motor symptoms in persons with PD and gait disturbances. Results of the exploratory analysis could add information in the field of biomarker research in PD rehabilitation.

Differences and Similarities in Empathy Deficit and Its Neural Basis between Logopenic and Amnesic Alzheimer's Disease.

The aims of the study were to assess empathy deficit and neuronal correlates in logopenic primary progressive aphasia (lv-PPA) and compare these data with those deriving from amnesic Alzheimer's disease (AD). Eighteen lv-PPA and thirty-eight amnesic AD patients were included. Empathy in both cognitive and affective domains was assessed by Informer-rated Interpersonal Reactivity Index (perspective taking, PT, and fantasy, FT, for cognitive empathy; empathic concern, EC, and personal distress, PD, for affective empathy) before (T0) and after (T1) cognitive symptoms' onset. Emotion recognition was explored through the Ekman 60 Faces Test. Cerebral FDG-PET was used to explore neural correlates underlying empathy deficits. From T0 to T1, PT scores decreased, and PD scores increased in both lv-PPA (PT z = -3.43, p = 0.001; PD z = -3.62, p < 0.001) and in amnesic AD (PT z = -4.57, p < 0.001; PD z = -5.20, p < 0.001). Delta PT (T0-T1) negatively correlated with metabolic disfunction of the right superior temporal gyrus, fusiform gyrus, and middle frontal gyrus (MFG) in amnesic AD and of the left inferior parietal lobule (IPL), insula, MFG, and bilateral superior frontal gyrus (SFG) in lv-PPA (p < 0.005). Delta PD (T0-T1) positively correlated with metabolic disfunction of the right inferior frontal gyrus in amnesic AD (p < 0.001) and of the left IPL, insula, and bilateral SFG in lv-PPA (p < 0.005). Lv-PPA and amnesic AD share the same empathic changes, with a damage of cognitive empathy and a heightening of personal distress over time. The differences in metabolic disfunctions correlated with empathy deficits might be due to a different vulnerability of specific brain regions in the two AD clinical presentations.

Comparing two picture naming tasks in primary progressive aphasia: Insights from behavioural and neural results.

Picture naming tests are widely used to evaluate language impairments in neurodegenerative diseases, especially in Primary Progressive Aphasia (PPA). The available tests differ for many factors affecting the performance, e.g. format of stimuli and their psycholinguistic properties. We aim to identify the most appropriate naming test to be used on PPA according to the clinical and research demands. We investigated the behavioural characteristics, i.e. proportion of correct responses and error type, and their neural correlates in two Italian naming tests, CaGi naming (CaGi) and naming subtest of the Screening for Aphasia in NeuroDegeneration battery (SAND), administered to 52 PPA patients who underwent an FDG-PET scan. We analysed the effectiveness of the tests in distinguishing PPA versus controls and among PPA variants, considering the psycholinguistic variables affecting performance. We explored the brain metabolic correlates of behavioural performance in the tests. SAND, differently from CaGi, has time limits for the response and its items are less frequent and acquired later. SAND and CaGi differed in terms of number of correct responses and error profile, suggesting a higher difficulty to name SAND items compared to CaGi. Semantic errors predominated in CaGi, while anomic and semantic errors were equally frequent in SAND. Both tests distinguished PPA from controls, but SAND outperformed CaGi in discriminating among PPA variants. FDG-PET imaging revealed a shared metabolic involvement of temporal areas associated with lexico-semantic processing, encompassing anterior fusiform, temporal pole, and extending to posterior fusiform in sv-PPA. Concluding, a picture naming test with response time limit and items which are less frequent and acquired later in life, as SAND, may be effective at highlighting subtle distinctions between PPA variants, improving the diagnosis. Conversely, a naming test without time limit for the response, as CaGi, may be useful for a better characterization of the nature of the naming impairment at the behavioural level, eliciting more naming errors than anomia, possibly helping in the development of rehabilitation protocols.

Loss of speech and functional impairment in Alzheimer's disease-related primary progressive aphasia: predictive factors of decline.

We aimed to identify features associated with different disease trajectories in Alzheimer's disease (AD)-related primary progressive aphasia (PPA). We considered 23 patients diagnosed with AD-related PPA. All patients underwent neuropsychological evaluation, 18F-Fluorodeoxyglucose-PET brain scan, CSF biomarkers measurement and APOE genotype analysis at baseline and underwent neurological follow-up for a mean time of 3 years. Patients who progressed to total loss of speech (TLoS+) had greater impairment in writing and higher t-tau concentration as compared to TLoS- patients. Patients who progressed to loss of functional autonomy (LoFA+) had greater impairment in single-word comprehension as compared to patients who maintained autonomy in self-care. Furthermore, 18F-FDG-PET SPM analyses revealed different brain metabolic patterns between TLoS+ and TLoS- and between LoFA+ and LoFA-. In conclusion, linguistic profile, CSF t-tau and brain metabolic pattern might be useful tools to predict progression to total loss of speech and loss of functional autonomy in AD-related PPA patients.

Brain metabolic connectivity reconfiguration in the semantic variant of primary progressive aphasia.

Functional network-level alterations in the semantic variant of Primary Progressive Aphasia (sv-PPA) are relevant to understanding the clinical features and the neural spreading of the pathology. We assessed the effect of neurodegeneration on brain systems reorganization in early sv-PPA, using advanced brain metabolic connectivity approaches. Forty-four subjects with sv-PPA and forty-four age-matched healthy controls (HC) were included. We applied two multivariate approaches to [18F]FDG-PET data - i.e., sparse inverse covariance estimation and seed-based interregional correlation analysis - to assess the integrity of (i) the whole-brain metabolic connectivity and (ii) the connectivity of brain regions relevant for cognitive and behavioral functions. Whole-brain analysis revealed a global-scale connectivity reconfiguration in sv-PPA, with widespread changes in metabolic connections of frontal, temporal, and parietal regions. In comparison to HC, the seed-based analysis revealed a) functional isolation of the left anterior temporal lobe (ATL), b) decreases in temporo-occipital connections and contralateral homologous regions, c) connectivity increases to the dorsal parietal cortex from the spared posterior temporal cortex, d) a disruption of the large-scale limbic brain networks. In sv-PPA, the severe functional derangement of the left ATL may lead to an extensive connectivity reconfiguration, encompassing several brain regions, including those not yet affected by neurodegeneration. These findings support the hypothesis that in sv-PPA the focal vulnerability of the core region (i.e., ATL) can potentially drive the widespread cerebral connectivity changes, already present in the early phase.