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Abstract Background Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

Abstract Episodic memory shows the largest degree of age-related decline. Anodal transcranial Direct Current Stimulation (tDCS) can enhance episodic memory in aging but there is also evidence of response variability even when using identical stimulation parameters. To explore which inter-individual factors (i.e. age, education, encoding performance, cognitive reserve, tDCS group and timing of tDCS application) may directly and/or indirectly modulate verbal memory recall, we used data from our previous tDCS studies that showed enhanced episodic memory recall in 80 healthy older adults. In these studies we used the same paradigm and stimulation parameters but tDCS was applied during different memory stages. Memory recall was tested 48 hours and 30 days after encoding. Univariate regression models showed that tDCS group (Anodal vs. Sham) predicted memory recall, indicating higher scores in the Anodal group than in the Sham group. Encoding performance predicted memory recall in both tDCS groups. Multiple regression models revealed that cognitive reserve, measured with a life experience questionnaire, predicted memory recall only for the Anodal group. Higher cognitive reserve was linked to better memory recall. Accounting for individual differences in cognitive reserve at baseline helps to explain tDCS responsiveness. This knowledge may contribute to optimize its use in older adults.

BackgroundIn recent years, an increasing number of studies have examined the potential efficacy of cognitive training procedures in individuals with normal ageing and mild cognitive impairment (MCI).ObjectiveThe aims of this study were to (i) evaluate the efficacy of the cognitive Virtual Reality Rehabilitation System (VRRS) combined with anodal transcranial direct current stimulation (tDCS) applied to the left dorsolateral prefrontal cortex compared to placebo tDCS stimulation combined with VRRS and (ii) to determine how to prolong the beneficial effects of the treatment. A total of 109 subjects with MCI were assigned to 1 of 5 study groups in a randomized controlled trial design: (a) face-to-face (FTF) VRRS during anodal tDCS followed by cognitive telerehabilitation (TR) (clinic-atDCS-VRRS+Tele@H-VRRS); (b) FTF VRRS during placebo tDCS followed by TR (clinic-ptDCS-VRRS+Tele@H-VRRS); (c) FTF VRRS followed by cognitive TR (clinic-VRRS+Tele@H-VRRS); (d) FTF VRRS followed by at-home unstructured cognitive stimulation (clinic-VRRS+@H-UCS); and (e) FTF cognitive treatment as usual (clinic-TAU).ResultsAn improvement in episodic memory was observed after the end of clinic-atDCS-VRRS (p

Abstract INTRODUCTION The goal of the present work was to assess the incidence of dementia with onset before the age of 65 years (i.e., young‐onset dementia [YOD]) and define the frequencies of young‐onset Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), and dementia with Lewy bodies (DLB) in the general population. METHODS The study was conducted from January 1, 2019 to December 31, 2019 in Brescia province (population: 1,268,455). During the study period, all new YOD cases (incident YOD) were counted, and all patients’ records reviewed. The incidence was standardized to the Italian general population in 2019. RESULTS A total of 29 YOD patients were diagnosed. The age‐sex standardized incidence rate was 4.58 (95% confidence interval, 3.07–6.58) per 100,000 person‐years. No difference in incidence rate between YOD due to AD or FTLD (P = 0.83) and between sexes (P = 0.81) was observed. YOD incidence increased with age, reaching its peak after 60 years. DISCUSSION Presenting neurodegenerative YOD phenotypes encompasses both AD and FTLD. Improved knowledge on YOD epidemiology is essential to adequately plan and organize health services.

BackgroundNon-fluent/agrammatic variant of Primary Progressive Aphasia (avPPA) is primarily characterized by language impairment due to atrophy of the inferior frontal gyrus and the insula cortex in the dominant hemisphere. The Screening for Aphasia in NeuroDegeneration (SAND) battery has been recently proposed as a screening tool for PPA, with several tasks designed to be specific for different language features. Applying multivariate approaches to neuroimaging data and verbal fluency tasks, Aachener Aphasie Test (AAT) naming subtest and SAND data may help in elucidating the neuroanatomical correlates of language deficits in avPPA.ObjectiveTo investigate the neuroanatomical correlates of language deficits in avPPA using verbal fluency tasks, AAT naming subtest and SAND scores as proxies of brain structural imaging abnormalities.MethodsThirty-one avPPA patients were consecutively enrolled and underwent extensive neuropsychological assessment and MRI scan. Raw scores of verbal fluency tasks, AAT naming subtest, and SAND subtests, namely living and non-living picture naming, auditory sentence comprehension, single-word comprehension, words and non-words repetition and sentence repetition, were used as proxies to explore structural (gray matter volume) neuroanatomical correlates. We assessed univariate (voxel-based morphometry, VBM) as well as multivariate (source-based morphometry, SBM) approaches. Age, gender, educational level, and disease severity were considered nuisance variables.ResultsSAND picture naming (total, living and non-living scores) and AAT naming scores showed a direct correlation with the left temporal network derived from SBM. At univariate analysis, the left middle temporal gyrus was directly correlated with SAND picture naming (total and non-living scores) and AAT naming score. When words and non-words repetition (total score) was considered, a direct correlation with the left temporal network (SBM) and with the left fusiform gyrus (VBM) was also evident.ConclusionNaming impairments that characterize avPPA are related to specific network-based involvement of the left temporal network, potentially expanding our knowledge on the neuroanatomical basis of this neurodegenerative condition.

Abstract Background Primary progressive aphasia (PPA) is a neurodegenerative disorder characterized by a gradual, insidious and progressive loss of language abilities, with naming difficulties being an early and persistent impairment common to all three variants. In the absence of effective pharmacological treatments and given the progressive nature of the disorder, in the past few decades, many studies have investigated the effectiveness of language training to minimize the functional impact of word-finding difficulties in daily life. Main body We review language treatments most commonly used in clinical practice among patients with different variants of PPA, with a focus on the enhancement of spoken and written naming abilities. Generalization of gains to the ability to name untrained stimuli or to other language abilities and the maintenance of these results over time are also discussed. Forty-eight studies were included in this literature review, identifying four main types of language treatment: a) lexical retrieval treatment, b) phonological and/or orthographic treatment, c) semantic treatment, and d) a multimodality approach treatment. Overall, language training is able to induce immediate improvements of naming abilities in all variants of PPA. Moreover, despite the large variability among results, generalization and long-term effects can be recorded after the training. The reviewed studies also suggest that one factor that determines the choice of a particular approach is the compromised components of the lexical/semantic processing system. Conclusion The majority of studies have demonstrated improvements of naming abilities following language treatments. Given the progressive nature of PPA, it is essential to apply language treatment in the early stages of the disease.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

Primary Progressive Aphasia (PPA) is a syndrome due to different neurodegenerative disorders selectively disrupting language functions. PPA specialist care is underdeveloped. There are very few specialists (neurologists, psychiatrists, neuropsychologists, and speech therapists) and few hospital- or community-based services dedicated to the diagnosis and continuing care of people with PPA. Currently, healthcare systems struggle to provide adequate coverage of care that is too often fragmented, uncoordinated, and unresponsive to the needs of people with PPA and their families. Recently, attention has been gained by non-invasive brain stimulation techniques that allow a personalized treatment approach, such as transcranial Direct Current Stimulation (tDCS). The MAINSTREAM trial looks forward to introducing and evaluating therapeutic innovations such as tDCS coupled with language therapy in rehabilitation settings. A Multimodal Approach for Clinical Diagnosis and Treatment of Primary Progressive Aphasia, MAINSTREAM (ID: 3430931) was registered in the clinicaltrials.gov database (identifier: NCT05730023) on 15 February 2023.

BackgroundMemory impairment is among one of the greatest cognitive complaints in midlife and in old age. Considering the importance of good memory functioning in everyday life, it is crucial to study interventions that can reduce the natural decline in this cognitive function. Transcranial Magnetic Stimulation (TMS) studies have demonstrated that the lateral prefrontal cortex (PFC) plays a causal role in enhancing episodic memory recall through reconsolidation. Using a similar paradigm with transcranial direct current stimulation (tDCS) over the left lateral PFC, facilitation effects were observed in delayed memory retrieval in older adults with subjective memory complaints (SMCs) and amnestic Mild Cognitive Impairment (aMCI). However, it remains unclear which potential factors (i.e., tDCS group, cognitive reserve, education level, diagnosis and encoding performance) directly and/or indirectly modulate the tDCS-induced memory reconsolidation effects.MethodsWe reanalyzed data acquired in our previous tDCS studies with 22 SMC and 18 aMCI participants from the perspective of predicting delayed memory retrieval performance. These studies included a learning session on Day 1, a reactivation by a contextual reminder followed by 15 min of tDCS session on Day 2 (24 h after Day 1), and two retrieval sessions (free recall and recognition) tested on Days 3 and 30 (48 h and 30 Days after Day 1).ResultsUnivariate models showed that tDCS group (sham vs. active) significantly predicted memory recognition (but not free recall), evidenced by higher scores in the active tDCS group than in sham group, confirming our previous results. Encoding performance and diagnosis (SMC vs. aMCI) significantly predicted memory retrieval, suggesting higher performances in individuals with SMC than in those with aMCI. Regarding cognitive reserve, higher leisure time activity subscores significantly predicted better memory recognition. Finally, multiple models did not show any tDCS group × predictor interaction effects, indicating that the effects of the predictors on retrieval occurred irrespective of tDCS group.ConclusionOur results shed light on predicting factors of episodic memory retrieval in this reconsolidation paradigm in individuals with SMC and aMCI. The findings suggest that multifactorial interventions program may be most promising to slow cognitive decline and delay the onset of dementia.

Background: In recent years, emphasis has been placed on cognitive enhancement to stimulate cognitive abilities and prevent functional decline. Considering that traditional face-to-face interventions can be very expensive and are not accessible to all individuals, the need to transfer care from the clinic to the patient's home is evident. In this regard, cognitive tele-enhancement interventions have received increased attention.Aim: The aim of this review was to provide an overview of protocols that apply remotely controlled cognitive training with individualized feedback on performance by the therapist in healthy older adults or participants with subjective memory complaints.Methods: Out of 35 articles assessed for eligibility, eight studies were identified. Of the selected studies, five included cognitively healthy older adults, while three included participants with subjective memory complaints.Results: Most of the reviewed studies showed beneficial effects of cognitive tele-enhancement interventions, reporting improvements in memory, sustained attention, working memory, executive functions, and language abilities. Moreover, reductions in anxiety and depression symptomatology levels, as well as in subjective memory difficulties, were described in some of the studies.Conclusions: Cognitive tele-enhancement treatment could be a good alternative to face-to-face intervention. This literature review highlights the importance of applying preventive cognitive interventions to subjects with initial subjective memory complaints. Remote modalities seem to facilitate the application of such interventions.

Alzheimer’s disease (AD) is a pathology characterized by the accumulation in the brain of intracellular and extracellular amyloid-β (Aβ) aggregates, especially of Aβ1–40 and Aβ1–42 peptides. It is known that N-terminally truncated or modified Aβ forms also exist in AD brains and cerebrospinal fluid (CSF), and they play a key role in the pathogenesis of the disease. Herein, we developed an antibody-free method based on Solid-Phase Extraction and Electrospray Ionization Liquid Chromatography Mass Spectrometry for the identification and quantitation in human CSF of Aβ isoforms. In human CSF, we could detect and quantify a panel of 19 Aβ isoforms, including N-terminally truncated and pyroglutamate-modified forms, never quantified before in CSF. Among these, we identified novel N-terminally truncated Aβ species: four bound to copper and two phosphorylated forms, which were found to be the most common proteoforms in human CSF along with Aβ1–40, Aβ3–40, and AβpE11–42. We tested the newly developed and validated method in a pilot study on CSF from elderly individuals with subjective memory complaints (SMCs, n = 9), mild cognitive impairment (MCI, n = 18), and AD (n = 15); along with Aβ1–42, five N-terminally truncated forms (Aβ11–40, Aβ3–42, AβpE11–42, AβpE3–40, and Aβ4–40 Cu2+) are altered in AD/MCI. Thus, we demonstrated that N-terminally truncated and pyroglutamate-modified Aβ can be quantified in human CSF, and five of them, along with Aβ1–42, are potential markers of AD progression. The described method could represent a useful tool for patients’ stratification and monitoring. Moreover, the newly identified Aβ CSF species might represent new potential therapeutic targets.

Alzheimer’s disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) are the three major neurodegenerative dementias. In this study, we provide evidence that an alteration in extracellular vesicles (EVs) release is common across the three most common neurodegenerative dementias, AD, DLB, and FTD. Specifically, we analyzed plasma EVs in three groups of patients affected by AD, DLB, and FTD, and we found a significant reduction in EVs concentration and larger EVs size in all patient groups. We then investigated whether the loss of neurotrophic factors is also a common pathogenic mechanism among FTD, DLB, and AD, and if levels of neurotrophic factors might affect EVs release. Plasma levels of progranulin and cystatin C (CysC) were partially altered; however, taking together all variables significantly associated with the diagnostic groups only EVs size and concentration were able to distinguish patients from controls. The diagnostic performance of these two EVs parameters together (ratio) was high, with a sensitivity of 83.3% and a specificity of 86.7%, able to distinguish patients from controls but not to differentiate the different forms of dementias. Among the candidate neurotrophic factors, only CysC levels were associated with EVs concentration. Our study suggests that an alteration in the intercellular communication mediated by EVs might be a common molecular pathway underlying neurodegenerative dementias. The identification of shared disease mechanisms is of pivotal importance to develop treatments to delay disease progression. To this aim, further studies investigating plasma EVs size and concentration as early biomarkers of dementia are required.

Eating behavior can change during aging due to physiological, psychological, and social changes. Modifications can occur at different levels: (1) in food choice, (2) in eating habits, and (3) in dietary intake. A good dietary behavior, like the Mediterranean dietary pattern, can be a protective factor for some aging related pathologies, such as dementia, while a worse eating behavior can lead to pathological conditions such as malnutrition. Changes in eating behavior can also be linked to the onset of dementia: for some types of dementia, such as frontotemporal dementia, dietary changes are one of the key clinical diagnostic feature, for others, like Alzheimer's disease, weight loss is a clinical reported feature. For these reasons, it is important to be able to assess eating behavior in a proper way, considering that there are normal age-related changes. An adequate assessment of dietary behavior can help to plan preventive intervention strategies for heathy aging or can help to identify abnormal behaviors that underline aging related-diseases. In this review, we have analyzed normal age-related and dementia-related changes and the tools that can be used to assess eating behavior. Thus, we make recommendations to screening and monitoring eating behavior in aging and dementia, and to adopt these tools in clinical practice.

BackgroundIn recent years, the potential usefulness of cognitive training procedures in normal aging and mild cognitive impairment (MCI) have received increased attention.ObjectiveThe main aim of this study was to evaluate the efficacy of the face-to-face cognitive virtual reality rehabilitation system (VRRS) and to compare it to that of face-to-face cognitive treatment as usual for individuals with MCI. Moreover, we assessed the possibility of prolonging the effects of treatment with a telerehabilitation system.MethodsA total of 49 subjects with MCI were assigned to 1 of 3 study groups in a randomized controlled trial design: (a) those who received face-to-face cognitive VRRS (12 sessions of individualized cognitive rehabilitation over 4 weeks) followed by telerehabilitation (36 sessions of home-based cognitive VRRS training, three sessions for week); (b) those who received face-to-face cognitive VRRS followed by at-home unstructured cognitive stimulation (36 sessions of home-based unstructured cognitive stimulation, three sessions for week); and (c) those who received face-to-face cognitive treatment as usual (12 sessions of face-to-face cognitive treatment as usual).ResultsAn improvement in memory, language and visuo-constructional abilities was observed after the end of face-to-face VRRS treatment compared to face-to-face treatment as usual. The application of home-based cognitive VRRS telerehabilitation seems to induce more maintenance of the obtained gains than home-based unstructured stimulation.DiscussionThe present study provides preliminary evidence in support of individualized VRRS treatment and telerehabilitation delivery for cognitive rehabilitation and should pave the way for future studies aiming at identifying optimal cognitive treatment protocols in subjects with MCI.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT03486704.

Abstract Background Cholinergic dysfunction is a key abnormality in Alzheimer disease (AD) that can be detected in vivo with transcranial magnetic stimulation (TMS) protocols. Although TMS has clearly demonstrated analytical validity, its clinical utility is still debated. In the present study, we evaluated the incremental diagnostic value, expressed in terms of diagnostic confidence of Alzheimer disease (DCAD; range 0–100), of TMS measures in addition to the routine clinical diagnostic assessment in patients evaluated for cognitive impairment as compared with validated biomarkers of amyloidosis. Methods One hundred twenty patients with dementia were included and scored in terms of DCAD in a three-step assessment based on (1) demographic, clinical, and neuropsychological evaluations (clinical work-up); (2) clinical work-up plus amyloid markers (cerebrospinal fluid or amyloid positron emission tomographic imaging); and (3) clinical work-up plus TMS intracortical connectivity measures. Two blinded neurologists were asked to review the diagnosis and diagnostic confidence at each step. Results TMS measures increased the discrimination of DCAD in two clusters (AD-like vs FTD-like) when added to the clinical and neuropsychological evaluations with levels comparable to established biomarkers of brain amyloidosis (cluster distance of 55.1 for clinical work-up alone, 76.0 for clinical work-up plus amyloid markers, 80.0 for clinical work-up plus TMS). Classification accuracy for the “gold standard” diagnosis (dichotomous - AD vs FTD - variable) evaluated in the three-step assessment, expressed as AUC, increased from 0.82 (clinical work-up alone) to 0.98 (clinical work-up plus TMS) and to 0.99 (clinical work-up plus amyloidosis markers). Conclusions TMS in addition to routine assessment in patients with dementia has a significant effect on diagnosis and diagnostic confidence that is comparable to well-established amyloidosis biomarkers.

Abstract One of the earliest pathological features characterizing Alzheimer’s disease (AD) is the loss of dendritic spines. Among the many factors potentially mediating this loss of neuronal connectivity, the contribution of Rho-GTPases is of particular interest. This family of proteins has been known for years as a key regulator of actin cytoskeleton remodeling. More recent insights have indicated how its complex signaling might be triggered also in pathological conditions. Here, we showed that the Rho-GTPase family member Rac1 levels decreased in the frontal cortex of AD patients compared to non-demented controls. Also, Rac1 increased in plasma samples of AD patients with Mini-Mental State Examination

Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) represent the three major neurodegenerative dementias characterized by abnormal brain protein accumulation. In this study, we investigated extracellular vesicles (EVs) and neurotrophic factors in the cerebrospinal fluid (CSF) of 120 subjects: 36 with AD, 30 with DLB, 34 with FTD and 20 controls. Specifically, CSF EVs were analyzed by Nanoparticle Tracking Analysis and neurotrophic factors were measured with ELISA. We found higher EV concentration and lower EV size in AD and DLB groups compared to the controls. Classification tree analysis demonstrated EV size as the best parameter able to discriminate the patients from the controls (96.7% vs. 3.3%, respectively). The diagnostic performance of the EV concentration/size ratio resulted in a fair discrimination level with an area under the curve of 0.74. Moreover, the EV concentration/size ratio was associated with the p-Tau181/Aβ42 ratio in AD patients. In addition, we described altered levels of cystatin C and progranulin in the DLB and AD groups. We did not find any correlation between neurotrophic factors and EV parameters. In conclusion, the results of this study suggest a common involvement of the endosomal pathway in neurodegenerative dementias, giving important insight into the molecular mechanisms underlying these pathologies.

Cutting-edge research suggests endosomal/immune dysregulation in GRN/C9orf72-associated frontotemporal lobar degeneration (FTLD). In this retrospective study, we investigated plasma small extracellular vesicles (sEVs) and complement proteins in 172 subjects (40 Sporadic FTLD, 40 Intermediate/Pathological C9orf72 expansion carriers, and 49 Heterozygous/Homozygous GRN mutation carriers, 43 controls). Plasma sEVs (concentration, size) were analyzed by nanoparticle tracking analysis; plasma and sEVs C1q, C4, C3 proteins were quantified by multiplex assay. We demonstrated that genetic/sporadic FTLD share lower sEV concentrations and higher sEV sizes. The diagnostic performance of the two most predictive variables (sEV concentration/size ratio) was high (AUC = 0.91, sensitivity 85.3%, specificity 81.4%). C1q, C4, and C3 cargo per sEV is increased in genetic and sporadic FTLD. C4 (cargo per sEV, total sEV concentration) is increased in Sporadic FTLD and reduced in GRN+ Homozygous, suggesting its specific unbalance compared with Heterozygous cases. C3 plasma level was increased in genetic vs. sporadic FTLD. Looking at complement protein compartmentalization, in control subjects, the C3 and C4 sEV concentrations were roughly half that in respect to those measured in plasma; interestingly, this compartmentalization was altered in different ways in patients. These results suggest sEVs and complement proteins as potential therapeutic targets to mitigate neurodegeneration in FTLD.

Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B, the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in the AD group. Overall, our study shows that AD patients fail to maintain a Cu metabolic balance and reveals the presence of a percentage of AD patients carrying ATP7B AG haplotype and presenting Non-Cp Cu excess, which suggest that a subset of AD subjects is prone to Cu imbalance. This AD subtype can be the target of precision medicine-based strategies tackling Cu dysregulation.

Genetic frontotemporal dementia is most commonly caused by mutations in the progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72) genes. Previous small studies have reported the presence of cerebral white matter hyperintensities (WMH) in genetic FTD but this has not been systematically studied across the different mutations. In this study WMH were assessed in 180 participants from the Genetic FTD Initiative (GENFI) with 3D T1- and T2-weighed magnetic resonance images: 43 symptomatic (7 GRN, 13 MAPT and 23 C9orf72), 61 presymptomatic mutation carriers (25 GRN, 8 MAPT and 28 C9orf72) and 76 mutation negative non-carrier family members. An automatic detection and quantification algorithm was developed for determining load, location and appearance of WMH. Significant differences were seen only in the symptomatic GRN group compared with the other groups with no differences in the MAPT or C9orf72 groups: increased global load of WMH was seen, with WMH located in the frontal and occipital lobes more so than the parietal lobes, and nearer to the ventricles rather than juxtacortical. Although no differences were seen in the presymptomatic group as a whole, in the GRN cohort only there was an association of increased WMH volume with expected years from symptom onset. The appearance of the WMH was also different in the GRN group compared with the other groups, with the lesions in the GRN group being more similar to each other. The presence of WMH in those with progranulin deficiency may be related to the known role of progranulin in neuroinflammation, although other roles are also proposed including an effect on blood-brain barrier permeability and the cerebral vasculature. Future studies will be useful to investigate the longitudinal evolution of WMH and their potential use as a biomarker as well as post-mortem studies investigating the histopathological nature of the lesions.

Episodic memory is critical to daily life functioning. This type of declarative memory declines with age and is the earliest cognitive function to be compromised in Alzheimer’s disease (AD). Subjective memory complaints are commonly reported by older adults and have been considered a risk factor for developing AD. The possibilities for prevention of memory disorders in older adults have increased substantially in recent years. Previous studies have shown that anodal transcranial Direct Current Stimulation (tDCS) applied over the left lateral prefrontal cortex (PFC) after a contextual reminder strengthened existing verbal episodic memories, conceivably through reconsolidation, in elderly people. In this study, we hypothesized that anodal tDCS applied over the left lateral PFC after a contextual reminder would improve delayed memory retrieval relative to placebo (sham) stimulation in elderly individuals with SMC. Twenty-two subjects learned a list of words. Twenty-four hour later, tDCS (anodal or placebo) was applied over the left lateral PFC after a contextual reminder. Memory retrieval was tested 48h and 30 days later. These findings showed that anodal tDCS over the left lateral PFC strengthened existing episodic memories, a behavioral effect documented by improved recognition up to 30 days, relative to placebo stimulation. This study suggests that tDCS after a contextual reminder can induce long-lasting beneficial effects by facilitating the consolidation processes and opens up the possibility to design specific non-invasive interventions aimed at preventing memory decline in this at-risk population.

Recent clinical, genetic and biochemical experimental evidences highlight the existence of common molecular pathways underlying neurodegenerative diseases. In this review, we will explore a key common pathological mechanism, i.e., the loss of neuroprotective factors, across the three major neurodegenerative diseases leading to dementia: Alzheimer's disease (AD), Frontotemporal dementia (FTD) and Lewy body dementia (LBD). We will report evidences that the Brain Derived Neurotrophic Factor (BDNF), the most investigated and characterized brain neurotrophin, progranulin, a multi-functional adipokine with trophic and growth factor properties, and cystatin C, a neuroprotective growth factor, are reduced in AD, FTD, and LBD. Moreover, we will review the molecular mechanism underlying the loss of neuroprotective factors in neurodegenerative diseases leading to dementia, with a special focus on endo-lysosomal pathway and intercellular communication mediated by extracellular vesicles. Exploring the shared commonality of disease mechanisms is of pivotal importance to identify novel potential therapeutic targets and to develop treatments to delay, slow or block disease progression.

Mutations in the progranulin gene (PGRN) are a major cause of frontotemporal lobar degeneration (FTLD). Herein we estimated the contribution of the PGRN Leu271LeufsX10 mutation to FTLD and related disorders in the Brescia cohort. The PGRN Leu271LeufsX10 mutation was found in 31% of corticobasal syndrome (CBS), 29% of frontotemporal dementia with motorneuron disease (FTD-MND), 15% of behavioral variant frontotemporal dementia (FTD), 9.5% of primary progressive aphasia (PPA), 2% dementia with Lewy bodies and 0% of progressive supranuclear palsy and multiple system atrophy cases. The prevalence strongly increased in familial forms (75% CBS, 50% FTD-MND, 27% FTD, 18% PPA): in our cohort this mutation is a major disease determinant for FTLD-related disorders with a prominent motor component. MAPT haplotype was demonstrated to be a disease modifier in PGRN Leu271LeufsX10 carriers: in H1H2 subjects the disease onset was earlier than in H2H2 individuals. Sequencing of the whole PGRN gene disclosed a previously described mutation (c.2T>C, Met1X) and three novel ones (c.709-3; c.1011delG, His340ThrfsX21; c.1021C>T, Gln341X) in single families. In the Brescia cohort, while MAPT mutations have low prevalence, mutations in PGRN were shown in 28% of familial FTLD and 75% of familial CBS cases. The PGRN Leu271LeufsX10 mutation becomes one of the most common mutations worldwide, since it was identified in 38 patients belonging to 27 unrelated families.

There is now considerable evidence that the gene encoding for tau protein (MAPT) is implicated in frontotemporal dementia (FTD). The role of MAPT haplotypes in neurodegenerative diseases has been suggested, but their contribution in familial dementia has not been extensively investigated. Here, we investigated (1) the association between the MAPT haplotypes and sporadic (sFTD) or familial FTD (FFTD) (controls n = 99, sFTD n = 53, FFTD n = 50), (2) the interactive effect between MAPT haplotypes and APOE gene. We found an overrepresentation of H2 haplotype (OR = 1.83, P = 0.029) and of H2H2 genotype in FFTD patients (OR = 6.09, P = 0.007). This association was even stronger in APOE e4 negatives FFTD (H2: OR = 2.9, P = 0.001; H2H2: OR = 12.67, P = 0.001). Our results support idea that the MAPT H2 haplotype is a risk factor for FFTD. This locus could contain this or other inheritable genetic determinants contributing to increase risk of developing dementia.

Mutations in the presenilin genes PS1 and PS2, the major cause of familial Alzheimer's disease (FAD), are associated with alterations in Ca2+ signalling. In contrast to the majority of FAD-linked PS1 mutations, which cause an overload of intracellular Ca2+ pools, the FAD-linked PS2 mutation M239I reduces Ca2+ release from intracellular stores [Zatti, G., Ghidoni, R., Barbiero, L., Binetti, G., Pozzan, T., Fasolato, C., Pizzo, P., 2004. The presenilin 2 M239I mutation associated with Familial Alzheimer's Disease reduces Ca2+ release from intracellular stores. Neurobiol. Dis. 15/2, 269–278]. We here show that in human FAD fibroblasts another PS2 mutation (T122R) reduces both Ca2+ release and capacitative Ca2+ entry. The observation, done in two monozygotic twins, is of note since only one of the subjects showed overt signs of disease at the time of biopsy whereas the other one developed the disease 3 years later. This finding indicates that Ca2+ dysregulation anticipates the onset of dementia. A similar Ca2+ alteration occurred in HeLa and HEK293 cells transiently expressing PS2-T122R. Based on these data, the “Ca2+ overload” hypothesis in AD pathogenesis is here discussed and reformulated.

Mutations in presenilin (PS) genes account for the majority of the cases of the familial form of Alzheimer's disease (FAD). PS mutations have been correlated with both over-production of the amyloid-β-42 (Aβ42) peptide and alterations of cellular Ca2+ homeostasis.We here show, for the first time, the effect of the recently described PS2 FAD-associated M239I mutation on two major parameters of intracellular Ca2+ homeostasis: the Ca2+ storing capacity of the endoplasmic reticulum (ER) and the activation level of capacitative Ca2+ entry (CCE), the Ca2+ influx pathway activated by depletion of intracellular stores.Ca2+ release from intracellular stores was significantly reduced in fibroblasts from FAD patients, compared to that found in cells from healthy individuals or patients affected by sporadic forms of Alzheimer's Disease (AD). No significant difference was however found in CCE between FAD and control fibroblasts. Similar results were obtained in two cell lines (HEK293 and HeLa) stably or transiently expressing the PS2 M239I mutation.

CST3 is the coding gene for cystatin C (CysC). CST3 B/B homozygosity is associated with an increased risk of developing Alzheimer disease. We performed CysC analysis on human primary skin fibroblasts obtained from donors carrying A/A, A/B, and B/B CST3. Pulse-chase experiments demonstrated that the release of the B variant of CysC has a different temporal pattern compared to that of the A one. Fibroblasts B/B homozygous displayed a reduced secretion of CysC due to a less efficient cleavage of the signal peptide, as suggested by high-resolution Western blot analysis and by in vitro assay. In the brain, the reduced level of CysC may represent the molecular factor responsible for the increased risk of Alzheimer disease.