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ObjectiveTo report the clinical and laboratory characteristics, as well as treatment and clinical outcomes of patients admitted for neurological diseases with COVID-19 in a Neuro-COVID unit compared to patients without COVID-19.MethodsIn this retrospective, single centre cohort study, we included all adult inpatients with confirmed COVID-19, who had been discharged or died by April 5, 2020. Demographic, clinical, treatment, and laboratory data were extracted from medical records.Results173 patients were included in this study, of whom 56 resulted positive for COVID-19 and 117 resulted negative for COVID-19. Patients with COVID-19 were older, had a different distribution regarding admission diagnoses, including cerebrovascular disorders, and had a higher quick Sequential Organ Failure Assessment (qSOFA) score on admission (all pIn-hospital mortality rates and incident delirium were significantly higher in the COVID-19 group (all pppMultivariable regressions showed increasing odds of in-hospital death associated with higher qSOFA scores (odds ratio 4.47, 95% CI 1.21-16.5; p=0.025), lower platelet count (0.98, 0.97-0.99; p=0.005) and higher lactate dehydrogenase (1.01, 1.00-1.03; p=0.009) on admission.ConclusionsCOVID-19 patients admitted with neurological disease, including stroke, have a significantly higher in-hospital mortality, incident delirium and higher disability than patients without COVID-19.

ObjectiveTo report clinical and laboratory characteristics, treatment, and clinical outcomes of patients admitted for neurologic diseases with and without coronavirus disease 2019 (COVID-19).MethodsIn this retrospective, single-center cohort study, we included all adult inpatients with confirmed COVID-19 admitted to a neuro-COVID unit beginning February 21, 2020, who had been discharged or died by April 5, 2020. Demographic, clinical, treatment, and laboratory data were extracted from medical records and compared (false discovery rate corrected) to those of neurologic patients without COVID-19 admitted in the same period.ResultsOne hundred seventy-three patients were included in this study, of whom 56 were positive and 117 were negative for COVID-19. Patients with COVID-19 were older (77.0 years, interquartile range [IQR] 67.0–83.8 years vs 70.1 years, IQR 52.9–78.6 years, p = 0.006), had a different distribution regarding admission diagnoses, including cerebrovascular disorders (n = 43, 76.8% vs n = 68, 58.1%), and had a higher quick Sequential Organ Failure Assessment (qSOFA) score on admission (0.9, IQR 0.7–1.1 vs 0.5, IQR 0.4–0.6, p = 0.006). In-hospital mortality rates (n = 21, 37.5% vs n = 5, 4.3%, p < 0.001) and incident delirium (n = 15, 26.8% vs n = 9, 7.7%, p = 0.003) were significantly higher in the COVID-19 group. Patients with COVID-19 and without COVID with stroke had similar baseline characteristics, but patients with COVID-19 had higher modified Rankin Scale scores at discharge (5.0, IQR 2.0–6.0 vs 2.0, IQR 1.0–3.0, p < 0.001), with a significantly lower number of patients with a good outcome (n = 11, 25.6% vs n = 48, 70.6%, p < 0.001). In patients with COVID-19, multivariable regressions showed increasing odds of in-hospital death associated with higher qSOFA scores (odds ratio [OR] 4.47, 95% confidence interval [CI] 1.21–16.5, p = 0.025), lower platelet count (OR 0.98, 95% CI 0.97–0.99, p = 0.005), and higher lactate dehydrogenase (OR 1.01, 95% CI 1.00–1.03, p = 0.009) on admission.ConclusionsPatients with COVID-19 admitted with neurologic disease, including stroke, have a significantly higher in-hospital mortality and incident delirium and higher disability than patients without COVID-19.

Corticobasal syndrome (CBS) has a heterogeneous neuropathological spectrum, ranging from the classical corticobasal degeneration to Alzheimer's disease (AD). The neuropathology of CBS is still unpredictable. CSF tau/abeta ratio is a reliable marker of AD.To evaluate the presence of a distinct clinical and neuroimaging CBS phenotype according to CSF pattern.30 patients fulfilling current clinical criteria for CBS entered the study. Each patient underwent a clinical and standardised neuropsychological assessment, and CSF analysis (total tau and abeta42 dosages). CSF AD-like pattern and CSF non-AD like pattern (nAD-like) were identified. In 23 CBS cases, (99m)Tc-ECD single photon emission computed tomography (SPECT) scan was performed and analysed by statistical parametric mapping.CSF AD-like pattern was reported in six cases (20%). The two subgroups did not differ in demographic characteristics or global cognitive impairment. The AD-like group showed greater impairment of memory performances, language and psychomotor speed while the nAD-like group had more severe extrapyramidal syndrome with comparable apraxia scores. Voxel by voxel analysis on SPECT images demonstrated that CBS AD-like patients had greater hypoperfusion in the brain areas typically affected by AD-namely, precuneus, posterior cingulate and hippocampus, bilaterally-compared with nAD-like patients (p0.001). No clusters above the pre-established threshold were detected when nAD-like were compared with AD-like patients.CSF AD-like profile in CBS is associated with earlier memory impairment and brain abnormalities typically found in classical AD. These findings argue for the usefulness of CSF testing to identify AD in CBS, and might suggest a different pharmacological approach on the basis of biological data.

The 43-kD transactive response (TAR)-DNA-binding protein (TARDBP) mutations have been demonstrated to be causative of sporadic and familial forms of amyotrophic lateral sclerosis. More recently, these mutations have been reported in cases of frontotemporal lobar degeneration (FTLD). The aim of this study was to evaluate the role of TARDBP genetic variations in a large sample of consecutive patients with FTLD. A total of 252 FTLD patients were investigated. Each subject had a clinical and neuropsychological evaluation and a brain imaging study. The clinical diagnosis was confirmed by at least 1 year of follow up. The entire TARDBP gene, the intronic flaking regions, and the 5'-untranslated region (5'-UTR) were screened. Six genetic variations were identified in patients with behavioral variant frontotemporal dementia (FTD) and FTD with motor neuron disease phenotypes. Two of these mutations, namely N267S and M359V, lead to amino acid changes within exon 6. We further identified three genetic variations, i.e., Y214Y, IVS-IV + 45C/T, and 5'-UTR G/A, that could potentially affect the normal splicing process as predicted by in silico analyses. None of these genetic variations was found in healthy age-matched controls. Moreover, we identified a previously described benign variant, A66A, in 5 patients. Our study has confirmed and extended the list of pathogenetic mutations in the TARDBP gene in both apparently sporadic and familial FTLD patients. This work further supports the need for TARDBP screening in FTLD. Also intronic splicing that affects mutations should be considered as well.

Background: Frontotemporal lobar degeneration (FTLD) encompasses different clinical subtypes but with overlapping features. Establishing whether FTLD represents a continuum or recognizes distinct subgroups may be crucial for diagnostic purposes and therapeutic approaches. Objective: To investigate whether cognitive profiles in a large sample of FTLD patients reflect qualitatively distinct subtypes, variants along a single continuum of severity, or severity differences within subtypes. Method: Latent class analysis (LCA), exploratory factor analysis (FA), and mixture factor analysis (MFA) modeling were applied to a wide neuropsychological assessment data. LCA corresponds to qualitatively distinct subtypes, FA corresponds to quantitatively severity differences, and MFA allows for both subtypes and severity differences within subtypes. Results: The authors consecutively enrolled 314 FTLD patients. A comparison of the different models shows that MFA models provided a superior fit to the data than any of the LCA or exploratory FA models. The "best" MFA model was defined by two continuous variables evaluating the disease severity within two groups of patients ("good" and "bad" performers). These two populations have been called "benign" and "malignant" FTLD. Conclusions: FTLD recognizes distinct subgroups beyond the disease severity, namely a benign form and a more malignant form. This observation needs to be taken into account in future clinical trials and for therapeutic approaches. © 2010 American Association for Geriatric Psychiatry.

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are in the spectrum of tauopathies and recognized to have a strong genetic background. It has been widely reported that MAPT tau haplotype H1 is a genetic risk factor in both conditions, but no other genetic determinants have so far been proposed. Recently, vascular endothelial growth factor (VEGF) haplotypes were reported to confer risk to frontotemporal dementia (FTD). The aim of this study was to evaluate the role of VEGF genetic determinants in PSP and CBS susceptibility. We evaluated a cohort of 687 unrelated Italian subjects, including 117 PSP, 108 CBS, 199 FTD, and 263 healthy controls. Genotype and allele frequencies of three well-known polymorphisms located within the VEGF promoter (-2578C/A, -1190G/A, and -1154G/A) were carried out. Genetic analysis revealed the presence of significant changes in terms of genotype and allele distributions in patients compared to healthy controls. A-G-G haplotype (-2578C/A, 1190G/A, -1154G/A) was overrepresented in both PSP (OR = 6.64, 95%CI = 2.3-19.6, P = 0.0003, CGG = reference) and CBS (OR = 5.20, 95%CI = 1.70-15.9, P = 0.003, CGG = reference) compared to healthy subjects. No differences between PSP and CBS and FTD were found, and the A-G-G haplotype was also overrepresented in FTD. Overall, these data suggest that VEGF gene variability represents a susceptibility factor for PSP and CBS. These data argue that additional genes may confer disease risk to PSP and CBS, and to FTD as well, beyond the MAPT tau haplotype. Further studies are warranted.

A correct clinical diagnosis in the early stage of Alzheimer Disease (AD) is mandatory given the current available treatment with acetylcholine esterase inhibitors. Moreover, a early to preclinical diagnosis would allow to identify patients eligible for future disease-modifying therapies. In the last ten years, we have focused our attention on peripheral markers, evaluating the role of platelet Amyloid Precursor Protein (APP) forms as a reliable tool for AD diagnosis since preclinical stages. APP is the key player in AD pathogenesis, and platelets contain all the enzymatic machinery to its processing, thus being the ideal candidate where to study AD pathogenetic mechanisms. In this review, we summarise the published data regarding the usefulness of platelet APP form ratio in the diagnosis of early AD. Approaches combining APP form ratio along with neuroimaging markers show the promise to accurately identify AD, even in the pre-symptomatic stage.

Background and purpose: Frontotemporal dementia (FTD) is the second most common neurodegenerative dementia in the young age after Alzheimer disease. Recent improvement in diagnostic assessment suggests that it is more common than previously, although with a great heterogeneity in clinical presentation. The different clinical patterns related to age of disease onset in behavioural variant FTD (bvFTD) have been fairly studied. Aim of the study was to evaluate whether age at disease onset modulate the heterogeneity of either cognitive impairment or behavioural disturbances in patients affected by bvFTD. Methods: One hundred and thirty-four patients with bvFTD entered the study. Age at onset and demographic characteristics were carefully recorded. Each patient underwent a wide neuropsychological and behavioural standardized assessment, as well as a brain SPECT perfusion imaging study. Results: Behavioural variant FTD were subdivided into four groups according to the age at onset. The four quartile groups did not differ for demographic characteristics and family history for dementia. Global cognitive impairment as well as analysis of the different cognitive domains and behavioural patterns were comparable. Conclusions: These findings provide evidence that the clinical heterogeneity of bvFTD is not explained by age at disease onset. Further studies are needed.

Objective – Frontotemporal lobar degeneration (FTLD) includes different heterogeneous conditions mainly characterized by personality changes and cognitive deficits in language and executive functions; movement disorders have also been associated with FTLD. The present study aimed to measure the primary motor cortex (M1) inhibitory and facilitatory functions in patients affected by FTLD. Materials and methods – The study included 17 FTLD patients, 8 age-matched healthy controls and 8 Alzheimer’s disease (AD) patients. Transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (ICI) and facilitation (ICF) by using a double-pulse paradigm. Results – FTLD patients were comparable with controls and AD patients for ICI and ICF. Corticobasal degeneration (CBD) patients presented significant reduced inhibition at ISI3; moreover two out of seven CBD patients had only ipsilateral responses. Discussion – The present study reveals a selective impairment of M1 ICI inhibitory response in CBD, which may help in distinguishing among the FTLD clinical spectrum.

Clinical criteria for DLB have been more and more accurate over time, and they had focused on psychotic symptoms for their high frequency. Recent literature suggests that behavioral and psychological symptoms of dementia (BPSD) are frequently associated with DLB, beyond the presence of psychosis. Notwithstanding, the occurrence of BPSD in DLB is under-investigated, and no data are available yet in the different stages. Aim of the present study was to evaluate BPSD pattern in the different stages of DLB, and characterize the relationship with both cognitive deficits and Parkinsonian signs. Ninety-two DLB patients were enrolled and were divided into mild (n=63, 68.5%) and moderate-severe (n=29, 31.5%) subgroups according to the severity of cognitive impairment. Considering the absence/presence of symptoms, anxiety was the most common BPSD (67.4%), followed by depression (61.9%), apathy (57.6%), agitation and sleep disorder (55.4%). Psychosis was present in half of the patients. These symptoms worsened over disease course and represented a core-feature of the disease. No association between BPSD severity and the degree of motor disability was found. These observations suggest that a careful and systematic evaluation of BPSD is mandatory for carefully characterizing disease-related features and for developing new therapeutic approaches. Knowledge of the specific weight of BPSD in DLB would contribute to improve the allocation of health resources for dementia and to a better management of the disease.

In the present study we aimed at evaluating the prevalence and the associated clinical, neuropsychological and behavioral features of extrapyramidal symptoms in Frontotemporal Dementia (FTD) patients. Seventy-five patients fulfilling clinical criteria of FTD were consecutively enrolled. Each patient underwent clinical and extrapyramidal sign examination, and neuropsychological and behavioral disturbance evaluation. Each patient was submitted to both brain MRI and SPECT, documenting frontotemporal atrophy/hypoperfusion pattern. Parkinsonian symptoms in FTD were associated with a specific endophenotype characterized by higher incidence of psychotic symptoms, memory deficits and psychomotor speed ability abnormalities. Careful description of the spectrum of presentation of FTD may be of help for further understanding the underpinnings of the disease.

Several studies have been conducted to understand the genetic correlates of Alzheimer disease (AD)-related behavioral and psychological symptoms in dementia (BPSD). However, given that BPSD rarely occur in isolation, it has been suggested that targeting BPSD individually is too narrow of an approach if one wants to accurately define all the associated risk factors. To date, we know of no work on genetic polymorphisms related to behavioral endophenotypes in AD. The present study sought to evaluate the relationship between such behavioral endophenotypes in AD and genetic variations in dopamine- or serotonin-related genes, such as catechol-O-methyltransferase (COMT) or 5-HTT gene-linked promoter region (5-HTTLPR), and apolipoprotein E (APOE). Among 232 AD patients who underwent clinical and neuropsychological examination, a behavioral and psychiatric evaluation, and genotyping at COMT, 5-HTTPLR, and APOE; 66.4% showed more than one behavioral symptom. By Principal Component Analysis of Neuropsychiatric Inventory (NPI) symptoms four endophenotypes were identified, these were termed "psychosis", "moods", "apathy", and "frontal". Modeling NPI symptom-endophenotype-genotype relationships, and taking into account possible confounds (i.e. demographic characteristics, comorbidities, concomitant pharmacological treatments, and disease severity) by latent variable models, COMT and 5-HTTLPR genetic variations correlated with "frontal" and "psychosis" endophenotypes. APOE genotype did not correlate with any endophenotype. These findings suggest that the possibility of identifying distinct phenotypes on a genetic basis among AD patients exists, and suggest that clustering of BPSD into endophenotypes might provide a new strategy for guiding future research on this issue.

Transient global amnesia (TGA) is a well-defined clinical syndrome of unknown etiology, which often occurs once in life. Several mechanisms have been proposed but only trigger events have been clearly associated with the attack such as physical exertion, emotional stress, sexual intercourse or immersion in cold water. According to our knowledge, this is the first study, which associates trigger events and TGA recurrency. The aim of this retrospective study was to evaluate the risk factors which contribute to TGA recurrency. TGA patients consecutively admitted, performed clinical and neurological evaluation, electroencephalogram and structural brain imaging scan. TGA-trigger events were evaluated and comorbidities were carefully recorded. The risk factor sum was calculated as the sum of the considered triggers. Eighty-five TGA patients were grouped according to the presence of single TGA (n = 73) or two episodes of TGA (n = 12). The 14.11% of patients experienced two episodes. A logistic regression analysis showed that the more increased number of TGA the more number of trigger events (P < 0.11; chi2 = 6.38; beta = -3.29). These observations claim that TGA may be considered a complex epiphenomenon, and the sum of the trigger factors can be responsible for recurring of this almost unique-in-life event.

Action naming has been reported to be disproportionately impaired in comparison to object naming in patients with frontotemporal dementia (FTD). This finding has been attributed to the crucial role of frontal cortex in action naming. The investigation of object and action naming in the different subtypes of FTD, as well as in the related conditions of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), may thus contribute to the elucidation of the cerebral correlates of the action-object discrepancy as well as provide clues to the underlying cognitive mechanisms. The results indicated that, with the exception of semantic dementia, action naming was more impaired than object naming in all patient groups. The discrepancy was similar in frontal variant of FTD and Alzheimer's disease patients, whereas patients with nonfluent primary progressive aphasia, PSP, and CBD were significantly more impaired in the oral production of actions than of objects. These findings indicate that action naming impairment is not a general feature of FTD, but rather is associated with conditions that affect the frontoparietal-subcortical circuits involved in action knowledge and action representation.

Objectives: To investigate the effect of cardiovascular changes (i.e., QT interval, QT dispersion (QTD), heart rate variability (HRV), and other cardiovascular measures) in subjects with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Design: Each subject underwent clinical and cognitive examination, a structural brain imaging study, echocardioDoppler, electrocardiogram (ECG), HRV analysis using 24-hour ECG monitoring, and 24-hour blood pressure monitoring. Setting: Community population-based sample of patients admitted to an AD center for investigation of cognitive disturbances. Participants: Thirty-three subjects with AD, 39 subjects with MCI, and 29 cognitive healthy subjects (controls) matched for demographic characteristics, hypertensive condition, smoking habits, and laboratory parameters were enrolled consecutively. Measurements: Clinical and cognitive examination, structural brain imaging study, echocardioDoppler, ECG, HRV analysis using 24-hour ECG monitoring, and 24-hour blood pressure monitoring. Results: QTD and QT corrected dispersion mean values were significantly higher in patients with AD than in patients with MCI and controls and higher in patients with MCI than in controls. HRV time and domain parameters were lower in patients with AD than in patients with MCI and controls. No difference in other cardiovascular measures was found. QTD and HRV were found to be significantly correlated with the degree of cognitive impairment. Conclusion: These findings support the presence of a peculiar neuroanatomic dysfunction in patients with AD and MCI that parallels the disease progression. These noninvasive parameters might prove to be powerful predictive tools in the worsening of cognitive function and mortality risk.

Increasing biological and clinical findings argue for a link between brain cholesterol turnover and Alzheimer Disease (AD), high cerebral levels of the former increasing Abeta load. Cerebral cholesterol elimination involves two mechanisms dependent on Apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46). The aim of this study was to evaluate an intronic variation in CYP46 (intron 2, T --> C ) along with ApoE genotype as risk factors for AD and to establish the correlation between CYP46/ApoE polymorphism and disease progression. One-hundred and fifty-seven AD patients, who had been followed periodically through 1-year follow-up after enrollment, and 134 age- and gender-matched controls entered the study. The distribution of CYP46 genotypes was significantly different in AD compared to controls (P

We report the case of an Italian family in which three sisters experienced transient global amnesia (TGA). Since its early description, this transitory pure memory deficit has attracted increasing interest, especially within the neurological community. In 1964 the term “TGA” was coined to identify the abrupt onset of anterograde amnesia, accompanied by repetitive queries lasting for hours and then gradually recovering, leaving an amnesic gap for the duration of the attack. Afterwards, many studies focused on TGA, and in 1990 clinical criteria were defined by Hodges and Warlow (1990). Further studies showed that meeting diagnostic criteria was a significant predictor for a better outcome than in other forms of transient amnesia, while amnesic patients who did not fulfil the TGA criteria had different outcomes. Precipitating and trigger events for TGA were identified and divided into physical and psychological factors (Inzitari et al., 1997; Quinette et al., 2006). Physical precipitants were found to be gardening, housework and sawing wood, contact with water and changes in body temperature occurring during hot baths or showers, or a cold swim at the swimming pool. Emotional trigger events included a major life or death event, emotional stress triggered by a gastric endoscopy, an exhausting work session, and anxiety resulting from conflicts at home or at work, health problems and money worries. Several hypotheses have been proposed for its pathogenesis such as psychogenic, venous dysfunction due to jugular venous valve incompetence, or ischemic aetiology, but the enigma of TGA still needs to be unravelled (Lewis, 1998; Akkawi et al., 2001).

It has been recently suggested that in Alzheimer disease (AD), the current available therapy with cholinesterase inhibitors (ChEIs) influences platelets amyloid precursor protein (APP) metabolism towards the nonamyloidogenic pathway. In order to investigate whether ChEIs may exert a protective role on vascular damage due to abeta deposition, several parameters of coagulation and fibrinolysis were assessed. Twenty patients with mild AD and 30 age-matched controls entered the study. All subjects performed a multidimensional neuropsychological assessment and a laboratory protocol. Individuals with vascular risk factors and systemic diseases were excluded. In mild AD patients, increased levels of markers of endothelial dysfunction, such as thrombomodulin (TM) and sE-selectin (sE-sel), were seen. After 1-month ChEIs treatment, a significant reduction of TM (p

Huntington's disease is an inherited disorder caused by expanded stretch of consecutive trinucleotides (cytosine–adenosine–guanine, CAG) within the first exon of the huntingtin ( HTT ) gene on chromosome 4 (p16.3). The mutated huntingtin (mHTT) gains toxic function, probably through mechanisms that involve aberrant interactions in several pathways, causing cytotoxicity. Pathophysiology of disease involves several tissues; indeed it has been shown that there is a broad toxic effect of mHTT in the peripheral tissue of patients with HD, not only in the central nervous system. In this study we compared gene expression profiles (GEP) of HD fibroblasts and matched controls using microarray technology. We used RT-PCR to test the consistency of the microarray data and we found four genes up-regulated in HD patients with respect to control individuals. The genes appear to be involved in different pathways that have been shown to be perturbed even in HD models and patients. Although our study is preliminary and has to be extended to a larger cohort of HD patients and controls, nevertheless it shows that gene expression profiles seem to be altered in the fibroblasts of HD patients. Validation of the differential expressions at the protein level is required to ascertain if this cell type can be considered a suitable model for the identification of HD biomarkers.

Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative syndrome characterized by supranuclear palsy, postural instability, and mild dementia. Neuropathologically, PSP is a four-repeat tauopathy, defined by the accumulation of neurofibrillary tangles and tufted astrocytes. Etiology remains elusive, but genetic background has a key-role in the disease pathogenesis. Recent studies have reported high familial aggregation in PSP patients, and it has been widely demonstrated that Microtuble Associated Protein Tau (MAPT) gene mutations are causative of monogenic autosomal dominant PSP. In sporadic cases, genetic advances have further confirmed the role of MAPT in increasing disease risk, and the H1 MAPT haplotype has been consistently associated with PSP, while the H2 haplotype seems protective. Conversely, no major environmental risk factors have been reported so far. A proper evaluation of known susceptibility factors related to PSP pathogenesis may help in defining neuroprotective therapeutic approaches.

Progranulin (PGRN) mutations have been recognized to be monogenic causes of frontotemporal lobar degeneration (FTLD). PGRN Thr272fs mutation in the Italian population has been previously identified. In the present study, we evaluated the occurrence of a founder effect studying 8 polymorphic microsatellite markers flanking the PGRN gene in 14 apparently unrelated families. We identified a common haplotype associated with PGRN Thr272fs carriers, assuming common ancestry. The inferred age analysis (range between 260 [95% credible set: 227-374] and 295 [95% credible set: 205-397] generations) places the introduction of the mutation back to the Neolithic era when the Celts, the population of that period, settled in Northern Italy. PGRN Thr272fs mutation appears to be as either behavioral frontotemporal dementia (80%) or primary progressive aphasia (20%), it was equally distributed between male and female, and the mean age at onset was 59.6 ± 5.9 (range 53-68). In 14 families, autosomal dominant pattern of inheritance was present in 64.2% of cases. No clinical predictors of disease onset were demonstrated. The identification of a large cohort of frontotemporal lobar degeneration (FTLD) patients with homogeneous genetic background well may be used in the search of disease modulators to elucidate genotype-phenotype correlations of progranulopathies.

Early-onset Alzheimer’s disease (EOAD) is a rare genetic disorder mainly attributable to a mutation in the presenilin 1 (PSEN1) gene. Clinical profile and instrumental findings share common features with adult neuronal ceroid lipofuscinosis. We documented the clinical course in EOAD patients bearing mutations in PSEN1. Genetic screening for dementia, EEG acquisition and determination of granular osmiophilic elements (GRODs) from skin biopsy were performed in a patient suffering from a severe cognitive decline and visual hallucinations. The pathogenic M146I mutation in PSEN1, and instrumental findings common to adult neuronal ceroid lipofuscinosis were found in the same patient. Posterior low pseudoperiodic sequences at EEG and GRODS elements at skin biopsy might constitute a signature in EOAD.

Though neuroimaging, pathology and pathophysiology suggest a subcortical and deep cortical involvement in Frontotemporal Lobar Degeneration (FTLD), no studies have comprehensively assessed the associated gray matter (GM) volume changes. We measured caudate, putamen, thalamus, and amygdala GM volume using probabilistic a-priori regions of interest (ROIs) in 53 early FTLD patients (38 behavioral variant FTD [bvFTD], 9 Semantic Dementia [SD], 6 Progressive Non-Fluent Aphasia [PNFA]), and 25 age-matched healthy controls (HC). ANOVA showed significant (P < 0.001) main effect of diagnosis, and significant interactions for diagnosis and region, and diagnosis and hemisphere. Post-hoc comparisons with HC showed bilateral GM atrophy in the caudate, putamen and thalamus, in bvFTD; a left-confined GM reduction in the amygdala in SD; and bilateral GM atrophy in the caudate and thalamus, and left-sided GM reduction in the putamen and amygdala in PNFA. Correlation analyses suggested an association between GM volumes and language, psychomotor speed and behavioral disturbances. This study showed a widespread involvement of subcortical and deep cortical GM in early FTLD with patterns specific for clinical entity.

The FOXP2 gene is mutated in a severe monogenic form of speech and language deficits, but no study on the influence of genetic variations within FOXP2 in neurological disorders characterized by language impairment is available yet. In the present study, we investigated the impact of common FOXP2 polymorphisms with regard to frontotemporal lobar degeneration (FTLD). Two-hundred ten FTLD patients underwent clinical and a wide standardized neuropsychological examination as well as brain imaging. In all patients, and in 200 age-matched healthy controls, four FOXP2 polymorphisms were evaluated, namely rs2396753, rs1456031, rs17137124 and rs1852469. SPECT images were analyzed by Statistical Parametric Mapping (SPM5). No significant differences of the four FOXP2 polymorphisms in genotype distribution and allele frequency between FTLD and controls were observed. A significant and specific association between rs1456031 TT and rs17137124 TT genotypes and verbal fluency scores was reported. The two polymorphisms showed an addictive effect. When the analysis was computed on the number of observations over time, and 391 assessments considered, comparable results were obtained. FTLD patients carrying at-risk polymorphisms showed greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus, and putamen, compared to the non-carriers (p < 0.005). Genetic variations within FOXP2 do not represent a genetic risk to FTLD per se, but modulate FTLD presentation when disease is overt, affecting language performances and leading to hypoperfusion in language-associated brain areas.

Cerebrospinal fluid (CSF) tau ratio decrease (33kDa/55kDa forms) and mid-saggital midbrain-to-pons (MP) atrophy have been suggested as diagnostic markers for progressive supranuclear palsy (PSP). The usefulness of their combined evaluation has never been tested. We evaluated the CSF tau ratio and the MP atrophy as a combined marker for early identification of PSP. A total of 87 subjects, namely 18 PSP, 25 controls (CON), 16 corticobasal syndrome (CBS), and 28 frontotemporal dementia (FTD), were included. Each subject underwent a lumbar puncture and a conventional MRI scan to assess CSF tau 33 kDa/55 kDa ratio and mid-saggital MP measure, respectively. CSF tau ratio and MP ratio were significantly reduced in PSP patients when compared to CON, CBS, and FTD (p< 0.001). Data-based "optimal" combination of CSF tau ratio and MP measure was defined, and the combined marker TrMp= sqrt[3]{CSF Tau ratio}} × {MP ratio} was considered. Considering the combined marker, the difference between the area under the curve (dAUC) of the receiver operating characteristic analysis in PSP versus the various subgroups was higher by about 10% than that obtained by each marker individually. In PSP versus others, a proposed "best" cut-off of TrMP = 0.182 resulted in 94.2% sensitivity and 84.0% specificity. When patients with onset of symptoms ≤ 2 years were included, TrMP resulted significantly decreased in PSP compared to CBS (p< 0.001) and FTD (p< 0.001). The combined marker increases the discriminative power in identifying PSP and suggests that the interplay of different markers should be considered in future trials to enhance diagnostic accuracy from the early stages.

Background/Aims: Different etiologies for transient global amnesia (TGA) have been proposed, such as venous flow abnormalities, spreading depression and migraine-related mechanisms like focal ischemia. Jugular vein valve incompetence (JVI) is commonly described in TGA patients, but its contributing role in TGA pathogenesis is still unknown. We investigated the possible relationship between JVI and pathogenetic mechanisms in TGA. Methods: 243 TGA patients underwent clinical and neurological assessment. Demographic characteristics, TGA-precipitating factors and vascular comorbidities were carefully recorded. In each patient, JVI was assessed by Doppler ultrasonography. Results: TGA patients were grouped according to the presence (n = 171, 70.4%) or absence (n = 72, 29.6%) of JVI. TGA patients with JVI showed a higher presence of precipitating factors, namely a Valsalva-like maneuver (JVI-positive vs. JVI-negative, 35.8 vs. 17.1%, p = 0.004) and emotional stress (36.6 vs. 21.4%, p = 0.023), but had fewer vascular comorbidities, namely hypertension (37.2 vs. 51.4%, p = 0.047) and carotid arteriosclerosis (20.5 vs. 31.9%, p = 0.050). Conclusions: These findings support the argument for the existence of at least 2 different TGA-associated mechanisms defined by JVI. On the one hand, JVI associated with a Valsalva-like maneuver and emotional stress supported the venous blood congestion hypothesis, and on the other, the JVI-negative group may have another vascular basis, unrelated to venous congestion.

Background A careful characterization of behavioral abnormalities in corticobasal degeneration syndrome (CBDS) and progressive supranuclear palsy (PSP) by reliable tools is still lacking. Literature data provided evidence of the usefulness of the Frontal Behavioral Inventory (FBI) to operationalize such disturbances, particularly in the frontotemporal lobar degeneration spectrum. The study aimed to evaluate the frequency and pattern of presentation of behavioral disturbances in a large sample of CBDS and PSP patients by FBI. Methods Sixty-eight CBDS and 57 PSP patients entered the study and underwent a standardized clinical and neuropsychological battery, and a structural brain imaging study. Behavioral disturbances were carefully analyzed by FBI. Results FBI scores were relatively low in both groups, being 6.7 +/- 8.2 and 5.6 +/- 6.1 in CBDS and PSP, respectively. Comparison of the behavioral profile between CBDS and PSP patients showed significant differences in apathy were more frequent in the latter (57.9% vs. 33.8%, P = 0.007), and the presence of alien hand/apraxia more frequent in the former group 39.7% vs. 10.5%, P = 0.001). Apathy correlated neither with age nor with motor disturbances as measured by UPDRS-III. Overall, the most frequent behavioral abnormalities present in both groups (>25%) were aspontaneity and logopenia. Aphasia (27.9%) and irritability (35.3%) were more frequent in CBDS compared to PSP, even if not statistically different. Discussion The present study has provided measures of behavioral disturbances in a population of PSP and CBDS patients, and further confirms the usefulness of the FBI scale.

Background: Literature data on Alzheimer’s disease suggest that years of schooling and occupational level are associated with a reserve mechanism. No data on patients with behavioral variant frontotemporal dementia (bvFTD) are available yet. Objective: To evaluate the impact of education, occupation, and midlife leisure activities on brain reserve in bvFTD. Methods: Fifty-four bvFTD patients entered the study and underwent neuropsychological and behavioral assessment, including the FTD-modified Clinical Dementia Rating for FTD (FTD-modified CDR), and SPECT imaging. We tested for the linear correlation of educational and occupational level, and midlife leisure activities with regional cerebral blood flow (rCBF), controlling for demographic variables (age and gender) and for cognitive performance (FTD-modified CDR) (statistical parametric mapping). Results: A significant relationship between higher educational and occupational attainments and lower rCBF in medial frontal cortex and dorsolateral frontal cortex, bilaterally, was found (p < 0.005). When midlife leisure activities were considered, no correlation was found. The correlation between a reserve index, accounting for both educational and occupational level, and rCBF showed the same pattern of hypoperfusion. Conclusions: This study suggests that education and occupation act as proxies for reserve capacity in bvFTD. These lifestyle attainments may counteract the onset of this genetic-based disease in at-risk individuals.

Background: Establishing survival rate in frontotemporal lobar degeneration (FTLD) is a clinical challenge for defining disease outcomes and monitoring therapeutic interventions. Using the latent profile analysis (LPA) approach, we have previously suggested that FTLD patients can be grouped into specific phenotypes-"pseudomanic behavior" (LC1), "cognitive" (LC2), and "pseudodepressed behavior" (LC3)-on the basis of neuropsychological, functional, and behavioral data. Objective: The aim of this study was to evaluate the rate of survival in FTLD, to identify predictors of survival, and to determine the likely usefulness of LPA in defining prognosis. Methods: A total of 252 FTLD patients entered the study. A clinical evaluation and standardized assessment were carried out, as well as a brain imaging study. LPA on neuropsychological, functional, and behavioral data was performed. Each patient was followed up over a 5-year period, and institutionalization or death was considered. Results: The survival rate was associated neither with demographic characteristics, co-morbidities, family history for dementia, nor clinical diagnosis. The presence of the three LC phenotypes was confirmed by LPA. A different survival rate was predicted by LCs, the worse prognosis being found in LC1 (hazard ratio [HR] = 15.7, 95% confidence interval [CI] = 7.2-34.9, p < 0.001, reference LC3). LC2 had a worse prognosis compared to LC3 (HR = 2.07, 95% CI = 0.98-4.37, p = 0.06). Greater hypoperfusion in the orbitomesial frontal cortex was specifically associated with LC1 compared with the other LCs. Conclusions: A data-driven approach regarding neuropsychological and behavioral assessment might be useful in clinical practice for defining a FTLD prognosis and hopefully will lead to the possibility of identifying patient groups for the evaluation of treatment response in future trials.

Frontotemporal lobar degeneration (FTLD) recognizes a strong genetic background, with 30-50% of cases with a positive family history. Despite several efforts to identify monogenic causes of the disease, no clear-cut genetic risk factors for sporadic FTLD are yet known. Recently, increasing evidence points to a pivotal role of vascular endothelial growth factor (VEGF) in the neurodegenerative process, suggesting functions not confined to its originally described vascular effects. The aim of this study was to investigate the role of VEGF as a genetic determinant to FTLD susceptibility. We evaluated a cohort of 274 unrelated Italian patients, including 161 subjects with frontotemporal dementia (FTD), 56 with corticobasal degeneration syndrome, and 57 with progressive supranuclear palsy. Genotype and allele frequencies of four well-known polymorphisms located within the VEGF promoter (-2578C/A, -1190G/A, -1154G/A, and -634G/C) were calculated in patients and in 216 age-matched healthy subjects. Genetic analysis revealed the presence of several significant changes in terms of allele, genotype, and haplotype frequency distributions between patients and controls. Marked differences were observed when the FTD patient subgroup was compared with healthy subjects. Overall, these data provide evidence for the first time that VEGF gene variability represents a susceptibility factor for sporadic FTLD, at least in an Italian population. Future confirmatory studies are mandatory.

Background and purpose: Transient global amnesia (TGA) is the abrupt onset of anterograde amnesia with repetitive queries. Different hypotheses have been considered for its aetiology, but it still remains obscure. In 1990, Hodges and Warlow proposed clinical criteria for TGA. Applying these criteria, clinical studies looked for an unifying theory, considering TGA almost a primary and benign disorder. However, spare descriptions of TGA in patients with brain structural lesions have been reported. The aim of this study was to evaluate the prevalence of brain structural lesions among TGA patients. Methods: One hundred and thirty clinically defined TGA were consecutively recruited. Among them, 13 patients (10%) showed brain structural lesions (TGA-b). Results: No significant difference in clinical features, duration of TGA episode, age of onset, gender between primary TGA (TGA-p) and TGA-b were found. Triggering factors were comparable, suggesting that TGA-b should be considered in the spectrum of TGA, being clinically indistinguishable. Conclusions: Transient global amnesia deserves a careful neuroimaging study and clinical follow-up considering the high prevalence of brain lesions among these patients and the impossibility to exclude TGA-b by clinical features. The follow-up of these patients and the evaluation of involved brain areas might help to further elucidate the pathogenetic mechanisms of the disease.

Mutations in the progranulin (PGRN) gene have been recently demonstrated as a cause of frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusion (FTD-U). Neuropathologic, clinical, and neuroimaging features associated with PGRN mutations have been carefully described. No studies on asymptomatic subjects carrying pathogenetic PGRN mutations are available yet. These would be crucial for establishing the timing of brain changes and bringing new insight into disease pathogenesis and disease course. The aim of this study was to evaluate structural brain morphology using diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) in asymptomatic carriers of PGRN delCACT mutation belonging to a four-generation FTLD pedigree (mean age, 37.0 +/- 12.0). The evaluation of the family proband presenting with progressive nonfluent aphasia at 53 years of age, revealed left frontotemporal hypoperfusion and atrophy. VBM analysis of gray and white matter reductions revealed no differences between asymptomatic carriers (n = 7) and controls (n = 15), and between no-carriers (n = 10) and controls (p0.001). DTI analysis revealed a reduction in fractional anisotropy in healthy PGRN mutation carriers in the left uncinate fasciculus, connecting the orbito-frontal regions to the temporal pole, and in the left inferior occipitofrontal fasciculus, connecting the parieto-occipital cortex to the dorsolateral frontal cortex (p0.001). No significant difference in fractional anisotropy between no-carriers and controls was found. Our data indicate loss of white matter integrity as an early preclinical feature in familial FTD that might antedate the onset of specific neurologic features. Alteration of fiber tracts within the perisylvian language network might represent the early hallmark of subsequent aphasia onset. The study of other pedigrees of asymptomatic PGRN mutation carriers is warranted.