CSF Alzheimer's disease-like pattern in corticobasal syndrome: evidence for a distinct disorder.

BACKGROUND: 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. OBJECTIVE: To evaluate the presence of a distinct clinical and neuroimaging CBS phenotype according to CSF pattern. METHODS: 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. RESULTS: 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 (p<0.001). No clusters above the pre-established threshold were detected when nAD-like were compared with AD-like patients. CONCLUSIONS: 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.

EEG and granular osmiophilic elements in early-onset Alzheimer's disease.

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.

Understanding the underpinnings of the frontotemporal lobar degeneration: evidence for benign and malignant forms.

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.

Clinical characteristics and outcomes of inpatients with neurologic disease and COVID-19 in Brescia, Lombardy, Italy.

OBJECTIVE: To report clinical and laboratory characteristics, treatment, and clinical outcomes of patients admitted for neurologic diseases with and without coronavirus disease 2019 (COVID-19). METHODS: In 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. RESULTS: One 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. CONCLUSIONS: Patients 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.

Progranulin genetic variations in frontotemporal lobar degeneration: evidence for low mutation frequency in an Italian clinical series.

Frontotemporal lobar degeneration (FTLD) recognises high familial incidence, with up to 50% of patients reported to have a family history of similar dementia. It has been reported that mutations within progranulin (PGRN) gene are a major cause of FTLD in the USA and worldwide, counting for 5-10% of FTLD and for 20-25% of familiar FTLD cases. The aim of the present study was to define the role of PGRN genetic variations in a large sample of consecutive patients with FTLD in Italy. Two-hundred forty-three FTLD patients were investigated. Each subject performed a clinical and neuropsychological evaluation, a functional and structural brain imaging, and the diagnosis was confirmed by at least 1 year follow-up. PGRN sequencing was performed in all FTLD patients and in 121 healthy age-matched controls drawn from the same geographic area. Only one PGRN pathogenetic mutation was found, consisting of a four-base pair deletion in the coding sequence of exon 8 (delCACT). This mutation was recognised in four patients, being the overall frequency of mutations in our clinical series of 1.64%. Considering only patients with a well-known family history for dementia, the frequency of this mutation was 6%. Moreover, four missense mutations within intron regions (g.100474G>A, g.100674G>A, g.101266G>A, g.102070G>A) were found. The frequency of these genetic variations did not differ in patients compared to controls, and they did not influence on clinical FTLD phenotype. In conclusion, this study supports a lower frequency of PGRN mutations amongst FTLD patients in Italy compared to literature data and further underlies the genetic heterogeneity of FTLD.

Increased prevalence of silent myocardial ischaemia and severe ventricular arrhythmias in untreated patients with Alzheimer's disease and mild cognitive impairment without overt coronary artery disease.

OBJECTIVE: To assess the prevalence and the characteristics of silent myocardial ischaemia (SMI) and ventricular arrhythmias (VA) in subjects with Alzheimer's disease (AD) and mild cognitive impairment (MCI) and their relationships with QT interval dispersion (QTD). METHODS: Thirty-three subjects with AD, 39 subjects with MCI, and 29 cognitive healthy control subjects matched for demographic characteristics, hypertensive condition, smoking habits, and laboratory parameters were enrolled. Each subject underwent clinical and cognitive examination, a structural brain imaging study, electrocardiogram (ECG), 24-h ECG recording, 24-h blood pressure monitoring, and echocardiogram. Detection and characterization of QT dispersion, SMI and VA were performed. RESULTS: The three groups were comparable regarding demographic and basal cardiovascular characteristics: notwithstanding this, SMI episodes were observed only in AD and MCI patients (19 and 14, respectively). A significantly greater prevalence of repetitive ventricular premature beats was observed in AD (mean 8.56+/-13.1) and in MCI (1.8+/-7.2) vs. control (0.7+/-1.7). The QTD, the ischaemic burden and the number of repetitive ventricular beats revealed to be significantly related. CONCLUSIONS: Increased prevalence of SMI and potentially ominous VA were found in AD and, to a lesser extent, in MCI. SMI and repetitive VA were significantly related with QTD. These findings could be related to an increased risk of sudden cardiac death in AD and MCI patients.

Evidence of white matter changes on diffusion tensor imaging in frontotemporal dementia.

BACKGROUND: Two major clinical variants of frontotemporal dementia (FTD) have been described: frontal variant (fvFTD) and temporal variant (tvFTD). OBJECTIVE: To analyze white matter (WM) and gray matter (GM) tissue organization in patients with fvFTD and tvFTD by means of diffusion tensor imaging and voxel-based morphometry, and the correlations with neuropsychological and behavioral variables. DESIGN AND SETTING: Frontotemporal dementia clinic-based cohort and structural magnetic resonance imaging acquisition for voxel-based morphometry and diffusion tensor imaging measurements. Abnormalities were detected by a comparison with healthy control subjects. These variables were also correlated with clinical scores. Patients Thirty-six patients (28 with fvFTD and 8 with tvFTD) in early disease stage and 23 healthy controls who underwent standardized clinical and neuropsychological evaluation and magnetic resonance imaging. INTERVENTIONS: Diffusion tensor imaging and voxel-based morphometry. MAIN OUTCOME MEASURES: Neuroimaging analyses resulted in localized GM atrophy and reductions of white matter densities; the latter correlated with behavioral scores. RESULTS: Voxel-based morphometry analysis showed separate patterns of GM atrophy in the 2 groups. Diffusion tensor imaging showed different WM reduction patterns in patients with fvFTD and tvFTD. The fvFTD group showed a selective WM reduction in the superior longitudinal fasciculus, interconnecting the frontal and occipital and the temporal and parietal regions. Conversely, patients with tvFTD were characterized by WM reductions in the inferior longitudinal fasciculus, which affected the connections between anterior temporal and frontal regions. The WM reductions in fvFTD paralleled both behavioral disturbances measured by Frontal Behavioral Inventory and neuropsychological deficits affecting frontal functions. CONCLUSIONS: The fvFTD and tvFTD variants are associated not only with selective local GM reductions but also with significant WM damage in early disease phase. The different WM patterns contribute to the different clinical syndromes in FTD and could be responsible for the further progression of atrophy in the later disease stages.

Extrapyramidal symptoms in Frontotemporal Dementia: prevalence and clinical correlations.

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.

Latent profile analysis in frontotemporal lobar degeneration and related disorders: clinical presentation and SPECT functional correlates.

BACKGROUND: Frontotemporal Lobar Degeneration (FTLD) thus recently renamed, refers to a spectrum of heterogeneous conditions. This same heterogeneity of presentation represents the major methodological limit for the correct evaluation of clinical designation and brain functional correlates. At present, no study has investigated clinical clusters due to specific cognitive and behavioural disturbances beyond current clinical criteria. The aim of this study was to identify clinical FTLD presentation, based on cognitive and behavioural profile, and to define their SPECT functional correlations. METHODS: Ninety-seven FTLD patients entered the study. A clinical evaluation and standardised assessment were preformed, as well as a brain SPECT perfusion imaging study. Latent Profile Analysis on clinical, neuropsychological, and behavioural data was performed. Voxel-basis analysis of SPECT data was computed. RESULTS: Three specific clusters were identified and named "pseudomanic behaviour" (LC1), "cognitive" (LC2), and "pseudodepressed behaviour" (LC3) endophenotypes. These endophenotypes showed a comparable hypoperfusion in left temporal lobe, but a specific pattern involving: medial and orbitobasal frontal cortex in LC1, subcortical brain region in LC2, and right dorsolateral frontal cortex and insula in LC3. CONCLUSION: These findings provide evidence that specific functional-cluster symptom relationship can be delineated in FTLD patients by a standardised assessment. The understanding of the different functional correlates of clinical presentations will hopefully lead to the possibility of individuating diagnostic and treatment algorithms.

Functional correlates of Apolipoprotein E genotype in Frontotemporal Lobar Degeneration.

BACKGROUND: It has been recently demonstrated that in Frontotemporal Lobar Degeneration (FTLD) memory deficits at presentation are commoner than previously thought. Apolipoprotein E (ApoE) genotype, the major genetic risk factor in sporadic late-onset Alzheimer Disease (AD), modulates cerebral perfusion in late middle-age cognitively normal subjects. ApoE epsilon4 homozygous have reduced glucose metabolism in the same regions involved in AD. The aim of this study was to determine whether ApoE genotype might play a key-role in influencing the cerebral functional pattern as well as the degree of memory deficits in FTLD patients. METHODS: Fifty-two unrelated FTLD patients entered the study and underwent a somatic and neurological evaluation, laboratory examinations, a brain structural imaging study, and a brain functional Single Photon Emission Tomography study. ApoE genotype was determined. RESULTS: ApoE genotype influenced both clinical and functional features in FTLD. ApoE epsilon4-carriers were more impaired in long-term memory function (ApoE epsilon4 vs. ApoE non epsilon4, 6.3 +/- 3.9 vs. 10.1 +/- 4.2, p = 0.004) and more hypoperfused in uncus and parahippocampal regions (x,y,z = 38,-6,-20, T = 2.82, cluster size = 100 voxels; -32,-12,-28, T= 2.77, cluster size = 40 voxels). CONCLUSION: The present findings support the view that ApoE genotype might be considered a disease-modifying factor in FTLD, thus contributing to define a specific clinical presentation, and might be of relevance for pharmacological approaches.

QT dispersion and heart rate variability abnormalities in Alzheimer's disease and in mild cognitive impairment.

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.

Pre-clinical diagnosis of Alzheimer disease combining platelet amyloid precursor protein ratio and rCBF spect analysis.

Platelet Amyloid Precursor Protein ratio of different abnormal forms and 99mTc-ECD SPECT perfusion analysis were evaluated in Mild Cognitive Impairment (MCI) subjects who progressed to Alzheimer Disease (AD) and in stable MCI. We report that their combined evaluation increases the discriminative power of the analysis in identifying presymptomatic AD. The positive predictive value of these combined markers in identifying progressive MCI was 0.87, and the negative predictive value was 0.90. This observation suggests that the interplay of different markers should be considered for enhancing diagnostic accuracy of pre-clinical AD.

Cholinesterase inhibitors exert a protective effect on endothelial damage in Alzheimer disease patients.

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<0.05) and sE-sel (p<0.05) values towards the normal range was observed. These findings suggest that endothelial-related ChEIs action might contribute to the clinical efficacy in AD, slowing down pathology progression.

Intronic CYP46 polymorphism along with ApoE genotype in sporadic Alzheimer Disease: from risk factors to disease modulators.

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<0.004), being CYP*C allele higher in AD patients ( P<0.002). ApoE 4 genotype was more frequent in AD (41.4%) than in controls (15.9%, P<0.0001). The odds ratio (OR) for AD risk in CYP46*C carriers was 2.8, and in ApoE epsilon4 carriers was 4.05; the OR for having both CYP46*C and ApoE epsilon4 was 17.75, demonstrating the their synergic effect on AD risk. In AD patients, CYP46*C along with ApoE epsilon4 genotype were associated with a higher cognitive decline at 1-year follow-up (P<0.02). These findings provide direct evidence that CYP46 and ApoE polymorphisms synergically increase the risk for AD development, and influence on the rate of cognitive decline.

Abnormalities in the pattern of platelet amyloid precursor protein forms in patients with mild cognitive impairment and Alzheimer disease.

CONTEXT: Patients affected by sporadic Alzheimer disease (AD) show a significant alteration of amyloid precursor protein (APP) forms in platelets when compared with patients with dementia but without AD and age-matched controls. OBJECTIVE: To evaluate the ratio of platelet APP forms (APPr) in early-stage AD and mild cognitive impairment (MCI) and its potential as a biomarker for the early identification of AD. SETTING: Community population-based sample of patients admitted to 4 AD centers for investigation of cognitive disturbances. DESIGN AND METHODS: Thirty-five patients with mild AD (mAD), 21 patients with very mild AD (vmAD), 30 subjects with MCI, and 25 age-matched controls were included. The APPr was evaluated by Western blot analysis in platelet homogenate. RESULTS: Compared with controls (mean +/- SD, 0.93 +/- 0.3), the mean APPr was decreased in patients with mAD (0.44 +/- 0.24; P<.001) and patients with vmAD (0.49 +/- 0.3; P<.001). Regarding the MCI group, a significant decrease in APPr was found compared with controls (0.62 +/- 0.33; P<.001). Fixing a cutoff score of 0.6, sensitivity was 88.6% (31/35) for patients with mAD and 85.7% (18/21) for patients with vmAD, whereas specificity was 88% (22/25) for controls. Among patients with MCI, 18 (60%) of 30 individuals displayed APPr values below the cutoff. CONCLUSIONS: Alteration of platelet APP forms is an early event in AD, and the measurement of APPr may be useful for the identification of preclinical AD in patients with MCI.

Is transient global amnesia a risk factor for amnestic mild cognitive impairment?

Transient Global Amnesia (TGA) is a common condition of unknown aetiology characterised by the abrupt onset of severe anterograde amnesia, which lasts less than 24 hours. Some authors have suggested that subclinical impairment of memory functions may persist for much longer, but neuropsychological assessment lasting years after TGA attack has not been performed so far. The aim of this study was to evaluate longterm cognitive functions in patients with a previous TGA episode. Fifty-five patients underwent a standardised neuropsychological assessment after at least one-year from the TGA attack, and were compared with 80 age-matched controls. TGA patients showed worse performances on tests evaluating verbal and nonverbal long-term memory and attention, with comparable global cognitive functions. By applying current criteria for amnestic Mild Cognitive Impairment (MCI-a) on TGA subjects, a group consisting of 18/55 (32.7%) MCI-a subjects was identified. There was no association between the presence of MCI-a and demographic variables, vascular risk factors, years since the TGA episode, or ApoE genotype. This study demonstrates that TGA appears to be a relatively benign syndrome although objective memory deficits fulfilling MCI-a criteria persist over time, as detected by multidimensional neuropsychological tasks performed at long-term follow-up.

Catechol-O-methyltransferase gene polymorphism is associated with risk of psychosis in Alzheimer Disease.

There is emerging evidence that psychosis in Alzheimer Disease (AD) represents a clinically relevant phenotype with a distinct biological process. It has been reported that a functional polymorphism of the catechol-O-methyltransferase (COMT) gene predisposes to an increased risk for schizophrenia and likely to psychosis susceptibility. Aim of this study was to evaluate functional COMT genetic variation as a risk factor for psychosis in Alzheimer Disease. One hundred eighty-one AD patients and 208 age-matched controls underwent clinical and neuropsychological examination, behavioural and psychiatric disturbances evaluation, and ApoE and COMT genotyping. The distribution of COMT genotypes did not significantly differ in AD compared to controls. Among patients with psychosis (32.6%), 88.1% were COMT*H carriers (COMT H/H or COMT H/L, p < .01). The Odds Ratio (OR) for risk of psychosis in COMT*H carriers was 2.66 (confidence interval, CI 95%: 1.6-6.62), taking into account possible confounding factors. A comparable influence of COMT polymorphism on psychosis over the course of the disease was reported. These findings suggest that COMT polymorphism influences on the risk of psychosis since the early stages, and claims for the possibility to identify distinct phenotypes on genetic basis among AD patients.

Gene expression profile in fibroblasts of Huntington's disease patients and controls.

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.

Genetic bases of Progressive Supranuclear Palsy: the MAPT tau disease.

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.