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Background: Differential diagnosis between frontotemporal dementia (FTD) and Alzheimer's disease (AD) is often challenging. Autopsy series have identified AD pathology in a consistent percentage of patients clinically diagnosed with frontotemporal dementia (FTD). It has been demonstrated that the levels of tau and Aβ42 in cerebrospinal fluid (CSF) are a reliable marker for AD., Objective: To evaluate the presence of a CSF AD-like pattern in patients with FTD, and the related brain changes, to assess whether these patients had features resembling an AD pattern of hypoperfusion., Methods: Clinically-diagnosed non-monogenic FTD patients underwent an extensive neuropsychological assessment, 99mTc-ECD SPECT, and CSF analysis (tau and Aβ42 levels). FTD AD-like and FTD non-AD-like patterns were identified, and neuropsychological and neuroimaging features compared., Results: CSF AD-like pattern was reported in 9 cases out of 43 (21%). FTD AD-like and non-AD-like patients did not differ in demographic characteristics, cognitive deficits, or behavioral changes. Both groups had greater hypoperfusion in frontotemporal lobes as compared to age-matched controls. When FTD AD-like patients were compared to the FTD non-AD-like group, the former had greater hypoperfusion in brain areas typically affected by AD, namely precuneus, temporal, and parietal areas., Conclusions: CSF AD-like profile in FTD is associated with brain abnormalities typically found in classical AD, confirming the usefulness of CSF testing. Detecting an ongoing AD pathological process in FTD has several implications for defining distinctive treatment approaches, guiding genetic screening, and helping in patient selection in future clinical trials in both FTLD and AD therapeutics.

Granulin (GRN) mutations have been identified as a major cause of frontotemporal lobar degeneration (FTLD) by haploinsufficiency mechanism, although their effects on brain tissue dysfunction and damage still remain to be clarified. In this study, we investigated the pattern of neuroimaging abnormalities in FTLD patients, carriers and noncarriers of GRN Thr272fs mutation, and in presymptomatic carriers. We assessed regional gray matter (GM) atrophy, and resting (RS)-functional magnetic resonance imaging (fMRI). The functional connectivity maps of the salience (SN) and the default mode (DMN) networks were considered. Frontotemporal gray matter atrophy was found in all FTLD patients (more remarkably in those GRN Thr272fs carriers), but not in presymptomatic carriers. Functional connectivity within the SN was reduced in all FTLD patients (again more remarkably in those mutation carriers), while it was enhanced in the DMN. Conversely, presymptomatic carriers showed increased connectivity in the SN, with no changes in the DMN. Our findings suggest that compensatory mechanisms of brain plasticity are present in GRN-related FTLD, but with different patterns at a preclinical and symptomatic disease stage., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Frontotemporal Lobar Degeneration (FTLD) is an heterogeneous neurodegenerative disorder characterized by behaviour and language disturbances, associated with degeneration of the frontal and temporal lobes. Three different clinical presentations have been described, namely behavioural variant Frontotemporal Dementia (bvFTD), Semantic Dementia (SD) and Progressive Non-Fluent Aphasia (PNFA). The associated histopathology includes different neuropathological hallmarks, the most frequent being tau-positive inclusions (FTLD-TAU) or tau-negative and TDP-43 positive inclusions (FTLD-TDP). The majority of familial FTLD cases are caused by mutations within Microtubule-Associated Protein Tau (MAPT) gene, leading to FTLD-TAU, or Progranulin (PGRN) gene, leading to FTLD-TDP. In the last few years, imaging, biological and genetic biomarkers have been developed, helping in clinical evaluation and diagnostic accuracy. Though current pharmacologic interventions are only symptomatic, recent research argues for possible disease-modifying strategies in the near future.

Background: Creutzfeldt-Jakob disease (CJD) is a subacute spongiform encephalopathy characterized by rapidly progressive dementia, hard to diagnose during life., Materials and Methods: We present a case of a patient with pathologically confirmed sporadic form of CJD in whom initial diagnostic tests were negative. Two sequential brain single-photon emission computed tomography with Tc-99m ethyl-cysteinate dimer were performed, the first one was performed few days after the admission into hospital and the second, 1 month later., Results: Both studies revealed a decrease in regional cerebral blood flow indicative of neuronal dysfunction, more pronounced in the second study., Conclusion: Current radionuclide scintigraphy can be an useful tool for the investigation of CJD.

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., (Copyright © 2009 Elsevier Inc. All rights reserved.)

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Establishing the short-term prognosis in Frontotemporal Lobar Degeneration (FTLD) is a clinical challenge for defining disease outcomes and monitoring therapeutic interventions. No reliable neuropsychological assessment balancing all FTLD aspects is available yet, thus no clear-cut follow-up study has been performed., Objective: To evaluate the rate of progression and the predictors of worsening in FTLD patients., Methods: One-hundred twenty-seven FTLD patients entered the study and were re-evaluated at 1-year follow-up. A statistical driven approach on wide neuropsychological, behavioral, and functional data was applied to identify homogeneous groups both at baseline and at follow-up within FTLD. Three set of predictors on disease progression were considered: (i) the demographic characteristics, (ii) the genetic background, i.e. Apolipoprotein E (APOE) genotype, Tau haplotype, and functional polymorphisms affecting serotonin and dopamine pathways, and (iii) the clinical phenotype., Results: Among FTLD, two groups of patients were recognized on the basis of the overall assessment, thus termed for different disease severity as "good performers" and "bad performers". At 1-year follow-up, almost 30% of FTLD patients progressed from "good" to "bad" performances, whilst 70% maintained stable "good" performances. APOE varepsilon4 allele, Tau H2 haplotype and behavioral variant FTD phenotype were associated with worse prognosis over time., Conclusions: This preliminary study proposed genetic and clinical predictors in FTLD progression. The identification of disease-modifying predictors of prognosis opens a new avenue in studying FTLD, and may contribute to define outcomes and to monitor pharmacological targets.

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.

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.

Background: The role of modifiable and non-modifiable variables in Frontotemporal Dementia (FTD) as compared to Alzheimer's dDisease (AD) and to Progressive Supranuclear Palsy (PSP) or Corticobasal Degeneration Syndrome (CBDS) has not been extensively evaluated. In particular, low education levels have been reported to be a risk factor for AD, but their contribution in FTD is yet not known., Objective: To investigate the role of education, other modifiable and non-modifiable factors in FTD as compared to AD, PSP and CBDS patients., Methods: One hundred and seventeen FTD patients, 400 AD, 55 PSP, and 55 CBDS entered the study. Demographic and clinical characteristics were carefully recorded. Age, gender, family history for dementia and Apolipoprotein E (APOE) genotype were considered as non-modifiable factors; education and comorbidities were included as modifiable variables. Regression analyses were applied in order to identify differences among groups., Results: FTD differed from AD patients in terms of younger age, positive family history and gender status. In regard to APOE genotype, no differences between FTD and AD were found, but FTD showed higher prevalence of epsilon 4 allele compared to both CBDS and PSP patients (p < 0.05). When modifiable factors were considered, FTD were higher educated than AD patients (p < 0.001). Regression analysis identified younger age, positive family history, and education levels as independently associated variables to FTD diagnosis compared to AD (F = 21.27, R(2) = 24.1, p = 0.036)., Conclusion: Our results highlight that the contribution of education and non-modifiable factors is likely different in FTD and AD. Further work is needed to completely establish the role of this modifiable variable as a potential area of intervention for dementias.

Few public health problems have captured the attention of the biomedical and lay communities alike as has Alzheimer Disease (AD). Several questions remain still open in disease management, as the necessity to delineate disease process from "normal ageing". In the last few years, Mild Cognitive Impairment (MCI) has received significant attention, thus it represents the major risk factor for AD. Not all people diagnosed as having MCI, however, will develop AD, hence there is a need to reliably predict progression. To this aim, different biomarkers have been proposed with the attempt to identify MCI people who already have pre-clinical AD. Neuropsychological assessment, peripheral and CSF biomarkers as well as neuroimaging findings (both structural and functional) have reported variable accuracy values, but better results have been obtained by combined biomarker approach. In this review, we summarise the most recent findings on combined biomarkers and their usefulness in clinical practice for the early and preclinical diagnosis of AD.