%0 Journal Article %J J Alzheimers Dis %D 2018 %T Biological, Neuroimaging, and Neurophysiological Markers in Frontotemporal Dementia: Three Faces of the Same Coin. %A Borroni, Barbara %A Benussi, Alberto %A Premi, Enrico %A Alberici, Antonella %A Marcello, Elena %A Gardoni, Fabrizio %A Di Luca, Monica %A Padovani, Alessandro %X

Frontotemporal dementia (FTD) is a heterogeneous clinical, genetic, and neuropathological disorder. Clinical diagnosis and prediction of neuropathological substrates are hampered by heterogeneous pictures. Diagnostic markers are key in clinical trials to differentiate FTD from other neurodegenerative dementias. In the same view, identifying the neuropathological hallmarks of the disease is key in light of future disease-modifying treatments. The aim of the present review is to unravel the progress in biomarker discovery, discussing the potential applications of available biological, imaging, and neurophysiological markers.

%B J Alzheimers Dis %V 62 %P 1113-1123 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171998?dopt=Abstract %R 10.3233/JAD-170584 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Diagnosis of Mild Cognitive Impairment Due to Alzheimer's Disease with Transcranial Magnetic Stimulation. %A Padovani, Alessandro %A Benussi, Alberto %A Cantoni, Valentina %A Dell'Era, Valentina %A Cotelli, Maria Sofia %A Caratozzolo, Salvatore %A Turrone, Rosanna %A Rozzini, Luca %A Alberici, Antonella %A Altomare, Daniele %A Depari, Alessandro %A Flammini, Alessandra %A Frisoni, Giovanni B %A Borroni, Barbara %X

BACKGROUND: Considering the increasing evidence that disease-modifying treatments for Alzheimer's disease (AD) must be administered early in the disease course, the development of diagnostic tools capable of accurately identifying AD at early disease stages has become a crucial target. In this view, transcranial magnetic stimulation (TMS) has become an effective tool to discriminate between different forms of neurodegenerative dementia.

OBJECTIVE: To determine whether a TMS multi-paradigm approach can be used to correctly identify mild cognitive impairment (MCI) due to AD (AD MCI).

METHODS: A sample of 69 subjects with MCI were included and classified as AD MCI or MCI unlikely due to AD (non-AD MCI) based on 1) extensive neurological and neuropsychological evaluation, 2) MRI imaging, and 3) cerebrospinal fluid analysis or/and amyloid PET imaging. A paired-pulse TMS multi-paradigm approach assessing short interval intracortical inhibition-facilitation (SICI-ICF), dependent on GABAergic and glutamatergic intracortical circuits, respectively, and short latency afferent inhibition (SAI), dependent on cholinergic circuits, was performed.

RESULTS: We observed a significant impairment of SAI and unimpaired SICI and ICF in AD MCI as compared to non-AD MCI. According to ROC curve analysis, the SICI-ICF / SAI index differentiated AD MCI from non-AD MCI with a specificity of 87.9% and a sensitivity of 94.4%.

CONCLUSIONS: The assessment of intracortical connectivity with TMS could aid in the characterization of MCI subtypes, correctly identifying AD pathophysiology. TMS can be proposed as an adjunctive, non-invasive, inexpensive, and time-saving screening tool in MCI differential diagnosis.

%B J Alzheimers Dis %V 65 %P 221-230 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010131?dopt=Abstract %R 10.3233/JAD-180293 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Frontotemporal Dementia due to the Novel GRN Arg161GlyfsX36 Mutation. %A Gazzina, Stefano %A Archetti, Silvana %A Alberici, Antonella %A Bonomi, Elisa %A Cosseddu, Maura %A Di Lorenzo, Diego %A Padovani, Alessandro %A Borroni, Barbara %X

Progranulin is a multifunctional growth factor mainly expressed in neurons and microglia. Loss-of-function mutations in the Granulin (GRN) gene are causative of frontotemporal dementia with TAR DNA-binding protein-43 inclusions. We reported the case of a 51-year-old male patient affected by sporadic agrammatic variant of primary progressive aphasia, in whom we identified a novel heterozygous deletion in the exon 6 (g.10338_39delAG, p.Arg161GlyfsX36). Plasma progranulin levels were significantly reduced and in silico analysis predicted a premature termination codon. This case expands our knowledge on GRN mutations in frontotemporal dementia.

%B J Alzheimers Dis %V 57 %P 1185-1189 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304311?dopt=Abstract %R 10.3233/JAD-170066 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Looking for Neuroimaging Markers in Frontotemporal Lobar Degeneration Clinical Trials: A Multi-Voxel Pattern Analysis Study in Granulin Disease. %A Premi, Enrico %A Cauda, Franco %A Costa, Tommaso %A Diano, Matteo %A Gazzina, Stefano %A Gualeni, Vera %A Alberici, Antonella %A Archetti, Silvana %A Magoni, Mauro %A Gasparotti, Roberto %A Padovani, Alessandro %A Borroni, Barbara %K Adult %K Aged %K Brain %K Brain Mapping %K Cohort Studies %K Female %K Frontotemporal Lobar Degeneration %K Humans %K Image Processing, Computer-Assisted %K Intercellular Signaling Peptides and Proteins %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Mutation %K Neural Pathways %K Oxygen %K Phenylalanine %K Threonine %X

In light of future pharmacological interventions, neuroimaging markers able to assess the response to treatment would be crucial. In Granulin (GRN) disease, preclinical data will prompt pharmacological trials in the future. Two main points need to be assessed: (1) to identify target regions in different disease stages and (2) to determine the most accurate functional and structural neuroimaging index to be used. To this aim, we have taken advantage of the multivariate approach of multi-voxel pattern analysis (MVPA) to explore the information of brain activity patterns in a cohort of GRN Thr272fs carriers at different disease stages (14 frontotemporal dementia (FTD) patients and 17 asymptomatic carriers) and a group of 33 healthy controls. We studied structural changes by voxel-based morphometry (VBM), functional connectivity by assessing salience, default mode, fronto-parietal, dorsal attentional, executive networks, and local connectivity by regional homogeneity, amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), degree centrality, and voxel-mirrored homotopic connectivity. In FTD patients with GRN mutation, the most predictive measure was VBM structural analysis, while in asymptomatic carriers the best predictor marker was the local connectivity measure (fALFF). Altogether, all indexes demonstrated fronto-temporo-parietal damage in GRN pathology, with widespread structural damage of fronto-parietal and temporal regions when disease is overt. MVPA could be of aid in identifying the most accurate neuroimaging marker for clinical trials. This approach was able to identify both the target region and the best neuroimaging approach, which would be specific in the different disease stages. Further studies are needed to simultaneously integrate multimodal indexes in a classifier able to trace the disease progression moving from preclinical to clinical stage of the disease.

%B J Alzheimers Dis %V 51 %P 249-62 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836150?dopt=Abstract %R 10.3233/JAD-150340 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vascular Risk Factors and Cognition in Parkinson's Disease. %A Pilotto, Andrea %A Turrone, Rosanna %A Liepelt-Scarfone, Inga %A Bianchi, Marta %A Poli, Loris %A Borroni, Barbara %A Alberici, Antonella %A Premi, Enrico %A Formenti, Anna %A Bigni, Barbara %A Cosseddu, Maura %A Cottini, Elisabetta %A Berg, Daniela %A Padovani, Alessandro %K Age of Onset %K Aged %K Attention %K Disability Evaluation %K Educational Status %K Executive Function %K Female %K Humans %K Male %K Motor Activity %K Neuropsychological Tests %K Parkinson Disease %K Prevalence %K Risk Factors %K Sex Factors %K Time Factors %K Vascular Diseases %X

Vascular risk factors have been associated with cognitive deficits and incident dementia in the general population, but their role on cognitive dysfunction in Parkinson's disease (PD) is still unclear. The present study addresses the single and cumulative effect of vascular risk factors on cognition in PD patients, taking clinical confounders into account. Standardized neuropsychological assessment was performed in 238 consecutive PD patients. We evaluated the association of single and cumulative vascular risk factors (smoking, diabetes, hypercholesterolemia, hypertension, and heart disease), with the diagnosis of PD normal cognition (PDNC, n = 94), mild cognitive impairment (PD-MCI, n = 111), and dementia (PDD, n = 33). The association between single neuropsychological tests and vascular risk factors was evaluated with covariance analyses adjusted for age at onset, educational levels, gender, disease duration, and motor performance. Age, educational levels, disease duration, and motor function were significantly different between PDNC, PD-MCI, and PDD. Heart disease was the only vascular factor significantly more prevalent in PDD compared with PDNC in adjusted analyses. Performance of tests assessing executive and attention functions were significantly worse in patients with hypertension, heart disease, and/or diabetes (p <  0.05). Heart disease is associated with dementia in PD, suggesting a potential window of intervention. Vascular risk factors act especially on attention and executive functions in PD. Vascular risk stratification may be useful in order to identify PD patients with a greater risk of developing dementia. These findings need to be verified in longitudinal studies.

%B J Alzheimers Dis %V 51 %P 563-70 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890741?dopt=Abstract %R 10.3233/JAD-150610