Stefano Gazzina

Effect of TMEM106B Polymorphism on Functional Network Connectivity in Asymptomatic GRN Mutation Carriers

IMPORTANCE Granulin (GRN) mutations represent one of the most frequent genetic causes of inherited frontotemporal dementia. The study of asymptomatic carriers of GRN Thr272fs mutation (aGRN+) provides a unique opportunity to study the natural history of the disease and the role of modulating factors on disease onset. It has been demonstrated that the TMEM106B polymorphism is associated with GRN-related frontotemporal dementia and affects age at onset in GRN mutation carriers. OBJECTIVE To ascertain whether TMEM106B genetic status modulates GRN disease by evaluating resting-state functional connectivity in aGRN+ individuals according to TMEM106 genetic variation. DESIGN, SETTING, AND PARTICIPANTS Academic tertiary referral center for neurodegenerative disorders in 17 asymptomatic carriers of aGRN+ and 14 healthy controls. MAIN OUTCOMES AND MEASURES Changes in resting-state functional connectivity, focusing on the default mode network, ventral and dorsal salience networks, executive network, frontoparietal networks, and attentive network and the effect of TMEM106B genotypes in aGRN+ participants and healthy controls (statistical nonparametric mapping). RESULTS aGRN+ participants showed decreased brain connectivity within the left frontoparietal network and increased connectivity in the executive network compared with healthy controls. The TMEM106B at-risk polymorphism (T/T) was associated with decreased connectivity within the ventral salience network (ie, middle frontal gyrus) and the left frontoparietal network (ie, left precuneus). CONCLUSIONS AND RELEVANCE This study suggests that the TMEM106B polymorphism modulates brain connectivity in aGRN+ individuals, with additional damage of the ventral salience network and left frontoparietal network observed. Genotyping TMEM106B is of importance in aGRN+ individuals for prognostic purposes and to assess early brain damage.

Cognitive Reserve in Granulin-Related Frontotemporal Dementia: from Preclinical to Clinical Stages

Objective Consistent with the cognitive reserve hypothesis, higher education and occupation attainments may help persons with neurodegenerative dementias to better withstand neuropathology before developing cognitive impairment. We tested here the cognitive reserve hypothesis in patients with frontotemporal dementia (FTD), with or without pathogenetic granulin mutations (GRN+ and GRN-), and in presymptomatic GRN mutation carriers (aGRN+). Methods Education and occupation attainments were assessed and combined to define Reserve Index (RI) in 32 FTD patients, i.e. 12 GRN+ and 20 GRN-, and in 17 aGRN+. Changes in functional connectivity were estimated by resting state fMRI, focusing on the salience network (SN), executive network (EN) and bilateral frontoparietal networks (FPNs). Cognitive status was measured by FTD-modified Clinical Dementia Rating Scale. Results In FTD patients higher level of premorbid cognitive reserve was associated with reduced connectivity within the SN and the EN. EN was more involved in FTD patients without GRN mutations, while SN was more affected in GRN pathology. In aGRN+, cognitive reserve was associated with reduced SN. Conclusions This study suggests that cognitive reserve modulates functional connectivity in patients with FTD, even in monogenic disease. In GRN inherited FTD, cognitive reserve mechanisms operate even in presymptomatic to clinical stages.

Looking for Neuroimaging Markers in Frontotemporal Lobar Degeneration Clinical Trials: A Multi-Voxel Pattern Analysis Study in Granulin Disease

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.

Iron in Frontotemporal Lobar Degeneration: A New Subcortical Pathological Pathway?

Introduction: Brain iron homeostasis dysregulation has been widely related to neurodegeneration. In particular, human haemochromatosis protein (HFE) is involved in iron metabolism, and HFE H63D polymorphism has been related to the risk of amyotrophic lateral sclerosis and Alzheimers disease. Recently, iron accumulation in the basal ganglia of frontotemporal lobar degeneration (FTLD) patients has been described. Objective: To explore the relationship between HFE genetic variation and demographic, clinical and imaging characteristics in a large cohort of FTLD patients. Methods: A total of 110 FTLD patients underwent neuropsychological and imaging evaluation and blood sampling for HFE polymorphism determination. HFE H63D polymorphism was considered in the present study. Two imaging approaches were applied to evaluate the effect of HFE genetic variation on brain atrophy, namely voxel-based morphometry and region of interest-based probabilistic approach (SPM8; Wellcome Trust Centre for Neuroimaging). Results: FTLD patients carrying the D* genotype (H/D or D/D) showed greater atrophy in the basal ganglia, bilaterally, compared to H/H carriers (x, y, z: -22, -4, 0; T = 3.45; cluster size: 33 voxels, x, y, z: 24, 4, -2; T = 3.38; cluster size: 36 voxels). The former group had even more pronounced behavioural symptoms, as defined by the Frontal Behavioural Inventory total scores. Conclusions: Our data suggest that H63D polymorphism could represent a disease-modifying gene in FTLD, fostering iron deposition in the basal ganglia. This suggests a new possible mechanism of FTLD-associated neurodegeneration.

Subcortical and Deep Cortical Atrophy in Frontotemporal Dementia due to Granulin Mutations

Background/Aims: Parkinsonism is often associated with symptoms of frontotemporal dementia (FTD), but its pathogenesis has been largely neglected. In genetic inherited FTD-related granulin (GRN) mutations, parkinsonism is an early sign, and it is more common than in sporadic disorders. Our aim was to study grey matter (GM) volume changes in subcortical and deep cortical regions in GRN-related FTD. Methods: A total of 33 FTD patients (13 carriers of the GRN mutation, GRN+, and 20 non-carriers, GRN-) and 12 healthy controls (HC) were included in the study. Each subject underwent an MRI examination (1) for voxel-based morphometry to study GM differences in cortical and subcortical regions, and (2) for a region of interest approach using a probabilistic atlas of subcortical regions (caudate nucleus, putamen, thalamus and amygdala) to assess the regional differences. Results: The GRN+ group showed greater damage in frontotemporal regions than the GRN- group. The FTD patients had greater GM atrophy in the caudate nucleus and in the thalamus bilaterally than the HC. Damage to these subcortical and deep cortical regions was greater in the GRN+ than in the GRN- patients. Discussion: Subcortical and deep cortical involvement is a key feature of FTD, and more pronounced in GRN-related disease. Damage to the caudate region in GRN+ patients may explain the parkinsonism frequently associated since the early stages of the disease.

The neuroimaging signature of frontotemporal lobar degeneration associated with Granulin mutations: an effective connectivity study.

It has been suggested that monogenic frontotemporal lobar degeneration (FTLD) due to Granulin (GRN) mutations might present a specific pattern of atrophy, as compared with FTLD GRN-negative disease. Recent literature has suggested that the study of functional neural networks, rather than regional structural damage, might better elucidate the pathogenic mechanisms, showing complex relationships among structural alterations observed with conventional neuroimaging. The aim of this study was to evaluate effective brain connectivity in FTLD patients carrying GRN mutations (GRN+), compared with FTLD patients without pathogenetic GRN mutations (GRN−) and healthy controls (HCs). Methods: Twenty-six FTLD patients (13 GRN+ and 13 GRN− matched for age, sex, and phenotype) and 13 age- and sex-matched HCs underwent brain perfusion SPECT. Brain regions involved in FTLD (dorsolateral, anterior cingulate, orbitofrontal, posterior temporal, temporal pole, and parietal) were used as regions of interest to identify functionally interconnected areas. An effective connectivity (path) analysis was defined with a PC algorithm (named after its inventors Peter Spirtes and Clark Glymour) search procedure and structural equation fitting. Statistically significant differences among the 3 groups were determined. Results: The best-fitting model was obtained by the data-driven approach, and brain connectivity pathways resembling state-of-the-art anatomic knowledge were obtained. When GRN+ and GRN− groups were considered, the former presented a selective bilateral parietotemporal disconnection, compared with GRN− patients. Furthermore, in FTLD GRN+ patients an increased compensative connectivity of the temporal regions (temporal pole and posterior temporal cortices) was observed. Conclusion: The present work suggests that impairment of effective functional connectivity of the parietotemporal regions is the hallmark of GRN-related FTLD. However, compensative mechanisms—which should be further investigated—may occur.

Overlap between Frontotemporal Dementia and Alzheimer's Disease: Cerebrospinal Fluid Pattern and Neuroimaging Study

BACKGROUND Differential diagnosis between frontotemporal dementia (FTD) and Alzheimers 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.

Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: a GENFI study

Frontotemporal dementia (FTD) shows substantial phenotypic variability. In a multicentre study, Premi et al. explore the effect of cognitive reserve and TMEM106B genotype in modulating grey matter volume in presymptomatic FTD. Environmental as well as genetic factors affect rates of brain atrophy, suggesting a possible strategy for delaying disease onset.

Modulating risky decision-making in Parkinson's disease by transcranial direct current stimulation

Performance on gambling tasks in Parkinsons disease (PD) is of particular interest, as pathological gambling is often associated with dopamine replacement therapy in these patients. We aimed to evaluate the effects of transcranial direct current stimulation (tDCS) over the right dorsolateral prefrontal cortex (DLPFC) in modulating gambling behaviour in PD.

Subcortical matter in the α-synucleinopathies spectrum: an MRI pilot study

Abstractα-Synucleinopathies, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), are characterized by α-synuclein accumulation from brainstem structures to the neocortex. PD and DLB are clinically distinguishable, while discrimination between Parkinson Disease Dementia (PDD) and DLB can be subtle and based on the temporal relationship between motor and cognitive symptoms. To explore patterns of subcortical atrophy in PD, PDD and DLB, and assess specific differences between PD and PDD, and between DLB and PDD. 16 PD, 11 PDD and 16 DLB patients were recruited and underwent 1.5 Tesla structural MRI scanning. Segmentation of subcortical structures was performed with a well-validated, fully-automated tool, and volume and shape for each structure were compared between groups. PDD and DLB patients showed global subcortical atrophy compared to PD patients. Greater hippocampal atrophy was the specific trait that distinguished PDD from PD, while greater atrophy of the pallidi discriminated DLB from PDD. Vertex analysis revealed specific shape differences in both structures. Our results suggest that automated, time-sparing, subcortical volumetry may provide diagnostically useful information in α-synucleinopathies. Future studies on larger samples and with iron-sensitive MRI contrasts are needed.