Sex influences clinical phenotype in frontotemporal dementia

INTRODUCTION: Frontotemporal dementia (FTD) encompasses a wide spectrum of genetic, clinical, and histological findings. Sex is emerging as a potential biological variable influencing FTD heterogeneity; however, only a few studies explored this issue with nonconclusive results. OBJECTIVE: To estimate the role of sex in a single-center large cohort of FTD patients. METHODS: Five hundred thirty-one FTD patients were consecutively enrolled. Demographic, clinical, and neuropsychological features, survival rate, and serum neurofilament light (NfL) concentration were determined and compared between sex. RESULTS: The behavioral variant of FTD was more common in men, whereas primary progressive aphasia was overrepresented in women (p < 0.001). While global cognitive impairment was comparable, females had a more severe cognitive impairment, namely in Trail Making Test parts A and B (p = 0.003), semantic fluency (p = 0.03), Short Story Recall Test (p = 0.003), and the copy of Rey Complex Figure (p = 0.005). On the other hand, men exhibited more personality/behavioral symptoms (Frontal Behavior Inventory [FBI] AB, p = 0.003), displaying higher scores in positive FBI subscales (FBI B, p < 0.001). In particular, apathy (p = 0.02), irritability (p = 0.006), poor judgment (p = 0.033), aggressivity (p = 0.008), and hypersexuality (p = 0.006) were more common in men, after correction for disease severity. NfL concentration and survival were not statistically different between men and women (p = 0.167 and p = 0.645, respectively). DISCUSSION: The present study demonstrated that sex is a potential factor in determining FTD phenotype, while it does not influence survival. Although the pathophysiological contribution of sex in neurodegeneration is not well characterized yet, our findings highlight its role as deserving biological variable in FTD

Modifiable potential risk factors in familial and sporadic frontotemporal dementia

Objective: Only a few studies have evaluated modifiable risk factors for frontotemporal dementia (FTD). Here, we evaluated several modifiable factors and their association with disease phenotype, genotype, and prognosis in a large study population including Finnish and Italian patients with FTD and control groups. Methods: In this case-control study, we compared the presence of several cardiovascular and other lifestyle-related diseases and education between Finnish and Italian patients with familial (n = 376) and sporadic (n = 654) FTD, between different phenotypes of FTD, and between a subgroup of Finnish FTD patients (n = 221) and matched Finnish patients with Alzheimer's disease (AD) (n = 214) and cognitively healthy controls (HC) (n = 100). Results: Patients with sporadic FTD were less educated (p = 0.042, B = -0.560, 95% CI -1.101 to -0.019) and had more heart diseases (p < 0.001, OR = 2.265, 95% CI 1.502-3.417) compared to patients with familial FTD. Finnish FTD patients were less educated (p = 0.032, B = 0.755, 95% CI 0.064-1.466) compared with AD patients. The Finnish FTD group showed lower prevalence of hypertension than the HC group (p = 0.003, OR = 2.162, 95% CI 1.304-3.583) and lower prevalence of hypercholesterolemia than in the HC group (p < 0.001, OR = 2.648, 95%CI 1.548-4.531) or in the AD group (p < 0.001, OR = 1.995, 95% CI 1.333-2.986). Within the FTD group, clinical phenotypes also differed regarding education and lifestyle-related factors. Interpretation: Our study suggests distinct profiles of several modifiable factors in the FTD group depending on the phenotype and familial inheritance history and that especially sporadic FTD may be associated with modifiable risk factors.Peer reviewe

Neuroanatomical correlates of screening for aphasia in NeuroDegeneration (SAND) battery in non-fluent/agrammatic variant of primary progressive aphasia

Background: Non-fluent/agrammatic variant of Primary Progressive Aphasia (avPPA) is primarily characterized by language impairment due to atrophy of the inferior frontal gyrus and the insula cortex in the dominant hemisphere. The Screening for Aphasia in NeuroDegeneration (SAND) battery has been recently proposed as a screening tool for PPA, with several tasks designed to be specific for different language features. Applying multivariate approaches to neuroimaging data and verbal fluency tasks, Aachener Aphasie Test (AAT) naming subtest and SAND data may help in elucidating the neuroanatomical correlates of language deficits in avPPA. Objective: To investigate the neuroanatomical correlates of language deficits in avPPA using verbal fluency tasks, AAT naming subtest and SAND scores as proxies of brain structural imaging abnormalities. Methods: Thirty-one avPPA patients were consecutively enrolled and underwent extensive neuropsychological assessment and MRI scan. Raw scores of verbal fluency tasks, AAT naming subtest, and SAND subtests, namely living and non-living picture naming, auditory sentence comprehension, single-word comprehension, words and non-words repetition and sentence repetition, were used as proxies to explore structural (gray matter volume) neuroanatomical correlates. We assessed univariate (voxel-based morphometry, VBM) as well as multivariate (source-based morphometry, SBM) approaches. Age, gender, educational level, and disease severity were considered nuisance variables. Results: SAND picture naming (total, living and non-living scores) and AAT naming scores showed a direct correlation with the left temporal network derived from SBM. At univariate analysis, the left middle temporal gyrus was directly correlated with SAND picture naming (total and non-living scores) and AAT naming score. When words and non-words repetition (total score) was considered, a direct correlation with the left temporal network (SBM) and with the left fusiform gyrus (VBM) was also evident. Conclusion: Naming impairments that characterize avPPA are related to specific network-based involvement of the left temporal network, potentially expanding our knowledge on the neuroanatomical basis of this neurodegenerative condition

Unravelling neurotransmitters impairment in primary progressive aphasias

: Primary progressive aphasias (PPAs) are a group of neurodegenerative diseases mainly characterized by language impairment, and with variably presence of dysexecutive syndrome, behavioural disturbances and parkinsonism. Detailed knowledge of neurotransmitters impairment and its association with clinical features hold the potential to develop new tailored therapeutic approaches. In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of magnetic resonance imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission. We included 103 PPA patients and 80 age-matched healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in PPA patients (relative to HC) are correlated with specific neurotransmitter systems. As compared to HC, voxel-based brain changes in PPA were significantly associated with spatial distribution of serotonin, dopamine, and glutamatergic pathways (p < .05, False Discovery Rate corrected-corrected). Disease severity was negatively correlated with the strength of GMV colocalization of D1 receptors (p = .035) and serotonin transporter (p = .020). Moreover, we observed a significant negative correlation between positive behavioural symptoms, as measured with Frontal Behavioural Inventory, and GMV colocalization of D1 receptors (p = .007) and serotonin transporter (p < .001). This pilot study suggests that JuSpace is a helpful tool to indirectly assess neurotransmitter deficits in neurodegenerative dementias and may provide novel insight into disease mechanisms and associated clinical features

Differences and similarities between familial and sporadic frontotemporal dementia: An Italian single‐center cohort study

Abstract Introduction The possibility to generalize our understandings on treatments and assessments to both familial frontotemporal dementia (f‐FTD) and sporadic FTD (s‐FTD) is a fundamental perspective for the near future, considering the constant advancement in potential disease‐modifying therapies that target particular genetic forms of FTD. We aimed to investigate differences in clinical features, cerebrospinal fluid (CSF), and blood‐based biomarkers between f‐FTD and s‐FTD. Methods In this longitudinal cohort study, we evaluated a consecutive sample of symptomatic FTD patients, classified as f‐FTD and s‐FTD according to Goldman scores (GS). All patients underwent clinical, behavioral, and neuropsychiatric symptom assessment, CSF biomarkers and serum neurofilament light (NfL) analysis, and brain atrophy evaluation with magnetic resonance imaging. Results Of 570 patients with FTD, 123 were classified as f‐FTD, and 447 as s‐FTD. In the f‐FTD group, 95 had a pathogenic FTD mutation while 28 were classified as GS = 1 or 2; of the s‐FTD group, 133 were classified as GS = 3 and 314 with GS = 4. f‐FTD and s‐FTD cases showed comparable demographic features, except for younger age at disease onset, age at diagnosis, and higher years of education in the f‐FTD group (all P < .05). f‐FTD showed worse behavioral disturbances as measured with Frontal Behavioral Inventory (FBI) negative behaviors (14.0 ± 7.6 vs. 11.6 ± 7.4, P = .002), and positive behaviors (20.0 ± 11.0 vs. 17.4 ± 11.8, P = .031). Serum NfL concentrations were higher in patients with f‐FTD (70.9 ± 37.9 pg/mL) compared to s‐FTD patients (37.3 ± 24.2 pg/mL, P < .001), and f‐FTD showed greater brain atrophy in the frontal and temporal regions and basal ganglia. Patients with f‐FTD had significantly shorter survival than those with s‐FTD (P = .004). Discussion f‐FTD and s‐FTD are very similar clinical entities, but with different biological mechanisms, and different rates of progression. The parallel characterization of both f‐FTD and s‐FTD will improve our understanding of the disease, and aid in designing future clinical trials for both genetic and sporadic forms of FTD. Highlights Do clinical features and biomarkers differ between patients with familial frontotemporal dementia (f‐FTD) and sporadic FTD (s‐FTD)? In this cohort study of 570 patients with FTD, f‐FTD and s‐FTD share similar demographic features, but with younger age at disease onset and diagnosis in the f‐FTD group. f‐FTD showed higher serum neurofilament light concentrations, greater brain damage, and shorter survival, compared to s‐FTD. f‐FTD and s‐FTD are very similar clinical entities, but with different cognitive reserve mechanisms and different rates of progression

Modifiable potential risk factors in familial and sporadic frontotemporal dementia

Abstract Objective: Only a few studies have evaluated modifiable risk factors for frontotemporal dementia (FTD). Here, we evaluated several modifiable factors and their association with disease phenotype, genotype, and prognosis in a large study population including Finnish and Italian patients with FTD and control groups. Methods: In this case–control study, we compared the presence of several cardiovascular and other lifestyle-related diseases and education between Finnish and Italian patients with familial (n = 376) and sporadic (n = 654) FTD, between different phenotypes of FTD, and between a subgroup of Finnish FTD patients (n = 221) and matched Finnish patients with Alzheimer’s disease (AD) (n = 214) and cognitively healthy controls (HC) (n = 100). Results: Patients with sporadic FTD were less educated (p = 0.042, B = -0.560, 95% CI −1.101 to −0.019) and had more heart diseases (p &lt; 0.001, OR = 2.265, 95% CI 1.502–3.417) compared to patients with familial FTD. Finnish FTD patients were less educated (p = 0.032, B = 0.755, 95% CI 0.064–1.466) compared with AD patients. The Finnish FTD group showed lower prevalence of hypertension than the HC group (p = 0.003, OR = 2.162, 95% CI 1.304–3.583) and lower prevalence of hypercholesterolemia than in the HC group (p &lt; 0.001, OR = 2.648, 95%CI 1.548–4.531) or in the AD group (p &lt; 0.001, OR = 1.995, 95% CI 1.333–2.986). Within the FTD group, clinical phenotypes also differed regarding education and lifestyle-related factors. Interpretation: Our study suggests distinct profiles of several modifiable factors in the FTD group depending on the phenotype and familial inheritance history and that especially sporadic FTD may be associated with modifiable risk factors

Serum total TDP-43 levels are decreased in frontotemporal dementia patients with C9orf72 repeat expansion or concomitant motoneuron disease phenotype

Abstract Background: Frontotemporal dementia (FTD) covers a spectrum of neurodegenerative disorders with various clinical and neuropathological subtypes. The two major pathological proteins accumulating in the brains of FTD patients, depending on their genetic background, are TDP-43 and tau. We aimed to evaluate whether total TDP-43 levels measured from the serum associate with the genotype or clinical phenotype of the FTD patients and whether serum TDP-43 provides prognostic or diagnostic value in the FTD spectrum disorders. Methods: The study cohort included 254 participants with a clinical diagnosis of FTD (including all major genotypes and clinical phenotypes) and 105 cognitively healthy controls. Serum total TDP-43 levels measured with a single-molecule array (Simoa) were compared within the FTD group according to the genotype, clinical phenotype, and predicted neuropathological subtype of the patients. We also evaluated the associations between the TDP-43 levels and disease severity or survival in FTD. Results: Total TDP-43 levels in the serum were significantly lower in the FTD group as compared to the healthy control group (275.3 pg/mL vs. 361.8 pg/mL, B = 0.181, 95%CI = 0.014–0.348, p = 0.034). The lowest TDP-43 levels were observed in the subgroup of FTD patients harboring predicted TDP-43 brain pathology (FTD-TDP, 241.4 pg/mL). The low levels in the FTD-TDP group were especially driven by C9orf72 repeat expansion carriers (169.2 pg/mL) and FTD patients with concomitant motoneuron disease (FTD-MND, 113.3 pg/mL), whereas GRN mutation carriers did not show decreased TDP-43 levels (328.6 pg/mL). Serum TDP-43 levels showed no correlation with disease severity nor progression in FTD. Conclusions: Our results indicate that the total levels of TDP-43 in the serum are decreased especially in FTD patients with the C9orf72 repeat expansion or FTD-MND phenotype, both subtypes strongly associated with TDP-43 type B brain pathology. Serum-based measurement of TDP-43 could represent a useful tool in indicating C9orf72 repeat expansion and FTD-MND-related TDP-43 neuropathology for future diagnostics and intervention studies