Cognitive impairment is not uncommon in patients with biallelic RFC1 AAGGG repeat expansion, but the expansion is rare in patients with cognitive disease

Introduction: The biallelic repeat expansion (AAGGG)(exp) in RFC1 causes cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). Recently, cognitive impairment has been reported in patients with CANVAS and a broader neurodegenerative process associated with RFC1 has been suggested. Furthermore, rare cases of multiple system atrophy, Parkinson's disease, amyotrophic lateral sclerosis or CANVAS with features of dementia with Lewy bodies have been found. Objective: We hypothesized that the biallelic (AAGGG)(exp) is associated with neurodegeneration manifested as cognitive symptoms and that atypical RFC1 disease may be found among patients with cognitive disorder. Methods: Clinical data on nine patients with biallelic (AAGGG()exp) were reviewed and 564 patients with Alz-heimer's disease or frontotemporal dementia (FTD) were investigated for biallelic RFC1 (AAGGG)(exp). Results: Five patients with biallelic (AAGGG)(exp) were found with a cognitive impairment and in four of them the phenotype resembled FTD. However, biallelic (AAGGG)(exp) was not detected among patients with Alzheimer's disease or FTD. Conclusion: Cognitive impairment is a feature in patients with the biallelic (AAGGG)(exp), but the pathogenic expansion seems to be rare in patients with dementia. Studies on patients with diverse phenotypes would be useful to further explore the involvement of RFC1 in neuronal degeneration and to identify atypical phenotypes, which should be taken into account in clinical practice.Peer reviewe

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

Astrocytes and Microglia as Potential Contributors to the Pathogenesis of C9orf72 Repeat Expansion-Associated FTLD and ALS

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases with a complex, but often overlapping, genetic and pathobiological background and thus they are considered to form a disease spectrum. Although neurons are the principal cells affected in FTLD and ALS, increasing amount of evidence has recently proposed that other central nervous system-resident cells, including microglia and astrocytes, may also play roles in neurodegeneration in these diseases. Therefore, deciphering the mechanisms underlying the disease pathogenesis in different types of brain cells is fundamental in order to understand the etiology of these disorders. The major genetic cause of FTLD and ALS is a hexanucleotide repeat expansion (HRE) in the intronic region of the C9orf72 gene. In neurons, specific pathological hallmarks, including decreased expression of the C9orf72 RNA and proteins and generation of toxic RNA and protein species, and their downstream effects have been linked to C9orf72 HRE-associated FTLD and ALS. In contrast, it is still poorly known to which extent these pathological changes are presented in other brain cells. Here, we summarize the current literature on the potential role of astrocytes and microglia in C9orf72 HRE-linked FTLD and ALS and discuss their possible phenotypic alterations and neurotoxic mechanisms that may contribute to neurodegeneration in these diseases

Prodromal and early bvFTD:evaluating clinical features and current biomarkers

Abstract Despite the current diagnostic criteria, early diagnostics of behavioral variant of frontotemporal dementia (bvFTD) has remained challenging. Patients with bvFTD often present with misleading psychiatric phenotype, and, on the other hand, impairment in memory functions have increasingly been reported. However, impaired episodic memory is currently considered as an exclusion criterion for bvFTD. Single biofluid-based or imaging biomarkers do not currently provide sufficient sensitivity or specificity for early bvFTD diagnosis at single-subject level, although studies have suggested improved accuracy with different biomarker combinations. In this mini review, we evaluate the core clinical features of early bvFTD and summarize the most potential imaging and fluid biomarkers for bvFTD diagnostics

Otsa-ohimolohkorappeumat:miten tunnistan ja hoidan?

Tiivistelmä Otsa-ohimolohkorappeumat ovat työikäisten toiseksi yleisin etenevän muistisairauden aiheuttaja. Yleisin tämän ryhmän oireyhtymistä on otsalohkodementia, jolle ovat tyypillisiä persoonallisuuden ja käyttäytymisen muutokset. Toisen ryhmän muodostavat primaariset etenevät afasiat, joihin liittyy etupäässä kielellisiä ongelmia. Otsa-ohimolohkorappeumien diagnosointi on vaativaa, sillä ensioireet voivat herättää epäilyn esimerkiksi psykiatrisesta sairaudesta eikä taudille spesifisiä biomarkkereita tai kognitiivisia seulontatestejä ole kliinisessä käytössä. Siksi laaja neuropsykologinen tutkimus on tarpeen osana diagnostiikkaa. Näköpiirissä olevien uusien biomarkkerien käyttöönotto helpottaa jatkossa varhaista diagnostiikkaa. Toistaiseksi otsa-ohimolohkorappeumiin ei ole käytettävissä taudinkulkuun vaikuttavaa hoitoa, mutta varhaisen tunnistamisen ja oikean diagnoosin merkitys korostuvat, kun kehitteillä olevat lääkkeet tulevat saataville

Psychopharmacological medication use in frontotemporal dementia at the time of diagnosis:comparison with Alzheimer’s disease

Abstract Background: Due to the significant presence of neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) spectrum disorders, psychiatric misdiagnoses, diagnostic delay, and use of psychiatric treatments are common prior to the FTD diagnosis. Furthermore, treatment of diagnosed FTD patients mainly relies on off-label psychopharmacological approaches. Currently, limited real-world data are available regarding the actual use of psychopharmacological medications in FTD. Objective: To evaluate psychopharmacological medication use at the time of FTD diagnosis. Methods: Psychopharmacological medication use was evaluated in a Finnish FTD cohort containing 222 FTD patients, including the major clinical disease phenotypes (behavioral, language, and motor variants) and genetic patients carrying the C9orf72 repeat expansion. A cohort of 214 Alzheimer’s disease (AD) patients was used as a neurodegenerative disease reference group. Results: Active use of psychopharmacological medications at the time of diagnosis was significantly more common in FTD compared to AD, especially in the case of antidepressants (26.1% versus 15.0%, OR = 2.01, p = 0.008), antipsychotics (23.9% versus 9.3%, OR = 3.15, p &lt; 0.001), and mood-stabilizers (6.3% versus 1.9%, OR = 2.93, p = 0.085; not statistically significant), whereas the use of cholinesterase inhibitors or memantine was nearly nonexistent in FTD patients. Female gender and behavioral variant of FTD phenotype alongside with depressive and psychotic symptoms were the most prominent factors associating with the use of these medications among the FTD spectrum patients. Conclusions: Use of off-label psychopharmacological medication and polypharmacy is substantially common at the time of FTD diagnosis. This likely reflects the challenges in using symptom-driven treatment approaches, especially prior to the eventual diagnosis

C9orf72 repeat expansion does not affect the phenotype in primary progressive aphasia

Abstract Primary progressive aphasia (PPA) forms the spectrum of language variants of frontotemporal lobar degeneration (FTLD), including three subtypes each consisting of distinctive speech and language features. Repeat expansion in C9orf72 gene is the most common genetic cause of FTLD. However, thus far only little is known about the effects of the C9orf72 repeat expansion on the phenotype of PPA. This retrospective study aimed at determining the differences between the PPA phenotypes of the C9orf72 expansion carriers and non-carriers. Our results demonstrated no significant differences between these groups, indicating that the C9orf72 repeat expansion does not substantially affect the phenotype of PPA

Astrocytes and microglia as potential contributors to the pathogenesis of C9orf72 repeat expansion-associated FTLD and ALS

Abstract Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases with a complex, but often overlapping, genetic and pathobiological background and thus they are considered to form a disease spectrum. Although neurons are the principal cells affected in FTLD and ALS, increasing amount of evidence has recently proposed that other central nervous system-resident cells, including microglia and astrocytes, may also play roles in neurodegeneration in these diseases. Therefore, deciphering the mechanisms underlying the disease pathogenesis in different types of brain cells is fundamental in order to understand the etiology of these disorders. The major genetic cause of FTLD and ALS is a hexanucleotide repeat expansion (HRE) in the intronic region of the C9orf72 gene. In neurons, specific pathological hallmarks, including decreased expression of the C9orf72 RNA and proteins and generation of toxic RNA and protein species, and their downstream effects have been linked to C9orf72 HRE-associated FTLD and ALS. In contrast, it is still poorly known to which extent these pathological changes are presented in other brain cells. Here, we summarize the current literature on the potential role of astrocytes and microglia in C9orf72 HRE-linked FTLD and ALS and discuss their possible phenotypic alterations and neurotoxic mechanisms that may contribute to neurodegeneration in these diseases

Traumatic brain injury associates with an earlier onset in sporadic frontotemporal dementia

Abstract Background: Currently, there are few studies considering possible modifiable risk factors of frontotemporal dementia (FTD). Objectives: In this retrospective case-control study, we evaluated whether a history of traumatic brain injury (TBI) associates with a diagnosis of FTD or modulates the clinical phenotype or onset age in FTD patients. Methods: We compared the prevalence of prior TBI between individuals with FTD (N = 218) and age and sex-matched AD patients (N = 214) or healthy controls (HC; N = 100). Based on the patient records, an individual was categorized to the TBI+ group if they were reported to have suffered from TBI during lifetime. The possible associations of TBI with age of onset and disease duration were also evaluated in the whole FTD patient group or separately in the sporadic and genetic FTD groups. Results: The prevalence of previous TBI was the highest in the FTD group (19.3%) when compared to the AD group (13.1%, p = 0.050) or HC group (12%, p = 0.108, not significant). Preceding TBI was more often associated with the sporadic FTD cases than the C9orf72 repeat expansion-carrying FTD cases (p = 0.003). Furthermore, comparison of the TBI+ and TBI- FTD groups indicated that previous TBI was associated with an earlier onset age in the FTD patients (B = 3.066, p = 0.010). Conclusions: A preceding TBI associates especially with sporadic FTD and with earlier onset of symptoms. The results of this study suggest that TBI may be a triggering factor for the neurodegenerative processes in FTD. However, understanding the precise underlying mechanisms still needs further studies