Objectives: Frontotemporal dementia (FTD) is the second most common form of degenerative dementia in early onset dementia (EOD) patients. The core disorders in the FTD spectrum are: behavioral variant of FTD (FTDbv) with predominant early changes in behavior (such are disinhibition, apathy, loss of empathy, compulsive behaviour..); and language variants - primary progressive aphasias (PPA) where language is the primary impairment (difficulties in speech, understanding, repetition..). Patients with sporadic, as well as genetic forms of FTD, can develop motor symptoms of motor neuron disease (before, after or at the same time with cognitive/behavioural features) or atypical parkinsonism-progressive supranuclear palsy or corticobasal syndrome, which are all part of the clinical FTD spectrum. The FTD is still poorly recognised entity and the heterogeneity of clinical presentations, early onset (most frequently before the age of 65), as well as overlap of early FTDbv symptoms and psychiatric diseases, often results in wrong diagnosis and presents a challenge, even in tertiary referral centres. It has been shown that delay in correct dementia diagnosis contributes to the caregiver's and patient's distress. The early and precise diagnosis is important for consideration of prognosis and course of the disease with family members; possibilities of improving patient's quality of life by giving them adequate symptomatic therapy; guiding the genetic analysis which is especially important for family members who also could be in risk of carring or passing the mutation to their offspring. Aim: In this mini review paper we tried to point out the specificity of clinical manifestation in the FTD spectrum, which could be helpful in making the early and accurate diagnosis among the variety of EOD cases. Conclusion: Early and accurate FTD diagnosis is important for the insight of the disease course, giving adequate symptomatic therapy and guiding the genetic analysis which reduces the caregiver's and patient's distress.

Background/Objectives: Early-onset dementia (EOD), defined as symptom onset before 65 years of age, is a clinically and genetically heterogeneous group. Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are its most common neurodegenerative causes. Methods: We investigated the family history, genetic spectrum, and diagnostic yield of targeted genetic testing in a consecutive Serbian cohort of 130 patients with early-onset AD (EOAD) and 78 with early-onset FTD (EOFTD). Results: Approximately one-third of patients had a positive family history of dementia or another neurodegenerative disorder. Pathogenic or likely pathogenic variants were identified in 3.8% of patients with EOAD, whereas pathogenic or likely pathogenic variants or pathogenic repeat expansions were identified in 9.0% of patients with EOFTD. In EOAD, the diagnostic yield increased to 9.5% in those with a positive family history and, in an exploratory subgroup analysis, was 33.3% in those with symptom onset before 51 years. In EOFTD, the diagnostic yield was 25.0% among those with a positive family history. PSEN1 and APP were the only disease-causing genes identified in EOAD, whereas C9orf72 repeat expansion was the predominant genetic cause of EOFTD, with additional pathogenic variants identified in GRN and VCP. Conclusions: These findings support the clinical value of targeted genetic testing guided by family history, age at onset, and clinical phenotype in patients with EOD. Genetically unresolved familial cases may reflect incomplete assessment of known genetic causes, including genes and variant classes not covered by the targeted testing strategy used in this study.

Background/Objectives: Insulin resistance (IR) and metabolic Syndrome (MSy) have been linked to cognitive decline, but their presence in mild cognitive impairment (MCI) and Alzheimer disease (AD) remains unclear. We evaluated MSy and IR in nonobese, nondiabetic older adults with cognitive dysfunction. Methods: The cross-sectional study included 143 participants aged 65–90 years: 62 with AD, 41 with MCI, and 40 cognitively preserved controls. Anthropometric measures, blood pressure, fasting glucose, insulin, and lipid levels were assessed. Diabetes was excluded by oral glucose tolerance testing. IR was estimated using HOMA-IR, and MSy was diagnosed according to International Diabetes Federation (IDF) criteria. Group differences and associations with cognitive impairment were assessed using analysis of variance and regression analyses. Results: Fasting insulin increased from controls to MCI and AD (7.18 ± 4.32, 13.76 ± 6.89, and 18.58 ± 8.19 mU/L), as did HOMA-IR (1.49 ± 0.98, 3.35 ± 1.72, and 4.59 ± 2.19, p < 0.05). Compared with controls, both cognitively impaired groups had higher fasting glucose, TCh, LDL-ch and lower HDL-ch (all p < 0.05), whereas triglycerides did not differ (p = 0.266). MSy prevalence was 22.5% in controls, 46.3% in MCI, and 35.5% in AD; however, the overall difference was not statistically significant (p = 0.079). In binary logistic regression analysis, sex, age, LDL-ch, and HOMA-IR were independently associated with cognitive impairment (all p < 0.05). Conclusions: Increased IR was more consistently associated with cognitive impairment than the presence of MSy, with the highest degree of IR observed in AD. These findings support an association between metabolic dysfunction and cognitive impairment and suggest that IR may represent a potential target for preventive and therapeutic strategies.

Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are recognized as a spectrum of neurodegenerative disorders with overlapping clinical, pathological, and genetic features. The identification of C9orf72 hexanucleotide repeat expansion as the most common genetic cause of both conditions has prompted further investigation of genetic modifiers that may contribute to disease heterogeneity. We aimed to analyze the frequency of C9orf72 repeat expansions and potential modifying roles of APOE, ATXN1, and ATXN2 in Serbian ALS/FTD patients. Methods: Our study included an ALS/FTD cohort (n = 22) and healthy controls (n = 94). Repeat sizing in C9orf72, ATXN1 and ATXN2 was performed by fluorescent polymerase chain reaction (PCR) and capillary electrophoresis, while repeat-primed PCR was used to confirm C9orf72 expansions. APOE genotyping was conducted using real-time PCR assays targeting SNPs rs429358 and rs7412. Results: In the ALS/FTD cohort, 31.82% of the patients had heterozygous C9orf72 repeat expansion. The most common APOE genotype among patients was ε3/ε3 (72.73%). Intermediate-length ATXN1 alleles (32–44 repeats) were detected in 13.64% of patients and ATXN2 intermediate-length alleles (27–33 repeats) were found in 9% of patients. No significant differences were observed between ALS/FTD patients and controls in APOE ε4 frequency or intermediate ATXN1/ATXN2 repeats. Conclusions: Larger, population-specific studies and meta-analyses are needed to better understand the role of genetic modifiers in ALS/FTD pathogenesis and their influence on clinical heterogeneity. By integrating genetic and clinical data, this study represents a step toward the development of precision medicine strategies for ALS/FTD.