Comprehensive incidence and prevalence rates of frontotemporal dementia are currently not available. To estimate the incidence and prevalence of frontotemporal dementia and its clinical variants in the overall population and age subgroups. We systematically searched PubMed, EMBASE, and Scopus between January 1, 1990, and October 22, 2024, for population-based studies estimating the incidence and/or prevalence of FTD. Studies and data were screened and extracted independently by 2 investigators in accordance with PRISMA guidelines. Incident and prevalent cases together with the population at risk were pooled using random-effects meta-analysis. Differences in heterogeneity by FTD variants and populations at risk were estimated. Prevalent and incident cases as numerator were based on well-defined clinical criteria. Denominators were derived either from census population data or from author-defined populations at risk. From 1854 screened articles, 32 eligible population-based studies were identified. Sixteen were on prevalence and 22 on incidence reporting FTD measures, including those with estimates for the whole population and for specific age subgroups. Pooled crude incidence for FTD was 2.28 (95% CI, 1.55-3.36) per 100 000 person-years and prevalence, 9.17 (95% CI, 3.59-23.42) per 100 000 people. The behavioral-variant FTD pooled crude incidence was 1.20 (95% CI, 0.67-2.16) per 100 000 person-years and prevalence, 9.74 (95% CI, 2.90-32.73) per 100 000 people. The primary progressive aphasia variant pooled crude incidence was 0.52 (95% CI, 0.35-0.79) per 100 000 person-years and prevalence, 3.67 (95% CI, 3.05-4.43). FTD incidence among individuals younger than 65 years was 1.84 (95% CI, 0.79-4.30) per 100 000 person-years and prevalence, 7.47 (95% CI, 4.13-13.49) per 100 000 people. The denominator based on census data showed less heterogeneity than the population at risk defined by the authors (I2: for incidence, 91.6% vs 97.6%, respectively, and for prevalence, 98.8% vs 99.2%, respectively). In this systematic review and meta-analysis, estimates indicate that FTD is comparable in frequency to dementia with Lewy bodies and occurs at higher rates than progressive supranuclear palsy, corticobasal syndrome, and amyotrophic lateral sclerosis. These results provide a foundation for future research and public health strategy, especially for underrepresented populations, to better comprehend the global burden of FTD. Our findings provide robust pooled estimates of the incidence and prevalence of FTD and its subtypes, offering a foundation for future research and public health planning.

Pathogenic hexanucleotide repeat expansions in C9orf72 are the commonest genetic cause of frontotemporal dementia and/or amyotrophic lateral sclerosis. There is growing interest in intermediate repeat expansions in C9orf72 and their relationship to a wide range of neurological presentations, including Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, corticobasal degeneration, and corticobasal syndromes. To assess the prevalence of intermediate C9orf72 repeat expansions in a large cohort of prospectively-recruited patients clinically diagnosed with progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and atypical parkinsonism (APS), compared with healthy controls. We also sought to replicate the association between C9orf72 repeat length and CBD in neuropathologically confirmed cases. 626 cases, including PSP (n = 366), CBS (n = 130), and APS (n = 53) from the PROSPECT study, and 77 cases with pathologically confirmed CBD were screened for intermediate repeat expansions in C9orf72 using repeat-primed PCR. These were compared to controls from the PROSPECT-M-UK study and from the 1958 Birth Cohort. There was no difference in the mean or largest allele size in any affected patient group compared with controls. A higher proportion of our affected cohort had large C9orf72 repeat expansions compared to controls, but there was no difference when comparing the frequency of intermediate expansions between affected patients and controls. There was no relationship between repeat length and age at onset, level of disability, or survival. Intermediate expansions in C9orf72 do not appear to be a genetic risk factor for PSP, CBS, CBD, or atypical parkinsonism. They are not associated with age at onset, disability, or survival in our study.

Neurodegenerative diseases are increasingly recognized as complex disorders involving multiple protein pathologies, with α-synuclein frequently observed beyond classical synucleinopathies such as Parkinson's disease and multiple system atrophy. Recent advances in seed amplification assays (SAAs) have enabled the highly sensitive and specific detection of misfolded α-synuclein in vivo, particularly in cerebrospinal fluid (CSF). This review focuses on CSF-based α-synuclein SAAs and their application in detecting co-pathology across non-synucleinopathies, including Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, idiopathic normal pressure hydrocephalus, and traumatic brain injury. Evidence indicates a role for α-synuclein in clinical heterogeneity and disease progression. Emerging diagnostic frameworks increasingly support integrating co-pathologies into classification and therapeutic strategies. Addressing key knowledge gaps, such as α-synuclein interactions with other protein pathologies, and current limitations of α-syn SAA, such as the lack of quantification of misfolded α-synuclein seeds, will refine precision medicine and improve outcomes for patients with neurodegenerative diseases.

This narrative review evaluates the diagnostic potential of serum biomarkers for progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and related neurodegenerative diseases. Hyperphosphorylated tau species (p-tau), particularly p-tau217 and p-tau181, show promise in distinguishing PSP and CBS from other neurodegenerative diseases, though not from each other. While serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) exhibit limited individual utility, their combination with p-tau species enhances diagnostic accuracy. Other genome-associated, inflammatory, metabolic biomarkers, and neuropeptides yield interesting though inconsistent results. The majority of serum biomarkers yielded non-specific results in differentiating PSP and/or CBS from each other and from other related neurodegenerative diseases. Future large-scale, multi-center studies with autopsy confirmation in early-stage patients are essential for developing reliable biomarker panels. Direct comparative studies of PSP and CBS subtypes are also necessary for accurate phenotypic discrimination.

Serum anti-IgLON5 antibodies, which were tested in 223 patients meeting the diagnostic criteria for progressive supranuclear palsy/corticobasal syndrome (PSP/CBS), were negative in all patients. Our study suggests that the frequency of anti-IgLON5 disease is extremely rare in patients with typical presentation of PSP/CBS.