Our aim was to investigate the association between behavioral symptoms of agitation, disinhibition, irritability, elation, and aberrant motor behavior to frontal brain volumes in a cohort with various neurodegenerative diseases. A total of 121 patients with mild cognitive impairment (MCI, n = 58), Alzheimer's disease (AD, n = 45) and behavioral variant frontotemporal dementia (bvFTD, n = 18) were evaluated with a Neuropsychiatric Inventory (NPI). A T1-weighted MRI scan was acquired for each participant and quantified with a multi-atlas segmentation method. The volumetric MRI measures of the frontal lobes were associated with neuropsychiatric symptom scores with a linear model. In the regression model, we included CDR score and TMT B time as covariates to account for cognitive and executive functions. The brain volumes were corrected for age, gender and head size. The total behavioral symptom score of the five symptoms of interest was negatively associated with the volume of the subcallosal area (β = −0.32, p = 0.002). High disinhibition scores were associated with reduced volume in the gyrus rectus (β = −0.30, p = 0.002), medial frontal cortex (β = −0.30, p = 0.002), superior frontal gyrus (β = −0.28, p = 0.003), inferior frontal gyrus (β = −0.28, p = 0.005) and subcallosal area (β = −0.28, p = 0.005). Elation scores were associated with reduced volumes of the medial orbital gyrus (β = −0.30, p = 0.002) and inferior frontal gyrus (β = −0.28, p = 0.004). Aberrant motor behavior was associated with atrophy of frontal pole (β = −0.29, p = 0.005) and the subcallosal area (β = −0.39, p < 0.001). No significant associations with frontal brain volumes were found for agitation and irritability. We conclude that the subcallosal area may be common neuroanatomical area for behavioral symptoms in neurodegenerative diseases, and it appears to be independent of disease etiology.

ImportanceDiagnostic incidence data for syndromes associated with frontotemporal lobar degeneration (FTLD) in multinational studies are urgent in light of upcoming therapeutic approaches.ObjectiveTo assess the incidence of FTLD across Europe.Design, Setting, and ParticipantsThe Frontotemporal Dementia Incidence European Research Study (FRONTIERS) was a retrospective cohort study conducted from June 1, 2018, to May 31, 2019, using a population-based registry from 13 tertiary FTLD research clinics from the UK, the Netherlands, Finland, Sweden, Spain, Bulgaria, Serbia, Germany, and Italy and including all new FTLD-associated cases during the study period, with a combined catchment population of 11 023 643 person-years. Included patients fulfilled criteria for the behavioral variant of frontotemporal dementia (BVFTD), the nonfluent variant or semantic variant of primary progressive aphasia (PPA), unspecified PPA, progressive supranuclear palsy, corticobasal syndrome, or frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Data were analyzed from July 19 to December 7, 2021.Main Outcomes and MeasuresRandom-intercept Poisson models were used to obtain estimates of the European FTLD incidence rate accounting for geographic heterogeneity.ResultsBased on 267 identified cases (mean [SD] patient age, 66.70 [9.02] years; 156 males [58.43%]), the estimated annual incidence rate for FTLD in Europe was 2.36 cases per 100 000 person-years (95% CI, 1.59-3.51 cases per 100 000 person-years). There was a progressive increase in FTLD incidence across age, reaching its peak at the age of 71 years, with 13.09 cases per 100 000 person-years (95% CI, 8.46-18.93 cases per 100 000 person-years) among men and 7.88 cases per 100 000 person-years (95% CI, 5.39-11.60 cases per 100 000 person-years) among women. Overall, the incidence was higher among men (2.84 cases per 100 000 person-years; 95% CI, 1.88-4.27 cases per 100 000 person-years) than among women (1.91 cases per 100 000 person-years; 95% CI, 1.26-2.91 cases per 100 000 person-years). BVFTD was the most common phenotype (107 cases [40.07%]), followed by PPA (76 [28.46%]) and extrapyramidal phenotypes (69 [25.84%]). FTD-ALS was the rarest phenotype (15 cases [5.62%]). A total of 95 patients with FTLD (35.58%) had a family history of dementia. The estimated number of new FTLD cases per year in Europe was 12 057.Conclusions and RelevanceThe findings suggest that FTLD-associated syndromes are more common than previously recognized, and diagnosis should be considered at any age. Improved knowledge of FTLD incidence may contribute to appropriate health and social care planning and in the design of future clinical trials.

Behavioural variant frontotemporal dementia (bvFTD) and idiopathic normal pressure hydrocephalus (iNPH) are neurodegenerative diseases that can present with similar symptoms. These include decline in executive functions, psychomotor slowness, and behavioural and personality changes. Ventricular enlargement is a key radiological finding in iNPH that may also be present in bvFTD caused by the C9ORF72 expansion mutation. Due to this, bvFTD has been hypothesized as a potential comorbidity to iNPH but bvFTD patients have never been identified in studies focusing in clinical comorbidities with iNPH. Here we describe a patient with the C9ORF72 expansion-associated bvFTD who also showed enlarged ventricles on brain imaging. The main clinical symptoms were severe gait disturbances and psychiatric problems with mild cognitive decline. Cerebrospinal fluid removal increased the patient’s walking speed, so a ventriculoperitoneal shunt was placed. After insertion of the shunt, there was a significant improvement in walking speed as well as mild improvement in cognitive function but not in neuropsychiatric symptoms relating to bvFTD. Comorbid iNPH should be considered in bvFTD patients who have enlarged ventricles and severely impaired gait.

A hexanucleotide expansion in chromosome 9 open-reading frame 72 (C9ORF72) has been found to be a major cause of frontotemporal lobar degeneration (FTLD). We describe a 20-year follow-up of a unique case with very slowly progressive FTLD caused by the C9ORF72 repeat expansion. In serial neuropsychological examinations, the patient's cognitive decline was exceptionally slow and after 20 years the patient still was mainly independent in activities of daily living. Our case indicates that there is great individual variation in the progression and duration of C9ORF72-associated FTLD, and also language variants or mixed phenotypes may be present.