Mutation Frequency of the Major Frontotemporal Dementia Genes, MAPT, GRN and C9ORF72 in a Turkish Cohort of Dementia Patients

AbstractLoss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn−/− mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing.

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Alterations of Cerebral Blood Flow Network in Behavioral Variant Frontotemporal Dementia patients with and without Apathy

Psychiatry Research Neuroimaging ◽

10.1016/j.pscychresns.2020.111203 ◽

2021 ◽

Vol 307 ◽

pp. 111203

Author(s):

Zhi Zhou ◽

Xiaoyun Zheng ◽

Rui Li ◽

Yumin Zheng ◽

Yi Jin ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Frontotemporal Dementia ◽

Behavioral Variant Frontotemporal Dementia ◽

Flow Network ◽

Dementia Patients

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P4-664: A PHASE 1 STUDY OF AL001 IN HEALTHY VOLUNTEERS AND FRONTOTEMPORAL DEMENTIA PATIENTS CARRYING A GRANULIN MUTATION

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.09.030 ◽

2019 ◽

Vol 15 ◽

pp. P1585-P1586

Author(s):

Robert Paul ◽

Michael Ward ◽

Omer Siddiqui ◽

Mackenzie Hagey ◽

Hua Long ◽

...

Keyword(s):

Healthy Volunteers ◽

Frontotemporal Dementia ◽

Phase 1 ◽

Phase 1 Study ◽

Dementia Patients

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Anosognosia in Early- and Late-Onset Dementia and Its Association With Neuropsychiatric Symptoms

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.658934 ◽

2021 ◽

Vol 12 ◽

Author(s):

Manuela Tondelli ◽

Chiara Galli ◽

Giulia Vinceti ◽

Luigi Fiondella ◽

Simone Salemme ◽

...

Keyword(s):

Regression Analysis ◽

Disease Progression ◽

Frontotemporal Dementia ◽

Late Onset ◽

Neuropsychiatric Symptoms ◽

Diagnostic Delay ◽

Early Onset Dementia ◽

Dementia Patients ◽

Clinical Variants ◽

Late Onset Dementia

Background: The symptom anosognosia or unawareness of disease in dementia has mainly been studied in patients with late-onset dementia (LOD, ≥65 years), whereas little is known on whether it is also present in patients with early-onset dementia (EOD, <65 years). We aimed at investigating differences in anosognosia between LOD and EOD, by also studying its association with different clinical variants of EOD and the presence of neuropsychiatric symptoms.Methods: A total of 148 patients, 91 EOD and 57 LOD, were recruited and underwent extended clinical assessment and caregiver interview that included questionnaires aimed at measuring anosognosia and neuropsychiatric symptoms. Differences in anosognosia between EOD and LOD and between subgroups with different clinical variants were investigated, as well as correlation between anosognosia and neuropsychiatric symptoms. A regression analysis was applied to explore the association between anosognosia and development of neuropsychiatric symptoms during disease progression.Results: Median levels of anosognosia were not significantly different between EOD and LOD. Anosognosia increased overtime with disease progression and was higher in frontotemporal dementia patients or, more precisely, in frontotemporal dementia and Alzheimer's disease variants associated with involvement of the frontal lobes. Higher levels of early anosognosia were associated with higher frequency and severity of subsequent neuropsychiatric symptoms, in particular apathy, later in the course of the disease.Conclusion: Anosognosia is a frequent symptom of EOD, occurring in 94.5% of all-cause EOD, and it is associated with higher risk of developing neuropsychiatric symptoms during disease progression. Recognising anosognosia may be helpful for clinicians and families to reduce diagnostic delay and improve disease managment.

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