CSF-Progranulin levels were significantly lower in FTD type patients with semantic dementia and behavioral variant FTD mainly attributed to the Tar-DNA-Binding-Protein (TDP) 43 compared to predominantly Tau-mediated PNFA (<i>p</i> < 0.05).
There are three major associated clinical syndromes, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA); three principal histologies, involving tau, TDP-43 and FUS proteins; and mutations in three major genes, MAPT, GRN and C9orf72, along with several other less common gene mutations.
In particular, mutations in GRN account for 5-10% of all cases and give rise to a wide spectrum of clinical phenotypes, ranging from behavioral frontotemporal dementia (bvFTD) to primary progressive aphasia, including progressive non-fluent aphasia (PNFA) and semantic dementia, and corticobasal syndrome (CBS).
Progranulin gene (GRN) mutations cause frontotemporal lobar degeneration (FTLD) with TDP43-positive inclusions, although its clinical phenotype is heterogeneous and includes patients classified as behavioral variant-FTLD (bvFTLD), progressive non-fluent aphasia (PNFA), corticobasal syndrome, Alzheimer's disease (AD), or Parkinson's disease (PD).
Here we undertook a systematic study of nonverbal sound processing in patient groups with canonical dementia syndromes comprising clinically diagnosed typical amnestic Alzheimer's disease (AD; n=21), progressive nonfluent aphasia (PNFA; n=5), logopenic progressive aphasia (LPA; n=7) and aphasia in association with a progranulin gene mutation (GAA; n=1), and in healthy age-matched controls (n=20).
Certain prominent features of this case (in particular, the profile of semantic impairment) have not been emphasised in previous descriptions of LPA or PNFA, suggesting that GRN may cause an overlapping PPA syndrome but with a distinctive cognitive profile.
The importance of these findings is threefold: firstly, the clinico-anatomical entity of LPA has a profile of brain damage that is complementary to the network-based disorders of SD and PNFA; secondly, the core phonological processing deficit in LPA is likely to arise from temporo-parietal junction damage but disease spread occurs through the dorsal language network (and in GRN-PPA, also the ventral language network); and finally, GRN mutations provide a specific molecular substrate for language network dysfunction.
33 PPA patients (9 semantic dementia, SD, 14 progressive nonfluent aphasia, PNFA, 7 logopenic/phonological aphasia, LPA and 3 patients with a PPA syndrome in association with progranulin mutations, GRN-PPA) were assessed using the Neuropsychiatric Inventory to record behavioural changes, as well as volumetric MR imaging.
There are three major associated clinical syndromes, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA); three principal histologies, involving tau, TDP-43 and FUS proteins; and mutations in three major genes, MAPT, GRN and C9orf72, along with several other less common gene mutations.
In the case of the MAPT mutation, the family presented with both bvFTD and PNFA phenotypes, while the VCP mutation was also related to an early-onset AD phenotype.
As a result, 2 novel mutations in MAPT (p.D177V and p.P513A) were identified in a sporadic and familial patient with PNFA respectively, and one known mutation in MAPT (p.N279K) was detected in an FTD-parkinsonism family.
The V363I mutation of the microtubule-associated protein tau gene has previously been associated with a case of primary progressive nonfluent aphasia with variable penetrance.
There are three major associated clinical syndromes, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA); three principal histologies, involving tau, TDP-43 and FUS proteins; and mutations in three major genes, MAPT, GRN and C9orf72, along with several other less common gene mutations.
Certain syndromic signatures were identified: pain and temperature symptoms were particularly prevalent in behavioural variant frontotemporal dementia (71% of cases) and semantic dementia (65% of cases) and in association with C9orf72 mutations (6/6 cases), but also developed in Alzheimer's disease (45% of cases) and progressive non-fluent aphasia (25% of cases).