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Review
. 2012 Sep;124(3):353-72.
doi: 10.1007/s00401-012-1029-x. Epub 2012 Aug 14.

The genetics and neuropathology of frontotemporal lobar degeneration

Anne Sieben  1 , Tim Van Langenhove, Sebastiaan Engelborghs, Jean-Jacques Martin, Paul Boon, Patrick Cras, Peter-Paul De Deyn, Patrick Santens, Christine Van Broeckhoven, Marc Cruts
Affiliations
Review

The genetics and neuropathology of frontotemporal lobar degeneration

Anne Sieben et al. Acta Neuropathol. 2012 Sep.

Abstract

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of disorders characterized by disturbances of behavior and personality and different types of language impairment with or without concomitant features of motor neuron disease or parkinsonism. FTLD is characterized by atrophy of the frontal and anterior temporal brain lobes. Detailed neuropathological studies have elicited proteinopathies defined by inclusions of hyperphosphorylated microtubule-associated protein tau, TAR DNA-binding protein TDP-43, fused-in-sarcoma or yet unidentified proteins in affected brain regions. Rather than the type of proteinopathy, the site of neurodegeneration correlates relatively well with the clinical presentation of FTLD. Molecular genetic studies identified five disease genes, of which the gene encoding the tau protein (MAPT), the growth factor precursor gene granulin (GRN), and C9orf72 with unknown function are most frequently mutated. Rare mutations were also identified in the genes encoding valosin-containing protein (VCP) and charged multivesicular body protein 2B (CHMP2B). These genes are good markers to distinguish underlying neuropathological phenotypes. Due to the complex landscape of FTLD diseases, combined characterization of clinical, imaging, biological and genetic biomarkers is essential to establish a detailed diagnosis. Although major progress has been made in FTLD research in recent years, further studies are needed to completely map out and correlate the clinical, pathological and genetic entities, and to understand the underlying disease mechanisms. In this review, we summarize the current state of the rapidly progressing field of genetic, neuropathological and clinical research of this intriguing condition.

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Figures

Fig. 1
Fig. 1
Diagram illustrating the clinical, genetic and neuropathological correlations in FTLD. The gray background of the genetics box represents the genetically unexplained fraction in FTLD cases overall (as compared to familial cases in Table 2)
Fig. 2
Fig. 2
FTLD-tau pathology in brain sections of a Pick disease patient with bvFTD after immunostaining with AT8 antibody. a Frontal cortex (F-cx), b temporal neocortex (T-cx), c hippocampus. Arrowheads indicate the characteristic Pick bodies representing neuronal intracytoplasmatic spheroid tau inclusions
Fig. 3
Fig. 3
Different types of TDP-43 pathology in brains of patients with GRN mutation, C9orf72 hexanucleotide repeat expansion and VCP mutation after immunostaining with TDP-43 antibody. a–c TDP-43 type A pathology in a bvFTD patient of family DR8, carrying the GRN IVS0 + 5G>C mutation [14, 28]. Arrowhead, double arrowhead and arrow show moderate NCI, DN and NII load, respectively, in layer II of temporal (a) and frontal (b) neocortex. c Higher magnification of NCI load in frontal cortex. d–f TDP-43 type B pathology in a bvFTD patient with the C9orf72 hexanucleotide repeat expansion [55]. Arrowhead and arrow show NCI and DN, respectively, spread throughout the entire cortical thickness in frontal cortex (d), temporal neocortex (e) and NCI in neostriatum (f, higher magnification). g–i TDP-43 type D pathology in a bvFTD patient carrying the VCP p.Arg159His mutation [168]. Note the extensive NCI (arrowhead), NII (double arrowhead) and DN (arrow) in frontal cortex (g), temporal neocortex (h, i, higher magnification)
Fig. 4
Fig. 4
aFTLD-U patient with FUS pathology without any known mutation after immunostaining with FUS antibody. The arrowhead shows the kidney-shaped NCI in affected neostriatum (a) and frontal cortex (b, c, higher magnification)
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