Creating the Pick's disease International Consortium: Association study of MAPT H2 haplotype with risk of Pick's disease

Abstract

Background: Pick's disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by the MAPT gene. The MAPT H2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association between MAPT H2 and risk of PiD.

Methods: We established the Pick's disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped for MAPT H1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variant MAPT H1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521).

Findings: Our primary analysis found that the MAPT H2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotype MAPT H1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65).

Interpretation: The PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, the MAPT H2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.

Keywords: MAPT; Pick’s disease; frontotemporal dementia; genetics; haplotype; tau.

Figure 1:

Global map and table reporting countries and recruitment sites that have contributed Pick’s disease tissues to the Pick’s disease International Consortium (PIC) to date. Dark red= countries that have collected and donated Pick’s disease tissues.

Figure 2:

Pathological assessments of Pick’s disease brains at Mayo Clinic Brain Bank for Neurodegenerative Diseases in Jacksonville, FL, USA. [A] The superior and dorsolateral surfaces of the frontal cortex and temporal lobe often show severe circumscribed ‘knife-edge’ edge atrophy. [B] Coronal sections of the brain show markedly dilated ventricles, cortical atrophy, and hippocampal affection. [C] Enlarged, amorphous ballooned neurons. [D] In regions with severe astrogliosis and neuronal loss, staining against αβ-crystallin may highlight ballooned neurons. [E] Phosphorylated tau antibodies highlight spherical cytoplasmic neuronal inclusions and may also show marked neuropil staining, especially in cases with concomitant Alzheimer’s type pathology. [F] Gallyas silver stains may stain isolated glial lesions or neurofibrillary tangles; however, Pick bodies do not show any significant degree of silver staining. [G] 3R tau staining of the dentate fascia of the hippocampus show strong immunoreactivity of spherical inclusions. [H] 4R tau staining of the dentate fascia show negative spherical inclusion, although isolated neurofibrillary tangles may stain positive. Images are from Pick cases submitted to MCJ.]

Figure 3:

Pathological assessments of Pick’s disease brains at Queen Square Brain Bank for Neurological Disorders (QSBB), UCL Queen Square Institute of Neurology, London, UK. The top row shows a Pick’s disease case that was positive for AT8 and 3R-tau immunoreactive Pick bodies. The bottom row shows a non-Pick’s disease case (that was originally pathologically diagnosed with Pick’s disease) that was positive for AT8 and 4R-tau but negative for 3R tau immunoreactive Pick bodies. Images are from Pick cases submitted to UCL.