Selective functional, regional, and neuronal vulnerability in frontotemporal dementia

Abstract

Purpose of review: The molecular neuroscience revolution has begun to rekindle interest in fundamental neuroanatomy. Blending these disciplines may prove critical to our understanding of neurodegenerative diseases, which target specific anatomical systems. Recent research on frontotemporal dementia highlights the potential value of these approaches.

Recent findings: The behavioral variant of frontotemporal dementia leads to progressive social-emotional processing deficits accompanied by anterior cingulate and frontal insular degeneration. These sites form a discrete human neural network and feature a class of layer 5b projection neurons, von Economo neurons, found only in large-brained, socially complex mammals. von Economo neurons have been shown to represent an early target in the behavioral variant of frontotemporal dementia but not in Alzheimer's disease.

Summary: Integrative approaches to selective vulnerability may help clarify neurodegenerative disease pathogenesis.

Figure 1. Converging evidence implicates the ACC and FI in bvFTD

ACC and FI local maxima are shown from imaging six neuroimaging studies, whose major findings are summarized below the images. For illustration purposes, dots are projected onto single coronal and sagittal slices of the Montreal Neurological Institute (MNI) template brain; therefore, actual maxima may have fallen on neighboring sections of the same plane. TBM = tensor-based morphometry, VBM = voxel-based morphometry.

Figure 2. Normal VEN morphology and inclusion pathology in bvFTD

VENs are large bipolar projection neurons (A) which often form vertical clusters of 3–6 cells (B). Neurologically unaffected control, cresyl violet stain. In patients with bvFTD, (C) Pick’s disease (CP-13 antibody for hyperphosphorylated tau) and (D) FTLD-U (TDP-43 antibody) cause similar diffusely speckled disease protein aggregates in VENs (arrowheads in C & D). Surrounding Layer 5 pyramidal neurons (arrows in D) show normal nuclear TDP-43 immunoreactivity, which is lost in inclusion-bearing VENs. Scale bars indicate 25 µM (A), 50 µM (B), and 20 µM (C & D).

Figure 3. Emerging bvFTD selective vulnerability model

Diverse molecular abnormalities may converge on a core set of selectively vulnerable neurons, the VENs of the ACC and FI, which anchor dynamic local microcircuits that participate in a large-scale distributed social-emotional processing network. FTD molecular pathophysiologies may target this system through one or several VEN characteristics that promote their vulnerability. Treatment strategies could be directed toward neuronal or circuit-level survival mechanisms, as well as upstream disease proteins (e.g. TDP-43, tau) and gene products (PGRN, VCP, CHMP2b). Dashed lines represent progressive system dysfunction expected to arise from VEN molecular pathophyiology. FP = frontal pole.