Clinicopathological correlates in the frontotemporal lobar degeneration-motor neuron disease spectrum

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease (MND) that shares a common clinical, genetic and pathologic spectrum with frontotemporal dementia (FTD). It is highly heterogeneous in its presentation and features. Up to 50% of patients with MND develop cognitive-behavioural symptoms during the course of the disease, meeting criteria for FTD in 10%-15% of cases. In the absence of a precise biomarker, neuropathology is still a valuable tool to understand disease nosology, reach a definite diagnostic confirmation and help define specific subgroups of patients with common phenotypic, genetic and biomarker profiles. However, few neuropathological series have been published, and the frequency of frontotemporal lobar degeneration (FTLD) in MND is difficult to estimate. In this work we describe a large clinicopathological series of MND patients, analysing the frequency of concurrent FTLD changes and trying to define specific subgroups of patients based on their clinical, genetic and pathological characteristics. We performed an observational, retrospective, multicentre case study. We included all cases meeting neuropathological criteria for MND from the Neurological Tissue Bank of the FRCB-IDIBAPS-Hospital Clínic Barcelona Biobank between 1994 and 2022, regardless of their last clinical diagnosis. While brain donation is encouraged in all patients, it is performed in very few, and representativeness of the cohort might not be precise for all patients with MND. We retrospectively reviewed clinical and neuropathological data and describe the main clinical, genetic and pathogenic features, comparing neuropathologic groups between MND with and without FTLD changes and aiming to define specific subgroups. We included brain samples from 124 patients, 44 of whom (35.5%) had FTLD neuropathologic features (i.e. FTLD-MND). Pathologic TDP-43 aggregates were present in 93.6% of the cohort and were more extensive (higher Brettschneider stage) in those with concurrent FTLD (P < 0.001). Motor symptom onset was more frequent in the bulbar region in FTLD-MND cases than in those with isolated MND (P = 0.023), with no differences in survival. We observed a better clinicopathological correlation in the MND group than in the FTLD-MND group (93.8% versus 61.4%; P < 0.001). Pathogenic genetic variants were more common in the FTLD-MND group, especially C9orf72. We describe a frequency of FTLD of 35.5% in our series of neuropathologically confirmed cases of MND. The FTLD-MND spectrum is highly heterogeneous in all aspects, especially in patients with FTLD, in whom it is particularly difficult to define specific subgroups. In the absence of definite biomarkers, neuropathology remains a valuable tool for a definite diagnosis, increasing our knowledge in disease nosology.

Keywords: amyotrophic lateral sclerosis; frontotemporal dementia; motor neuron disease; neuropathology.

Figure 1

Motor neuron disease (MND) and frontotemporal lobar degeneration (FTLD)-MND distribution of the cohort’s main clinical, neuropathologic and genetic features. The bar plot visually represents the distribution of the cohort’s main features. The columns represent the absolute count (n) of patients in both neuropathological groups for every feature: MND on the left (n = 80) and FTLD on the right (n= 44). Note the global heterogeneity among both groups in every characteristic analysed, especially in the FTLD-MND group.

Figure 2

Representation of the neuropathological overlap between motor neuron disease (MND) and frontotemporal lobar degeneration (FTLD). Gross examination (A and B), histological overview (C and D) (Klüver-Barrera/Luxol Fast Blue) and immunohistochemistry. Macroscopic thinning of anterior roots of the spinal cord in amyotrophic lateral sclerosis (ALS) (A) may be associated with a narrowing of gyri in fronto-temporal regions and ventricular enlargement (B). The major neuropathological features of ALS are a secondary degeneration of the corticospinal tracts due to the loss of upper motor neurons and extensive loss of lower motor neurons in the brainstem and/or anterior horn cells. (C) Cross-section through the thoracic spinal cord shows prominent degeneration of the lateral and anterior corticospinal tract and atrophy of the anterior horns (Klüver-Barrera; blue colour highlights myelin sheaths). (D) Representation of normal hippocampus with preserved neuronal densities in all sectors. (E) Accumulation of pTDP43 protein in motor neurons in fine-granular cytoplasmic or mesh-like threads in MND (i and ii), or as small compact cytoplasmic inclusion in the granular neurons of the dentate gyrus (iii). (F) The intronic expansion in C9orf72 may manifest as MND-FTLD continuum and shares neuropathological features consistent of small ubiquitin and p62positive star-like inclusions (representing dipeptide repeats, DPR) in cortical neurons (i) or granular cytoplasmic inclusions in granule cells of the cerebellar cortex (ii), independently of TPD43 pathology and clinicopathological phenotype, which is determined by TDP but not by DPR. (G) FUS pathology may also be observed in ALS as fibrillar inclusions (i) or more compact (ii) and basophilic on haemotoxylin and eosin stained sections (not shown), as well as in FTLD, either in the neuronal intermediate filament inclusion disease (NIFID) phenotype (iii) or atypical FTLD (aFTLD). [G(iv)] Vermiform nuclear inclusion in a granule cell of the dentate gyrus of the hippocampus.

Figure 3

Survival analysis. Comparison of survival analysis between neuropathological groups [i.e. frontotemporal lobar degeneration (FTLD)-motor neuron disease (MND) versus MND]. There was no difference between groups (P = 0.64). M = months.