Clinical and pathological continuum of multisystem TDP-43 proteinopathies

Abstract

Objective: To determine the extent of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system of patients with clinically and autopsy-confirmed diagnoses of frontotemporal lobar degeneration with and without motor neuron disease and amyotrophic lateral sclerosis with and without cognitive impairment.

Design: Performance of immunohistochemical whole-central nervous system scans for evidence of pathological TDP-43 and retrospective clinical medical record review.

Setting: An academic medical center.

Participants: We included 64 patients with clinically and pathologically confirmed frontotemporal lobar degeneration with ubiquitinated inclusions with or without motor neuron disease and amyotrophic lateral sclerosis with or without cognitive impairment.

Main outcome measure: Neuronal and glial TDP-43 pathology.

Results: We found evidence of neuronal and glial TDP-43 pathology in all disease groups throughout the neuraxis, albeit with variations in the frequency, morphology, and distribution of TDP-43 lesions. Moreover, the major clinical manifestations (eg, cognitive impairments, motor neuron signs, extrapyramidal symptoms, neuropsychiatric features) were reflected by the predominant distribution and burden of TDP-43 pathology.

Conclusion: These findings strongly suggest that amyotrophic lateral sclerosis, frontotemporal lobar degeneration with amyotrophic lateral sclerosis or motor neuron disease, and frontotemporal lobar degeneration with ubiquitinated inclusions are different manifestations of a multiple-system TDP-43 proteinopathy linked to similar mechanisms of neurodegeneration.

Figure 1

Whole-brain heat map of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system based on the severity of TDP-43 deposits according to the frontotemporal degeneration with ubiquitinated inclusions subtype, which is subtype 1 here. Sagittal, lateral, coronal, and cross sections of central nervous system regions are shown (not every brain area was available for all cases). Colors reflect median scores across all cases calculated from grouped data. The subjacent color scale depicts median scores from zero (green) to highest scores (red) in each region examined, and blue indicates unexamined regions. Numbers identify the following: 1, frontal lobe gray matter; 2, orbital gyrus gray matter; 3, motor gyrus gray matter; 4, sensory gyrus gray matter; 5, temporal lobe gray matter; 6, parietal lobe gray matter; 7, occipital lobe gray matter; 8, cingulate gyrus gray matter; 9, midbrain; 10, pons; 11, medulla; 12, cervical spinal cord; 13, cerebellum gray matter; 14, cerebellum white matter; 15, dentate nucleus in the cerebellum; 16, substantia nigra; 17, frontal lobe white matter; 18, temporal lobe white matter; 19, basal ganglia; 20, amygdala; 21, cingulate gyrus white matter; 22, motor gyrus white matter; 23, sensory gyrus white matter; 24, parietal lobe white matter; 25, thalamus; 26, entorhinal gray matter; 27, hippocampus (CA4-CA1/subiculum and dentate gyrus); 28, entorhinal white matter; 29, medulla dorsal motor plate; 30, medulla inferior olive; 31, Broca area gray matter; 32, Broca area white matter; 33, orbital gyrus white matter; 34, periamygdaloid gray matter; and 35, periamygdaloid white matter.

Figure 2

Whole-brain heat map of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system based on the severity of TDP-43 deposits according to the frontotemporal degeneration with ubiquitinated inclusions subtype, which is subtype 2 here. The grading and numbering system are as described in Figure 1.

Figure 3

Whole-brain heat map of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system based on the severity of TDP-43 deposits according to the frontotemporal degeneration with ubiquitinated inclusions subtype, which is subtype 3 here. The grading and numbering system are as described in Figure 1.

Figure 4

Whole-brain heat map of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system based on the severity of TDP-43 deposits according to the frontotemporal degeneration with ubiquitinated inclusions (FTLD-U) subtype, which is FTLD-U unclassified as described in the text. The grading and numbering system are as described in Figure 1.

Figure 5

Whole-brain heat map of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system based on the severity of TDP-43 deposits according to the clinical diagnosis, which is frontotemporal dementia here. The grading and numbering system are as described in Figure 1.

Figure 6

Whole-brain heat map of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system based on the severity of TDP-43 deposits according to the clinical diagnosis, which is mixed frontotemporal dementia and motor neuron disease here. The grading and numbering system are as described in Figure 1.

Figure 7

Whole-brain heat map of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system based on the severity of TDP-43 deposits according to the clinical diagnosis, which is amyotrophic lateral sclerosis here. The grading and numbering system are as described in Figure 1. This Figure is similar to Figure 1B in Geser et al, but cases with dementia have been excluded, a new amyotrophic lateral sclerosis case has been included, and the color code has been modified.