Table 1.

Description of assessed pathology features.

Pathology feature	Description/Reason for inclusion
Beta amyloid	The presence of excess beta amyloid protein, typically in tangles or inclusions, is a known feature of AD [10]. However, beta amyloid changes have also been seen in the CSF of ALS patients [10].
Lewy body formation	Alpha-synuclein immunohistochemistry is used to identify lewy bodies, which are abnormal aggregates of protein present in Parkinson’s Disease, lewy body disease, and other disorders, including some cases of ALS [13, 14].
Tauopathy	The presence of tau protein aggregates is a known feature of AD and frontotemporal dementia. The presence of such aggregates in ALS is presently controversial [45, 47–52].
TDP-43 Inclusions	TDP-43, or transactive response (TAR) DNA-Binding Protein 43 kDa [53], is a common pathological feature of both FTD/FTLD and ALS [11, 12]. Cytoplasmic inclusions particularly in the anterior horn, are a common feature of ALS. TDP-43 has been shown to affect neuronal activity response factor in the dendrites of hippocampal neurons suggesting possible roles in regulating mRNA stability, transport and local translation in neurons [54].
Neurofibrillary Tangles (NFTs)	Primarily comprising hyperphosphorylated tau proteins, NFTs are, along with senile plaques, pathological features of Alzheimer’s disease. Quantity of NFTs is thought to be related to the degree of dementia, suggesting that their accumulation is possibly related to neuron dysfunction [29, 55]. They have been found in ALS populations in the hippocampus [15].
Atherosclerosis	A specific form of arteriosclerosis in which an artery wall thickens as a result of invasion and accumulation of white blood cells. It has been proposed that ALS could potentially be caused by constrictions in veins draining the spinal cord and brain [56] or from inflammatory disease [16].
Infarcts/microinfarcts	Areas of tissue death due to lack of oxygen. Common in stroke patients. Multi-infarct dementia (MID) can cause a dementia similar to Alzheimer disease (AD). Infarcts/microinfarcts could also be a hemodynamic contributor to ALS [56].
Ventricular dilation	Enlargement of the ventricles may occur for a number of reasons, such as loss of brain volume or impaired outflow or absorption of cerebrospinal fluid. It has been noted in ALS mice as well as some clinical ALS patients [57].
Degeneration of Corticospinal Tract(s)	Corticospinal tracts carry nerve impulses from the brain to the spinal cord, with the majority of fibers crossing at the medulla. Involved in voluntary movement. Both anterior and lateral corticospinal tract degeneration is common in ALS [58].
Denervation	Loss of nerve supply to a given region. Retrograde retraction from the neuromuscular junction is thought to initiate denervation in ALS [59, 60].
Neuronal loss	Neurodegenerative diseases such as ALS are characterized by the loss of certain neurons. ALS, specifically, is characterized by the loss of neurons in regions such as the spinal cord, brainstem, and other areas of the brain, especially the motor cortex [3].
Betz cell (loss)	Large neurons localized to the primary motor cortex. Loss of Betz cells is a feature of motor neuron disease [61].
Purkinje cell (loss)	Large neurons localized to the cerebellum. Loss of Purkinje cells has been implied in ALS. One theory suggests that abnormal trafficking and proteolytic processing of the P2X(4) receptor protein may be involved [29].
Pigmentary incontinence	Caused by external deposits of (typically) intracellular pigments. Is as an indicator of the loss of neurons in pigmented nuclei [62, 63]. We specifically assess the locus ceruleus and substantia niagra, for which pigmentary incontinence has been associated with Parkinson’s disease.
Neural atrophy	Shrinking of the neural structure, and more specifically of the ventral roots, diaphragm, paraspinal muscle nerve fiber, and general brain and spinal cord, which have been shown in ALS [17].
Alzheimer’s Disease	Neurodegenerative disorder that typically causes dementia. The most common pathological biomarker is amyloid beta plaques or tangles. AD in this study was diagnosed based on pathological CERAD criteria [18, 22].
Frontotemporal lobar degeneration, FTLD	A pathological process that occurs in frontotemporal dementia. Characterized by atrophy in the frontal and temporal lobe of the brain, with sparing of the parietal and occipital lobes. Seen in combination with ALS in some patients [55].