Table 3:

Systems anatomical principles to guide C9orf72-FTD/ALS neuropathological research

Relevant syndrome	Regions most often evaluated in human NP studies to date	Functional role of region	Involvement of region in syndrome	Recommended region*	Functional role of region	Involvement of region in syndrome
bvFTD	“Frontal cortex”, usually middle frontal gyrus when specified	Executive	Variable, often late	ACC or AI, esp. Layer 5 VENs/fork cells	Social-emotional	Universal, often early
bvFTD	Hippocampus, usually dentate gyrus or CA1	Memory	Variable	Amygdala, esp. central nucleus	Emotion	Universal, often early
bvFTD	“Cerebellum” usually granule or Purkinje cells from unspecified cerebellar lobule	Cannot determine w/o anatomical details	Variable, may be absent, usually late	Thalamus, esp. medial pulvinar nucleus**	Social-emotional, reward	Universal, may be earliest-affected region in C9-bvFTD
ALS	Primary motor cortex	Voluntary motor	Universal, often early	Primary motor cortex, esp. Layer 5 upper motor neurons	Voluntary motor	Universal, often early
ALS	Spinal cord anterior horn cells	Motor, muscle trophic support	Universal, often early	Spinal cord anterior horn cells or bulbar motor neurons	Motor, muscle trophic support	Universal, often early

^*based on in vivo whole brain imaging, quantitative neuropathology, or established clinico-anatomical relationships.

^**If medial pulvinar thalamus not available, ventral/anterior striatum makes a suitable alternative. Abbreviations: ACC: anterior cingulate cortex; AI: anterior insula; ALS: amyotrophic lateral sclerosis; bvFTD: behavioral variant frontotemporal dementia; NP: neuropathological; and VENs: von Economo neurons.