Canine cognitive dysfunction (CCD) patients have reduced total hippocampal volume compared with aging control dogs: a comparative MRI study

Hippocampal atrophy is a key pathologic and MRI feature of human Alzheimer’s disease (AD). Hippocampal atrophy has not been documented via MRI in canine cognitive dysfunction (CCD), which is considered the dog model of human AD. The purpose of this retrospective comparative volumetric MRI study was to compare total hippocampal volumes between successfully aging (control) dogs and dogs diagnosed with CCD. Mimics® software was used to derive total hippocampal volumes and total brain volumes from the MRI studies of 42 aging dogs (≥ 9 years): 16 dogs diagnosed with CCD and 26 successfully aging controls. Total hippocampal volume normalized to total brain volume was significantly less for CCD patients compared with control dogs (p=0.04). The results of this study suggest that-similar to human AD-hippocampal atrophy is a pathological feature of CCD. This finding has potential importance for both investigating disease mechanisms related to dementia as well as future hippocampal-targeted therapies.

Hippocampal atrophy is a key pathologic and MRI feature of human Alzheimer's disease (AD). 43 Hippocampal atrophy has not been documented via MRI in canine cognitive dysfunction (CCD), 44 which is considered the dog model of human AD. The purpose of this retrospective comparative 45 volumetric MRI study was to compare total hippocampal volumes between successfully aging 46 (control) dogs and dogs diagnosed with CCD. Mimics ® software was used to derive total 47 hippocampal volumes and total brain volumes from the MRI studies of 42 aging dogs (> 9 48 years): 16 dogs diagnosed with CCD and 26 successfully aging controls. Total hippocampal 49 volume normalized to total brain volume was significantly less for CCD patients compared with 50 control dogs (p=0.04). The results of this study suggest that-similar to human AD-hippocampal 51 atrophy is a pathological feature of CCD. This finding has potential importance for both 52 investigating disease mechanisms related to dementia as well as future hippocampal-targeted 53 therapies.

63
Alzheimer's disease, a degenerative brain disorder of people, shares many clinical and 64 pathological features with canine cognitive dysfunction (CCD), a disorder affecting aging dogs. 65 Consequently, investigators consider CCD a naturally occurring model for studying human 66 Alzheimer's disease. Furthermore, CCD commonly causes frustration for dog owners and The use of MRI to assess hippocampal volume in dogs with CCD has not been reported. The 76 purpose of this MR imaging study was to compare total hippocampal volumes between dogs 77 with CCD and similarly aged control dogs. We hypothesized that dogs with CCD would have 78 smaller total hippocampal volumes compared with controls. neurologically normal small-breed dogs whose owners volunteered for a no-cost brain MRI prior 94 to scheduled dentistry procedures. Because of the nature of this study, the need for IACUC 95 approval was waived by Cornell University's Institute for Animal Care and Use Committee. 96 We based our diagnosis of CCD on previously established historical and clinical criteria together 97 with characteristic MRI abnormalities (excluding hippocampal measurements). 1,10,11 In addition, 98 we only included cases of CCD for which this diagnosis was clearly stated in the medical record 99 and supported by the MRI report.   For each dog, three-dimensional volumes were measured from T2-weighted brain images using We then normalized total hippocampal volumes to total brain volume (rather than bodyweight) 116 under the assumption that total brain volume would not change with CCD, and that total brain Because hippocampal volume represents a small percentage of total brain volume, we multiplied 120 the volume ratio by 1000 to have more easily understood values.

122
We compared all continuous variables (i.e. normalized hippocampal volumes, age) between the 123 CCD dogs and control dogs using Mann Whitney U Tests.

124
To assess for both intra and inter-observer variability in measurements, 20 patient scans were

129
We included 16 dogs with CCD and 26 control dogs in the study. Dogs with CCD were older 130 than control dogs (median age 13 yrs vs 11.5 yrs; P=0.0002); however, we could detect no

171
There are several limitations to this study, most of which are related to its retrospective nature.

172
Although multiple institutions were involved in recruiting case material, the case numbers are 9 173 still small. Also, the MR images evaluated were derived from multiple different machines, which 174 could introduce some level of variability in the resultant data. We restricted case enrollment to 175 dogs 9 yrs and older, in accordance with previous publications dealing with aging dogs. 10,23,24

176
Although the median ages of our CCD and control groups was not large (11.5 yrs vs 13 yrs), it