Appendix e-1: METHODS
Subjects
All 7 non-path proven sCJD subjects met WHO 1998 criteria,e1 which do not require brain MRI; 5 had disease durations less than 9 months, 2 with durations just less than 2.5 years (one with a positive EEG (negative 14-3-3, but markedly elevated t-tau and NSE) and one with non-diagnostic EEG, but positive CSF 14-3-3, t-tau and NSE). Codon 129 polymorphism data was available on 41, and prion typing on 27, sCJD subjects. Two GSS subjects had no complaints of symptoms, but had psychiatric symptoms (e.g., depression, anxiety, and/or irritability) and subtle motor abnormalities on exam that might have been early symptoms, but could have been unrelated to mutation status. All other gPrD subjects were symptomatic.
Non-pathology proven, non-prion RPD subjects
Fourteen of 29 npRPD subjects had prion gene, PRNP, testing (National Prion Disease Pathology Surveillance Center, Cleveland, OH) and none had a mutation. Fifteen of 29 npRPD subjects were not pathologically-proven, but included in the analysis. They were ruled out for prion disease because either their survival was outside the range of sCJD subjects (> 3 years), they had definitive (e.g., serological or genetic) evidence of another disorder, and/or they improved with (or without) treatment. Eight of these non-pathologically proven npRPD subjects also had PRNP testing. All neurodegenerative disease patients met established diagnostic clinical criteria.e2-e5 Specifically, for the 7 non-pathology proven subjects with neurodegenerative disease, all but one have lived for at least 3.5 years from first symptom; one DLB case improved dramatically with acetylcholinesterase inhibition therapy with survival, but died suddenly from a fall after only one year. Five of these seven neurodegenerative disease subjects had PRNP testing. Among the four non-pathology-proven autoimmune cases, one had definitive serological diagnoses (anti-GAD; stabilized with treatment and survival > 6 years since onset), two with Hashimoto’s Encephalopathy (elevated anti-TPO and/or anti-TG antibodies) improved with treatment, and one with MS improved with treatment and has had prolonged survival (>6 years). Three of these four autoimmune subjects had PRNP testing. Two patients were diagnosed with strokes and improved; neither had PRNP testing. One subject with toxic-metabolic (alcohol) encephalopathy had initial significant improvement but died a few years later, after a more than 4.5 year course, from continued alcohol use; this subject did not have PRNP testing. One patient with subacute encephalopathy improved spontaneously, is alive after more than four years, and was diagnosed with MELAS by genetic testing.
Reading of FLAIR and DWI MRIs
To help determine what regions were abnormally bright and which were brighter on FLAIR versus DWI, the neuroradiologists used the same window for background (white matter) for both FLAIR and DWI sequences.
MRI Acquisition
Due to MRI protocol improvement over the course of the study, 44 subjects (18 prion, 26 npRPD) had DWI with the B=1000 gradients applied along 3 directions. Forty-six (43 prion, 3 npRPD) had diffusion tensor imaging (DTI) with diffusion gradients applied along 6 or 15 directions (18 prion cases with 6 directions, 25 with 15 directions; the 3 npRPD were 6 or 15 directions).
Subdivision of gray matter brain regions
Subgyral divisions difficult to identify were combined (e.g., opercular, triangular, and orbital pars of the inferior frontal gyrus). Based on our knowledge of regions affected in sCJD,e6 certain Tzourio-Mazoyer regions were further subdivided. The cingulate and the insula were separated into anterior and posterior parts by a coronal plane passing through the anterior commissure. The thalamus was divided by visual assessment based on knowledge of thalamic anatomy from the Morel atlas into two parts: anterolateral (mainly ventral anterior, ventral lateral, ventral posterior nuclei), and posteromesial (mainly ventral mesial and pulvinar).e7Cortical regions were grouped divided into neocortical and limbic (cingulate, hippocampus and parahippocampal region, and insula).
e-References
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e7.Niemann K, Mennicken VR, Jeanmonod D, Morel A. The Morel stereotactic atlas of the human thalamus: atlas-to-MR registration of internally consistent canonical model. Neuroimage 2000;12(6):601-616.