Divergent Effects of the Nonselective Adenosine Receptor Antagonist Caffeine in Pre-Manifest and Motor-Manifest Huntington’s Disease
Abstract
:1. Introduction
2. Methods
2.1. Investigating the ENROLL-HD Database
2.2. Statistical Analyses
3. Results
3.1. Participants and Data Analyses
3.2. Comparison of Premanifest HD Participants
3.3. Longitudinal Data of Premanifest HD Mutation Carriers
3.4. Comparison of Manifest HD Participants
3.5. Longitudinal Data of Manifest HD Participants
3.6. Family Controls and Genotype Negative Participants within the Database
4. Discussion
Limitations
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Premanifest HD No Caffeine Consumption (n = 841) M (SD) | Premanifest HD >3 Cups Caffeine/Day (n = 1901) M (SD) | F | p | Part. Eta2 | |
---|---|---|---|---|---|
Age (y) | 37.1 (12.0) | 41.9 (11.6) | 99.35 | <0.001 | 0.035 |
CAG high | 42.7 (2.9) | 42.2 (2.7) | 19.54 | <0.001 | 0.007 |
CAP-Score | 316.6 (90.9) | 340.9 (93.6) | 39.88 | <0.001 | 0.014 |
Calculated years to onset | 18.3 (10.5) | 16.2 (10.0) | 29.97 | <0.001 | 0.009 |
ISCED | 3.9 (1.1) (n = 836) | 3.8 (1.1) (n = 1894) | 6.25 | 0.012 | 0.002 |
Sex (f/m) (%f/%m) | 545/295 (64.9/35.1) | 1012/888 (53.3/46.7) | 32.04 | <0.001 | 0.000 |
UHDRS TMS # | 2.6 (4.3) | 3.3 (4.4) | 2.32 | 0.128 | 0.001 |
TFC + | 12.7 (1.1) (n = 834) | 12.7 (0.9) (n = 1890) | 0.62 | 0.430 | 0.000 |
IS + | 99.1 (4.1) (n = 836) | 98.8 (3.9) (n = 1892) | 0.00 | 0.956 | 0.000 |
SDMT + | 50.1 (12.6) (n = 826) | 47.9 (12.2) (n = 1884) | 0.09 | 0.764 | 0.000 |
VFc + | 21.2 (5.8) (n = 823) | 20.9 (5.7) (n = 1882) | 0.60 | 0.439 | 0.000 |
SCNT + | 73.9 (15.0) (n = 825) | 70.7 (14.8) (n = 1877) | 8.22 | <0.005 | 0.003 |
SWRT + | 94.3 (18.9) (n = 825) | 90.1 (18.5) (n = 1881) | 12.44 | <0.001 | 0.005 |
SIT + | 43.9 (12.3) (n = 790) | 41.7 (10.8) (n = 1780) | 1.18 | 0.277 | 0.000 |
MMSE + | 28.7 (1.8) (n = 622) | 28.6 (1.7) (n = 1256) | 0.07 | 0.786 | 0.000 |
PBA-Depression # | 4.2 (5.9) (n = 833) | 4.7 (6.2) (n = 1889) | 4.23 | <0.050 | 0.002 |
PBA-Irritability # | 1.8 (3.6) | 2.6 (3.8) | 7.78 | <0.050 | 0.003 |
PBA-Psychosis # | 0.15 (1.1) | 0.09 (0.8) | 2.67 | 0.103 | 0.001 |
PBA-Apathy # | 1.0 (2.5) | 1.1 (2.4) | 0.42 | 0.518 | 0.000 |
PBA-Executive function # | 1.2 (3.1) | 1.4 (3.3) | 1.39 | 0.238 | 0.001 |
HADS-Anxiety # | 5.4 (4.2) (n = 610) | 5.8 (4.0) (n = 1241) | 5.19 | <0.050 | 0.003 |
HADS-Depression # | 3.3 (3.4) | 3.9 (3.7) | 7.46 | <0.050 | 0.004 |
SIS-Irritability # | 4.5 (3.9) | 5.6 (4.2) | 21.46 | <0.001 | 0.012 |
SIS-Outward irritability # | 2.8 (2.4) | 3.5 (2.5) | 23.66 | <0.001 | 0.013 |
SIS-Inward irritability # | 1.7 (2.1) | 2.1 (2.3) | 9.67 | <0.005 | 0.005 |
Premanifest HD No Caffeine Consumption (n = 197) M (SD) | Premanifest HD >3 Cups Caffeine/Day (n = 527) M (SD) | F | p | Part. Eta2 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
BL | FU 1 | FU 2 | FU3 |
Δ FU3-BL | BL | FU1 | FU2 | FU3 |
Δ FU3-BL | ||||
UHDRS- TMS # | 2.8 (4.6) (n = 195) | 3.5 (5.3) | 4.1 (6.5) | 4.7 (7.1) | 1.9 | 3.3 (4.2) (n = 524) | 4.5 (5.6) | 5.3 (6.7) | 6.1 (7.6) | 2.8 | 0.99 | 0.321 | 0.001 |
TFC+ | 12.6 (1.2) (n = 197) | 12.5 (1.2) | 12.5 (1.3) | 12.4 (1.4) | −0.2 | 12.7 (0.8) (n = 526) | 12.6 (1.0) | 12.3 (1.3) | 12.3 (1.4) | −0.4 | 0.61 | 0.435 | 0.001 |
IS + | 98.9 (4.4) (n = 197) | 98.4 (4.7) | 97.8 (5.7) | 97.4 (6.4) | −1.5 | 99.0 (3.3) (n = 527) | 98.1 (4.8) | 97.1 (6.8) | 96.4 (7.5) | −2.6 | 0.12 | 0.728 | 0.000 |
SDMT + | 51.1(11.9) (n = 186) | 51.7 (12.4) | 52.3 (13.1) | 52.1 (14.3) | 1.0 | 48.9 (12.2) (n = 519) | 49.1 (12.9) | 49.1 (13.4) | 48.5 (13.8) | −0.4 | 0.56 | 0.454 | 0.001 |
VFc + | 21.3 (6.0) (n = 192) | 21.9 (5.5) | 22.3 (5.8) | 21.5 (5.9) | 0.2 | 21.3 (5.6) (n = 515) | 21.4 (5.6) | 21.3 (5.7) | 21.5 (5.8) | 0.2 | 0.06 | 0.805 | 0.000 |
SCNT + | 72.6 (15.6) (n = 191) | 73.3 (15.6) | 74.2 (15.6) | 73.1 (17.0) | 0.5 | 72.1 (14.1) (n = 519) | 71.7 (14.9) | 71.0 (16.1) | 70.9 (16.0) | −1.2 | 0.12 | 0.727 | 0.000 |
SWRT + | 94.5 (19.5) (n = 191) | 93.8 (19.5) | 93.7 (20.2) | 93.5 (20.9) | −1.0 | 90.6 (18.1) (n = 517) | 89.9 (18.8) | 88.3 (19.8) | 88.0 (20.5) | −2.6 | 40.42 | 0.036 | 0.006 |
SIT + | 43.8 (11.5) (n = 174) | 44.5 (11.1) | 44.1 (11.4) | 44.4 (11.6) | 0.6 | 42.8 (10.8) (n = 472) | 43.4 (11.7) | 43.6 (13.1) | 42.8 (11.9) | 0.0 | 0.61 | 0.433 | 0.001 |
MMSE + | 28.8 (1.5) (n = 118) | 29.0 (1.4) | 29.0 (1.5) | 28.9 (1.6) | 0.1 | 28.6 (1.6) (n = 281) | 28.5 (1.9) | 28.7 (1.8) | 28.7 (1.8) | 0.1 | 0.86 | 0.353 | 0.002 |
Manifest HD No caffeine Consumption (n = 2243) M (SD) | Manifest HD >3 Cups Caffeine/Day (n = 4072) M (SD) | F | P | Part. Eta2 | |
---|---|---|---|---|---|
Age (y) | 53.4 (13.8) | 52.1 (12.1) | 15.10 | <0.001 | 0.002 |
CAG high | 44.6 (4.6) | 43.8 (3.6) | 54.04 | <0.001 | 0.009 |
CAP-Score | 536.7 (108.0) | 497.6 (93.8) | 223.17 | <0.001 | 0.034 |
ISCED | 3.2 (1.4) (n = 2217) | 3.4 (1.1) (n = 4064) | 32.91 | <0.001 | 0.005 |
Sex (f/m) (%f/m) | 1202/1040 (53.6/46.4) | 1955/2116 (48.0/52.0) | 18.07 | <0.001 | 0.000 |
Onset of symptoms | |||||
Noticed by rater | 45.4 (13.1) (n = 2145) | 45.9 (11.7) (n = 3993) | 72.35 | <0.001 | 0.012 |
Noticed by subject | 45.6 (13.3) (n = 2002) | 45.9 (12.4) (n = 3800) | 55.25 | <0.001 | 0.009 |
Noticed by family | 44.8 (13.3) (n = 2027) | 45.2 (12.2) (n = 3664) | 70.95 | <0.001 | 0.012 |
HD-Diagnosis (y) | 48.2 (13.6) (n = 2131) | 48.6 (12.2) (n = 3945) | 122.48 | <0.001 | 0.020 |
UHDRS TMS # | 45.1 (24.8) (n = 2168) | 33.8 (18.8) (n = 4026) | 205.18 | <0.001 | 0.032 |
TFC+ | 6.9 (4.1) (n = 2185) | 8.8 (3.3) (n = 4055) | 227.22 | <0.001 | 0.035 |
IS + | 69.4 (23.6) (n = 2184) | 80.4 (15.2) (n = 4049) | 293.95 | <0.001 | 0.045 |
SDMT + | 19.5 (13.4) (n = 1848) | 24.8 (12.1) (n = 3862) | 111.92 | <0.001 | 0.019 |
Verfct + | 10.4 (5.9) (n = 2012) | 12.9 (5.6) (n = 4000) | 144.87 | <0.001 | 0.024 |
SCNT + | 26.7 (19.5) (n = 1971) | 44.3 (16.5) (n = 3959) | 139.47 | <0.001 | 0.023 |
SWRT + | 49.2 (26.3) (n = 1955) | 58.3 (21.2) (n = 3951) | 101.53 | <0.001 | 0.017 |
SIT + | 21.1 (12.3) (n = 1654) | 24.5 (11.1) (n = 3489) | 47.60 | <0.001 | 0.009 |
MMSE + | 23.5 (5.4) (n = 1418) | 25.6 (3.8) (n = 2385) | 118.32 | <0.001 | 0.030 |
PBA-Depression # | 5.1 (6.4) (n = 2097) | 5.6 (6.7) (n = 4040) | 1.63 | 0.202 | 0.000 |
PBA-Irritability # | 3.4 (5.2) | 3.7 (5.2) | 1.87 | 0.172 | 0.000 |
PBA-Psychosis # | 0.4 (1.9) | 0.4 (1.8) | 0.34 | 0.558 | 0.000 |
PBA-Apathy # | 4.2 (5.0) | 3.3 (4.2) | 34.61 | <0.001 | 0.006 |
PBA-Executive function # | 4.0 (5.9) | 3.4 (5.2) | 11.29 | <0.005 | 0.002 |
HADS-Anxiety # | 5.8 (4.3) (n = 1168) | 6.3 (4.3) (n = 2229) | 4.18 | <0.050 | 0.001 |
HADS-Depression # | 6.6 (4.4) | 6.1 (4.1) | 10.79 | <0.005 | 0.003 |
HADS-Irritability # | 5.6 (4.7) | 6.5 (4.7) | 15.59 | <0.001 | 0.005 |
SIS-Outward irritability # | 3.4 (2.8) | 3.9 (2.8) | 19.81 | <0.001 | 0.006 |
SIS-Inward irritability # | 2.2 (2.5) | 2.5 (2.5) | 5.23 | <0.050 | 0.002 |
Manifest HD No Caffeine Consumption (n = 522) M (SD) | Manifest HD > 3/Cups Caffeine/Day (n = 1120) M (SD) | F | p | Part. Eta2 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
BL | FU 1 | FU 2 | FU3 | Δ FU3-BL | BL | FU1 | FU2 | FU3 | Δ FU3-BL | ||||
UHDRS TMS # | 40.1 (22.8) (n = 515) | 43.5 (23.2) | 47.3 (23.7) | 51.2 (23.9) | 11.1 | 32.1 (18.1) (n = 1083) | 35.3 (19.3) | 38.6 (20.6) | 42.0 (22.0) | 9.9 | 29.29 | <0.001 | 0.018 |
TFC + | 7.8 (3.9) | 7.1 (3.9) | 6.5 (3.9) | 5.8 (3.8) | −2.0 | 8.9 (3.2) | 8.3 (3.3) | 7.7 (3.5) | 7.1 (3.6) | −1.8 | 22.32 | <0.001 | 0.013 |
IS + | 73.9 (20.5) (n = 520) | 70.8 (20.8) | 67.5 (21.5) | 63.5 (22.5) | −10.4 | 80.9 (14.5) (n = 1117) | 78.0 (15.5) | 74.9 (16.8) | 71.9 (18.5) | −10.0 | 37.49 | <0.001 | 0.022 |
SDMT + | 25.0 (12.0) (n = 341) | 23.4 (12.3) | 21.5 (12.8) | 19.4 (12.7) | −5.6 | 28.3 (11.9) (n = 918) | 27.1 (12.1) | 25.6 (12.3) | 23.4 (13.2) | −4.9 | 13.27 | <0.001 | 0.010 |
VFc + | 12.1 (5.3) (n = 426) | 11.4 (5.2) | 10.7 (5.3) | 10.1 (5.4) | −2.0 | 13.9 (5.5) (n = 1027) | 13.1 (5.5) | 12.4 (5.6) | 11.7 (5.7) | −2.2 | 15.72 | <0.001 | 0.011 |
SCNT + | 41.7 (16.1) (n = 407) | 39.9 (16.3) | 37.7 (16.3) | 34.1 (17.2) | −7.6 | 47.3 (16.0) (n = 997) | 44.9 (15.7) | 42.6 (16.1) | 40.0 (16.6) | −7.3 | 19.12 | <0.001 | 0.013 |
SWRT + | 57.8 (21.4) (n = 392) | 53.2 (21.5) | 50.3 (21.2) | 45.1 (21.6) | −12.7 | 61.6 (19.8) (n = 987) | 58.6 (20.6) | 55.4 (21.0) | 51.5 (21.3) | −10.1 | 8.15 | <0.005 | 0.006 |
SIT + | 25.8 (10.9) (n = 301) | 23.7 (10.9) | 22.4 (11.1) | 20.5 (11.0) | −5.3 | 27.2 (11.0) (n = 780) | 26.5 (10.6) | 25.3 (10.9) | 23.8 (11.3) | −3.4 | 7.79 | <0.050 | 0.007 |
MMSE + | 25.3 (3.5) (n = 253) | 25.1 (3.9) | 24.7 (4.3) | 23.6 (5.0) | −1.7 | 26.4 (3.0) (n = 482) | 26.3 (3.4) | 25.9 (3.7) | 25.4 (4.0) | −1.0 | 15.11 | <0.001 | 0.020 |
Family Control & Genotype Negative No Caffeine Consumption (n = 861) M (SD) | Family Control & Genotype Negative >3 Cups Caffeine/Day (n = 1528) M (SD) | F | P | Part. Eta2 | |
---|---|---|---|---|---|
Age (y) | 45.3 (16.1) | 48.3 (13.4) | 23.946 | <0.001 | 0.010 |
CAG high | 19.9 (3.6) | 20.5 (3.7) | 10.076 | <0.005 | 0.004 |
ISCED | 3.7 (1.3) (n = 855) | 3.8 (1.1) (n = 1527) | 1.178 | 0.278 | 0.000 |
Sex (f/m) (%f/m) | 553/309 (64.2/35.8) | 817/713 (53.4/46.6) | 26.286 | <0.001 | 0.000 |
UHDRS TMS # | 1.4 (3.3) | 1.9 (3.2) | 13.988 | <0.050 | 0.003 |
TFC + | 12.8 (1.1) | 12.9 (0.5) (n = 1528) | 17.352 | <0.001 | 0.007 |
IS + | 99.3 (3.8) (n = 862) | 99.6 (2.3) (n = 1529) | 8.805 | <0.001 | 0.004 |
SDMT + | 48.8 (13.2) (n = 852) | 49.1 (11.6) (n = 1520) | 7.740 | <0.050 | 0.003 |
VFc + | 21.4 (5.8) (n = 851) | 21.8 (5.7) (n = 1523) | 4.952 | <0.050 | 0.002 |
SCNT + | 73.1 (14.7) (n = 848) | 73.8 (14.3) (n = 1514) | 4.745 | <0.050 | 0.002 |
SWRT + | 94.1 (18.4) (n = 850) | 94.3 (17.3) (n = 1517) | 1.743 | 0.187 | 0.001 |
SIT + | 41.9 (11.4) (n = 812) | 41.7 (10.9) (n = 1419) | 2.019 | 0.156 | 0.001 |
MMSE + | 28.9 (1.5) (n = 667) | 28.8 (1.6) (n = 1028) | .029 | 0.865 | 0.000 |
PBA-Depression # | 3.3 (5.1) (n = 860) | 3.6 (5.0) (n = 1527) | 1.283 | 0.257 | 0.001 |
PBA-Irritability # | 1.1 (2.6) | 1.5 (2.9) | 11.096 | <0.005 | 0.005 |
PBA-Psychosis # | 0.04 (0.4) | 0.09 (0.8) | 4.655 | <0.050 | 0.002 |
PBA-Apathy # | 0.4 (1.5) | 0.5 (1.6) | 1.761 | 0.185 | 0.001 |
PBA-Executive function # | 0.7 (2.2) | 0.7 (2.3) | .565 | 0.452 | 0.000 |
HADS-Anxiety # | 5.0 (3.9) (n = 648) | 5.5 (3.7) (n = 1158) | 8.733 | <0.005 | 0.005 |
HADS-Depression # | 3.3 (3.4) | 3.7 (3.3) | 4.594 | <0.050 | 0.003 |
HADS-Irritability # | 4.0 (3.5) | 4.6 (3.5) | 15.726 | <0.001 | 0.009 |
SIS-Outward irritability # | 2.6 (2.2) | 3.0 (2.2) | 12.549 | <0.001 | 0.007 |
SIS-Inward irritability # | 1.4 (1.8) | 1.7 (1.8) | 10.286 | <0.005 | 0.006 |
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Achenbach, J.; Matusch, A.; Elmenhorst, D.; Bauer, A.; Saft, C. Divergent Effects of the Nonselective Adenosine Receptor Antagonist Caffeine in Pre-Manifest and Motor-Manifest Huntington’s Disease. Biomedicines 2022, 10, 1258. https://doi.org/10.3390/biomedicines10061258
Achenbach J, Matusch A, Elmenhorst D, Bauer A, Saft C. Divergent Effects of the Nonselective Adenosine Receptor Antagonist Caffeine in Pre-Manifest and Motor-Manifest Huntington’s Disease. Biomedicines. 2022; 10(6):1258. https://doi.org/10.3390/biomedicines10061258
Chicago/Turabian StyleAchenbach, Jannis, Andreas Matusch, David Elmenhorst, Andreas Bauer, and Carsten Saft. 2022. "Divergent Effects of the Nonselective Adenosine Receptor Antagonist Caffeine in Pre-Manifest and Motor-Manifest Huntington’s Disease" Biomedicines 10, no. 6: 1258. https://doi.org/10.3390/biomedicines10061258
APA StyleAchenbach, J., Matusch, A., Elmenhorst, D., Bauer, A., & Saft, C. (2022). Divergent Effects of the Nonselective Adenosine Receptor Antagonist Caffeine in Pre-Manifest and Motor-Manifest Huntington’s Disease. Biomedicines, 10(6), 1258. https://doi.org/10.3390/biomedicines10061258