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PLOS Currents Huntington Disease) >> endobj 6 0 obj << /Type /Page /Parent 3 0 R /Annots [ 14 0 R 16 0 R 18 0 R 20 0 R 22 0 R 24 0 R 26 0 R 28 0 R 30 0 R 32 0 R 36 0 R 38 0 R 40 0 R 42 0 R 44 0 R 46 0 R 48 0 R 50 0 R 52 0 R 54 0 R 58 0 R 60 0 R 62 0 R 64 0 R 66 0 R 68 0 R 70 0 R 72 0 R 74 0 R 76 0 R ] /Contents 7 0 R >> endobj 7 0 obj << /Length 18630 >> stream q 375.000 0 0 39.000 222.000 738.000 cm /I2 Do Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Is a Motor Criterion Essential for the Diagnosis of Clinical )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(Huntington Disease?)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(April 11, 2013)] TJ ET BT 76.483 675.088 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 81.358 675.088 Td /F3 9.8 Tf [(Clinical Assessment)] TJ ET BT 26.250 663.247 Td /F1 9.8 Tf [(Clement T Loy)] TJ ET 0.271 0.267 0.267 rg BT 89.644 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 95.066 663.247 Td /F1 9.8 Tf [(Elizabeth A McCusker)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Loy CT, McCusker EA. Is a Motor Criterion Essential for the Diagnosis of Clinical Huntington Disease?. PLOS Currents )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(Huntington Disease. 2013 Apr 11 . Edition 1. doi: 10.1371/currents.hd.f4c66bd51e8db11f55e1701af937a419.)] TJ ET q 15.000 35.580 577.500 601.477 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(While there has been a guideline for laboratory/genetic diagnosis of Huntington Disease \(HD\) since 1998, no such statement )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(exists for the diagnosis of clinical HD. Informally, the most frequently used criteria for diagnosis of clinical HD is Motor 4 within )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(the Unified Huntington Disease Rating Scale 99 \(motor\), made when the rater is highly confident that motor abnormalities )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(observed are unequivocal signs of HD. Recent studies involving pre-manifest individuals illustrated the shortcomings of this )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(motor-only diagnostic approach. For instance, PREDICT-HD found cognitive changes decades before the expected date of )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(motor diagnosis. Using a number of case studies, we highlight some of the subtleties involved in diagnosing clinical HD, in the )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(absence of unequivocal motor signs for HD. New, broader, criteria for the diagnosis of clinical HD would be helpful in many )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(ways. However its formulation will need to flexible rather than prescriptive, and will require extensive consultation with clinicians )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(and families with HD.)] TJ ET BT 26.250 458.540 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 438.586 Td /F1 9.8 Tf [(CTL was supported by a National Health & Medical Research Council Translating Research Into Practice Fellowship.)] TJ ET BT 26.250 409.484 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 389.529 Td /F1 9.8 Tf [(While there has been a guideline for laboratory/genetic diagnosis of Huntington Disease \(HD\) since 1998)] TJ ET 0.267 0.267 0.267 rg BT 478.202 391.037 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 483.020 389.529 Td /F1 9.8 Tf [( , no such statement )] TJ ET BT 26.250 377.625 Td /F1 9.8 Tf [(exists for the diagnosis of clinical HD. This partly reflects the complexity of clinical HD. HD is a multi-system disease with a )] TJ ET BT 26.250 365.720 Td /F1 9.8 Tf [(continuum of manifestations, and it is diagnosed in a variety of clinical settings, with significant social and legal consequences.)] TJ ET BT 26.250 346.315 Td /F1 9.8 Tf [(Informally, the most frequently used criteria for diagnosis of clinical HD is Motor 4- a rating within the Unified Huntington )] TJ ET BT 26.250 334.410 Td /F1 9.8 Tf [(Disease Rating Scale 99 \(motor\))] TJ ET 0.267 0.267 0.267 rg BT 169.292 335.918 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 174.111 334.410 Td /F1 9.8 Tf [( , made when the rater is highly confident that motor abnormalities observed are unequivocal )] TJ ET BT 26.250 322.506 Td /F1 9.8 Tf [(signs of HD. There is no single agreed threshold in the motor score, which automatically determines whether a person qualifies )] TJ ET BT 26.250 310.601 Td /F1 9.8 Tf [(as Motor 4 or not. Further judgment based on the nature of the observed motor impairment is required, and some variability )] TJ ET BT 26.250 298.696 Td /F1 9.8 Tf [(between raters is likely. Nonetheless, Motor 4 usually means that chorea is present, although most HD centres would have )] TJ ET BT 26.250 286.791 Td /F1 9.8 Tf [(diagnosed clinical HD without chorea for some of their patients.)] TJ ET BT 26.250 267.387 Td /F1 9.8 Tf [(Recent studies involving pre-manifest individuals have highlighted the shortcomings of this motor-only diagnostic approach. For )] TJ ET BT 26.250 255.482 Td /F1 9.8 Tf [(instance, PREDICT-HD demonstrated cognitive changes decades before the expected date of motor diagnosis.)] TJ ET 0.267 0.267 0.267 rg BT 506.389 256.989 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 511.207 255.482 Td /F1 9.8 Tf [( In addition, )] TJ ET BT 26.250 243.577 Td /F1 9.8 Tf [(over 35% of participants diagnosed with clinical HD during the PREDICT-HD study, were diagnosed with clinical HD prior to )] TJ ET BT 26.250 231.672 Td /F1 9.8 Tf [(reaching the Motor 4 criteria.)] TJ ET 0.267 0.267 0.267 rg BT 154.667 233.180 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 159.486 231.672 Td /F1 9.8 Tf [( An alternative criteria for diagnosis of clinical HD would be helpful in many ways, but its )] TJ ET BT 26.250 219.768 Td /F1 9.8 Tf [(formulation will involve much subtlety, as illustrated by the following case studies \(details altered to protect privacy\).)] TJ ET BT 26.250 183.165 Td /F4 12.0 Tf [(Cases Studies)] TJ ET BT 26.250 163.211 Td /F1 9.8 Tf [(Diagrammatically, diagnosis of clinical HD can be represented by two concentric circles, divided into quadrants \(Fig.1\))] TJ ET 0.965 0.965 0.965 rg 26.250 35.580 555.000 117.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 153.330 m 581.250 153.330 l 581.250 152.580 l 26.250 152.580 l f q 225.000 0 0 102.000 35.250 41.580 cm /I4 Do Q q 35.250 35.580 537.000 0.000 re W n Q Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Is a Motor Criterion Essential for the Diagnosis of Clinical )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(Huntington Disease?)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(April 11, 2013)] TJ ET BT 76.483 675.088 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 81.358 675.088 Td /F3 9.8 Tf [(Clinical Assessment)] TJ ET BT 26.250 663.247 Td /F1 9.8 Tf [(Clement T Loy)] TJ ET 0.271 0.267 0.267 rg BT 89.644 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 95.066 663.247 Td /F1 9.8 Tf [(Elizabeth A McCusker)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Loy CT, McCusker EA. Is a Motor Criterion Essential for the Diagnosis of Clinical Huntington Disease?. PLOS Currents )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(Huntington Disease. 2013 Apr 11 . Edition 1. doi: 10.1371/currents.hd.f4c66bd51e8db11f55e1701af937a419.)] TJ ET q 15.000 35.580 577.500 601.477 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(While there has been a guideline for laboratory/genetic diagnosis of Huntington Disease \(HD\) since 1998, no such statement )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(exists for the diagnosis of clinical HD. Informally, the most frequently used criteria for diagnosis of clinical HD is Motor 4 within )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(the Unified Huntington Disease Rating Scale 99 \(motor\), made when the rater is highly confident that motor abnormalities )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(observed are unequivocal signs of HD. Recent studies involving pre-manifest individuals illustrated the shortcomings of this )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(motor-only diagnostic approach. For instance, PREDICT-HD found cognitive changes decades before the expected date of )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(motor diagnosis. Using a number of case studies, we highlight some of the subtleties involved in diagnosing clinical HD, in the )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(absence of unequivocal motor signs for HD. New, broader, criteria for the diagnosis of clinical HD would be helpful in many )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(ways. However its formulation will need to flexible rather than prescriptive, and will require extensive consultation with clinicians )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(and families with HD.)] TJ ET BT 26.250 458.540 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 438.586 Td /F1 9.8 Tf [(CTL was supported by a National Health & Medical Research Council Translating Research Into Practice Fellowship.)] TJ ET BT 26.250 409.484 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 389.529 Td /F1 9.8 Tf [(While there has been a guideline for laboratory/genetic diagnosis of Huntington Disease \(HD\) since 1998)] TJ ET 0.267 0.267 0.267 rg BT 478.202 391.037 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 483.020 389.529 Td /F1 9.8 Tf [( , no such statement )] TJ ET BT 26.250 377.625 Td /F1 9.8 Tf [(exists for the diagnosis of clinical HD. This partly reflects the complexity of clinical HD. HD is a multi-system disease with a )] TJ ET BT 26.250 365.720 Td /F1 9.8 Tf [(continuum of manifestations, and it is diagnosed in a variety of clinical settings, with significant social and legal consequences.)] TJ ET BT 26.250 346.315 Td /F1 9.8 Tf [(Informally, the most frequently used criteria for diagnosis of clinical HD is Motor 4- a rating within the Unified Huntington )] TJ ET BT 26.250 334.410 Td /F1 9.8 Tf [(Disease Rating Scale 99 \(motor\))] TJ ET 0.267 0.267 0.267 rg BT 169.292 335.918 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 174.111 334.410 Td /F1 9.8 Tf [( , made when the rater is highly confident that motor abnormalities observed are unequivocal )] TJ ET BT 26.250 322.506 Td /F1 9.8 Tf [(signs of HD. There is no single agreed threshold in the motor score, which automatically determines whether a person qualifies )] TJ ET BT 26.250 310.601 Td /F1 9.8 Tf [(as Motor 4 or not. Further judgment based on the nature of the observed motor impairment is required, and some variability )] TJ ET BT 26.250 298.696 Td /F1 9.8 Tf [(between raters is likely. Nonetheless, Motor 4 usually means that chorea is present, although most HD centres would have )] TJ ET BT 26.250 286.791 Td /F1 9.8 Tf [(diagnosed clinical HD without chorea for some of their patients.)] TJ ET BT 26.250 267.387 Td /F1 9.8 Tf [(Recent studies involving pre-manifest individuals have highlighted the shortcomings of this motor-only diagnostic approach. For )] TJ ET BT 26.250 255.482 Td /F1 9.8 Tf [(instance, PREDICT-HD demonstrated cognitive changes decades before the expected date of motor diagnosis.)] TJ ET 0.267 0.267 0.267 rg BT 506.389 256.989 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 511.207 255.482 Td /F1 9.8 Tf [( In addition, )] TJ ET BT 26.250 243.577 Td /F1 9.8 Tf [(over 35% of participants diagnosed with clinical HD during the PREDICT-HD study, were diagnosed with clinical HD prior to )] TJ ET BT 26.250 231.672 Td /F1 9.8 Tf [(reaching the Motor 4 criteria.)] TJ ET 0.267 0.267 0.267 rg BT 154.667 233.180 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 159.486 231.672 Td /F1 9.8 Tf [( An alternative criteria for diagnosis of clinical HD would be helpful in many ways, but its )] TJ ET BT 26.250 219.768 Td /F1 9.8 Tf [(formulation will involve much subtlety, as illustrated by the following case studies \(details altered to protect privacy\).)] TJ ET BT 26.250 183.165 Td /F4 12.0 Tf [(Cases Studies)] TJ ET BT 26.250 163.211 Td /F1 9.8 Tf [(Diagrammatically, diagnosis of clinical HD can be represented by two concentric circles, divided into quadrants \(Fig.1\))] TJ ET 0.965 0.965 0.965 rg 26.250 35.580 555.000 117.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 153.330 m 581.250 153.330 l 581.250 152.580 l 26.250 152.580 l f q 225.000 0 0 102.000 35.250 41.580 cm /I6 Do Q q 35.250 35.580 537.000 0.000 re W n Q Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Is a Motor Criterion Essential for the Diagnosis of Clinical )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(Huntington Disease?)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(April 11, 2013)] TJ ET BT 76.483 675.088 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 81.358 675.088 Td /F3 9.8 Tf [(Clinical Assessment)] TJ ET BT 26.250 663.247 Td /F1 9.8 Tf [(Clement T Loy)] TJ ET 0.271 0.267 0.267 rg BT 89.644 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 95.066 663.247 Td /F1 9.8 Tf [(Elizabeth A McCusker)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Loy CT, McCusker EA. Is a Motor Criterion Essential for the Diagnosis of Clinical Huntington Disease?. PLOS Currents )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(Huntington Disease. 2013 Apr 11 . Edition 1. doi: 10.1371/currents.hd.f4c66bd51e8db11f55e1701af937a419.)] TJ ET q 15.000 35.580 577.500 601.477 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(While there has been a guideline for laboratory/genetic diagnosis of Huntington Disease \(HD\) since 1998, no such statement )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(exists for the diagnosis of clinical HD. Informally, the most frequently used criteria for diagnosis of clinical HD is Motor 4 within )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(the Unified Huntington Disease Rating Scale 99 \(motor\), made when the rater is highly confident that motor abnormalities )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(observed are unequivocal signs of HD. Recent studies involving pre-manifest individuals illustrated the shortcomings of this )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(motor-only diagnostic approach. For instance, PREDICT-HD found cognitive changes decades before the expected date of )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(motor diagnosis. Using a number of case studies, we highlight some of the subtleties involved in diagnosing clinical HD, in the )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(absence of unequivocal motor signs for HD. New, broader, criteria for the diagnosis of clinical HD would be helpful in many )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(ways. However its formulation will need to flexible rather than prescriptive, and will require extensive consultation with clinicians )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(and families with HD.)] TJ ET BT 26.250 458.540 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 438.586 Td /F1 9.8 Tf [(CTL was supported by a National Health & Medical Research Council Translating Research Into Practice Fellowship.)] TJ ET BT 26.250 409.484 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 389.529 Td /F1 9.8 Tf [(While there has been a guideline for laboratory/genetic diagnosis of Huntington Disease \(HD\) since 1998)] TJ ET 0.267 0.267 0.267 rg BT 478.202 391.037 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 483.020 389.529 Td /F1 9.8 Tf [( , no such statement )] TJ ET BT 26.250 377.625 Td /F1 9.8 Tf [(exists for the diagnosis of clinical HD. This partly reflects the complexity of clinical HD. HD is a multi-system disease with a )] TJ ET BT 26.250 365.720 Td /F1 9.8 Tf [(continuum of manifestations, and it is diagnosed in a variety of clinical settings, with significant social and legal consequences.)] TJ ET BT 26.250 346.315 Td /F1 9.8 Tf [(Informally, the most frequently used criteria for diagnosis of clinical HD is Motor 4- a rating within the Unified Huntington )] TJ ET BT 26.250 334.410 Td /F1 9.8 Tf [(Disease Rating Scale 99 \(motor\))] TJ ET 0.267 0.267 0.267 rg BT 169.292 335.918 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 174.111 334.410 Td /F1 9.8 Tf [( , made when the rater is highly confident that motor abnormalities observed are unequivocal )] TJ ET BT 26.250 322.506 Td /F1 9.8 Tf [(signs of HD. There is no single agreed threshold in the motor score, which automatically determines whether a person qualifies )] TJ ET BT 26.250 310.601 Td /F1 9.8 Tf [(as Motor 4 or not. Further judgment based on the nature of the observed motor impairment is required, and some variability )] TJ ET BT 26.250 298.696 Td /F1 9.8 Tf [(between raters is likely. Nonetheless, Motor 4 usually means that chorea is present, although most HD centres would have )] TJ ET BT 26.250 286.791 Td /F1 9.8 Tf [(diagnosed clinical HD without chorea for some of their patients.)] TJ ET BT 26.250 267.387 Td /F1 9.8 Tf [(Recent studies involving pre-manifest individuals have highlighted the shortcomings of this motor-only diagnostic approach. For )] TJ ET BT 26.250 255.482 Td /F1 9.8 Tf [(instance, PREDICT-HD demonstrated cognitive changes decades before the expected date of motor diagnosis.)] TJ ET 0.267 0.267 0.267 rg BT 506.389 256.989 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 511.207 255.482 Td /F1 9.8 Tf [( In addition, )] TJ ET BT 26.250 243.577 Td /F1 9.8 Tf [(over 35% of participants diagnosed with clinical HD during the PREDICT-HD study, were diagnosed with clinical HD prior to )] TJ ET BT 26.250 231.672 Td /F1 9.8 Tf [(reaching the Motor 4 criteria.)] TJ ET 0.267 0.267 0.267 rg BT 154.667 233.180 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 159.486 231.672 Td /F1 9.8 Tf [( An alternative criteria for diagnosis of clinical HD would be helpful in many ways, but its )] TJ ET BT 26.250 219.768 Td /F1 9.8 Tf [(formulation will involve much subtlety, as illustrated by the following case studies \(details altered to protect privacy\).)] TJ ET BT 26.250 183.165 Td /F4 12.0 Tf [(Cases Studies)] TJ ET BT 26.250 163.211 Td /F1 9.8 Tf [(Diagrammatically, diagnosis of clinical HD can be represented by two concentric circles, divided into quadrants \(Fig.1\))] TJ ET 0.965 0.965 0.965 rg 26.250 35.580 555.000 117.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 153.330 m 581.250 153.330 l 581.250 152.580 l 26.250 152.580 l f q 225.000 0 0 102.000 35.250 41.580 cm /I8 Do Q q 35.250 35.580 537.000 0.000 re W n Q Q q 225.000 0 0 102.000 35.250 41.580 cm /I10 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(1)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 8 0 obj << /Type /Font /Subtype /Type1 /Name /F1 /BaseFont /Helvetica /Encoding /WinAnsiEncoding >> endobj 9 0 obj << /Type /Font /Subtype /Type1 /Name /F2 /BaseFont /Times-Bold /Encoding /WinAnsiEncoding >> endobj 10 0 obj << /Type /Font /Subtype /Type1 /Name /F3 /BaseFont /Times-Italic /Encoding /WinAnsiEncoding >> endobj 11 0 obj << /Type /Font /Subtype /Type1 /Name /F4 /BaseFont /Helvetica-Bold /Encoding /WinAnsiEncoding >> endobj 12 0 obj << /Type /XObject /Subtype /Image /Width 500 /Height 52 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 500 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 144>> stream x1 0 'ݲ؎"e{dzAdzAdzAdzAdzAdzAdzAdzAdzAdzAdzAdzAtlM0\ endstream endobj 13 0 obj << /Type /XObject /Subtype /Image /Width 500 /Height 52 /SMask 12 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 500 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 4223>> stream xە8=,8C#h!hGv#0=j$q1uaNĥT*J&a_Zaa0 a0 a0 H^UUUUX!0 3SY|^G0 ÌÔ{]wa_>"OeYaG!8e}a6̖{4M&d:"qʲ\QUUMS<ϛNld2l6Z a<=2B(2vK7M\.GW0 rrWWavߖe9C?Eq8Gqy~~}_qdϽ(neYʒGjK4EQNjͷm{X?|7m۶mqP:Ȳp8Kmu]lNzuZ,NTeY"jlUUQW\,aRiVbȗLkHkEsjd.L6=Iו P]1t7Sc2uIuMM; K5>A$Ǒ$I׋nY 0_Hat;aq䃰U$nR ,zO7bT mhhԫܻu1F*qm'P}ܙ<ϕALO6Lw3nB.T4co{߽.lV $laԀIu!gwChxJ]Ne (+M"d-Eqc=P ! 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E4NRRR.]ƏvԩofÆ &Ml۶e˖'O^b /p8!& @ܹsǏmv_~3oFdddVVj|~~~ӧOL^GYjɓ[l lp8>S`Xh?.s?n۶%KKҌ'>A[nܸ&!-Z<äpСC_}UttnҤN?[ȑ# jذN>=,,lqqqÇ~W!K,Ynb8p4EGGO0B8wӰ>EKMc*5͚5k֬ـHv:xVtRTs5h!0Sl q+I >̟~)&&f׮]v[|yqqqBB¨Q&O?d2eJBB¾}Zn3vX &;;o 9r̙cǎ}ꩧڵkءC՚l2ztRصkWlp,}`0<3pʔ)!!!wݽ{wټtңG<?2dHdd6mZݷn:dȐTyիW8qb-[|'!C;ڶmsΌ7no~l@j#''[o q0CqmS+ڲ஫jڅ䶪[s1ڊ'n+(/,YrEl[QQqȑUV?~ٲeTbm>_z%{n>("-[??'T Œ UO-\7T`*pGuuVI+8TU< ˗-[ߦM{Lj2>_bN8 m endstream endobj 82 0 obj << /Type /Page /Parent 3 0 R /Annots [ 84 0 R 88 0 R 92 0 R 96 0 R 100 0 R 104 0 R ] /Contents 83 0 R >> endobj 83 0 obj << /Length 19330 >> stream q 15.000 34.171 577.500 742.829 re W n 0.965 0.965 0.965 rg 26.250 712.873 555.000 64.127 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 712.873 m 581.250 712.873 l 581.250 713.623 l 26.250 713.623 l f q 35.250 724.123 537.000 52.877 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 1: Diagrammatic representation of HD)] TJ ET BT 35.250 748.106 Td /F1 9.8 Tf [(The four quadrants represent the four domains of manifestations, and the inner circle represents the thresholds for clinical )] TJ ET BT 35.250 734.370 Td /F1 9.8 Tf [(significance.)] TJ ET Q BT 26.250 695.849 Td /F1 9.8 Tf [(The four quadrants represent the four domains of manifestations, and the inner circle represents the thresholds for clinical )] TJ ET BT 26.250 683.944 Td /F1 9.8 Tf [(significance.The four quadrants represent HD manifestations involving the motor, cognitive/behavioral, psychiatric and others )] TJ ET BT 26.250 672.039 Td /F1 9.8 Tf [(\(eg. metabolic/weight loss\) domains. The inner circle represents thresholds for clinical significance. These thresholds are )] TJ ET BT 26.250 660.135 Td /F1 9.8 Tf [(somewhat arbitrary- for instance, jerky pursuit eye movements in a HD expansion carrier is often not regarded as a sign )] TJ ET BT 26.250 648.230 Td /F1 9.8 Tf [(sufficient for diagnosis of clinical HD, whilst chorea is. The shaded-in areas represent degrees of impairment along the )] TJ ET BT 26.250 636.325 Td /F1 9.8 Tf [(continuum of symptoms/signs for each domain. For instance, Figure 1 represents a typical person with HD- with chorea, )] TJ ET BT 26.250 624.420 Td /F1 9.8 Tf [(enough cognitive impairment to affect work performance, some depression and weight loss. To satisfy the Motor 4 criteria, a )] TJ ET BT 26.250 612.516 Td /F1 9.8 Tf [(person will need to have motor impairment beyond the inner circle/threshold in the top left quadrant.)] TJ ET BT 26.250 593.111 Td /F1 9.8 Tf [(Case 1: A 40 year old barrister has a family history of HD, involving his father who was diagnosed with HD with motor )] TJ ET BT 26.250 581.206 Td /F1 9.8 Tf [(manifestations aged 55. This barrister carries the HD expansion, but has otherwise been healthy apart from moderate alcohol )] TJ ET BT 26.250 569.301 Td /F1 9.8 Tf [(use. His wife has noted increasing crankiness over the past year, which he attributed to busyness at work. There has been no )] TJ ET BT 26.250 557.397 Td /F1 9.8 Tf [(change in his work performance. Motor examination found jerky pursuit eye movements only. Neuropsychological examination )] TJ ET BT 26.250 545.492 Td /F1 9.8 Tf [(identified mild but definite decline in cognitive function, compared to cognitive examination a year ago, in a pattern consistent )] TJ ET BT 26.250 533.587 Td /F1 9.8 Tf [(with HD. He was not depressed \(Fig 2\).)] TJ ET 0.965 0.965 0.965 rg 26.250 376.801 555.000 146.905 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 523.706 m 581.250 523.706 l 581.250 522.956 l 26.250 522.956 l f 26.250 376.801 m 581.250 376.801 l 581.250 377.551 l 26.250 377.551 l f q 225.000 0 0 102.000 35.250 411.956 cm /I12 Do Q q 35.250 388.051 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 396.432 Td /F4 9.8 Tf [(Fig. 2: Case Study One)] TJ ET Q BT 26.250 359.778 Td /F1 9.8 Tf [(Discussion: This man did not satisfy the Motor 4 criteria for clinical HD. He had measurable cognitive decline over a year, )] TJ ET BT 26.250 347.873 Td /F1 9.8 Tf [(which may prompt a diagnosis of clinical HD- but this needs to be moderated by the apparent lack of functional consequences )] TJ ET BT 26.250 335.968 Td /F1 9.8 Tf [(\(normal work performance according to work colleagues\). Incorporation of cognitive impairment into the new diagnostic criteria )] TJ ET BT 26.250 324.063 Td /F1 9.8 Tf [(raises the challenge of a suitable threshold. Functional measures \(eg. inability to work in a persons usual job\) have been used )] TJ ET BT 26.250 312.159 Td /F1 9.8 Tf [(as thresholds for diagnosis in other conditions. However this may represent different levels of cognitive impairment for different )] TJ ET BT 26.250 300.254 Td /F1 9.8 Tf [(people when measured in absolute terms, because ability to work can depend on the nature of the occupation and social )] TJ ET BT 26.250 288.349 Td /F1 9.8 Tf [(circumstances. Premature clinical diagnosis for this man could cost him his career. This man was a known expansion carrier in )] TJ ET BT 26.250 276.444 Td /F1 9.8 Tf [(a stable social setting, so it was safe to stretch the process of clinical diagnosis over a longer period of time. Therefore we )] TJ ET BT 26.250 264.540 Td /F1 9.8 Tf [(explained that, overall, he was still regarded as pre-manifest, but we would like to review him on a six monthly basis. A year )] TJ ET BT 26.250 252.635 Td /F1 9.8 Tf [(later, his crankiness has resolved with an improved work environment, but his neuropsychological impairment remained.)] TJ ET BT 26.250 233.230 Td /F1 9.8 Tf [(Case 2: A 23 year old man attended our clinic requesting a genetic test for HD. His mother developed clinical manifestations of )] TJ ET BT 26.250 221.325 Td /F1 9.8 Tf [(HD in her 30s and was known to our Service. At the time of consultation this man was an inpatient in a mental health facility. He )] TJ ET BT 26.250 209.421 Td /F1 9.8 Tf [(was admitted following a second episode of psychosis, with auditory hallucinations and some atypical features \(a body )] TJ ET BT 26.250 197.516 Td /F1 9.8 Tf [(dysmorphic delusion\). Motor examination was normal except for mildly impaired eye movements. He was on a moderate dose )] TJ ET BT 26.250 185.611 Td /F1 9.8 Tf [(of atypical anti-psychotic medication but his neurologic examination was reported to be normal prior to initiating medication. He )] TJ ET BT 26.250 173.706 Td /F1 9.8 Tf [(was somewhat reluctant during neuropsychological examination and performed poorly in a range of measures, over a broader )] TJ ET BT 26.250 161.802 Td /F1 9.8 Tf [(range of cognitive domains than one would expect for a typical, early, HD patient. \(Fig.3\))] TJ ET 0.965 0.965 0.965 rg 26.250 34.171 555.000 117.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 151.921 m 581.250 151.921 l 581.250 151.171 l 26.250 151.171 l f q 225.000 0 0 102.000 35.250 40.171 cm /I14 Do Q q 35.250 34.171 537.000 0.000 re W n Q Q q 15.000 34.171 577.500 742.829 re W n 0.965 0.965 0.965 rg 26.250 712.873 555.000 64.127 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 712.873 m 581.250 712.873 l 581.250 713.623 l 26.250 713.623 l f q 35.250 724.123 537.000 52.877 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 1: Diagrammatic representation of HD)] TJ ET BT 35.250 748.106 Td /F1 9.8 Tf [(The four quadrants represent the four domains of manifestations, and the inner circle represents the thresholds for clinical )] TJ ET BT 35.250 734.370 Td /F1 9.8 Tf [(significance.)] TJ ET Q BT 26.250 695.849 Td /F1 9.8 Tf [(The four quadrants represent the four domains of manifestations, and the inner circle represents the thresholds for clinical )] TJ ET BT 26.250 683.944 Td /F1 9.8 Tf [(significance.The four quadrants represent HD manifestations involving the motor, cognitive/behavioral, psychiatric and others )] TJ ET BT 26.250 672.039 Td /F1 9.8 Tf [(\(eg. metabolic/weight loss\) domains. The inner circle represents thresholds for clinical significance. These thresholds are )] TJ ET BT 26.250 660.135 Td /F1 9.8 Tf [(somewhat arbitrary- for instance, jerky pursuit eye movements in a HD expansion carrier is often not regarded as a sign )] TJ ET BT 26.250 648.230 Td /F1 9.8 Tf [(sufficient for diagnosis of clinical HD, whilst chorea is. The shaded-in areas represent degrees of impairment along the )] TJ ET BT 26.250 636.325 Td /F1 9.8 Tf [(continuum of symptoms/signs for each domain. For instance, Figure 1 represents a typical person with HD- with chorea, )] TJ ET BT 26.250 624.420 Td /F1 9.8 Tf [(enough cognitive impairment to affect work performance, some depression and weight loss. To satisfy the Motor 4 criteria, a )] TJ ET BT 26.250 612.516 Td /F1 9.8 Tf [(person will need to have motor impairment beyond the inner circle/threshold in the top left quadrant.)] TJ ET BT 26.250 593.111 Td /F1 9.8 Tf [(Case 1: A 40 year old barrister has a family history of HD, involving his father who was diagnosed with HD with motor )] TJ ET BT 26.250 581.206 Td /F1 9.8 Tf [(manifestations aged 55. This barrister carries the HD expansion, but has otherwise been healthy apart from moderate alcohol )] TJ ET BT 26.250 569.301 Td /F1 9.8 Tf [(use. His wife has noted increasing crankiness over the past year, which he attributed to busyness at work. There has been no )] TJ ET BT 26.250 557.397 Td /F1 9.8 Tf [(change in his work performance. Motor examination found jerky pursuit eye movements only. Neuropsychological examination )] TJ ET BT 26.250 545.492 Td /F1 9.8 Tf [(identified mild but definite decline in cognitive function, compared to cognitive examination a year ago, in a pattern consistent )] TJ ET BT 26.250 533.587 Td /F1 9.8 Tf [(with HD. He was not depressed \(Fig 2\).)] TJ ET 0.965 0.965 0.965 rg 26.250 376.801 555.000 146.905 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 523.706 m 581.250 523.706 l 581.250 522.956 l 26.250 522.956 l f 26.250 376.801 m 581.250 376.801 l 581.250 377.551 l 26.250 377.551 l f q 225.000 0 0 102.000 35.250 411.956 cm /I16 Do Q q 35.250 388.051 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 396.432 Td /F4 9.8 Tf [(Fig. 2: Case Study One)] TJ ET Q BT 26.250 359.778 Td /F1 9.8 Tf [(Discussion: This man did not satisfy the Motor 4 criteria for clinical HD. He had measurable cognitive decline over a year, )] TJ ET BT 26.250 347.873 Td /F1 9.8 Tf [(which may prompt a diagnosis of clinical HD- but this needs to be moderated by the apparent lack of functional consequences )] TJ ET BT 26.250 335.968 Td /F1 9.8 Tf [(\(normal work performance according to work colleagues\). Incorporation of cognitive impairment into the new diagnostic criteria )] TJ ET BT 26.250 324.063 Td /F1 9.8 Tf [(raises the challenge of a suitable threshold. Functional measures \(eg. inability to work in a persons usual job\) have been used )] TJ ET BT 26.250 312.159 Td /F1 9.8 Tf [(as thresholds for diagnosis in other conditions. However this may represent different levels of cognitive impairment for different )] TJ ET BT 26.250 300.254 Td /F1 9.8 Tf [(people when measured in absolute terms, because ability to work can depend on the nature of the occupation and social )] TJ ET BT 26.250 288.349 Td /F1 9.8 Tf [(circumstances. Premature clinical diagnosis for this man could cost him his career. This man was a known expansion carrier in )] TJ ET BT 26.250 276.444 Td /F1 9.8 Tf [(a stable social setting, so it was safe to stretch the process of clinical diagnosis over a longer period of time. Therefore we )] TJ ET BT 26.250 264.540 Td /F1 9.8 Tf [(explained that, overall, he was still regarded as pre-manifest, but we would like to review him on a six monthly basis. A year )] TJ ET BT 26.250 252.635 Td /F1 9.8 Tf [(later, his crankiness has resolved with an improved work environment, but his neuropsychological impairment remained.)] TJ ET BT 26.250 233.230 Td /F1 9.8 Tf [(Case 2: A 23 year old man attended our clinic requesting a genetic test for HD. His mother developed clinical manifestations of )] TJ ET BT 26.250 221.325 Td /F1 9.8 Tf [(HD in her 30s and was known to our Service. At the time of consultation this man was an inpatient in a mental health facility. He )] TJ ET BT 26.250 209.421 Td /F1 9.8 Tf [(was admitted following a second episode of psychosis, with auditory hallucinations and some atypical features \(a body )] TJ ET BT 26.250 197.516 Td /F1 9.8 Tf [(dysmorphic delusion\). Motor examination was normal except for mildly impaired eye movements. He was on a moderate dose )] TJ ET BT 26.250 185.611 Td /F1 9.8 Tf [(of atypical anti-psychotic medication but his neurologic examination was reported to be normal prior to initiating medication. He )] TJ ET BT 26.250 173.706 Td /F1 9.8 Tf [(was somewhat reluctant during neuropsychological examination and performed poorly in a range of measures, over a broader )] TJ ET BT 26.250 161.802 Td /F1 9.8 Tf [(range of cognitive domains than one would expect for a typical, early, HD patient. \(Fig.3\))] TJ ET 0.965 0.965 0.965 rg 26.250 34.171 555.000 117.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 151.921 m 581.250 151.921 l 581.250 151.171 l 26.250 151.171 l f q 225.000 0 0 102.000 35.250 40.171 cm /I18 Do Q q 35.250 34.171 537.000 0.000 re W n Q Q q 15.000 34.171 577.500 742.829 re W n 0.965 0.965 0.965 rg 26.250 712.873 555.000 64.127 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 712.873 m 581.250 712.873 l 581.250 713.623 l 26.250 713.623 l f q 35.250 724.123 537.000 52.877 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 1: Diagrammatic representation of HD)] TJ ET BT 35.250 748.106 Td /F1 9.8 Tf [(The four quadrants represent the four domains of manifestations, and the inner circle represents the thresholds for clinical )] TJ ET BT 35.250 734.370 Td /F1 9.8 Tf [(significance.)] TJ ET Q BT 26.250 695.849 Td /F1 9.8 Tf [(The four quadrants represent the four domains of manifestations, and the inner circle represents the thresholds for clinical )] TJ ET BT 26.250 683.944 Td /F1 9.8 Tf [(significance.The four quadrants represent HD manifestations involving the motor, cognitive/behavioral, psychiatric and others )] TJ ET BT 26.250 672.039 Td /F1 9.8 Tf [(\(eg. metabolic/weight loss\) domains. The inner circle represents thresholds for clinical significance. These thresholds are )] TJ ET BT 26.250 660.135 Td /F1 9.8 Tf [(somewhat arbitrary- for instance, jerky pursuit eye movements in a HD expansion carrier is often not regarded as a sign )] TJ ET BT 26.250 648.230 Td /F1 9.8 Tf [(sufficient for diagnosis of clinical HD, whilst chorea is. The shaded-in areas represent degrees of impairment along the )] TJ ET BT 26.250 636.325 Td /F1 9.8 Tf [(continuum of symptoms/signs for each domain. For instance, Figure 1 represents a typical person with HD- with chorea, )] TJ ET BT 26.250 624.420 Td /F1 9.8 Tf [(enough cognitive impairment to affect work performance, some depression and weight loss. To satisfy the Motor 4 criteria, a )] TJ ET BT 26.250 612.516 Td /F1 9.8 Tf [(person will need to have motor impairment beyond the inner circle/threshold in the top left quadrant.)] TJ ET BT 26.250 593.111 Td /F1 9.8 Tf [(Case 1: A 40 year old barrister has a family history of HD, involving his father who was diagnosed with HD with motor )] TJ ET BT 26.250 581.206 Td /F1 9.8 Tf [(manifestations aged 55. This barrister carries the HD expansion, but has otherwise been healthy apart from moderate alcohol )] TJ ET BT 26.250 569.301 Td /F1 9.8 Tf [(use. His wife has noted increasing crankiness over the past year, which he attributed to busyness at work. There has been no )] TJ ET BT 26.250 557.397 Td /F1 9.8 Tf [(change in his work performance. Motor examination found jerky pursuit eye movements only. Neuropsychological examination )] TJ ET BT 26.250 545.492 Td /F1 9.8 Tf [(identified mild but definite decline in cognitive function, compared to cognitive examination a year ago, in a pattern consistent )] TJ ET BT 26.250 533.587 Td /F1 9.8 Tf [(with HD. He was not depressed \(Fig 2\).)] TJ ET 0.965 0.965 0.965 rg 26.250 376.801 555.000 146.905 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 523.706 m 581.250 523.706 l 581.250 522.956 l 26.250 522.956 l f 26.250 376.801 m 581.250 376.801 l 581.250 377.551 l 26.250 377.551 l f q 225.000 0 0 102.000 35.250 411.956 cm /I20 Do Q q 35.250 388.051 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 396.432 Td /F4 9.8 Tf [(Fig. 2: Case Study One)] TJ ET Q BT 26.250 359.778 Td /F1 9.8 Tf [(Discussion: This man did not satisfy the Motor 4 criteria for clinical HD. He had measurable cognitive decline over a year, )] TJ ET BT 26.250 347.873 Td /F1 9.8 Tf [(which may prompt a diagnosis of clinical HD- but this needs to be moderated by the apparent lack of functional consequences )] TJ ET BT 26.250 335.968 Td /F1 9.8 Tf [(\(normal work performance according to work colleagues\). Incorporation of cognitive impairment into the new diagnostic criteria )] TJ ET BT 26.250 324.063 Td /F1 9.8 Tf [(raises the challenge of a suitable threshold. Functional measures \(eg. inability to work in a persons usual job\) have been used )] TJ ET BT 26.250 312.159 Td /F1 9.8 Tf [(as thresholds for diagnosis in other conditions. However this may represent different levels of cognitive impairment for different )] TJ ET BT 26.250 300.254 Td /F1 9.8 Tf [(people when measured in absolute terms, because ability to work can depend on the nature of the occupation and social )] TJ ET BT 26.250 288.349 Td /F1 9.8 Tf [(circumstances. Premature clinical diagnosis for this man could cost him his career. This man was a known expansion carrier in )] TJ ET BT 26.250 276.444 Td /F1 9.8 Tf [(a stable social setting, so it was safe to stretch the process of clinical diagnosis over a longer period of time. Therefore we )] TJ ET BT 26.250 264.540 Td /F1 9.8 Tf [(explained that, overall, he was still regarded as pre-manifest, but we would like to review him on a six monthly basis. A year )] TJ ET BT 26.250 252.635 Td /F1 9.8 Tf [(later, his crankiness has resolved with an improved work environment, but his neuropsychological impairment remained.)] TJ ET BT 26.250 233.230 Td /F1 9.8 Tf [(Case 2: A 23 year old man attended our clinic requesting a genetic test for HD. His mother developed clinical manifestations of )] TJ ET BT 26.250 221.325 Td /F1 9.8 Tf [(HD in her 30s and was known to our Service. At the time of consultation this man was an inpatient in a mental health facility. He )] TJ ET BT 26.250 209.421 Td /F1 9.8 Tf [(was admitted following a second episode of psychosis, with auditory hallucinations and some atypical features \(a body )] TJ ET BT 26.250 197.516 Td /F1 9.8 Tf [(dysmorphic delusion\). Motor examination was normal except for mildly impaired eye movements. He was on a moderate dose )] TJ ET BT 26.250 185.611 Td /F1 9.8 Tf [(of atypical anti-psychotic medication but his neurologic examination was reported to be normal prior to initiating medication. He )] TJ ET BT 26.250 173.706 Td /F1 9.8 Tf [(was somewhat reluctant during neuropsychological examination and performed poorly in a range of measures, over a broader )] TJ ET BT 26.250 161.802 Td /F1 9.8 Tf [(range of cognitive domains than one would expect for a typical, early, HD patient. \(Fig.3\))] TJ ET 0.965 0.965 0.965 rg 26.250 34.171 555.000 117.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 151.921 m 581.250 151.921 l 581.250 151.171 l 26.250 151.171 l f q 225.000 0 0 102.000 35.250 40.171 cm /I22 Do Q q 35.250 34.171 537.000 0.000 re W n Q Q q 225.000 0 0 102.000 35.250 411.956 cm /I24 Do Q q 225.000 0 0 102.000 35.250 40.171 cm /I26 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(2)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 84 0 obj << /Type /Annot /Subtype /Link /A 85 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 411.9562 260.2500 513.9562 ] >> endobj 85 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2013/03/Fig2.png) >> endobj 86 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 136 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 301>> stream xA 0 =fy9뀟\ * endstream endobj 87 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 136 /SMask 86 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 20855>> stream x}w\TG̲4"`T`A hbaM1Q7M[+biB( *H_^f]@w>Ν9si Z-$!!dBT"hByZGV\MВ;S$< %TA 2(/USN=|ҹsݻ'{ L*7<-C1% ČxMxL=4ED077ܹsǎq$B(&&FӲ@LLVy=q޽ɓ'ggg3YKqZZSҥK~fI%gϞݴiX 0}K-Ӄ)+lْt T|acJJC%bbIs+pt^*)9cǎ 80::ΝaBRqqfeeO5k]x*--MLL,++#jnGB矅g[vmnnOJwe%!!СC9ԩStuu_WZ[oyxxDGG_v o>OOχb ]LH0剁" ~PgP ӨĂ*D!bWZ^9y`>|xFɒ= Wի111>>>7n3f̙3gݣlll͇ faa1ܙ3gC`׳yoBXZZz޽v233O<}z n߾ФIVVV^x?tss۾}6mݻ׭[WVVC=<<+Wرc !ܰaCii͛CCC;v8}ti9s̐!C$H_u֭RQQ1j(sssJ5n8iuoBBBBCCׯ_!ٳ t===F2TVV>|0???22222r񖖖ssseEEEff!Ç:4i$D!$)--888 ֯_b ;;rAyUnn}z>}<<<B 6㋊LҠAÇyxxX[[#7o<00^zNNN҉ȥRaJ\ F"U)Q.hXWSɜ19](wIKK{QVV4LLL322ׯ/.''͛k] LK y!-SRR" 'NݻW("n.>ADA+Bjȑ#Gܹsg߾}w>o<E2rѝxP.!aiyœ 0`@PPѣG5k&GTy yj y0yڡC>>L%̎{ W̡H@)>ҌC4`- ٔj ?yʙѹBF3o޼۷o={e˖J*<$ Ó4NZ=w~.\Ԕ(v/ O@"ѭ䉤xV :ʠ*c dEB%ˤd6)vvgΜgTɠΝ;GFF;999DjaRS$$Af-@xT+h(T" 73>>~РAϞ5.K@LP%R“ͮ]ۯ_۷o3aPqԋ#įp4 ^-WBD  ^R+4!(| 4F 0KA<<o$:u:}@@ii[oEy1Ȏ>T(I`(*ǰj.ysOg=JD+gr%%믏=&=MY@ /&$ LZV<+\Z<{l@@@Y ^/ YAq[\h,*b}(# tN !=hC˙mJfxi֭Gg O^ … M6+bgΜ =tMOO>}{woպz9;8`VJ5R'wڸt4Uxձc^tIz, s/AK8nCU)^+@u6GUVV0`#G$gp֭͛7?o߾cF~ ֆ&IIVj rJ*5^ͽ]#q 'W_]~}ǎ/ F\a:d]y>`/sDs ma*J[lޱJ[Mׯ_3f̄ <==6nӻ/sAHI7yӖvM,S~vr?>yL}K{^|٩ONOqFk*bB%&b4 8-n-&tۚ_kJ>ׯ_\llC;b_DZpkז,Yobb؟9ZBH]-k$ -dxu bq;3 AUImY,%4FDW+%-osU0 >3ym *++ܺO^zǏ1B=R aա?@PAР^7YX'}^ ؾ}zKz@R A%|G_^3LIz8e xD2:9g )a /N L"<]E#fvAƩ. 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This illustrates some of the )] TJ ET BT 26.250 707.012 Td /F1 9.8 Tf [(difficulties in incorporating psychiatric symptoms into the diagnosis of clinical HD. Since these psychotic episodes occurred in )] TJ ET BT 26.250 695.107 Td /F1 9.8 Tf [(his early twenties, they could potentially be due to schizophrenia rather than HD. If the first psychotic episode had occurred in )] TJ ET BT 26.250 683.202 Td /F1 9.8 Tf [(his early 50s instead, then it would have been a little more specific for HD. This case also demonstrates the flow-on effect of the )] TJ ET BT 26.250 671.298 Td /F1 9.8 Tf [(clinical diagnostic criteria, on the decision to carry out genetic testing on a pre-symptomatic basis or not. Given the uncertainty )] TJ ET BT 26.250 659.393 Td /F1 9.8 Tf [(in his diagnosis, we suggested genetic testing on a pre-symptomatic, rather than diagnostic basis. The geneticist advised him to )] TJ ET BT 26.250 647.488 Td /F1 9.8 Tf [(reconsider the decision to test, given his cognitive impairment. This man has an identical twin who was uncontactable at the )] TJ ET BT 26.250 635.583 Td /F1 9.8 Tf [(time, which added to our hesitation to offer testing. When seen twelve months later, his psychosis had resolved, cognitive )] TJ ET BT 26.250 623.679 Td /F1 9.8 Tf [(performance improved and he no longer wanted to have a genetic test.)] TJ ET BT 26.250 604.274 Td /F1 9.8 Tf [(Case 3: A 37 year old man presented with a three year history of forgetfulness and inability to cope with his work as a )] TJ ET BT 26.250 592.369 Td /F1 9.8 Tf [(handyman. His mother died aged 48 with a dementia but a more detailed diagnosis was not available. He attended the clinic of )] TJ ET BT 26.250 580.464 Td /F1 9.8 Tf [(an experienced neurologist during that period who noted worsening dementia of moderate severity. He also clearly documented )] TJ ET BT 26.250 568.560 Td /F1 9.8 Tf [(that there has been no chorea. The patient was initially tested for mutations in the Alzheimer Disease genes, but was eventually )] TJ ET BT 26.250 556.655 Td /F1 9.8 Tf [(tested for HD, about 6 months prior to presentation to our Service. He had 49/18 CAG repeats, confirming a diagnosis of HD. )] TJ ET BT 26.250 544.750 Td /F1 9.8 Tf [(\(Fig.4\))] TJ ET 0.965 0.965 0.965 rg 26.250 387.965 555.000 146.905 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 534.869 m 581.250 534.869 l 581.250 534.119 l 26.250 534.119 l f 26.250 387.965 m 581.250 387.965 l 581.250 388.715 l 26.250 388.715 l f q 225.000 0 0 102.000 35.250 423.119 cm /I28 Do Q q 35.250 399.215 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 407.595 Td /F4 9.8 Tf [(Fig. 4: Case Study Three)] TJ ET Q BT 26.250 370.941 Td /F1 9.8 Tf [(Discussion: When interviewed, this patients wife said she wished the diagnosis had been made earlier. It would have helped )] TJ ET BT 26.250 359.036 Td /F1 9.8 Tf [(her and her young child to better understand the illness and plan for the future. New diagnostic criteria highlighting the cognitive )] TJ ET BT 26.250 347.131 Td /F1 9.8 Tf [(aspects of HD, may help lead to earlier diagnosis in similar situations. Interestingly, many families encountering HD for the first )] TJ ET BT 26.250 335.226 Td /F1 9.8 Tf [(time express wish for early diagnosis, while families with established family histories often prefer to delay diagnosis. Any new )] TJ ET BT 26.250 323.322 Td /F1 9.8 Tf [(diagnostic criteria will need to allow some flexibility in this regard.)] TJ ET BT 26.250 303.917 Td /F1 9.8 Tf [(Case 4: This 36 year old man underwent pre-symptomatic genetic testing in his twenties and was found to carry the HD )] TJ ET BT 26.250 292.012 Td /F1 9.8 Tf [(expansion. He presented with depression without suicidality, and responded well to citalopram. On examination he had mild )] TJ ET BT 26.250 280.107 Td /F1 9.8 Tf [(impairment in eye movements and some possible fidgetiness in his feet only. Bedside cognitive examination was borderline )] TJ ET BT 26.250 268.203 Td /F1 9.8 Tf [(normal. He spent most days playing computer games and had been unsuccessful in finding employment. He lived with his )] TJ ET BT 26.250 256.298 Td /F1 9.8 Tf [(mother and would like to live in his own flat. \(Fig.5\))] TJ ET 0.965 0.965 0.965 rg 26.250 99.512 555.000 146.905 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 246.417 m 581.250 246.417 l 581.250 245.667 l 26.250 245.667 l f 26.250 99.512 m 581.250 99.512 l 581.250 100.262 l 26.250 100.262 l f q 225.000 0 0 102.000 35.250 134.667 cm /I30 Do Q q 35.250 110.762 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 119.143 Td /F4 9.8 Tf [(Fig. 5: Case Study Four)] TJ ET Q BT 26.250 82.488 Td /F1 9.8 Tf [(Discussion: This patients motor signs were not significant enough to justify a Motor 4 designation, and his cognitive )] TJ ET BT 26.250 70.584 Td /F1 9.8 Tf [(performance was borderline normal. He was depressed but this may or may not be due to HD. Nonetheless he already )] TJ ET BT 26.250 58.679 Td /F1 9.8 Tf [(regarded himself as symptomatic, and a clinical diagnosis would also allow him to access a Disability Support Pension, and )] TJ ET BT 26.250 46.774 Td /F1 9.8 Tf [(prioritized public housing. We made the clinical diagnosis of early HD. Twelve months later, he developed a paranoid delusion )] TJ ET Q q 15.000 32.489 577.500 744.511 re W n 0.965 0.965 0.965 rg 26.250 747.845 555.000 29.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 747.845 m 581.250 747.845 l 581.250 748.595 l 26.250 748.595 l f q 35.250 759.095 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 3: Case Study Two)] TJ ET Q BT 26.250 730.821 Td /F1 9.8 Tf [(Discussion: It is possible that this mans psychosis was part of HD, although his cognitive impairment did not lend as much )] TJ ET BT 26.250 718.917 Td /F1 9.8 Tf [(support to the diagnosis of clinical HD as it would have, if the pattern had been typical for HD. This illustrates some of the )] TJ ET BT 26.250 707.012 Td /F1 9.8 Tf [(difficulties in incorporating psychiatric symptoms into the diagnosis of clinical HD. Since these psychotic episodes occurred in )] TJ ET BT 26.250 695.107 Td /F1 9.8 Tf [(his early twenties, they could potentially be due to schizophrenia rather than HD. If the first psychotic episode had occurred in )] TJ ET BT 26.250 683.202 Td /F1 9.8 Tf [(his early 50s instead, then it would have been a little more specific for HD. This case also demonstrates the flow-on effect of the )] TJ ET BT 26.250 671.298 Td /F1 9.8 Tf [(clinical diagnostic criteria, on the decision to carry out genetic testing on a pre-symptomatic basis or not. Given the uncertainty )] TJ ET BT 26.250 659.393 Td /F1 9.8 Tf [(in his diagnosis, we suggested genetic testing on a pre-symptomatic, rather than diagnostic basis. The geneticist advised him to )] TJ ET BT 26.250 647.488 Td /F1 9.8 Tf [(reconsider the decision to test, given his cognitive impairment. This man has an identical twin who was uncontactable at the )] TJ ET BT 26.250 635.583 Td /F1 9.8 Tf [(time, which added to our hesitation to offer testing. When seen twelve months later, his psychosis had resolved, cognitive )] TJ ET BT 26.250 623.679 Td /F1 9.8 Tf [(performance improved and he no longer wanted to have a genetic test.)] TJ ET BT 26.250 604.274 Td /F1 9.8 Tf [(Case 3: A 37 year old man presented with a three year history of forgetfulness and inability to cope with his work as a )] TJ ET BT 26.250 592.369 Td /F1 9.8 Tf [(handyman. His mother died aged 48 with a dementia but a more detailed diagnosis was not available. He attended the clinic of )] TJ ET BT 26.250 580.464 Td /F1 9.8 Tf [(an experienced neurologist during that period who noted worsening dementia of moderate severity. He also clearly documented )] TJ ET BT 26.250 568.560 Td /F1 9.8 Tf [(that there has been no chorea. The patient was initially tested for mutations in the Alzheimer Disease genes, but was eventually )] TJ ET BT 26.250 556.655 Td /F1 9.8 Tf [(tested for HD, about 6 months prior to presentation to our Service. He had 49/18 CAG repeats, confirming a diagnosis of HD. )] TJ ET BT 26.250 544.750 Td /F1 9.8 Tf [(\(Fig.4\))] TJ ET 0.965 0.965 0.965 rg 26.250 387.965 555.000 146.905 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 534.869 m 581.250 534.869 l 581.250 534.119 l 26.250 534.119 l f 26.250 387.965 m 581.250 387.965 l 581.250 388.715 l 26.250 388.715 l f q 225.000 0 0 102.000 35.250 423.119 cm /I32 Do Q q 35.250 399.215 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 407.595 Td /F4 9.8 Tf [(Fig. 4: Case Study Three)] TJ ET Q BT 26.250 370.941 Td /F1 9.8 Tf [(Discussion: When interviewed, this patients wife said she wished the diagnosis had been made earlier. It would have helped )] TJ ET BT 26.250 359.036 Td /F1 9.8 Tf [(her and her young child to better understand the illness and plan for the future. New diagnostic criteria highlighting the cognitive )] TJ ET BT 26.250 347.131 Td /F1 9.8 Tf [(aspects of HD, may help lead to earlier diagnosis in similar situations. Interestingly, many families encountering HD for the first )] TJ ET BT 26.250 335.226 Td /F1 9.8 Tf [(time express wish for early diagnosis, while families with established family histories often prefer to delay diagnosis. Any new )] TJ ET BT 26.250 323.322 Td /F1 9.8 Tf [(diagnostic criteria will need to allow some flexibility in this regard.)] TJ ET BT 26.250 303.917 Td /F1 9.8 Tf [(Case 4: This 36 year old man underwent pre-symptomatic genetic testing in his twenties and was found to carry the HD )] TJ ET BT 26.250 292.012 Td /F1 9.8 Tf [(expansion. He presented with depression without suicidality, and responded well to citalopram. On examination he had mild )] TJ ET BT 26.250 280.107 Td /F1 9.8 Tf [(impairment in eye movements and some possible fidgetiness in his feet only. Bedside cognitive examination was borderline )] TJ ET BT 26.250 268.203 Td /F1 9.8 Tf [(normal. He spent most days playing computer games and had been unsuccessful in finding employment. He lived with his )] TJ ET BT 26.250 256.298 Td /F1 9.8 Tf [(mother and would like to live in his own flat. \(Fig.5\))] TJ ET 0.965 0.965 0.965 rg 26.250 99.512 555.000 146.905 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 246.417 m 581.250 246.417 l 581.250 245.667 l 26.250 245.667 l f 26.250 99.512 m 581.250 99.512 l 581.250 100.262 l 26.250 100.262 l f q 225.000 0 0 102.000 35.250 134.667 cm /I34 Do Q q 35.250 110.762 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 119.143 Td /F4 9.8 Tf [(Fig. 5: Case Study Four)] TJ ET Q BT 26.250 82.488 Td /F1 9.8 Tf [(Discussion: This patients motor signs were not significant enough to justify a Motor 4 designation, and his cognitive )] TJ ET BT 26.250 70.584 Td /F1 9.8 Tf [(performance was borderline normal. He was depressed but this may or may not be due to HD. Nonetheless he already )] TJ ET BT 26.250 58.679 Td /F1 9.8 Tf [(regarded himself as symptomatic, and a clinical diagnosis would also allow him to access a Disability Support Pension, and )] TJ ET BT 26.250 46.774 Td /F1 9.8 Tf [(prioritized public housing. We made the clinical diagnosis of early HD. Twelve months later, he developed a paranoid delusion )] TJ ET Q q 15.000 32.489 577.500 744.511 re W n 0.965 0.965 0.965 rg 26.250 747.845 555.000 29.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 747.845 m 581.250 747.845 l 581.250 748.595 l 26.250 748.595 l f q 35.250 759.095 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 3: Case Study Two)] TJ ET Q BT 26.250 730.821 Td /F1 9.8 Tf [(Discussion: It is possible that this mans psychosis was part of HD, although his cognitive impairment did not lend as much )] TJ ET BT 26.250 718.917 Td /F1 9.8 Tf [(support to the diagnosis of clinical HD as it would have, if the pattern had been typical for HD. This illustrates some of the )] TJ ET BT 26.250 707.012 Td /F1 9.8 Tf [(difficulties in incorporating psychiatric symptoms into the diagnosis of clinical HD. Since these psychotic episodes occurred in )] TJ ET BT 26.250 695.107 Td /F1 9.8 Tf [(his early twenties, they could potentially be due to schizophrenia rather than HD. If the first psychotic episode had occurred in )] TJ ET BT 26.250 683.202 Td /F1 9.8 Tf [(his early 50s instead, then it would have been a little more specific for HD. This case also demonstrates the flow-on effect of the )] TJ ET BT 26.250 671.298 Td /F1 9.8 Tf [(clinical diagnostic criteria, on the decision to carry out genetic testing on a pre-symptomatic basis or not. Given the uncertainty )] TJ ET BT 26.250 659.393 Td /F1 9.8 Tf [(in his diagnosis, we suggested genetic testing on a pre-symptomatic, rather than diagnostic basis. The geneticist advised him to )] TJ ET BT 26.250 647.488 Td /F1 9.8 Tf [(reconsider the decision to test, given his cognitive impairment. This man has an identical twin who was uncontactable at the )] TJ ET BT 26.250 635.583 Td /F1 9.8 Tf [(time, which added to our hesitation to offer testing. When seen twelve months later, his psychosis had resolved, cognitive )] TJ ET BT 26.250 623.679 Td /F1 9.8 Tf [(performance improved and he no longer wanted to have a genetic test.)] TJ ET BT 26.250 604.274 Td /F1 9.8 Tf [(Case 3: A 37 year old man presented with a three year history of forgetfulness and inability to cope with his work as a )] TJ ET BT 26.250 592.369 Td /F1 9.8 Tf [(handyman. His mother died aged 48 with a dementia but a more detailed diagnosis was not available. He attended the clinic of )] TJ ET BT 26.250 580.464 Td /F1 9.8 Tf [(an experienced neurologist during that period who noted worsening dementia of moderate severity. He also clearly documented )] TJ ET BT 26.250 568.560 Td /F1 9.8 Tf [(that there has been no chorea. The patient was initially tested for mutations in the Alzheimer Disease genes, but was eventually )] TJ ET BT 26.250 556.655 Td /F1 9.8 Tf [(tested for HD, about 6 months prior to presentation to our Service. He had 49/18 CAG repeats, confirming a diagnosis of HD. )] TJ ET BT 26.250 544.750 Td /F1 9.8 Tf [(\(Fig.4\))] TJ ET 0.965 0.965 0.965 rg 26.250 387.965 555.000 146.905 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 534.869 m 581.250 534.869 l 581.250 534.119 l 26.250 534.119 l f 26.250 387.965 m 581.250 387.965 l 581.250 388.715 l 26.250 388.715 l f q 225.000 0 0 102.000 35.250 423.119 cm /I36 Do Q q 35.250 399.215 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 407.595 Td /F4 9.8 Tf [(Fig. 4: Case Study Three)] TJ ET Q BT 26.250 370.941 Td /F1 9.8 Tf [(Discussion: When interviewed, this patients wife said she wished the diagnosis had been made earlier. It would have helped )] TJ ET BT 26.250 359.036 Td /F1 9.8 Tf [(her and her young child to better understand the illness and plan for the future. New diagnostic criteria highlighting the cognitive )] TJ ET BT 26.250 347.131 Td /F1 9.8 Tf [(aspects of HD, may help lead to earlier diagnosis in similar situations. Interestingly, many families encountering HD for the first )] TJ ET BT 26.250 335.226 Td /F1 9.8 Tf [(time express wish for early diagnosis, while families with established family histories often prefer to delay diagnosis. Any new )] TJ ET BT 26.250 323.322 Td /F1 9.8 Tf [(diagnostic criteria will need to allow some flexibility in this regard.)] TJ ET BT 26.250 303.917 Td /F1 9.8 Tf [(Case 4: This 36 year old man underwent pre-symptomatic genetic testing in his twenties and was found to carry the HD )] TJ ET BT 26.250 292.012 Td /F1 9.8 Tf [(expansion. He presented with depression without suicidality, and responded well to citalopram. On examination he had mild )] TJ ET BT 26.250 280.107 Td /F1 9.8 Tf [(impairment in eye movements and some possible fidgetiness in his feet only. Bedside cognitive examination was borderline )] TJ ET BT 26.250 268.203 Td /F1 9.8 Tf [(normal. He spent most days playing computer games and had been unsuccessful in finding employment. He lived with his )] TJ ET BT 26.250 256.298 Td /F1 9.8 Tf [(mother and would like to live in his own flat. \(Fig.5\))] TJ ET 0.965 0.965 0.965 rg 26.250 99.512 555.000 146.905 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 246.417 m 581.250 246.417 l 581.250 245.667 l 26.250 245.667 l f 26.250 99.512 m 581.250 99.512 l 581.250 100.262 l 26.250 100.262 l f q 225.000 0 0 102.000 35.250 134.667 cm /I38 Do Q q 35.250 110.762 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 119.143 Td /F4 9.8 Tf [(Fig. 5: Case Study Four)] TJ ET Q BT 26.250 82.488 Td /F1 9.8 Tf [(Discussion: This patients motor signs were not significant enough to justify a Motor 4 designation, and his cognitive )] TJ ET BT 26.250 70.584 Td /F1 9.8 Tf [(performance was borderline normal. He was depressed but this may or may not be due to HD. Nonetheless he already )] TJ ET BT 26.250 58.679 Td /F1 9.8 Tf [(regarded himself as symptomatic, and a clinical diagnosis would also allow him to access a Disability Support Pension, and )] TJ ET BT 26.250 46.774 Td /F1 9.8 Tf [(prioritized public housing. We made the clinical diagnosis of early HD. 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In HD the purpose of clinical diagnosis can take on a )] TJ ET BT 26.250 687.110 Td /F1 9.8 Tf [(different significance. For instance, for a pre-manifest individual, the underlying cause \(genetic status\) may already be known, )] TJ ET BT 26.250 675.205 Td /F1 9.8 Tf [(and symptomatic treatment \(such as antidepressants\) may already be in place. The focus of clinical diagnosis may then lie in )] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(prognostication and social/legal consequences instead.)] TJ ET BT 26.250 643.896 Td /F1 9.8 Tf [(HD is a multi-system disease with a continuum of manifestations. Brain autopsy reports of pre-manifest individuals)] TJ ET 0.267 0.267 0.267 rg BT 518.255 645.403 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 523.073 647.784 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 525.483 645.403 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 530.301 643.896 Td /F1 9.8 Tf [( suggest )] TJ ET BT 26.250 631.991 Td /F1 9.8 Tf [(that changes in cellular composition/organization may begin very early in life. PREDICT-HD)] TJ ET 0.267 0.267 0.267 rg BT 420.170 633.498 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 424.988 631.991 Td /F1 9.8 Tf [( and TRACK-HD)] TJ ET 0.267 0.267 0.267 rg BT 497.041 633.498 Td /F4 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 501.859 631.991 Td /F1 9.8 Tf [( provide further )] TJ ET BT 26.250 620.086 Td /F1 9.8 Tf [(evidence that measures of neuronal dysfunction can be detected years prior to development of definite motor signs. However, )] TJ ET BT 26.250 608.181 Td /F1 9.8 Tf [(biologically, there may not be a single threshold that we can use to define disease onset, as different biomarkers may become )] TJ ET BT 26.250 596.277 Td /F1 9.8 Tf [(abnormal at different times in a persons life. In addition, depending on the threshold chosen, sensitivity will have to be traded )] TJ ET BT 26.250 584.372 Td /F1 9.8 Tf [(off against specificity for each biomarker, and not every biomarker will have the same clinical significance for different aspects of )] TJ ET BT 26.250 572.467 Td /F1 9.8 Tf [(HD. Expert consensus may be the only way to determine a threshold for diagnosis of clinical HD.)] TJ ET BT 26.250 553.062 Td /F1 9.8 Tf [(Despite this uncertainty, the notion of disease onset remains important for people with HD and their families. Likely age of )] TJ ET BT 26.250 541.158 Td /F1 9.8 Tf [(disease onset is one of the most frequently asked questions by families with HD, and this information is often used for life and )] TJ ET BT 26.250 529.253 Td /F1 9.8 Tf [(financial planning. Delayed diagnosis may unfairly disadvantage people with HD and cognitive-behavioral symptoms, )] TJ ET BT 26.250 517.348 Td /F1 9.8 Tf [(particularly in legal proceedings. A diagnosis of clinical HD can also release superannuation, insurance, and other social )] TJ ET BT 26.250 505.443 Td /F1 9.8 Tf [(benefits for people with HD.)] TJ ET BT 26.250 486.039 Td /F1 9.8 Tf [(A number of recent efforts have aimed to achieve earlier diagnosis for neurodegenerative conditions such as Alzheimer Disease)] TJ ET 0.267 0.267 0.267 rg BT 26.250 475.641 Td /F4 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 31.069 474.134 Td /F1 9.8 Tf [( and Parkinson Disease)] TJ ET 0.267 0.267 0.267 rg BT 134.029 475.641 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 138.847 474.134 Td /F1 9.8 Tf [( . The rationale for earlier diagnosis is to identify people likely to develop disease, and capture the )] TJ ET BT 26.250 462.229 Td /F1 9.8 Tf [(therapeutic window of opportunity before neuronal damage becomes irreversible. However for HD, genetic testing already )] TJ ET BT 26.250 450.324 Td /F1 9.8 Tf [(provides a highly accurate marker for future disease. While broadening the diagnostic spectrum may incidentally lead to earlier )] TJ ET BT 26.250 438.420 Td /F1 9.8 Tf [(diagnosis of clinical HD in some people, earlier diagnosis is not the primary intention.)] TJ ET BT 26.250 419.015 Td /F1 9.8 Tf [(Our current Motor 4 criteria does not reflect the full spectrum of manifestations in HD. A consensus statement broadening the )] TJ ET BT 26.250 407.110 Td /F1 9.8 Tf [(diagnostic spectrum will be particularly helpful for clinicians outside the HD centres. It will lend support to the diagnosis of non-)] TJ ET BT 26.250 395.205 Td /F1 9.8 Tf [(motor HD by individual clinicians, if challenged in the legal setting or in the context of social benefits. This could be achieved by )] TJ ET BT 26.250 383.301 Td /F1 9.8 Tf [(expert consensus and consultation with families with HD. As illustrated above, the diagnosis of clinical HD is made in a variety )] TJ ET BT 26.250 371.396 Td /F1 9.8 Tf [(of settings with social and legal consequences. A flexible rather than prescriptive approach is required, and extensive )] TJ ET BT 26.250 359.491 Td /F1 9.8 Tf [(consultation will be essential.)] TJ ET BT 26.250 322.889 Td /F4 12.0 Tf [(Ethics Statement)] TJ ET BT 26.250 302.934 Td /F1 9.8 Tf [(This paper was prepared in accordance to the World Medical Association Declaration of Helsinki. The Western Sydney Local )] TJ ET BT 26.250 291.030 Td /F1 9.8 Tf [(Health District Human Research Ethics Committee waived the requirement for consent as details of the cases were altered to )] TJ ET BT 26.250 279.125 Td /F1 9.8 Tf [(prevent identification)] TJ ET BT 26.250 242.522 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 222.568 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 185.966 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 158.511 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 158.511 Td /F1 9.8 Tf [(ACMG/ASHG statement. Laboratory guidelines for Huntington disease genetic testing. The American College of Medical )] TJ ET BT 26.250 146.607 Td /F1 9.8 Tf [(Genetics/American Society of Human Genetics Huntington Disease Genetic Testing Working Group. Am J Hum Genet. 1998 )] TJ ET BT 26.250 134.702 Td /F1 9.8 Tf [(May;62\(5\):1243-7. PubMed PMID:9545416.)] TJ ET BT 26.250 115.297 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 115.297 Td /F1 9.8 Tf [(Unified Huntington's Disease Rating Scale: reliability and consistency. Huntington Study Group. Mov Disord. 1996 )] TJ ET BT 26.250 103.392 Td /F1 9.8 Tf [(Mar;11\(2\):136-42. PubMed PMID:8684382.)] TJ ET BT 26.250 83.988 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 83.988 Td /F1 9.8 Tf [(Paulsen JS, Langbehn DR, Stout JC, Aylward E, Ross CA, Nance M, Guttman M, Johnson S, MacDonald M, Beglinger LJ, )] TJ ET BT 26.250 72.083 Td /F1 9.8 Tf [(Duff K, Kayson E, Biglan K, Shoulson I, Oakes D, Hayden M. Detection of Huntington's disease decades before diagnosis: the )] TJ ET BT 26.250 60.178 Td /F1 9.8 Tf [(Predict-HD study. J Neurol Neurosurg Psychiatry. 2008 Aug;79\(8\):874-80. PubMed PMID:18096682.)] TJ ET Q q 15.000 50.297 577.500 726.703 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(which was successfully managed with a low dose of atypical psychotic.)] TJ ET BT 26.250 730.874 Td /F4 12.0 Tf [(Concluding Remarks)] TJ ET BT 26.250 710.919 Td /F1 9.8 Tf [(Broadly speaking, the purpose of clinical diagnosis is to infer the underlying cause of a persons symptoms and signs, in order )] TJ ET BT 26.250 699.015 Td /F1 9.8 Tf [(to provide prognostic information, and to guide treatment if available. In HD the purpose of clinical diagnosis can take on a )] TJ ET BT 26.250 687.110 Td /F1 9.8 Tf [(different significance. For instance, for a pre-manifest individual, the underlying cause \(genetic status\) may already be known, )] TJ ET BT 26.250 675.205 Td /F1 9.8 Tf [(and symptomatic treatment \(such as antidepressants\) may already be in place. The focus of clinical diagnosis may then lie in )] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(prognostication and social/legal consequences instead.)] TJ ET BT 26.250 643.896 Td /F1 9.8 Tf [(HD is a multi-system disease with a continuum of manifestations. Brain autopsy reports of pre-manifest individuals)] TJ ET 0.267 0.267 0.267 rg BT 518.255 645.403 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 523.073 647.784 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 525.483 645.403 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 530.301 643.896 Td /F1 9.8 Tf [( suggest )] TJ ET BT 26.250 631.991 Td /F1 9.8 Tf [(that changes in cellular composition/organization may begin very early in life. PREDICT-HD)] TJ ET 0.267 0.267 0.267 rg BT 420.170 633.498 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 424.988 631.991 Td /F1 9.8 Tf [( and TRACK-HD)] TJ ET 0.267 0.267 0.267 rg BT 497.041 633.498 Td /F4 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 501.859 631.991 Td /F1 9.8 Tf [( provide further )] TJ ET BT 26.250 620.086 Td /F1 9.8 Tf [(evidence that measures of neuronal dysfunction can be detected years prior to development of definite motor signs. However, )] TJ ET BT 26.250 608.181 Td /F1 9.8 Tf [(biologically, there may not be a single threshold that we can use to define disease onset, as different biomarkers may become )] TJ ET BT 26.250 596.277 Td /F1 9.8 Tf [(abnormal at different times in a persons life. In addition, depending on the threshold chosen, sensitivity will have to be traded )] TJ ET BT 26.250 584.372 Td /F1 9.8 Tf [(off against specificity for each biomarker, and not every biomarker will have the same clinical significance for different aspects of )] TJ ET BT 26.250 572.467 Td /F1 9.8 Tf [(HD. Expert consensus may be the only way to determine a threshold for diagnosis of clinical HD.)] TJ ET BT 26.250 553.062 Td /F1 9.8 Tf [(Despite this uncertainty, the notion of disease onset remains important for people with HD and their families. Likely age of )] TJ ET BT 26.250 541.158 Td /F1 9.8 Tf [(disease onset is one of the most frequently asked questions by families with HD, and this information is often used for life and )] TJ ET BT 26.250 529.253 Td /F1 9.8 Tf [(financial planning. Delayed diagnosis may unfairly disadvantage people with HD and cognitive-behavioral symptoms, )] TJ ET BT 26.250 517.348 Td /F1 9.8 Tf [(particularly in legal proceedings. A diagnosis of clinical HD can also release superannuation, insurance, and other social )] TJ ET BT 26.250 505.443 Td /F1 9.8 Tf [(benefits for people with HD.)] TJ ET BT 26.250 486.039 Td /F1 9.8 Tf [(A number of recent efforts have aimed to achieve earlier diagnosis for neurodegenerative conditions such as Alzheimer Disease)] TJ ET 0.267 0.267 0.267 rg BT 26.250 475.641 Td /F4 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 31.069 474.134 Td /F1 9.8 Tf [( and Parkinson Disease)] TJ ET 0.267 0.267 0.267 rg BT 134.029 475.641 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 138.847 474.134 Td /F1 9.8 Tf [( . The rationale for earlier diagnosis is to identify people likely to develop disease, and capture the )] TJ ET BT 26.250 462.229 Td /F1 9.8 Tf [(therapeutic window of opportunity before neuronal damage becomes irreversible. However for HD, genetic testing already )] TJ ET BT 26.250 450.324 Td /F1 9.8 Tf [(provides a highly accurate marker for future disease. While broadening the diagnostic spectrum may incidentally lead to earlier )] TJ ET BT 26.250 438.420 Td /F1 9.8 Tf [(diagnosis of clinical HD in some people, earlier diagnosis is not the primary intention.)] TJ ET BT 26.250 419.015 Td /F1 9.8 Tf [(Our current Motor 4 criteria does not reflect the full spectrum of manifestations in HD. A consensus statement broadening the )] TJ ET BT 26.250 407.110 Td /F1 9.8 Tf [(diagnostic spectrum will be particularly helpful for clinicians outside the HD centres. It will lend support to the diagnosis of non-)] TJ ET BT 26.250 395.205 Td /F1 9.8 Tf [(motor HD by individual clinicians, if challenged in the legal setting or in the context of social benefits. This could be achieved by )] TJ ET BT 26.250 383.301 Td /F1 9.8 Tf [(expert consensus and consultation with families with HD. As illustrated above, the diagnosis of clinical HD is made in a variety )] TJ ET BT 26.250 371.396 Td /F1 9.8 Tf [(of settings with social and legal consequences. A flexible rather than prescriptive approach is required, and extensive )] TJ ET BT 26.250 359.491 Td /F1 9.8 Tf [(consultation will be essential.)] TJ ET BT 26.250 322.889 Td /F4 12.0 Tf [(Ethics Statement)] TJ ET BT 26.250 302.934 Td /F1 9.8 Tf [(This paper was prepared in accordance to the World Medical Association Declaration of Helsinki. The Western Sydney Local )] TJ ET BT 26.250 291.030 Td /F1 9.8 Tf [(Health District Human Research Ethics Committee waived the requirement for consent as details of the cases were altered to )] TJ ET BT 26.250 279.125 Td /F1 9.8 Tf [(prevent identification)] TJ ET BT 26.250 242.522 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 222.568 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 185.966 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 158.511 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 158.511 Td /F1 9.8 Tf [(ACMG/ASHG statement. Laboratory guidelines for Huntington disease genetic testing. The American College of Medical )] TJ ET BT 26.250 146.607 Td /F1 9.8 Tf [(Genetics/American Society of Human Genetics Huntington Disease Genetic Testing Working Group. Am J Hum Genet. 1998 )] TJ ET BT 26.250 134.702 Td /F1 9.8 Tf [(May;62\(5\):1243-7. PubMed PMID:9545416.)] TJ ET BT 26.250 115.297 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 115.297 Td /F1 9.8 Tf [(Unified Huntington's Disease Rating Scale: reliability and consistency. Huntington Study Group. Mov Disord. 1996 )] TJ ET BT 26.250 103.392 Td /F1 9.8 Tf [(Mar;11\(2\):136-42. PubMed PMID:8684382.)] TJ ET BT 26.250 83.988 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 83.988 Td /F1 9.8 Tf [(Paulsen JS, Langbehn DR, Stout JC, Aylward E, Ross CA, Nance M, Guttman M, Johnson S, MacDonald M, Beglinger LJ, )] TJ ET BT 26.250 72.083 Td /F1 9.8 Tf [(Duff K, Kayson E, Biglan K, Shoulson I, Oakes D, Hayden M. Detection of Huntington's disease decades before diagnosis: the )] TJ ET BT 26.250 60.178 Td /F1 9.8 Tf [(Predict-HD study. J Neurol Neurosurg Psychiatry. 2008 Aug;79\(8\):874-80. PubMed PMID:18096682.)] TJ ET Q q 15.000 50.297 577.500 726.703 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(which was successfully managed with a low dose of atypical psychotic.)] TJ ET BT 26.250 730.874 Td /F4 12.0 Tf [(Concluding Remarks)] TJ ET BT 26.250 710.919 Td /F1 9.8 Tf [(Broadly speaking, the purpose of clinical diagnosis is to infer the underlying cause of a persons symptoms and signs, in order )] TJ ET BT 26.250 699.015 Td /F1 9.8 Tf [(to provide prognostic information, and to guide treatment if available. In HD the purpose of clinical diagnosis can take on a )] TJ ET BT 26.250 687.110 Td /F1 9.8 Tf [(different significance. For instance, for a pre-manifest individual, the underlying cause \(genetic status\) may already be known, )] TJ ET BT 26.250 675.205 Td /F1 9.8 Tf [(and symptomatic treatment \(such as antidepressants\) may already be in place. The focus of clinical diagnosis may then lie in )] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(prognostication and social/legal consequences instead.)] TJ ET BT 26.250 643.896 Td /F1 9.8 Tf [(HD is a multi-system disease with a continuum of manifestations. Brain autopsy reports of pre-manifest individuals)] TJ ET 0.267 0.267 0.267 rg BT 518.255 645.403 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 523.073 647.784 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 525.483 645.403 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 530.301 643.896 Td /F1 9.8 Tf [( suggest )] TJ ET BT 26.250 631.991 Td /F1 9.8 Tf [(that changes in cellular composition/organization may begin very early in life. PREDICT-HD)] TJ ET 0.267 0.267 0.267 rg BT 420.170 633.498 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 424.988 631.991 Td /F1 9.8 Tf [( and TRACK-HD)] TJ ET 0.267 0.267 0.267 rg BT 497.041 633.498 Td /F4 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 501.859 631.991 Td /F1 9.8 Tf [( provide further )] TJ ET BT 26.250 620.086 Td /F1 9.8 Tf [(evidence that measures of neuronal dysfunction can be detected years prior to development of definite motor signs. However, )] TJ ET BT 26.250 608.181 Td /F1 9.8 Tf [(biologically, there may not be a single threshold that we can use to define disease onset, as different biomarkers may become )] TJ ET BT 26.250 596.277 Td /F1 9.8 Tf [(abnormal at different times in a persons life. In addition, depending on the threshold chosen, sensitivity will have to be traded )] TJ ET BT 26.250 584.372 Td /F1 9.8 Tf [(off against specificity for each biomarker, and not every biomarker will have the same clinical significance for different aspects of )] TJ ET BT 26.250 572.467 Td /F1 9.8 Tf [(HD. Expert consensus may be the only way to determine a threshold for diagnosis of clinical HD.)] TJ ET BT 26.250 553.062 Td /F1 9.8 Tf [(Despite this uncertainty, the notion of disease onset remains important for people with HD and their families. Likely age of )] TJ ET BT 26.250 541.158 Td /F1 9.8 Tf [(disease onset is one of the most frequently asked questions by families with HD, and this information is often used for life and )] TJ ET BT 26.250 529.253 Td /F1 9.8 Tf [(financial planning. Delayed diagnosis may unfairly disadvantage people with HD and cognitive-behavioral symptoms, )] TJ ET BT 26.250 517.348 Td /F1 9.8 Tf [(particularly in legal proceedings. A diagnosis of clinical HD can also release superannuation, insurance, and other social )] TJ ET BT 26.250 505.443 Td /F1 9.8 Tf [(benefits for people with HD.)] TJ ET BT 26.250 486.039 Td /F1 9.8 Tf [(A number of recent efforts have aimed to achieve earlier diagnosis for neurodegenerative conditions such as Alzheimer Disease)] TJ ET 0.267 0.267 0.267 rg BT 26.250 475.641 Td /F4 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 31.069 474.134 Td /F1 9.8 Tf [( and Parkinson Disease)] TJ ET 0.267 0.267 0.267 rg BT 134.029 475.641 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 138.847 474.134 Td /F1 9.8 Tf [( . The rationale for earlier diagnosis is to identify people likely to develop disease, and capture the )] TJ ET BT 26.250 462.229 Td /F1 9.8 Tf [(therapeutic window of opportunity before neuronal damage becomes irreversible. However for HD, genetic testing already )] TJ ET BT 26.250 450.324 Td /F1 9.8 Tf [(provides a highly accurate marker for future disease. While broadening the diagnostic spectrum may incidentally lead to earlier )] TJ ET BT 26.250 438.420 Td /F1 9.8 Tf [(diagnosis of clinical HD in some people, earlier diagnosis is not the primary intention.)] TJ ET BT 26.250 419.015 Td /F1 9.8 Tf [(Our current Motor 4 criteria does not reflect the full spectrum of manifestations in HD. A consensus statement broadening the )] TJ ET BT 26.250 407.110 Td /F1 9.8 Tf [(diagnostic spectrum will be particularly helpful for clinicians outside the HD centres. It will lend support to the diagnosis of non-)] TJ ET BT 26.250 395.205 Td /F1 9.8 Tf [(motor HD by individual clinicians, if challenged in the legal setting or in the context of social benefits. This could be achieved by )] TJ ET BT 26.250 383.301 Td /F1 9.8 Tf [(expert consensus and consultation with families with HD. As illustrated above, the diagnosis of clinical HD is made in a variety )] TJ ET BT 26.250 371.396 Td /F1 9.8 Tf [(of settings with social and legal consequences. A flexible rather than prescriptive approach is required, and extensive )] TJ ET BT 26.250 359.491 Td /F1 9.8 Tf [(consultation will be essential.)] TJ ET BT 26.250 322.889 Td /F4 12.0 Tf [(Ethics Statement)] TJ ET BT 26.250 302.934 Td /F1 9.8 Tf [(This paper was prepared in accordance to the World Medical Association Declaration of Helsinki. The Western Sydney Local )] TJ ET BT 26.250 291.030 Td /F1 9.8 Tf [(Health District Human Research Ethics Committee waived the requirement for consent as details of the cases were altered to )] TJ ET BT 26.250 279.125 Td /F1 9.8 Tf [(prevent identification)] TJ ET BT 26.250 242.522 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 222.568 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 185.966 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 158.511 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 158.511 Td /F1 9.8 Tf [(ACMG/ASHG statement. Laboratory guidelines for Huntington disease genetic testing. The American College of Medical )] TJ ET BT 26.250 146.607 Td /F1 9.8 Tf [(Genetics/American Society of Human Genetics Huntington Disease Genetic Testing Working Group. Am J Hum Genet. 1998 )] TJ ET BT 26.250 134.702 Td /F1 9.8 Tf [(May;62\(5\):1243-7. PubMed PMID:9545416.)] TJ ET BT 26.250 115.297 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 115.297 Td /F1 9.8 Tf [(Unified Huntington's Disease Rating Scale: reliability and consistency. Huntington Study Group. Mov Disord. 1996 )] TJ ET BT 26.250 103.392 Td /F1 9.8 Tf [(Mar;11\(2\):136-42. PubMed PMID:8684382.)] TJ ET BT 26.250 83.988 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 83.988 Td /F1 9.8 Tf [(Paulsen JS, Langbehn DR, Stout JC, Aylward E, Ross CA, Nance M, Guttman M, Johnson S, MacDonald M, Beglinger LJ, )] TJ ET BT 26.250 72.083 Td /F1 9.8 Tf [(Duff K, Kayson E, Biglan K, Shoulson I, Oakes D, Hayden M. Detection of Huntington's disease decades before diagnosis: the )] TJ ET BT 26.250 60.178 Td /F1 9.8 Tf [(Predict-HD study. J Neurol Neurosurg Psychiatry. 2008 Aug;79\(8\):874-80. PubMed PMID:18096682.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(4)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 144 0 obj << /Type /Annot /Subtype /Link /A 145 0 R /Border [0 0 0] /H /I /Rect [ 518.2545 644.6012 523.0732 653.4195 ] >> endobj 145 0 obj << /Type /Action >> endobj 146 0 obj << /Type /Annot /Subtype /Link /A 147 0 R /Border [0 0 0] /H /I /Rect [ 525.4825 644.6012 530.3012 653.4195 ] >> endobj 147 0 obj << /Type /Action >> endobj 148 0 obj << /Type /Annot /Subtype /Link /A 149 0 R /Border [0 0 0] /H /I /Rect [ 420.1695 632.6964 424.9882 641.5147 ] >> endobj 149 0 obj << /Type /Action >> endobj 150 0 obj << /Type /Annot /Subtype /Link /A 151 0 R /Border [0 0 0] /H /I /Rect [ 497.0407 632.6964 501.8593 641.5147 ] >> endobj 151 0 obj << /Type /Action >> endobj 152 0 obj << /Type /Annot /Subtype /Link /A 153 0 R /Border [0 0 0] /H /I /Rect [ 26.2500 474.8394 31.0687 483.6577 ] >> endobj 153 0 obj << /Type /Action >> endobj 154 0 obj << /Type /Annot /Subtype /Link /A 155 0 R /Border [0 0 0] /H /I /Rect [ 134.0287 474.8394 138.8473 483.6577 ] >> endobj 155 0 obj << /Type /Action >> endobj 156 0 obj << /Type /Annot /Subtype /Link /A 157 0 R /Border [0 0 0] /H /I /Rect [ 518.2545 644.6012 523.0732 653.4195 ] >> endobj 157 0 obj << /Type /Action >> endobj 158 0 obj << /Type /Annot /Subtype /Link /A 159 0 R /Border [0 0 0] /H /I /Rect [ 525.4825 644.6012 530.3012 653.4195 ] >> endobj 159 0 obj << /Type /Action >> endobj 160 0 obj << /Type /Annot /Subtype /Link /A 161 0 R /Border [0 0 0] /H /I /Rect [ 420.1695 632.6964 424.9882 641.5147 ] >> endobj 161 0 obj << /Type /Action >> endobj 162 0 obj << /Type /Annot /Subtype /Link /A 163 0 R /Border [0 0 0] /H /I /Rect [ 497.0407 632.6964 501.8593 641.5147 ] >> endobj 163 0 obj << /Type /Action >> endobj 164 0 obj << /Type /Annot /Subtype /Link /A 165 0 R /Border [0 0 0] /H /I /Rect [ 26.2500 474.8394 31.0687 483.6577 ] >> endobj 165 0 obj << /Type /Action >> endobj 166 0 obj << /Type /Annot /Subtype /Link /A 167 0 R /Border [0 0 0] /H /I /Rect [ 134.0287 474.8394 138.8473 483.6577 ] >> endobj 167 0 obj << /Type /Action >> endobj 168 0 obj << /Type /Annot /Subtype /Link /A 169 0 R /Border [0 0 0] /H /I /Rect [ 518.2545 644.6012 523.0732 653.4195 ] >> endobj 169 0 obj << /Type /Action >> endobj 170 0 obj << /Type /Annot /Subtype /Link /A 171 0 R /Border [0 0 0] /H /I /Rect [ 525.4825 644.6012 530.3012 653.4195 ] >> endobj 171 0 obj << /Type /Action >> endobj 172 0 obj << /Type /Annot /Subtype /Link /A 173 0 R /Border [0 0 0] /H /I /Rect [ 420.1695 632.6964 424.9882 641.5147 ] >> endobj 173 0 obj << /Type /Action >> endobj 174 0 obj << /Type /Annot /Subtype /Link /A 175 0 R /Border [0 0 0] /H /I /Rect [ 497.0407 632.6964 501.8593 641.5147 ] >> endobj 175 0 obj << /Type /Action >> endobj 176 0 obj << /Type /Annot /Subtype /Link /A 177 0 R /Border [0 0 0] /H /I /Rect [ 26.2500 474.8394 31.0687 483.6577 ] >> endobj 177 0 obj << /Type /Action >> endobj 178 0 obj << /Type /Annot /Subtype /Link /A 179 0 R /Border [0 0 0] /H /I /Rect [ 134.0287 474.8394 138.8473 483.6577 ] >> endobj 179 0 obj << /Type /Action >> endobj 180 0 obj << /Type /Page /Parent 3 0 R /Contents 181 0 R >> endobj 181 0 obj << /Length 9277 >> stream 0.271 0.267 0.267 rg q 15.000 478.905 577.500 298.095 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 759.976 Td /F1 9.8 Tf [(Biglan KM, Zhang Y, Long J, Geschwind M, Kang G, Killoran A, Lu W, McCusker E, Mills JA, Raymond LA, Testa C, )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Wojcieszek J and Paulsen JS. Refining the diagnosis of Huntington Disease: The PREDICT-HD study. Front. Aging Neurosci. )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(2013; 5:12.)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 716.762 Td /F1 9.8 Tf [(Albin RL, Young AB, Penney JB, Handelin B, Balfour R, Anderson KD, Markel DS, Tourtellotte WW, Reiner A. Abnormalities )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(of striatal projection neurons and N-methyl-D-aspartate receptors in presymptomatic Huntington's disease. N Engl J Med. 1990 )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(May 3;322\(18\):1293-8. PubMed PMID:1691447.)] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 673.548 Td /F1 9.8 Tf [(Gmez-Tortosa E, MacDonald ME, Friend JC, Taylor SA, Weiler LJ, Cupples LA, Srinidhi J, Gusella JF, Bird ED, Vonsattel )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(JP, Myers RH. Quantitative neuropathological changes in presymptomatic Huntington's disease. Ann Neurol. 2001 Jan;49\(1\):29-)] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(34. PubMed PMID:11198293.)] TJ ET BT 26.250 630.333 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 630.333 Td /F1 9.8 Tf [(Tabrizi SJ, Scahill RI, Durr A, Roos RA, Leavitt BR, Jones R, Landwehrmeyer GB, Fox NC, Johnson H, Hicks SL, Kennard )] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(C, Craufurd D, Frost C, Langbehn DR, Reilmann R, Stout JC. Biological and clinical changes in premanifest and early stage )] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol. 2011 Jan;10\(1\):31-42. )] TJ ET BT 26.250 594.619 Td /F1 9.8 Tf [(PubMed PMID:21130037.)] TJ ET BT 26.250 575.214 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 575.214 Td /F1 9.8 Tf [(Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, )] TJ ET BT 26.250 563.310 Td /F1 9.8 Tf [(Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. )] TJ ET BT 26.250 551.405 Td /F1 9.8 Tf [(Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-)] TJ ET BT 26.250 539.500 Td /F1 9.8 Tf [(Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7\(3\):280-)] TJ ET BT 26.250 527.595 Td /F1 9.8 Tf [(92. PubMed PMID:21514248.)] TJ ET BT 26.250 508.191 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 508.191 Td /F1 9.8 Tf [(Berg D. Is pre-motor diagnosis possible? The European experience. Parkinsonism Relat Disord. 2012 Jan;18 Suppl 1:S195-)] TJ ET BT 26.250 496.286 Td /F1 9.8 Tf [(8. PubMed PMID:22166433.)] TJ ET Q q 15.000 478.905 577.500 298.095 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 759.976 Td /F1 9.8 Tf [(Biglan KM, Zhang Y, Long J, Geschwind M, Kang G, Killoran A, Lu W, McCusker E, Mills JA, Raymond LA, Testa C, )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Wojcieszek J and Paulsen JS. Refining the diagnosis of Huntington Disease: The PREDICT-HD study. Front. Aging Neurosci. )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(2013; 5:12.)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 716.762 Td /F1 9.8 Tf [(Albin RL, Young AB, Penney JB, Handelin B, Balfour R, Anderson KD, Markel DS, Tourtellotte WW, Reiner A. Abnormalities )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(of striatal projection neurons and N-methyl-D-aspartate receptors in presymptomatic Huntington's disease. N Engl J Med. 1990 )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(May 3;322\(18\):1293-8. PubMed PMID:1691447.)] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 673.548 Td /F1 9.8 Tf [(Gmez-Tortosa E, MacDonald ME, Friend JC, Taylor SA, Weiler LJ, Cupples LA, Srinidhi J, Gusella JF, Bird ED, Vonsattel )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(JP, Myers RH. Quantitative neuropathological changes in presymptomatic Huntington's disease. Ann Neurol. 2001 Jan;49\(1\):29-)] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(34. PubMed PMID:11198293.)] TJ ET BT 26.250 630.333 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 630.333 Td /F1 9.8 Tf [(Tabrizi SJ, Scahill RI, Durr A, Roos RA, Leavitt BR, Jones R, Landwehrmeyer GB, Fox NC, Johnson H, Hicks SL, Kennard )] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(C, Craufurd D, Frost C, Langbehn DR, Reilmann R, Stout JC. Biological and clinical changes in premanifest and early stage )] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol. 2011 Jan;10\(1\):31-42. )] TJ ET BT 26.250 594.619 Td /F1 9.8 Tf [(PubMed PMID:21130037.)] TJ ET BT 26.250 575.214 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 575.214 Td /F1 9.8 Tf [(Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, )] TJ ET BT 26.250 563.310 Td /F1 9.8 Tf [(Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. )] TJ ET BT 26.250 551.405 Td /F1 9.8 Tf [(Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-)] TJ ET BT 26.250 539.500 Td /F1 9.8 Tf [(Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7\(3\):280-)] TJ ET BT 26.250 527.595 Td /F1 9.8 Tf [(92. PubMed PMID:21514248.)] TJ ET BT 26.250 508.191 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 508.191 Td /F1 9.8 Tf [(Berg D. Is pre-motor diagnosis possible? The European experience. Parkinsonism Relat Disord. 2012 Jan;18 Suppl 1:S195-)] TJ ET BT 26.250 496.286 Td /F1 9.8 Tf [(8. PubMed PMID:22166433.)] TJ ET Q q 15.000 478.905 577.500 298.095 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 759.976 Td /F1 9.8 Tf [(Biglan KM, Zhang Y, Long J, Geschwind M, Kang G, Killoran A, Lu W, McCusker E, Mills JA, Raymond LA, Testa C, )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Wojcieszek J and Paulsen JS. Refining the diagnosis of Huntington Disease: The PREDICT-HD study. Front. Aging Neurosci. )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(2013; 5:12.)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 716.762 Td /F1 9.8 Tf [(Albin RL, Young AB, Penney JB, Handelin B, Balfour R, Anderson KD, Markel DS, Tourtellotte WW, Reiner A. Abnormalities )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(of striatal projection neurons and N-methyl-D-aspartate receptors in presymptomatic Huntington's disease. N Engl J Med. 1990 )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(May 3;322\(18\):1293-8. PubMed PMID:1691447.)] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 673.548 Td /F1 9.8 Tf [(Gmez-Tortosa E, MacDonald ME, Friend JC, Taylor SA, Weiler LJ, Cupples LA, Srinidhi J, Gusella JF, Bird ED, Vonsattel )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(JP, Myers RH. Quantitative neuropathological changes in presymptomatic Huntington's disease. Ann Neurol. 2001 Jan;49\(1\):29-)] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(34. PubMed PMID:11198293.)] TJ ET BT 26.250 630.333 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 630.333 Td /F1 9.8 Tf [(Tabrizi SJ, Scahill RI, Durr A, Roos RA, Leavitt BR, Jones R, Landwehrmeyer GB, Fox NC, Johnson H, Hicks SL, Kennard )] TJ ET BT 26.250 618.429 Td /F1 9.8 Tf [(C, Craufurd D, Frost C, Langbehn DR, Reilmann R, Stout JC. Biological and clinical changes in premanifest and early stage )] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol. 2011 Jan;10\(1\):31-42. )] TJ ET BT 26.250 594.619 Td /F1 9.8 Tf [(PubMed PMID:21130037.)] TJ ET BT 26.250 575.214 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 575.214 Td /F1 9.8 Tf [(Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, )] TJ ET BT 26.250 563.310 Td /F1 9.8 Tf [(Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. )] TJ ET BT 26.250 551.405 Td /F1 9.8 Tf [(Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-)] TJ ET BT 26.250 539.500 Td /F1 9.8 Tf [(Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7\(3\):280-)] TJ ET BT 26.250 527.595 Td /F1 9.8 Tf [(92. PubMed PMID:21514248.)] TJ ET BT 26.250 508.191 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 508.191 Td /F1 9.8 Tf [(Berg D. Is pre-motor diagnosis possible? The European experience. Parkinsonism Relat Disord. 2012 Jan;18 Suppl 1:S195-)] TJ ET BT 26.250 496.286 Td /F1 9.8 Tf [(8. 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