Tomography in Progressive Supranuclear Palsy
Positron Emission
Mohit H. Bhatt, MD; Barry J. Snow, MBChB, FRACP; W. R. Wayne Martin, MD, FRCPC; Richard Peppard, MBBS, FRACP; Donald B. Calne, DM, FRCP, FRCPC
\s=b\ Positron emission tomography with 6-[18F]fluoro-L-dopa (6-FD) provides in vivo information on the function of nigrostriatal dopaminergic neurons. We used 6-FD and positron emission tomography to investigate the integrity of the nigrostriatal system in seven patients with progressive supranuclear palsy. All patients had axial hypertonia, vertical gaze palsy, and parkinsonian features. Dementia, pyramidal signs, and ataxia were seen in varying proportions. We analyzed the scans with a graphic method to calculate a steady-state 6-FD uptake rate
constant for the whole striatum. Results compared with those obtained in seven age-matched controls. As a group, the patients with progressive supranuclear palsy had reduced 6-FD uptake constants. The 6-FD uptake constant correlated inversely with the duration of the disease. Normal positron emission tographic findings in one patient with the shortest duration of symptoms suggests that in early progressive supranuclear palsy, parkinsonism may relate to dysfunction distal to the dopaminergic neurons. (Arcft Neuro/. 1991 ;48:389-391) were
supranuclear palsy (PSP) progressive is characterized by supranuclear
ophthalmoplegia, parkinsonism,
pseu-
Accepted for publication October 24,1990. From the Neurodegenerative Disorders Center, Department of Medicine, University Hospital, and the TRIUMF PET Program, University of British Columbia, Vancouver, Canada.
Presented, in part, at the World Federation of Neurology Meeting, New Delhi, India, October 22\x=req-\ 27, 1989, and at the First International Meeting of Movement Disorders, Washington, DC, April 25, 1990.
Reprint requests to Neurodegenerative Disorders Center, Department of Medicine, University of British Columbia, University Hospital, U.B.C. Site, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T1W5 (Dr Calne).
dobulbar palsy, axial hypertonia, and dementia with variable cerebellar atax¬ ia and pyramidal dysfunction.1"3 The parkinsonism in PSP may be related, at least in part, to dysfunction ofthe dopa¬ minergic pathway. In vivo studies with positron emission tomography (PET) should add to our understanding of the pathophysiologic processes involved in disorders in which the dopaminergic pathways may be preferentially af¬ fected, such as PSP. Positron emission tomography is particularly suited for the evaluation of early disease, in which postmortem information is seldom available. With 6-[laF]fluoro-L-dopa (6-FD) and PET, we can study the integrity of ni¬ grostriatal dopaminergic function. The injected 6-FD is transferred from blood to the striatum, where it is converted to
There were three men and four wom¬ with PSP; their ages ranged from 60 to 73 years (mean, 66.4 years). The av¬ erage duration of symptoms from onset to PET scan was was 42.5 months (range, 16 to 72 months).
the striatum is related to the functional integrity of the presynaptic nigrostria¬ tal dopaminergic nerve endings. This can be quantified by calculating a 6-FD uptake rate constant.4 In idiopathic par¬ kinsonism, the accumulation of 6-FD and its metabolites in the striatum is decreased, implying impairment in the
atrophy.
fluorodopamine by dopa-decarboxylase and trapped in the presynaptic vesicles. The retention of radioactivity within
presynaptic nigrostriatal dopaminergic function."
The aim of this study was to utilize PET to evaluate presynaptic nigrostria¬ tal dopaminergic function in PSP. The diagnosis of PSP was indepen¬ dently confirmed by two neurologists, using the clinical criteria of Maher and Lees.s The disease duration was esti¬ mated from history furnished by the pa¬ tients and other family members and from the medical records.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 06/17/2015
en
REPORT OF CASES
CASE 1.— A 67-year-old woman presented with a 36-month history of progressive mem¬ ory loss, falls, and difficulty in using her hands. Since onset, her mobility, memory, reasoning, and language had deteriorated, and she had developed urinary incontinence 1 year prior to her PET scan. On examination, there was marked perseveration of speech and motor tasks. She had loss of recent mem¬ ory. Conjugate eye movements were absent in downward and left gaze and impaired in up gaze but complete by vestibulo-ocular ma¬ neuver. She had hypomimia, brisk facial re¬ flexes, axial hypertonia, cogwheel rigidity at the wrists, and brisk deep tendon reflexes. The plantar responses were flexor. Com¬ puted tomography (CT) of the patient's head showed generalized brain-stem and cortical
CASE 2.—A 59-year-old man presented with a 49-month history of progressive im¬ balance and diplopia. He had a history of impairment in recent memory, dysphagia, and hypophonia. On examination, he had mild recent memory loss. His eye move¬ ments were impaired in down gaze by 50%, and up gaze was only possible to the midline. The limitation in gaze could not be overcome by the vestibulo-ocular maneuver. The blink rate was markedly reduced, and the facial reflexes were brisk. He had poor balance and walked with a broad-based gait, with his neck held in retroflexion. The tendon reflex¬ es were brisk. The plantar responses were flexor. Magnetic resonance imaging showed temporoparietal and generalized brain-stem
atrophy.
CASE 3.—A 61-year-old man presented with a 37-month history of progressively de¬ teriorating balance, frequent falls, loss of re-
change in personality. He difficulty in focusing his vision. On ex¬ amination, his speech was dysarthric and his recent memory was impaired. He had a 75% limitation in upward and downward gaze and
cent memory, and
had
25% limitation in horizontal gaze. Saccades absent vertically and impaired horizon¬ tally. Vestibulo-ocular responses were com¬ plete in both eyes. The patient's blink rate was less than one per minute, and he had hypomimia. His axial tone was normal. All his tendon reflexes were brisk. The plantar responses were flexor, and there was mini¬ mal hand ataxia. Magnetic resonance imag¬ ing showed predominant brain-stem a
were
atrophy.
CASE 4.—A 62-year-old woman presented with a 16-month history of frequent falls. On examination, there was no evidence of de¬ mentia. Her vertical conjugate eye move¬ ments were absent and horizontal move¬ ments impaired, with gaze-evoked horizontal nystagmus. She had mild cog¬ wheel rigidity at her wrists and increased axial tone. Her gait was wide based and she could not walk tandem. Her reflexes were normal. Magnetic resonance imaging showed prominent temporal atrophy, with midbrain and pontine atrophy. At the time of her PET scan, she was least affected and was symp¬ tomatic for the shortest duration compared with other patients. Two years after the PET scan, her illness had progressed with the development of marked parkinsonian fea¬ tures, dysarthria, and dysphagia without de¬ mentia. She declined a second PET scan. CASE 5.—A 69-year-old woman presented with a 72-month history of frequent falls, dysarthria, and diplopia. On examination, she had impaired recent memory and acalculia. Her upward and downward gaze were impaired, and there was abduction nystag¬ mus in both eyes. Conjugate eye movements were slow in all directions, especially down¬ ward. Vestibulo-ocular response was im¬ proved only in the upward direction. The blink rate was one per minute. She had hypo¬ mimia and brisk facial reflexes with an in¬ creased jaw jerk. Her axial tone was in¬ creased. Cogwheel rigidity was present in all limbs, and she had marked bradykinesia. The tendon reflexes were normal, and the plantar responses were flexor. Magnetic resonance imaging showed generalized cortical and midbrain atrophy. CASE 6.—A 73-year-old woman presented with a 40-month history of frequent falls, diplopia, and hand tremor. On examination, there was no evidence of dementia. Her ver¬ tical gaze was restricted, but her horizontal eye movements were full. Her saccadic eye movements were slow, and she had to use excessive neck movements to look to either side. Her vestibulo-ocular response im¬ proved the range of her vertical eye move¬ ments. Cogwheel rigidity was present at the wrists, and the axial tone was increased. She had a resting hand tremor with ataxia of the left arm and an ataxic gait. The tendon re¬ flexes were exaggerated with equivocal plantar responses. Magnetic resonance im¬ aging showed generalized cortical and brainstem atrophy.
CASE 7.—A 72-year-old with a 48-month history of
man a
presented shuffling
slow
gait and frequent falls. Subsequently, he de¬ veloped profound memory loss, dysphasic speech, urinary incontinence, and lack of spontaneity. On examination, he had profound dementia. Vertical gaze was re¬ stricted, pursuit was broken, and saccadic eye movements were slow. The vestibuloocular response was normal. The blink rate was two per minute. Axial tone was in¬
creased, and cogwheel rigidity
was
present
at both wrists. Tendon reflexes were exag¬ gerated with extensor plantar responses.
Magnetic resonance imaging showed gener¬ alized cortical and brain-stem atrophy. Patients 2, 3, 5, 6,and 7 were taking levo¬ dopa-carbidopa (Sinemet); patients 3 and 5 were also taking bromocriptine. Patients 1 and 4 had stopped all treatment because of poor response. There was no clinical im¬ provement noted among the patients who were taking medication. None ofthe patients were taking neuroleptics prior to their PET scan.
Seven age-matched controls underwent
PET scans. The controls were neurologically normal and not taking any medication. The ages of the controls ranged from 57 to 73 years (mean, 65.5 years). The individual ages of the controls and patients differed by a maximum of 3 years.
METHODS We used a PET protocol that has been approved by the University of British Co¬ lumbia, Vancouver, Canada. All medications were withdrawn the night before the scan. Positron-emitting fluorine 18 was incorpo¬ rated into a dopa derivative to produce 6-FD using a cyclotron (TRIUMF CP-42), as de¬ scribed elsewhere.'1'1" The PET studies were performed with the Uni versitv of British Co¬ lumbia TRIUMF PETT VI This apparatus permits emission data to be col¬ lected simultaneously from seven contiguous axial slices, with a center-to-center slice sep¬ aration of 14 mm, an average axial resolution of approximately 11-mm full width at half maximum, and an in-plane i'esolution aver¬ aging 9.2-mm full width at half maximum. All patients underwent a magnetic resonance imaging scan scan (Picker 0.15-T magnet), except for patient 1 who underwent a CT scan. Magnetic resonance imaging or CT was performed to locate the plane ofthe striatum. This plane was identified and marked above the orbitomeatal line with a pair of laser beams. The patient was then positioned so that the magnetic resonance imaging or CT plane that best visualized the striatum corre¬ sponded to the fifth PET slice. One hour before the scan, 100 mg of carbi¬ dopa was administered orally. This dose of
"system."
carbidopa prevents peripheral decarboxylation of labeled dopa.1- During scanning, the patient lay supine with head movements lim¬ ited by a molded thermoplastic face mask. A transmission scan was performed prior to tracer administration to permit attenuation correction to be applied to the emission data. Each subject received 74 to 129.5 MBq of 6-FD. Twelve sequential emission scans, each lasting 10 minutes, were performed, starting immediately after tracer admin¬ istration.
Sequential blood samples were obtained in
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 06/17/2015
Controls
PSP
Diagnosis Fig 1.—The individual 6-[,8F]fluoro-L-dopa (6-FD) uptake rate constants of the patients with progressive supranuclear palsy (PSP) and the controls are compared. As a group, patients with PSP had significantly reduced uptake rate constants compared with age-matched controls (PSP group mean[SD], 0.29[0.181]; controls, 0.71 [0.099];
P
Positron Emission
Mohit H. Bhatt, MD; Barry J. Snow, MBChB, FRACP; W. R. Wayne Martin, MD, FRCPC; Richard Peppard, MBBS, FRACP; Donald B. Calne, DM, FRCP, FRCPC
\s=b\ Positron emission tomography with 6-[18F]fluoro-L-dopa (6-FD) provides in vivo information on the function of nigrostriatal dopaminergic neurons. We used 6-FD and positron emission tomography to investigate the integrity of the nigrostriatal system in seven patients with progressive supranuclear palsy. All patients had axial hypertonia, vertical gaze palsy, and parkinsonian features. Dementia, pyramidal signs, and ataxia were seen in varying proportions. We analyzed the scans with a graphic method to calculate a steady-state 6-FD uptake rate
constant for the whole striatum. Results compared with those obtained in seven age-matched controls. As a group, the patients with progressive supranuclear palsy had reduced 6-FD uptake constants. The 6-FD uptake constant correlated inversely with the duration of the disease. Normal positron emission tographic findings in one patient with the shortest duration of symptoms suggests that in early progressive supranuclear palsy, parkinsonism may relate to dysfunction distal to the dopaminergic neurons. (Arcft Neuro/. 1991 ;48:389-391) were
supranuclear palsy (PSP) progressive is characterized by supranuclear
ophthalmoplegia, parkinsonism,
pseu-
Accepted for publication October 24,1990. From the Neurodegenerative Disorders Center, Department of Medicine, University Hospital, and the TRIUMF PET Program, University of British Columbia, Vancouver, Canada.
Presented, in part, at the World Federation of Neurology Meeting, New Delhi, India, October 22\x=req-\ 27, 1989, and at the First International Meeting of Movement Disorders, Washington, DC, April 25, 1990.
Reprint requests to Neurodegenerative Disorders Center, Department of Medicine, University of British Columbia, University Hospital, U.B.C. Site, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T1W5 (Dr Calne).
dobulbar palsy, axial hypertonia, and dementia with variable cerebellar atax¬ ia and pyramidal dysfunction.1"3 The parkinsonism in PSP may be related, at least in part, to dysfunction ofthe dopa¬ minergic pathway. In vivo studies with positron emission tomography (PET) should add to our understanding of the pathophysiologic processes involved in disorders in which the dopaminergic pathways may be preferentially af¬ fected, such as PSP. Positron emission tomography is particularly suited for the evaluation of early disease, in which postmortem information is seldom available. With 6-[laF]fluoro-L-dopa (6-FD) and PET, we can study the integrity of ni¬ grostriatal dopaminergic function. The injected 6-FD is transferred from blood to the striatum, where it is converted to
There were three men and four wom¬ with PSP; their ages ranged from 60 to 73 years (mean, 66.4 years). The av¬ erage duration of symptoms from onset to PET scan was was 42.5 months (range, 16 to 72 months).
the striatum is related to the functional integrity of the presynaptic nigrostria¬ tal dopaminergic nerve endings. This can be quantified by calculating a 6-FD uptake rate constant.4 In idiopathic par¬ kinsonism, the accumulation of 6-FD and its metabolites in the striatum is decreased, implying impairment in the
atrophy.
fluorodopamine by dopa-decarboxylase and trapped in the presynaptic vesicles. The retention of radioactivity within
presynaptic nigrostriatal dopaminergic function."
The aim of this study was to utilize PET to evaluate presynaptic nigrostria¬ tal dopaminergic function in PSP. The diagnosis of PSP was indepen¬ dently confirmed by two neurologists, using the clinical criteria of Maher and Lees.s The disease duration was esti¬ mated from history furnished by the pa¬ tients and other family members and from the medical records.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 06/17/2015
en
REPORT OF CASES
CASE 1.— A 67-year-old woman presented with a 36-month history of progressive mem¬ ory loss, falls, and difficulty in using her hands. Since onset, her mobility, memory, reasoning, and language had deteriorated, and she had developed urinary incontinence 1 year prior to her PET scan. On examination, there was marked perseveration of speech and motor tasks. She had loss of recent mem¬ ory. Conjugate eye movements were absent in downward and left gaze and impaired in up gaze but complete by vestibulo-ocular ma¬ neuver. She had hypomimia, brisk facial re¬ flexes, axial hypertonia, cogwheel rigidity at the wrists, and brisk deep tendon reflexes. The plantar responses were flexor. Com¬ puted tomography (CT) of the patient's head showed generalized brain-stem and cortical
CASE 2.—A 59-year-old man presented with a 49-month history of progressive im¬ balance and diplopia. He had a history of impairment in recent memory, dysphagia, and hypophonia. On examination, he had mild recent memory loss. His eye move¬ ments were impaired in down gaze by 50%, and up gaze was only possible to the midline. The limitation in gaze could not be overcome by the vestibulo-ocular maneuver. The blink rate was markedly reduced, and the facial reflexes were brisk. He had poor balance and walked with a broad-based gait, with his neck held in retroflexion. The tendon reflex¬ es were brisk. The plantar responses were flexor. Magnetic resonance imaging showed temporoparietal and generalized brain-stem
atrophy.
CASE 3.—A 61-year-old man presented with a 37-month history of progressively de¬ teriorating balance, frequent falls, loss of re-
change in personality. He difficulty in focusing his vision. On ex¬ amination, his speech was dysarthric and his recent memory was impaired. He had a 75% limitation in upward and downward gaze and
cent memory, and
had
25% limitation in horizontal gaze. Saccades absent vertically and impaired horizon¬ tally. Vestibulo-ocular responses were com¬ plete in both eyes. The patient's blink rate was less than one per minute, and he had hypomimia. His axial tone was normal. All his tendon reflexes were brisk. The plantar responses were flexor, and there was mini¬ mal hand ataxia. Magnetic resonance imag¬ ing showed predominant brain-stem a
were
atrophy.
CASE 4.—A 62-year-old woman presented with a 16-month history of frequent falls. On examination, there was no evidence of de¬ mentia. Her vertical conjugate eye move¬ ments were absent and horizontal move¬ ments impaired, with gaze-evoked horizontal nystagmus. She had mild cog¬ wheel rigidity at her wrists and increased axial tone. Her gait was wide based and she could not walk tandem. Her reflexes were normal. Magnetic resonance imaging showed prominent temporal atrophy, with midbrain and pontine atrophy. At the time of her PET scan, she was least affected and was symp¬ tomatic for the shortest duration compared with other patients. Two years after the PET scan, her illness had progressed with the development of marked parkinsonian fea¬ tures, dysarthria, and dysphagia without de¬ mentia. She declined a second PET scan. CASE 5.—A 69-year-old woman presented with a 72-month history of frequent falls, dysarthria, and diplopia. On examination, she had impaired recent memory and acalculia. Her upward and downward gaze were impaired, and there was abduction nystag¬ mus in both eyes. Conjugate eye movements were slow in all directions, especially down¬ ward. Vestibulo-ocular response was im¬ proved only in the upward direction. The blink rate was one per minute. She had hypo¬ mimia and brisk facial reflexes with an in¬ creased jaw jerk. Her axial tone was in¬ creased. Cogwheel rigidity was present in all limbs, and she had marked bradykinesia. The tendon reflexes were normal, and the plantar responses were flexor. Magnetic resonance imaging showed generalized cortical and midbrain atrophy. CASE 6.—A 73-year-old woman presented with a 40-month history of frequent falls, diplopia, and hand tremor. On examination, there was no evidence of dementia. Her ver¬ tical gaze was restricted, but her horizontal eye movements were full. Her saccadic eye movements were slow, and she had to use excessive neck movements to look to either side. Her vestibulo-ocular response im¬ proved the range of her vertical eye move¬ ments. Cogwheel rigidity was present at the wrists, and the axial tone was increased. She had a resting hand tremor with ataxia of the left arm and an ataxic gait. The tendon re¬ flexes were exaggerated with equivocal plantar responses. Magnetic resonance im¬ aging showed generalized cortical and brainstem atrophy.
CASE 7.—A 72-year-old with a 48-month history of
man a
presented shuffling
slow
gait and frequent falls. Subsequently, he de¬ veloped profound memory loss, dysphasic speech, urinary incontinence, and lack of spontaneity. On examination, he had profound dementia. Vertical gaze was re¬ stricted, pursuit was broken, and saccadic eye movements were slow. The vestibuloocular response was normal. The blink rate was two per minute. Axial tone was in¬
creased, and cogwheel rigidity
was
present
at both wrists. Tendon reflexes were exag¬ gerated with extensor plantar responses.
Magnetic resonance imaging showed gener¬ alized cortical and brain-stem atrophy. Patients 2, 3, 5, 6,and 7 were taking levo¬ dopa-carbidopa (Sinemet); patients 3 and 5 were also taking bromocriptine. Patients 1 and 4 had stopped all treatment because of poor response. There was no clinical im¬ provement noted among the patients who were taking medication. None ofthe patients were taking neuroleptics prior to their PET scan.
Seven age-matched controls underwent
PET scans. The controls were neurologically normal and not taking any medication. The ages of the controls ranged from 57 to 73 years (mean, 65.5 years). The individual ages of the controls and patients differed by a maximum of 3 years.
METHODS We used a PET protocol that has been approved by the University of British Co¬ lumbia, Vancouver, Canada. All medications were withdrawn the night before the scan. Positron-emitting fluorine 18 was incorpo¬ rated into a dopa derivative to produce 6-FD using a cyclotron (TRIUMF CP-42), as de¬ scribed elsewhere.'1'1" The PET studies were performed with the Uni versitv of British Co¬ lumbia TRIUMF PETT VI This apparatus permits emission data to be col¬ lected simultaneously from seven contiguous axial slices, with a center-to-center slice sep¬ aration of 14 mm, an average axial resolution of approximately 11-mm full width at half maximum, and an in-plane i'esolution aver¬ aging 9.2-mm full width at half maximum. All patients underwent a magnetic resonance imaging scan scan (Picker 0.15-T magnet), except for patient 1 who underwent a CT scan. Magnetic resonance imaging or CT was performed to locate the plane ofthe striatum. This plane was identified and marked above the orbitomeatal line with a pair of laser beams. The patient was then positioned so that the magnetic resonance imaging or CT plane that best visualized the striatum corre¬ sponded to the fifth PET slice. One hour before the scan, 100 mg of carbi¬ dopa was administered orally. This dose of
"system."
carbidopa prevents peripheral decarboxylation of labeled dopa.1- During scanning, the patient lay supine with head movements lim¬ ited by a molded thermoplastic face mask. A transmission scan was performed prior to tracer administration to permit attenuation correction to be applied to the emission data. Each subject received 74 to 129.5 MBq of 6-FD. Twelve sequential emission scans, each lasting 10 minutes, were performed, starting immediately after tracer admin¬ istration.
Sequential blood samples were obtained in
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 06/17/2015
Controls
PSP
Diagnosis Fig 1.—The individual 6-[,8F]fluoro-L-dopa (6-FD) uptake rate constants of the patients with progressive supranuclear palsy (PSP) and the controls are compared. As a group, patients with PSP had significantly reduced uptake rate constants compared with age-matched controls (PSP group mean[SD], 0.29[0.181]; controls, 0.71 [0.099];
P
