Brain Dopamine Transporter Binding and Glucose Metabolism in Progressive Supranuclear Palsy-Like Creutzfeldt-Jakob Disease
A 58-year-old male was referred to a neurologist specialised in movement disorders in June 2009. He had a 6-month history of increasing clumsiness, forgetfulness, and apathy. The patient had a history of atrial fibrillation and concomitant mild dilative cardiomyopathy. He was taking warfarin, bisoprolol, digitalis, and candesartan. A 1.5-T brain MRI did not show clinically significant findings. A neurological examination revealed mildly diminished arm swing bilaterally, slight hypomimia, hypokinesia, cervical axial rigidity, and decreased frequency of blinking. The combination of hypokinesia, axial rigidity, and symmetrical extrapyramidal symptoms, in the absence of tremor, gave rise to suspicion of PSP. Levodopa was initiated with increasing doses up to 400 mg/day. One month later, increased latency in saccadic eye movements in downward gaze was noted, and postural retropulsion was evident. No favorable response to levodopa was noted, and the patient reported visual hallucinations. Consequently, the medication was withdrawn.\nThe patient was referred to the Neurology Outpatient Clinic of the University Hospital for further diagnostics and clinical follow-up. Dopamine transporter imaging with [123I]-FP-CIT-SPECT was performed 9 months after the onset of symptoms. The scan showed clear reductions in tracer binding in the left caudate nucleus compared to the right side and bilaterally in the posterior putamen (striatal to occipital uptake ratio: 2.42 on the right and 2.02 on the left) (fig. ). Neuropsychological testing revealed marked cognitive impairment manifesting as slowed executive functions and impaired working and short-term memory as well as visual recognition and processing. Psychomotor slowing and mild apraxia were also noted. FDG-PET showed widespread reductions in FDG binding bilaterally in cortical and deep grey matter, with a small area of preserved cortical binding in the frontoparietal region (fig. ). The FDG-PET findings were clinically interpreted to be suggestive of Lewy body dementia.\nDuring follow-up, rigidity further increased axially and also became present in the lower extremities. The patient's gaze was staring, and saccadic eye movements were slow. No tremor was present, but bradykinesia had increased substantially. At this time, in January 2010, he was still ambulatory, although he needed bilateral walking aids intermittently. In April 2010, the patient was admitted to an emergency unit due to deteriorating condition. He was now bedbound and aphasic, his upper limbs were in constant flexion, and intermittent myoclonic jerks, especially in the left upper limb, were present. CT of the head only revealed increased central atrophy. An EEG showed posterior theta-delta background activity with 3 slowly generalising spike-slow-wave discharges frontally without clinical motor symptoms. After intravenous lorazepam, the abnormal discharge subsided without improvement in the clinical status. The EEG was interpreted to be consistent with nonconvulsive status epilepticus, and the patient was treated with an intravenous loading dose of fosphenytoin and further with sodium valproate. However, his clinical condition remained essentially the same, and the suspicion of prion disease was raised. A control EEG, performed the next day, showed no epileptiform discharges, whereas semi-rhythmic, slow, mixed activity periods alternating with rhythmic, triphasic PED activity were evident. Per oral clonazepam (via nasogastric tube) alleviated, but did not stop, the myoclonic jerks. A brain MRI showed no structural abnormalities, whereas pathological changes in diffusion tensor imaging concurrent with CJD were seen (fig. ); however, other infectious or inflammatory etiology could not be excluded.\nIn cerebrospinal fluid (CSF) analysis, the protein content was elevated to 1,216 mg/l (normal range 150–450 mg/l), but no discoloration or pleocytosis was present, and comprehensive examinations revealed no signs of active autoimmune or infectious diseases. CSF Western blot analysis showed small amounts of 14-3-3 protein. The patient was unable to communicate or react meaningfully to physical stimuli, and at this point, 1.5 years since the first symptoms, he was transferred to a nursing home for palliative care. The patient succumbed 22 months after the onset of initial symptoms.\nIn order to confirm the diagnosis, a neuropathological examination was performed. Under macroscopic inspection, the cerebral cortex appeared atrophic and slightly spongiform. Atrophy of the caudate nucleus was apparent, and moderate dilatation of brain ventricles was noted. However, the striatum did not show any marked macroscopic changes. There were no major changes in the substantia nigra, pons or medulla, whereas marked atrophy of the cerebellum was observed. The histological samples showed marked spongiform changes in the cerebral cortex (fig. ). Abundant spongiform changes and gliosis as well as nerve cell loss were found in the caudate nucleus, putamen, and thalamus (fig. ). The substantia nigra did not show any obvious loss of neurons, but slight spongiosis was noted. In the cerebellum, a marked loss of Purkinje cells as well as granular cells was observed with numerous torpedoes in the granular cell layer. Immunohistochemically, a positive finding for prion protein was discovered using the monoclonal antibody 12F10, confirming the diagnosis of CJD.\nThis case study was conducted according to the World Association's Declaration of Helsinki. Since it was an observational retrospective study of a clinical patient case following the local guidelines of investigation and treatment procedures, no separate permission from the local ethics committee was needed. Written informed consent was obtained from the patient's caregiver.