Yen F. Tai

Amyloid, hypometabolism, and cognition in Alzheimer disease: An [11C]PIB and [18F]FDG PET study

Objective: To investigate the association between brain amyloid load in Alzheimer disease (AD) measured by [11C]PIB-PET, regional cerebral glucose metabolism (rCMRGlc) measured by [18F]FDG-PET, and cognition. Methods: Nineteen subjects with AD and 14 controls had [11C]PIB-PET and underwent a battery of psychometric tests. Twelve of those subjects with AD and eight controls had [18F]FDG-PET. Parametric images of [11C]PIB binding and rCMRGlc were interrogated with a region-of-interest atlas and statistical parametric mapping. [11C]PIB binding and rCMRGlc were correlated with scores on psychometric tests. Results: AD subjects showed twofold increases in mean [11C]PIB binding in cingulate, frontal, temporal, parietal, and occipital cortical areas. Higher cortical amyloid load correlated with lower scores on facial and word recognition tests. Two patients fulfilling the clinical criteria for AD had normal [11C]PIB at baseline. Over 20 months this remained normal in one but increased in the cingulate of the other. Mean levels of temporal and parietal rCMRGlc were reduced by 20% in AD and these correlated with mini mental scores, immediate recall, and recognition memory test for words. Higher [11C]PIB uptake correlated with lower rCMRGlc in temporal and parietal cortices. Conclusion: [11C]PIB-PET detected an increased amyloid plaque load in 89% of patients with clinically probable Alzheimer disease (AD). The high frontal amyloid load detected by [11C]PIB-PET in AD in the face of spared glucose metabolism is of interest and suggests that amyloid plaque formation may not be directly responsible for neuronal dysfunction in this disorder.

Compulsive drug use linked to sensitized ventral striatal dopamine transmission.

A small group of Parkinsons disease (PD) patients compulsively use dopaminergic drugs despite causing harmful social, psychological, and physical effects and fulfil core Diagnostic and Statistical Manual (of Mental Disorders) Fourth Edition criteria for substance dependence (dopamine dysregulation syndrome [DDS]). We aimed to evaluate levodopa‐induced dopamine neurotransmission in the striatum of patients with DDS compared with PD control patients.

Clinical correlates of levodopa-induced dopamine release in Parkinson disease : A PET study

Objective: To evaluate the relationship between clinical improvement and in vivo synaptic dopamine (DA) release after a single oral dose of levodopa (LD) in patients with advanced Parkinson disease (PD). Methods: We studied 16 patients with advanced PD with [11C]raclopride (RAC) PET. Each patient had RAC PET twice: once when medication had been withdrawn and once after an LD challenge. On the day of the LD challenge scan, oral 250 mg LD/25 mg carbidopa was given before scanning. Unified Parkinsons Disease Rating Scale (UPDRS) motor scores were rated in an “off” state before LD and again at the end of PET. Results: All the patients were still in “on” state at the end of their LD challenge RAC PET scans. Following LD, mean caudate and putamen RAC binding potentials (BPs) were significantly lower vs baseline, consistent with increased synaptic DA. Individual LD-induced improvements in UPDRS score correlated significantly with reductions in putaminal BP. Additionally, large putaminal RAC BP changes were associated with higher dyskinesia scores. When motor UPDRS subitems were examined, improvements in rigidity and bradykinesia, but not in tremor or axial symptoms, correlated with putamen DA release. Conclusion: In advanced Parkinson disease, the improvement of rigidity and bradykinesia and the presence of dyskinesias after a single dose of oral levodopa are governed by the level of dopamine generated at striatal D2 receptors. In contrast, relief of parkinsonian tremor and axial symptoms is not related to striatal synaptic dopamine levels and presumably occurs via extrastriatal mechanisms.

Microglial activation in regions related to cognitive function predicts disease onset in Huntington's Disease: A multimodal imaging study

Huntingtons disease (HD) is an inherited neurodegenerative disorder associated with motor, cognitive and psychiatric deficits. This study, using a multimodal imaging approach, aims to assess in vivo the functional and structural integrity of regions and regional networks linked with motor, cognitive and psychiatric function. Predicting disease onset in at risk individuals is problematic and thus we sought to investigate this by computing the 5‐year probability of HD onset (p5 HD) and relating it to imaging parameters. Using MRI, 11C‐PK11195 and 11C‐raclopride PET, we have investigated volumes, levels of microglial activation and D2/D3 receptor binding in CAG repeat‐matched groups of premanifest and symptomatic HD gene carriers. Findings were correlated with disease‐burden and UHDRS scores. Atrophy was detected in sensorimotor striatum (SMST), substantia nigra, orbitofrontal and anterior prefrontal cortex in the premanifest HD. D2/D3 receptor binding was reduced and microglial activation increased in SMST and associative striatum (AST), bed nucleus of the stria terminalis, the amygdala and the hypothalamus. In symptomatic HD cases this extended to involve atrophy in globus pallidus, limbic striatum, the red nuclei, anterior cingulate cortex, and insula. D2/D3 receptor binding was additionally reduced in substantia nigra, globus pallidus, limbic striatum, anterior cingulate cortex and insula, and microglial activation increased in globus pallidus, limbic striatum and anterior prefrontal cortex. In premanifest HD, increased levels of microglial activation in the AST and in the regional network associated with cognitive function correlated with p5 HD onset. These data suggest that pathologically activated microglia in AST and other areas related to cognitive function, maybe better predictors of clinical onset and stresses the importance of early cognitive assessment in HD. Hum Brain Mapp, 2011.

Hypothalamic involvement in Huntington's disease: an in vivo PET study

Recent studies have shown alterations in metabolism, sleep and circadian rhythms as well as in several neuropeptides derived from the hypothalamic-pituitary axis in Huntingtons disease patients; however, the pathology underlying these abnormalities is not known. Our aim was to assess in vivo D(2) receptors loss/dysfunction and increases in microglial activation in the hypothalamus of symptomatic Huntingtons disease patients and premanifest Huntingtons disease gene carriers using PET with (11)C-raclopride (RAC), a specific D(2) receptor ligand and (11)C-(R)-PK11195 (PK), a marker of microglial activation. We have studied 9 symptomatic Huntingtons disease patients (age = 46.8 +/- 4.7 years; mean +/- SD) and 10 premanifest Huntingtons disease gene carriers (age = 41.9 +/- 8.2 years; mean +/- SD). RAC and PK findings for these subjects were compared with those of a group of normal controls (RAC, n = 9; PK, n = 10). In the symptomatic Huntingtons disease group, we found a significant decrease (P = 0.0012) in mean hypothalamic RAC binding potential (BP) and a significant increase in mean hypothalamic PK BP (P = 0.0008). Similarly, a significant decrease (P = 0.0143) in mean hypothalamic RAC BP and a significant increase in mean hypothalamic PK BP (P = 0.0057) were observed in the premanifest Huntingtons disease group. Hypothalamic RAC and PK BP values correlated with each other in combined Huntingtons disease groups (r = -0.6180, P = 0.0048) but not with striatal RAC and PK BP values. Our data demonstrate, for the first time, significant D(2) receptor loss and microglia activation in the hypothalamus of Huntingtons disease. These pathological changes occur very early in the course of the disease and may partly explain the development of commonly reported symptoms in Huntingtons disease including progressive weight loss, alterations in sexual behaviour and disturbances in the wake-sleep cycle.

Imaging microglial activation in Huntington's disease

Activated microglia have been proposed to play a major role in the pathogenesis of Huntingtons Disease (HD). PK11195 is a ligand which binds selectively to peripheral benzodiazepine binding sites, a type of receptor selectively expressed by activated microglia in the central nervous system. Using (11)C-(R)-PK11195 positron emission tomography (PET), we have recently shown in vivo evidence of increased microglial activation in both symptomatic and presymptomatic HD gene carriers and that the degree of microglial activation in the striatum correlates with the severity of striatal dopamine D2 receptor dysfunction measured with (11)C-raclopride PET. Our findings indicate that microglial activation is an early process in the HD pathology, occurring before the onset of symptoms. The close spatial and temporal relationship between microglial activation and neuronal dysfunction lends further support to the pathogenic link between the two processes in HD. Further longitudinal studies are needed to fully elucidate this link.

Long-term clinical and positron emission tomography outcome of fetal striatal transplantation in Huntington's disease

Two patients with moderate Huntington’s disease (HD) received bilateral fetal striatal allografts. One patient demonstrated, for the first time, increased striatal D2 receptor binding, evident with 11C-raclopride positron emission tomography, and prolonged clinical improvement over 5 years, suggesting long term survival and efficacy of the graft. The other patient did not improve clinically or radiologically. Our results indicate that striatal transplantation in HD may be beneficial but further studies are needed to confirm this.

The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease

Huntingtons disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the ‘NEST-UK’ consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3–10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the ‘Core assessment program for intracerebral transplantations-HD’ assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntingtons Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

Cortical dopamine dysfunction in symptomatic and premanifest Huntington's disease gene carriers

We used (11)C-raclopride PET, a marker of D(2) dopamine receptor binding, and statistical parametric mapping (SPM) to localise cortical D(2) receptor dysfunction in individual Huntingtons disease (HD) gene carriers (16 symptomatic and 11 premanifest subjects) and assess its clinical significance. 62.5% of symptomatic HD patients and 54.5% of premanifest carriers showed cortical reductions in D(2) binding. The most frequent decreases in cortical binding in individual HD subjects were seen in temporal and frontal areas. Symptomatic HD subjects with decreased cortical D(2) binding had worse scores on neuropsychological tests assessing attention and executive functions than subjects without cortical dopamine dysfunction, notwithstanding comparable reduction in striatal D(2) binding and motor disability. Our results indicate that cortical dopaminergic dysfunction is common in both symptomatic and premanifest HD gene carriers. It is an early event in HD pathophysiology and could contribute to the impairment in neuropsychological performance in these patients.

Genetic linkage of autosomal dominant progressive supranuclear palsy to 1q31.1

Progressive supranuclear palsy (PSP) is a disorder of unknown pathogenesis. Familial clusters of PSP have been reported related to mutations of protein tau. We report the linkage of a large Spanish family with typical autosomal dominant PSP to a new locus in chromosome 1. Four members of this family had typical PSP, confirmed by neuropathology in one case. At least five ancestors had similar disease. Other members of the family have incomplete phenotypes. The power of the linkage analysis was increased by detecting presymptomatic individuals with 18F‐fluoro‐dopa and 18F‐deoxyglucose positron emission tomography. We screened the human genome with 340 polymorphic markers and we enriched the areas of interest with additional markers. The disease status was defined according to the clinical and positron emission tomography data. We excluded linkage to the tau gene in chromosome 17. PSP was linked, in this family, to one area of 3.4cM in chromosome 1q31.1, with a maximal multipoint < OD score of +3.53. This area contains at least three genes, whose relevance in PSP is unknown. We expect to further define the gene responsible for PSP, which could help to understand the pathogenesis of this disease and to design effective treatment. Ann Neurol 2005;57:634–641