PET and MR imaging in Parkinson’s disease patients with cognitive impairment. A study of dopaminergic dysfunction, amyloid deposition, cortical hypometabolism and brain atrophy

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It is characterized by a severe loss of substantia nigra dopaminergic neurons leading to dopamine depletion in the striatum. PD affects movement, producing motor symptoms such as rigidity, tremor and bradykinesia. Non-motor symptoms include autonomic dysfunction, neurobehavioral problems and cognitive impairment, which may lead to dementia. The pathophysiological basis of cognitive impairment and dementia in PD is unclear. The aim of this thesis was to study the pathophysiological basis of cognitive impairment and dementia in PD. We evaluated the relation between frontostriatal dopaminergic dysfunction and the cognitive symptoms in PD patients with [18F]Fdopa PET. We also combined [C]PIB and [¹⁸F]FDG PET and magnetic resonance imaging in PD patients with and without dementia. In addition, we analysed subregional striatal [¹⁸F]Fdopa PET data to find out whether a simple ratio approach would reliably separate PD patients from healthy controls. The impaired dopaminergic function of the frontostriatal regions was related to the impairment in cognitive functions, such as memory and cognitive processing in PD patients. PD patients with dementia showed an impaired glucose metabolism but not amyloid deposition in the cortical brain regions, and the hypometabolism was associated with the degree of cognitive impairment. PD patients had atrophy, both in the prefrontal cortex and in the hippocampus, and the hippocampal atrophy was related to impaired memory. A single 15-min scan 75 min after a tracer injection seemed to be sufficient for separating patients with PD from healthy controls in a clinical research environment. In conclusion, the occurrence of cognitive impairment and dementia in PD seems to be multifactorial and relates to changes, such as reduced dopaminergic activity, hypometabolism, brain atrophy and rarely to amyloid accumulation.

Apolipoprotein E and Recovery from Traumatic Brain Injury

The outcome from traumatic brain injury (TBI) is variable and only partly explained by known prognostic factors. This is especially true for predicting long-term outcome. Genetic factors may influence the brain`s susceptibility to injury or capacity for repair and regeneration. To examine the association of apolipoproteinE (apoE) genotype with long-term outcome, hippocampal volumes and general brain atrophy, we determined the apoE genotype from 61 TBI patients who had been injured over on average 31 years earlier. The long-term outcome was evaluated with repeated neuropsychological testing and by applying various measures of everyday functioning and quality of life. Magnetic resonance imaging (MRI) based volumetric analyses of the hippocampus and lateral ventricles were performed. In the prospective study, the purpose was to examine the association between apoE genotype and visibility of traumatic brain lesions during the first year after TBI and the ability of apoE genotype, the Glasgow Coma Score (GCS), MRI findings and duration of posttraumatic amnesia (PTA) to predict the one-year outcome. Thirty-three patients with TBI were studied and the outcome was evaluated with the Head Injury Symptom Checklist (HISC) and the Glasgow Outcome Scale extended version (GOS-E) scores one year after the injury. MRI and apoE genotyping were carried out. After three decades, neither hippocampal nor lateral ventricle volumes differed significantly in those patients with the apoE ε4 allele vs those without this allele, but the TBI patients with the apoE ε4 allele showed significantly poorer general cognitive level than those without this allele. This decline was wholly accounted for by a subgroup of patients who had developed incident or clinical dementia. In the prospective study the apoE genotype was not associated with visible MRI changes or outcome. The duration of PTA and acute MRI were the best predictors of one-year outcome in TBI. A portion of the TBI patients with the apoE ε4 allele seem to be at risk of long-term cognitive decline. This association may involve mechanisms other than those responsible for the development of brain atrophy. The early MRI and PTA have an important role in assessing the injury severity and prognosis.

Early Detection of Alzheimer's Disease Beta-amyloid Pathology -Applicability of Positron Emission Tomography with the Amyloid Radioligand 11C-PIB

Early Detection of Alzheimer's Disease Beta-amyloid Pathology -Applicability of Positron Emission Tomography with the Amyloid Radioligand ¹¹C-PIB Accumulation of beta amyloid (Abeta) in the brain is characteristic for Alzheimer’s disease (AD). Carbon-11 labeled 2-(4’-methylaminophenyl)-6-hydroxybenzothiazole (¹¹C-PIB) is a novel positron emission tomography (PET) amyloid imaging agent that appears to be applicable for in vivo Abeta plaque detection and quantitation. The biodistribution and radiation dosimetry of ¹¹C-PIB were investigated in 16 healthy subjects. The reproducibility of a simplified ¹¹C-PIB quantitation method was evaluated with a test-retest study on 6 AD patients and 4 healthy control subjects. Brain ¹¹C-PIB uptake and its possible association with brain atrophy rates were studied over a two-year follow-up in 14 AD patients and 13 healthy controls. Nine monozygotic and 8 dizygotic twin pairs discordant for cognitive impairment and 9 unrelated controls were examined to determine whether brain Abeta accumulation could be detected with ¹¹C-PIB PET in cognitively intact persons who are at increased genetic risk for AD. The highest absorbed radiation dose was received by the gallbladder wall (41.5 mjuGy/MBq). About 20 % of the injected radioactivity was excreted into urine, and the effective whole-body radiation dose was 4.7 mjuSv/MBq. Such a dose allows repeated scans of individual subjects. The reproducibility of the simplified ¹¹C-PIB quantitation was good or excellent both at the regional level (VAR 0.9-5.5 %) and at the voxel level (VAR 4.2-6.4 %). ¹¹C-PIB uptake did not increase during 24 months’ follow-up of subjects with mild or moderate AD, even though brain atrophy and cognitive decline progressed. Baseline neocortical ¹¹C-PIB uptake predicted subsequent volumetric brain changes in healthy control subjects (r = 0.725, p = 0.005). Cognitively intact monozygotic co-twins – but not dizygotic co-twins – of memory-impaired subjects exhibited increased ¹¹C-PIB uptake (117-121 % of control mean) in their temporal and parietal cortices and the posterior cingulate (p<0.05), when compared with unrelated controls. This increased uptake may be representative of an early AD process, and genetic factors seem to play an important role in the development of AD-like Abeta plaque pathology. ¹¹C-PIB PET may be a useful method for patient selection and follow-up for early-phase intervention trials of novel therapeutic agents. AD might be detectable in high-risk individuals in its presymptomatic stage with ¹¹C-PIB PET, which would have important consequences both for future diagnostics and for research on disease-modifying treatments.

Mild Cognitive Impairment and Early Detection of Alzheimer`s Disease. A Positron Emission Tomography Study

Alzheimer`s disease (AD) is characterised neuropathologically by the presence of extracellular amyloid plaques, intraneuronal neurofibrillary tangles, and cerebral neuronal loss. The pathological changes in AD are believed to start even decades before clinical symptoms are detectable. AD gradually affects episodic memory, cognition, behaviour and the ability to perform everyday activities. Mild cognitive impairment (MCI) represents a transitional state between normal aging and dementia disorders, especially AD. The predictive accuracy of the current and commonly used MCI criteria devide this disorder into amnestic (aMCI) and non-amnestic (naMCI) MCI. It seems that many individuals with aMCI tend to convert to AD. However many MCI individuals will remain stable and some may even recover. At present, the principal drugs for the treatment of AD provide only symptomatic and palliative benefits. Safe and effective mechanism-based therapies are needed for this devastating neurodegenerative disease of later life. In conjunction with the development of new therapeutic drugs, tools for early detection of AD would be important. In future one of the challenges will be to detect at an early stage these MCI individuals who will convert to AD. Methods which can predict which MCI subjects will convert to AD will be much more important if the new drug candidates prove to have disease-arresting or even disease–slowing effects. These types of drugs are likely to have the best efficacy if administered in the early or even in the presymptomatic phase of the disease when the synaptic and neuronal loss has not become too widespread. There is no clinical method to determine with certainly which MCI individuals will progress to AD. However there are several methods which have been suggested as predictors of conversion to AD, e.g. increased [11C] PIB uptake, hippocampal atrophy in MRI, low CSF A beta 42 level, high CSF tau-protein level, apolipoprotein E (APOE) ε4 allele and impairment in episodic memory and executive functions. In the present study subjects with MCI appear to have significantly higher [¹¹C] PIB uptake vs healthy elderly in several brain areas including frontal cortex, the posterior cingulate, the parietal and lateral temporal cortices, putamen and caudate. Also results from this PET study indicate that over time, MCI subjects who display increased [¹¹C] PIB uptake appear to be significantly more likely to convert to AD than MCI subjects with negative [¹¹C] PIB retention. Also hippocampal atrophy seems to increase in MCI individuals clearly during the conversion to AD. In this study [¹¹C] PIB uptake increases early and changes relatively little during the AD process whereas there is progressive hippocampal atrophy during the disease. In addition to increased [¹¹C] PIB retention and hippocampal atrophy, the status of APOE ε4 allele might contribute to the conversion from MCI to AD.

Imaging Neuroinflammation in Progressive Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system CNS), where inflammation and neurodegeneration lead to irreversible neuronal damage. In MS, a dysfunctional immune system causes auto‐reactive lymphocytes to migrate into CNS where they initiate an inflammatory cascade leading to focal demyelination, axonal degeneration and neuronal loss. One of the hallmarks of neuronal injury and neuroinflammation is the activation of microglia. Activated microglia are found not only in the focal inflammatory lesions, but also diffusely in the normal‐appearing white matter (NAWM), especially in progressive MS. The purine base, adenosine is a ubiquitous neuromodulator in the CNS and also participates in the regulation of inflammation. The effect of adenosine mediated via adenosine A2A receptors has been linked to microglial activation, whereas modulating A2A receptors may exert neuroprotective effects. In the majority of patients, MS presents with a relapsing disease course, later advancing to a progressive phase characterised by a worsening, irreversible disability. Disease modifying treatments can reduce the severity and progression in relapsing MS, but no efficient treatment exists for progressive MS. The aim of this research was to investigate the prevalence of adenosine A2A receptors and activated microglia in progressive MS by using in vivo positron emission tomography (PET) imaging and [11C]TMSX and [11C](R)‐PK11195 radioligands. Magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) was performed to evaluate structural brain damage. Non‐invasive input function methods were also developed for the analyses of [11C]TMSX PET data. Finally, histopathological correlates of [11C](R)‐PK11195 radioligand binding related to chronic MS lesions were investigated in post‐mortem samples of progressive MS brain using autoradiography and immunohistochemistry. [11C]TMSX binding to A2A receptors was increased in NAWM of secondary progressive MS (SPMS) patients when compared to healthy controls, and this correlated to more severe atrophy in MRI and white matter disintegration (reduced fractional anisotropy, FA) in DTI. The non‐invasive input function methods appeared as feasible options for brain [11C]TMSX images obviating arterial blood sampling. [11C](R)‐PK11195 uptake was increased in the NAWM of SPMS patients when compared to patients with relapsing MS and healthy controls. Higher [11C](R)‐PK11195 binding in NAWM and total perilesional area of T1 hypointense lesions was associated with more severe clinical disability, increased brain atrophy, higher lesion load and reduced FA in NAWM in the MS patients. In autoradiography, increased perilesional [11C](R)‐PK11195 uptake was associated with increased microglial activation identified using immunohistochemistry. In conclusion, brain [11C]TMSX PET imaging holds promise in the evaluation of diffuse neuroinflammation in progressive MS. Being a marker of microglial activation, [11C](R)‐ PK11195 PET imaging could possibly be used as a surrogate biomarker in the evaluation of the neuroinflammatory burden and clinical disease severity in progressive MS.

Late-onset spinal motor neuronopathy- a new neuromuscular disease

The aim of this study was to clarify the clinical phenotype of late-onset spinal motor neuronopathy (LOSMoN), an adult-onset autosomal dominant lower motor neuron disorder identified first in two families in Eastern Finland, in order to clarify its genetic background. Motor neuron disorders (MNDs) are characterized by dysfunction and premature death of motor neurons in the brain and spinal cord. MNDs can manifest at any age of the human lifespan, ranging from pre- or neonatal forms such as spinal muscular atrophy type I (SMA I) to those preferentially affecting the older age groups exemplified by sporadic amyotrophic lateral sclerosis (ALS). With a combination of genetic linkage analysis and genome sequencing using DNA from a total of 55 affected members of 17 families and a whole genome scan, we were able to show that LOSMoN is caused by the c.197G>T p.G66V mutation in the gene CHCHD10. This study showed that LOSMoN has very characteristic features that help to differentiate it from other more malignant forms of motor neuron disease, such as ALS, which was erroneously diagnosed in many patients in our cohort. Lack of fibrillations in the first dorsal interosseus muscle on EMG and extensive grouping of non-atrophic type IIA/2A fibers on muscle biopsy were shown to be common findings in LOSMoN, but rare or absent in ALS patients. The results of this study will help clinicians recognize the characteristic phenotype of LOSMoN disease and thus improve their diagnostic accuracy, and will also allow physicians to provide adequate genetic counseling for patients.

Neuroreceptor availability and cerebral morphology in human obesity

Obesity is a major challenge to human health worldwide. Little is known about the brain mechanisms that are associated with overeating and obesity in humans. In this project, multimodal neuroimaging techniques were utilized to study brain neurotransmission and anatomy in obesity. Bariatric surgery was used as an experimental method for assessing whether the possible differences between obese and non-obese individuals change following the weight loss. This could indicate whether obesity-related altered neurotransmission and cerebral atrophy are recoverable or whether they represent stable individual characteristics. Morbidly obese subjects (BMI ≥ 35 kg/m2) and non-obese control subjects (mean BMI 23 kg/m2) were studied with positron emission tomography (PET) and magnetic resonance imaging (MRI). In the PET studies, focus was put on dopaminergic and opioidergic systems, both of which are crucial in the reward processing. Brain dopamine D2 receptor (D2R) availability was measured using [11C]raclopride and µ-opioid receptor (MOR) availability using [11C]carfentanil. In the MRI studies, voxel-based morphometry (VBM) of T1-weighted MRI images was used, coupled with diffusion tensor imaging (DTI). Obese subjects underwent bariatric surgery as their standard clinical treatment during the study. Preoperatively, morbidly obese subjects had significantly lower MOR availability but unaltered D2R availability in several brain regions involved in reward processing, including striatum, insula, and thalamus. Moreover, obesity disrupted the interaction between the MOR and D2R systems in ventral striatum. Bariatric surgery and concomitant weight loss normalized MOR availability in the obese, but did not influence D2R availability in any brain region. Morbidly obese subjects had also significantly lower grey and white matter densities globally in the brain, but more focal changes were located in the areas associated with inhibitory control, reward processing, and appetite. DTI revealed also signs of axonal damage in the obese in corticospinal tracts and occipito-frontal fascicles. Surgery-induced weight loss resulted in global recovery of white matter density as well as more focal recovery of grey matter density among obese subjects. Altogether these results show that the endogenous opioid system is fundamentally linked to obesity. Lowered MOR availability is likely a consequence of obesity and may mediate maintenance of excessive energy uptake. In addition, obesity has adverse effects on brain structure. Bariatric surgery however reverses MOR dysfunction and recovers cerebral atrophy. Understanding the opioidergic contribution to overeating and obesity is critical for developing new psychological or pharmacological treatments for obesity. The actual molecular mechanisms behind the positive change in structure and neurotransmitter function still remain unclear and should be addressed in the future research.