Brain network markers of abnormal cerebral glucose metabolism and blood flow in Parkinson＇s disease

Neuroimaging of cerebral glucose metabolism and blood flow is ideally suited to assay widely-distributed brain circuits as a result of local molecular events and behavioral modulation in the central nervous system. With the progress in novel analytical methodology, this endeavor has succeeded in unraveling the mechanisms underlying a wide spectrum of neurodegenerative diseases. In particular, statistical brain mapping studies have made significant strides in describing the pathophysiology of Parkinson＇s disease （PD） and related disorders by providing signature biomarkers to determine the systemic abnormalities in brain function and evaluate disease progression, therapeutic responses, and clinical correlates in patients. In this article, we review the relevant clinical applications in patients in relation to healthy volunteers with a focus on the generation of unique spatial covariance patterns associated with the motor and cognitive symptoms underlying PD. These characteristic biomarkers can be potentially used not only to improve patient recruitment but also to predict outcomes in clinical trials.     

Medication-induced hallucination and cerebral blood flow in Parkinson’s disease

Although hallucinations in Parkinson’s disease (PD) are not unusual in the long-term treatment with anti-parkinsonian agents, their mechanism is not fully understood. We compared both the neuropsychiatric state and the results of ^99mTc-labeled hexamethyl propyleneamine oxime single-photon emission computed tomography in 12 PD patients with medication-induced hallucinations and 21 PD patients without hallucinations. Hallucinatory patients showed significantly lower cerebral blood flow in left temporal regions than nonhallucinatory patients. The cerebral blood flow reduction in these regions may be related to the mechanism of medication-induced hallucinations in PD. Received: 19 May 1998 Received in revised form: 15 September 1998 Accepted: 26 September 1998     

CSF markers of neurodegeneration in Parkinson’s disease

Parkinson’s disease (PD) is a chronic, progressive, neurodegenerative disease with a multifactorial etiology. Protein accumulation is speculated by some to play a prominent role in the pathogenesis of PD. The severity of neurodegeneration should correlate with cerebrospinal fluid (CSF) levels of these neurodegenerative markers (NDMs). The aims of the study were to assess the CSF levels of tau protein, beta-amyloid (1–42), cystatin C, and clusterin in patients suffering from PD and in a control group, to compare the CSF levels between the two groups and to correlate them to PD duration. NDMs in the CSF were assessed in 32 patients suffering from PD and in a control group (CG) of 30 patients. The following statistically significant differences in the CSF were found: higher tau protein (p = 0.045) and clusterin levels (p = 0.004) in PD patients versus CG; higher tau protein levels (p = 0.033), tau protein/beta-amyloid (1–42) ratio (p = 0.011), and clusterin (p = 0.044) in patients suffering from PD for <2 years versus patients suffering PD for more than 2 years. No differences between beta-amyloid (1–42) and cystatin C CSF levels were found in the CG and PD patients groups. Significantly higher tau protein and clusterin CSF levels in the group of PD patients with disease duration of <2 years probably reflect the fact that most neurodegenerative changes in PD patients occur in the initial stage of disease.     

Brain functional specialization and cooperation in Parkinson’s disease

Brain Imaging and Behavior - Cerebral specialization and inter-hemispheric cooperation are two of the most prominent functional architectures of the human brain. Their dysfunctions may be related...     

Ultrasonographic measurement of cerebral blood flow,cerebral circulation time and cerebral blood volume in vascular and Alzheimer’s dementia

Vascular dementia (VD) and Alzheimer’s dementia (AD) are the most common differential diagnoses in patients with cognitive impairment. Although of different etiology, small vessel disease is postulated to be present in both conditions. We investigated global cerebral blood flow (CBF), global cerebral circulation time (CCT) and global cerebral blood volume (CBV) in VD and AD patients using a multimodal ultrasound (US) approach. 20 VD and 20 AD patients were included and compared with 12 age–matched controls. Duplex US of both internal carotid and vertebral arteries was performed to measure CBF. CCT was defined as the time delay of an echo–contrast bolus arrival between the internal carotid artery and internal jugular vein using extracranial Doppler. CBV was calculated as the product of CBF and CCT. CBF was significantly lower (VD: 570 ± 61; AD: 578 ± 77; controls: 733 ± 54ml/min) and CCT significantly longer (8.8 ± 2.6; 8.2 ± 1.4; 6.4 ± 0.8 s) in both patient groups compared with controls (p < 0.003). No difference in CBF and CCT was found between the two patient groups. CBV was similar in all three groups (82 ± 20; 79 ± 19; 78 ± 9 ml). The equally reduced CBF and prolonged CCT in VD and AD support the hypothesis, that small vessel disease is a relevant factor in both types of dementia. The presented multimodal US approach helps to assess the extent of changes in the global cerebral hemodynamics in patients with dementia but does not allow a differentiation between VD and AD. Drs. Schreiber and Doepp contributed equally to their work.     

Brain glucose metabolism: Role of Wnt signaling in the metabolic impairment in Alzheimer’s disease

The brain is an organ that has a high demand for glucose. In the brain, glucose is predominantly used in energy production, with almost 70% of the energy used by neurons. The importance of the energy requirement in neurons is clearly demonstrated by the fact that all neurodegenerative disorders exhibit a critical metabolic impairment that includes decreased glucose uptake/utilization and decreased mitochondrial activity, with a consequent diminution in ATP production. In fact, in Alzheimer’s disease, the measurement of the general metabolic rate of the brain has been reported to be an accurate tool for diagnosis. Additionally, the administration of metabolic activators such as insulin/glucagon-like peptide 1 can improve memory/learning performance. Despite the importance of energy metabolism in the brain, little is known about the cellular pathways involved in the regulation of this process. Several reports postulate a role for Wnt signaling as a general metabolic regulator. Thus, in the present review, we discuss the antecedents that support the relationship between Wnt signaling and energy metabolism in the Alzheimer’s disease.     

Pathological features of cerebral cortical capillaries are doubled in Alzheimer’s disease and Parkinson’s disease

Cerebral capillaries represent a major interface between the general circulation and the central nervous system and are responsible for sufficient and selective nutrient transport to the brain. Structural damage or dysfunctioning carrier systems of such an active barrier leads to compromised nutrient trafficking. Subsequently, a decreased nutrient availability in the neural tissue may contribute to hampered neuronal metabolism, hence to behavioral and cognitive functional deficiencies. Here we focus on the ultrastrucutral abnormalities of cerebral microvessels in Alzheimer’s disease (AD; n = 5) and Parkinson’s diseasse (PD; n = 10). The capillary microanatomy in samples from the cingulate cortex was investigated by electron microscopy and severe damage to the vessel walls was observed. Characteristic pathological changes including capillary basement membrane thickening and collagen accumulation in the basement membrane were enhanced in both AD and PD. The incidence of capillaries with basement membrane deposits was two times higher in AD and PD than in age-matched controls. Degenerative pericytes in all groups appeared at a similar frequency. The data indicate that basement membrane deposists, as opposed to pericytic degeneration, represent an important pathological feature of AD and PD and suggest that capillary dysfunction may play a causal role in the development of these two major neurodegenerative diseases. Received: 21 July 1999 / Revised, accepted: 21 December 1999     

Temporal prolongation of decreased skin blood flow causes cold limbs in Parkinson’s disease

To unravel the pathogenesis of cold limbs in Parkinson’s disease, we evaluated cutaneous vasomotor neural function in 25 Parkinson’s disease patients with or without cold limbs and 20 healthy controls. We measured resting skin sympathetic nerve activity, as well as reflex changes of skin blood flow and skin sympathetic nerve activity after electrical stimulation, with the parameters including skin sympathetic nerve activity frequency at rest, the amplitude of reflex bursts, the absolute decrease and percent reduction of blood flow, and the recovery time which was calculated as the interval from the start of blood flow reduction until the return to baseline cutaneous blood flow. The resting frequency of skin sympathetic nerve activity was significantly lower in patients with Parkinson’s disease than in controls (p < 0.01). There were no significant differences between the patients and controls with respect to the amplitude of skin sympathetic nerve activity and the absolute decrease or percent reduction of blood flow volume. In the controls, the recovery time (9.4 ± 1.2), which was similar to Parkinson’s disease patients without cold limbs (9.0 ± 0.7), while the recovery time ranged (15.7 ± 3.2) in Parkinson’s disease patients with cold limbs. Recovery was significantly slower in these patients compared with the other groups (p < 0.05). It is possible that cold limbs might arise due to impaired circulation based on prolonged vasoconstriction by peripheral autonomic impairments, in addition to central autonomic dysfunction in Parkinson’s disease.     

Brain flow changes before and after deep brain stimulation of the subthalamic nucleus in Parkinson’s disease

Abstract. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) markedly improves motor symptoms and reduces medication needs in Parkinsons disease (PD) patients. However, its effect on brain function has remained unclear. We used SPECT and the tracer ECD to measure regional cerebral blood flow before and 6 months after DBS of the STN in 22 PD patients and 13 healthy controls. PD patients were divided into good and poor responders to DBS, if changes in off UPDRS motor scores after surgery were >60% or <40%, respectively. Statistical analysis was performed using the SPM99 software. At baseline, all PD patients showed significant perfusion reductions in cortical areas (premotor frontal, parietal, and occipital). After DBS, changes were normalized only in the good responders, while cortical defects in the poor responders were unchanged. No flow decrements were detected in basal ganglia and thalamus in both groups, suggesting that DBS does not have a lesion-like effect. We conclude that good surgery outcome is associated with normalization of cortical flow abnormalities in PD.     

Risk factors and prodromal markers and the development of Parkinson’s disease

Identification of risk factors and prodromal markers for Parkinson’s disease (PD) and the understanding of the point in time of first occurrence is essential for the early detection of incident PD. In this three-center longitudinal, observational study, we evaluated the specific risk for PD associated with single or combinations of risk factors and prodromal markers. In addition, we evaluated which risk factors and prodromal markers emerge at which time before the diagnosis of PD. Of the 1,847 at-baseline PD-free individuals ≥50 years, 1,260 underwent the 5-year follow-up assessment. There were 21 cases of incident PD during the study period. Enlarged hyperechogenic substantia nigra was the most frequent baseline sign in individuals developing PD after 3 years (80.0 %) and 5 years (85.7 %) compared to healthy controls (17.5 %) followed by the occurrence of mild parkinsonian signs and hyposmia. Evaluation of the signs at the first follow-up assessment showed that individuals developing PD after two additional years showed the same pattern of signs as individuals who developed PD 3 years after baseline assessment.     

Longitudinal PET evaluation of cerebral glucose metabolism in rivastigmine treated patients with mild Alzheimer’s disease

Summary. In this study 11 patients with mild Alzheimer’s disease (AD) were treated with the cholinesterase inhibitor rivastigmine (mean dose 8.6 ± 1.3’mg) for 12 months and underwent positron emission tomography (PET) studies of cerebral glucose metabolism (CMRglc) and neuropsychological testing at baseline and after 12 months. An untreated group of 10 AD patients served as control group. While the untreated AD patients showed a significant decline of CMRglc in the temporo-parietal and frontal cortical regions after 12 months follow-up the rivastigmine-treated patients showed no decline in CMRglc in corresponding cortical brain regions. Furthermore, a significant dose-related increase in CMRglc was recorded in the right frontal association region after 12 months rivastigmine treatment. A positive correlation was observed between changes in CMRglc and several cognitive tests in patients receiving higher doses (10.5–12’mg) of rivastigmine. These results suggest a stabilization effect of rivastigmine on CMRglc in mild AD patients receiving long-term rivastigmine treatment.     

Characteristic deterioration of ADAS-Jcog subscale scores and correlations with regional cerebral blood flow reductions in Alzheimer’s disease

Neurological Sciences - The Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale (ADAS-Jcog) is composed of a number of subscale tasks. However, it is not clear which subscale...     

Acute effects of adaptive Deep Brain Stimulation in Parkinson’s disease

BackgroundBeta-based adaptive Deep Brain Stimulation (aDBS) is effective in Parkinson’s disease (PD), when assessed in the immediate post-implantation phase. However, the potential benefits of aDBS in patients with electrodes chronically implanted, in whom changes due to the microlesion effect have disappeared, are yet to be assessed.MethodsTo determine the acute effectiveness and side-effect profile of aDBS in PD compared to conventional continuous DBS (cDBS) and no stimulation (NoStim), years after DBS implantation, 13 PD patients undergoing battery replacement were pseudo-randomised in a crossover fashion, into three conditions (NoStim, aDBS or cDBS), with a 2-min interval between them. Patient videos were blindly evaluated using a short version of the Unified Parkinson’s Disease Rating Scale (subUPDRS), and the Speech Intelligibility Test (SIT).ResultsMean disease duration was 16 years, and the mean time since DBS-implantation was 6.9 years. subUPDRS scores (11 patients tested) were significantly lower both in aDBS (p=<.001), and cDBS (p = .001), when compared to NoStim. Bradykinesia subscores were significantly lower in aDBS (p = .002), and did not achieve significance during cDBS (p = .08), when compared to NoStim. Two patients demonstrated re-emerging tremor during aDBS. SIT scores of patients who presented stimulation-induced dysarthria significantly worsened in cDBS (p = .009), but not in aDBS (p = .407), when compared to NoStim. Overall, stimulation was applied 48.8% of the time during aDBS.ConclusionBeta-based aDBS is effective in PD patients with bradykinetic phenotypes, delivers less stimulation than cDBS, and potentially has a more favourable speech side-effect profile. Patients with prominent tremor may require a modified adaptive strategy.     

Plasma oxidative and inflammatory markers in patients with idiopathic Parkinson’s disease

Parkinson's disease (PD) is the most common neurodegenerative disorder after alzheimer's disease. Neuroinflammation and oxidative damage are implicated to be responsible for the pathogenesis of neurodegenerative diseases. However, there are a few studies showing the changes in the biomarkers for neuroinflammation and oxidative damage in neurodegenerative diseases. In our study we aimed to examine the role of the molecules that are involved in oxidative stress and inflammation in PD patients taking L: -dopa treatment. Oxidized-LDL (ox-LDL), high-sensitivity C-reactive protein (hs-CRP) and the soluble intracellular adhesion molecule (ICAM) were chosen as biomarkers for systemic inflammation and oxidative damage. The patients were classified according to the Hoehn-Yahr staging system. Forty-five idiopathic L: -dopa-given PD patients and 25 age-matched healthy controls were examined. Plasma ox-LDL and ICAM levels were significantly higher in PD patients when compared with controls (p?相似文献   

Regional cerebral blood flow and abnormal eating behavior in Prader–Willi syndrome

Background: Prader–Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder and is generally regarded as a genetic model of obesity. Individuals with PWS exhibit behavioral symptoms including temper tantrums, rigid thinking, and compulsive behavior. The most striking feature of PWS is abnormal eating behavior, including hyperphagia, intense preoccupation with food, and incessant food seeking. To explore brain regions associated with the behavioral symptoms of PWS, we investigated differences in resting-state regional cerebral blood flow (rCBF) between individuals with PWS and healthy controls. Correlation analyses were also performed to examine the relationship between rCBF and altered eating behavior in PWS individuals. Methods: Twelve adults with PWS and 13 age- and gender-matched controls underwent resting-state single photon emission computerized tomography (SPECT) with N-isopropyl-p-[¹²³I] iodoamphetamine (IMP). The rCBF data were analyzed on a voxel-by-voxel basis using SPM5 software. Results: The results demonstrated that compared with controls, individuals with PWS had significantly lower rCBF in the right thalamus, left insular cortex, bilateral lingual gyrus, and bilateral cerebellum. They had significantly higher rCBF in the right inferior frontal gyrus, left middle/inferior frontal gyrus (anterior and posterior clusters), and bilateral angular gyrus. Additionally, rCBF in the left insula, which was significantly lower in PWS individuals, was negatively correlated with the eating behavior severity score. Conclusions: These results suggest that specific brain regions, particularly the left insula, may be partly responsible for the behavioral symptoms in PWS.     

Relation of risk factors and putative premotor markers for Parkinson’s disease

As both risk and premotor markers are increasingly discussed to play a key role in the pre-diagnostic phase of Parkinson’s disease (PD) the aim of this study was to determine the relation between the risk factors hyperechogenicity of the substantia nigra (SN+) and/or positive family history of PD (faPD+) and putative premotor markers for PD. In a cross-sectional analysis of data of the PRIPS cohort, 1,149 volunteers older than 50 years free of PD were included. In addition to the risk factors SN+ and faPD+, olfactory dysfunction was tested using the Sniffin’ sticks test and motor examination was performed. History of depression and constipation was evaluated by a semi-structured interview. Of all 1,149 individuals, 880 had none of the risk markers (76.6%), 143 persons (12.4%) had SN+, 84 (7.3%) were classified as faPD+ and 42 (3.7%) persons had both risk factors. Volunteers with SN+ showed olfactory dysfunction and mild motor impairment (p ≤ 0.001) more often. Depression was more prominent in individuals having two risk factors (p = 0.05). An accumulation of premotor markers was seen in the SN+ group with or without concomitant faPD+, but not in persons with faPD+ only. The profile of premotor markers seems to differ in participants having SN+ and/or faPD+, with SN+ showing the overall highest association with most premotor markers, which implies that SN+ might be a strong indicator for a neurodegenerative process.     

Parkinson’s disease in patients and obligate carriers of Gaucher disease

BackgroundGaucher disease is an autosomal recessive disorder caused by glucocerebrosidase gene mutations. Accumulating evidence from several Parkinson’s disease cohorts of varying ethnicities suggests that glucocerebrosidase mutations even in the heterozygous state (carriers) may be a susceptibility factor for Parkinson’s. Very few studies have analyzed the frequency of Parkinson’s in carriers and individuals with Gaucher disease.ObjectiveTo determine frequency of Parkinson’s in patients with Gaucher disease and obligate carriers of glucocerebrosidase mutations and compare it with a control group.MethodsA questionnaire was completed by 100 Ashkenazi Jewish Gaucher patients followed at our center and 109 ethnicity-matched controls with no personal or family history of Gaucher disease.ResultsFrequency of Parkinson’s was higher in Gaucher patients (8/100) than in controls (0/109; P = 0.0024). Frequency of Parkinson’s in obligate carriers (11/200) was higher than controls (6/218), but the difference was not statistically significant (P = 0.215). Average age of onset of Parkinson’s was earlier in Gaucher patients (57.2) than the general population and in obligate carriers (60) when compared with controls (76.8; P = 0.01). The L444P genotype was more frequent in Gaucher patients who reported a parent with Parkinson’s (36.40%) than those who did not (4.50%).ConclusionOur study suggests that the risk for developing Parkinson’s may be higher in affected versus carriers of glucocerebrosidase mutations and suggests that L444P may pose a higher risk of developing Parkinson’s than other mutations. It also confirms previous findings that the age of onset of Parkinson’s associated with glucocerebrosidase mutations is earlier than in the general population.     

Brain perfusion effects of cholinesterase inhibitors in Parkinson’s disease with dementia

Summary. Several evidences suggest that cholinergic deficits may significantly contribute to dementia in Parkinson’s disease (PDD) and acetylcholinesterase inhibitors (ChEIs) have been reported to improve cognitive symptoms in PDD, without worsening parkinsonism. Nineteen PDD patients underwent brain perfusion SPECT with ^99mTc-ethyl cysteinate dimer after 6 months ChEIs treatment in order to evaluate the functional correlates of clinical improvement. A clear-cut cognitive improvement was reported in PDD patients with a significant improvement of ADAS-cog total score as well as of subscores exploring executive functions (p < 0.01). MMSE total score did not significantly change after ChEIs but the subscore of attention significantly improved after therapy (p < 0.01). No difference in motor performance as evaluated by UPDRS was reported. SPM analysis showed a significant increase of perfusion (p < 0.0001) in bilateral cingulate, and frontal regions after ChEIs. Our data confirm the efficacy of ChEIs in the treatment of dementia associated with PD mainly on attention and executive functions, and the functional findings indicate that this cognitive improvement could be associated with a sort of pharmacological frontal “re-afferentation”.     

Depression and apathy in Parkinson’s disease

This article provides an update on depression and apathy in Parkinson’s disease (PD), both of which are common but often misunderstood. The diagnosis of depression in PD can be challenging and we still do not have solid evidence on which to base our treatment decisions. Apathy is most commonly seen in the setting of dementia or depression but emerging evidence suggests that it may be a core feature of PD. There are conflicting reports about the effects of deep brain stimulation (DBS) on mood and apathy, but studies suggest that at least some patients may develop depression and apathy after the procedure. Although we are making strides toward a better understanding of depression and apathy in PD, it is clear that more research is needed about these non-motor features.