Clinical and brain imaging characteristics in leucine-rich repeat kinase 2-associated PD and asymptomatic mutation carriers.

The objective of this research was to evaluate a possible endophenotype in leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Ten symptomatic LRRK2 patients, 24 sporadic Parkinson's disease patients as well as 10 asymptomatic LRRK2 mutation carriers and 29 matched healthy controls underwent comprehensive clinical assessments with respect to motor and non-motor symptoms. Transcranial sonography and magnetic resonance imaging (voxel-based morphometry [VBM]) were assessed to evaluate morphological imaging characteristics. LRRK2 patients had an earlier onset of motor symptoms and a more benign phenotype of motor and non-motor characteristics compared to sporadic Parkinson's disease patients. However, depression scores were higher in LRRK2 patients. No clinical differences were found regarding motor and non-motor symptoms in asymptomatic LRRK2 mutation carriers in comparison to controls. Transcranial sonography showed hyperechogenicity of the substantia nigra in both patients' cohorts as well as in asymptomatic LRRK2 mutation carriers. Voxel-based morphometry revealed increased gray matter volume of the cerebellum and precentral gyrus in LRRK2 patients and of the cuneus in asymptomatic LRRK2 mutation carriers. In contrast, we found decreased basal ganglia gray matter volume in LRRK2 patients compared to controls. Increased gray matter volume of different anatomical structures associated with motor loops in LRRK2 patients and asymptomatic LRRK2 mutation carriers compared to age-matched sporadic Parkinson's disease patients and controls might indicate compensatory mechanism in LRRK2 mutation carriers due to motor network plasticity not only in the symptomatic stage of the disease but even in the premotor phase. Substantia nigra hyperechogenicity in yet unaffected LRRK2 mutation carriers indicates morphologic alterations in an asymptomatic stage of disease.

Pros and cons of a prion-like pathogenesis in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder which affects widespread areas of the brainstem, basal ganglia and cerebral cortex. A number of proteins are known to accumulate in parkinsonian brains including ubiquitin and α-synuclein. Prion diseases are sporadic, genetic or infectious disorders with various clinical and histopathological features caused by prion proteins as infectious proteinaceous particles transmitting a misfolded protein configuration through brain tissue. The most important form is Creutzfeldt-Jakob disease which is associated with a self-propagating pathological precursor form of the prion protein that is physiologically widely distributed in the central nervous system. DISCUSSION: It has recently been found that α-synuclein may behave similarly to the prion precursor and propagate between cells. The post-mortem proof of α-synuclein containing Lewy bodies in embryonic dopamine cells transplants in PD patient suggests that the misfolded protein might be transmitted from the diseased host to donor neurons reminiscent of prion behavior. The involvement of the basal ganglia and brainstem in the degenerative process are other congruencies between Parkinson's and Creutzfeldt-Jakob disease. However, a number of issues advise caution before categorizing Parkinson's disease as a prion disorder, because clinical appearance, brain imaging, cerebrospinal fluid and neuropathological findings exhibit fundamental differences between both disease entities. Most of all, infectiousness, a crucial hallmark of prion diseases, has never been observed in PD so far. Moreover, the cellular propagation of the prion protein has not been clearly defined and it is, therefore, difficult to assess the molecular similarities between the two disease entities. SUMMARY: At the current state of knowledge, the molecular pathways of transmissible pathogenic proteins are not yet fully understood. Their exact involvement in the pathophysiology of prion disorders and neurodegenerative diseases has to be further investigated in order to elucidate a possible overlap between both disease categories that are currently regarded as distinct entities.

Frontline ADAPT therapy to treat patients with symptomatic M2 and M3 occlusions in acute ischemic stroke: initial experience with the Penumbra ACE and 3MAX reperfusion system.

BACKGROUND: After a series of positive studies for mechanical thrombectomy in large vessel occlusion acute ischemic stroke, the question remains, can symptomatic patients with distal vessel occlusion benefit from mechanical thrombectomy? PURPOSE: To assess the safety and efficacy of the 3MAX reperfusion system as frontline therapy for M2 and M3 occlusions. METHODS: This study retrospectively collected data on 58 patients treated for M2 and M3 occlusions between January and September 2016. Of these 58 patients, 31 had an isolated M2 or M3 occlusion. Eligible patients were treated with 3MAX by adirect first pass aspiration (ADAPT) technique within 6 hours following stroke onset. Effectiveness was defined by functional independence (90-day modified Rankin Scale core 0-2) and revascularization to modified Thrombolysis in Cerebral Infarction (mTICI) 2b-3 scores adjudicated by a core laboratory, while complication rates were used to determine safety of the device and the procedure. RESULTS: Patients with an isolated M2 or M3 occlusion had a mean age of 68.6±13.3 years (range 18-90 years), a median National Institutes of Health Stroke Score of 15 (IQR 9-19), and ASPECTS score of 9 (IQR 8-10). After intervention, 100% (31/31) of patients were revascularized to mTICI 2b-3; 77.4% (24/31) of patients showed revascularization to mTICI 3. Aspiration alone led to revascularization in 83.9% (26/31) of patients. At 90 days, 96.8% (30/31) of patients had achieved functional independence. The incidence of symptomatic intracranial hemorrhage was 0% (0/31). CONCLUSIONS: Results suggest that the 3MAX reperfusion system is safe and effective in achieving successful revascularization and functional independence for patients with acute ischemic stroke secondary to M2 and M3 occlusions using ADAPT, either as frontline monotherapy, or in combination with adjunctive devices.

Functional brain imaging in combined motor and sleep disorders.

The pathophysiology of sleep-related motor diseases and sleep dysfunction in movement disorders is widely unknown as yet. Functional brain imaging, in particular radioisotope and magnetic resonance techniques, are powerful tools to investigate possible pathomechanisms of combined sleep and motor dysregulation. In patients with Restless legs syndrome (RLS), only a subtle striatal dopamine deficit was found in PET and SPECT despite a good treatment effect of dopaminergic drugs. Functional MRI suggested a central generator of periodic limb movements during sleep (PLMs) in RLS. In contrast, a marked striatal dopamine depletion was demonstrated in patients with REM sleep behaviour disorder (RBD) as the base for the clinical and nosological overlap of RBD with parkinsonian disorders. PET and SPECT also suggested that sleep abnormalities in Parkinson's disease (PD), such as REM sleep diminution or increased PLMs, are indirect manifestations of the primary striatal dopamine deficiency.

Nonlinear progression of Parkinson disease as determined by serial positron emission tomographic imaging of striatal fluorodopa F 18 activity.

BACKGROUND: The investigation of disease progression provides important information on the dynamics of cell death in Parkinson disease (PD). OBJECTIVE: To determine the progression of dopaminergic impairment in PD with the use of positron emission tomography (PET). DESIGN: Longitudinal prospective cohort study with a follow-up period of 64.5 +/- 22.6 months (mean +/- SD). SETTING: University hospital. PATIENTS: A consecutive sample of patients with PD (N = 31; age at symptom onset, 53.6 +/- 11.3 years) with a wide range of symptom duration and severity at the time of study entry. INTERVENTIONS: Investigation by serial fluorodopa F 18 ([(18)F]fluorodopa) PET as a marker for striatal dopaminergic function. MAIN OUTCOME MEASURES: Changes in caudate and putaminal [(18)F]fluorodopa influx constant (K(i)) values. RESULTS: In patients with PD, the decline rate of putaminal [(18)F]fluorodopa K(i) correlated inversely with disease duration before study inclusion (r = -0.46, P = .01) and positively with baseline K(i) values (r = 0.44, P = .01), indicating a negative exponential loss of dopamine neurons. Annual disease progression rates ranged from 4.4% in the caudate nucleus to 6.3% in the putamen. A mean preclinical period of 5.6 +/- 3.2 years was calculated with symptom onset at a putaminal K(i) threshold of 69% from controls. Assuming nonlinear progression kinetics, the required sample size to prove neuroprotection with the use of [(18)F]fluorodopa PET was found to increase strongly with the preceding symptom duration of study subjects. CONCLUSION: These data suggest that the neurodegenerative process in PD follows a negative exponential course and slows down with increasing symptom duration, contradicting the long-latency hypothesis of PD.

Nosocomial pneumonia after acute stroke: implications for neurological intensive care medicine.

BACKGROUND AND PURPOSE: Pneumonia has been estimated to occur in about one third of patients after acute stroke. Only limited data are available on stroke-associated pneumonia (SAP) in specialized neurological intensive care units (NICUs). METHODS: We enrolled 124 patients with acute stroke who were treated at our university hospital NICU in a prospective observational study. Incidence rates and risk factors of SAP and long-term clinical outcome were determined. RESULTS: SAP incidence was 21% with a spectrum of pathogens, which is comparable to previously published data on general ICU patients. Mechanical ventilation, multiple location, and vertebrobasilar stroke, as well as dysphagia and abnormal chest x-ray findings, were identified as risk factors for the disease. SAP patients showed higher mortality rates than nondiseased subjects (acute, 26.9% versus 8.2%; long-term, 35.3% versus 14.3%) and a significantly poorer long-term clinical outcome (Barthel Index, 50.5+/-42.4 versus 81.5+/-27.8; Rankin Scale, 3.5+/-1.7 versus 2.2+/-1.6). CONCLUSIONS: Our data underline the considerable epidemiological and prognostic impact of SAP for the treatment of acute stroke patients in a specialized NICU setting. They demonstrate that the occurrence of SAP deteriorates clinical outcome in these patients. Our results allow us to identify high-risk stroke patients at time of NICU admission in whom the use of preventive treatment strategies is most promising.

Subthalamic nucleus stimulation restores glucose metabolism in associative and limbic cortices and in cerebellum: evidence from a FDG-PET study in advanced Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a highly effective surgical treatment in patients with advanced Parkinson's disease (PD). Because the STN has been shown to represent an important relay station not only in motor basal ganglia circuits, the modification of brain areas also involved in non-motor functioning can be expected by this intervention. To determine the impact of STN-DBS upon the regional cerebral metabolic rate of glucose (rCMRGlc), we performed positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) in eight patients with advanced PD before surgery as well as in the DBS on- and off-conditions 4 months after electrode implantation and in ten age-matched healthy controls. Before surgery, PD patients showed widespread bilateral reductions of cortical rCMRGlc versus controls but a hypermetabolic state in the left rostral cerebellum. In the STN-DBS on-condition, clusters of significantly increased rCMRGlc were found in both lower thalami reaching down to the midbrain area and remote from the stimulation site in the right frontal cortex, temporal cortex, and parietal cortex, whereas rCMRGlc significantly decreased in the left rostral cerebellum. Therefore, STN-DBS was found to suppress cerebellar hypermetabolism and to partly restore physiologic glucose consumption in limbic and associative projection territories of the basal ganglia. These data suggest an activating effect of DBS upon its target structures and confirm a central role of the STN in motor as well as associative, limbic, and cerebellar basal ganglia circuits.

[18F]fluorodopa uptake in the upper brainstem measured with positron emission tomography correlates with decreased REM sleep duration in early Parkinson's disease.

Sleep disturbances are common in patients with Parkinson's disease (PD). Previous studies have shown alterations of polysomnographic sleep parameters in PD, such as overall diminution of slow-wave and REM sleep duration, absence of muscle atonia during REM and increased occurrence of periodic leg movements during sleep. The pathogenesis of sleep dysregulation in PD is unknown. The aim of this study was to determine relations of abnormal polysomnographic sleep parameters and the dopaminergic function of the striatum and the upper brainstem measured with the use of positron emission and magnetic resonance tomography in 10 early-stage PD patients with a history of sleep disturbances. Our data demonstrated a significant inverse correlation of absolute and percentage REM sleep duration with the mesopontine [18F]6-fluorodopa (FDOPA) uptake in PD patients. Therefore, the results point to a REM inhibiting effect of increased monaminergic transmission within the upper brainstem in early-stage PD. This finding emphasises the pathophysiological significance of a disturbed neurotransmitter equilibrium in the rostral brainstem for REM sleep alterations in PD.

GBA-associated PD. Neurodegeneration, altered membrane metabolism, and lack of energy failure.

OBJECTIVE: To elucidate possible mechanisms leading to neurodegeneration in patients with glucocerebrosidase (GBA)-associated Parkinson disease (PD) using combined proton ((1)H) and phosphorus ((31)P) magnetic resonance spectroscopic imaging (MRSI) in vivo. METHODS: (1)H and (1)H-decoupled (31)P MRSI was performed in 13 patients with PD with heterozygous GBA mutations (GBA-PD) and 19 age- and sex-matched healthy controls to investigate metabolite concentrations in the mesostriatal target regions of PD pathology. NAA as marker of neuronal integrity, choline and ethanolamine containing compounds as markers of membrane phospholipid metabolism, and energy metabolites (notably high-energy phosphates) were quantified. RESULTS: Compared to controls, NAA was significantly reduced in the putamen (p = 0.012) and in the midbrain of GBA-PD (p = 0.05). The choline concentration obtained from (1)H MRSI was significantly decreased in the midbrain of GBA-PD (p = 0.010). The phospholipid degradation product glycerophosphoethalonamine was increased in the putamen of GBA-PD (p = 0.05). Changes of energy metabolism were not detected in any region of interest. CONCLUSION: The pattern of neurodegeneration in GBA-associated PD is more pronounced in the putamen than in the midbrain. Our MRSI findings suggest that the neurodegenerative process in GBA-PD is associated with alterations of membrane phospholipid metabolism which might be also involved in abnormal α-synuclein aggregation.

The bioenergetic status relates to dopamine neuron loss in familial PD with PINK1 mutations.

Mutations in the PINK1 gene cause autosomal recessive familial Parkinson's disease (PD). The gene encodes a mitochondrial protein kinase that plays an important role in maintaining mitochondrial function and integrity. However, the pathophysiological link between mutation-related bioenergetic deficits and the degenerative process in dopaminergic neurons remains to be elucidated. We performed phosphorous ((31)P) and proton ((1)H) 3-T magnetic resonance spectroscopic imaging (MRSI) in 11 members of a German family with hereditary PD due to PINK1 mutations (PARK6) compared to 23 age-matched controls. All family members had prior 18-Fluorodopa (FDOPA) positron emission tomography (PET). The striatal FDOPA uptake was correlated with quantified metabolic brain mapping in MRSI. At group level, the heterozygous PINK1 mutation carriers did not show any MRSI abnormalities relative to controls. In contrast, homozygous individuals with manifest PD had putaminal GPC, PCr, HEP and ß-ATP levels well above the 2SD range of controls. Across all subjects, the FDOPA K(i) values correlated positively with MI (r = 0.879, p<0.001) and inversely with ß-ATP (r = -0.784, p = 0.008) and GPC concentrations (r = -0.651, p = 0.030) in the putamen. Our combined imaging data suggest that the dopaminergic deficit in this family with PD due to PINK1 mutations relates to osmolyte dysregulation, while the delivery of high energy phosphates was preserved. Our results corroborate the hypothesis that PINK1 mutations result in reduced neuronal survival, most likely due to impaired cellular stress resistance.

Belly dancer's syndrome following central pontine and extrapontine myelinolysis.

We report on a woman with delayed-onset of belly dancer's syndrome 5 months after central pontine and extrapontine myelinolysis (CPM/EPM) and severe hyponatriemia. This case demonstrates that basal ganglia lesions in EPM can be the underlying pathoanatomic substrate for the rarely observed belly dancer's syndrome. The sequential appearance of extrapyramidal symptoms might reflect an ongoing but ineffective or deficient remyelination process. The presence of CPM/EPM should be considered in patients with involuntary dyskinesias of the abdominal wall.

Brain parenchyma sonography detects preclinical parkinsonism.

Substantia nigra (SN) hyperechogenicity on brain parenchyma sonography (BPS) is highly characteristic for idiopathic PD. We studied 7 symptomatic and 7 asymptomatic parkin mutation carriers (PMC) from a large kindred with adult-onset parkinsonism. BPS revealed larger SN echogenic sizes in PMC with parkin mutations on both alleles (homozygous, compound-heterozygous), compared to PMC with only one mutated allele (Mann-Whitney U test, P = 0.007). In symptomatic PMC, larger SN echogenic size was correlated with younger age at onset of the disease (Spearman rank correlation, Rho = -0.937, P = 0.002) but not with age, disease duration, or disease severity. BPS demonstrated SN hyperechogenicity, in concordance with abnormal nigrostriatal (18)F-dopa positron emission tomography (PET), in all symptomatic and 3 asymptomatic PMC. In 2 asymptomatic PMC, PET and BPS were normal. However, in another 2 asymptomatic PET-normal PMC, SN hyperechogenicity could be detected. Data suggest SN hyperechogenicity as an early marker to detect preclinical parkinsonism.

Deep brain stimulation of the subthalamic nucleus does not increase the striatal dopamine concentration in parkinsonian humans.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) has become an effective treatment option in advanced Parkinson's disease (PD). Recent animal studies showed an increase of neuronal firing in dopaminergic neurons under effective STN-DBS. Increased striatal dopamine levels may also contribute to the stimulation's mechanism of action in humans. We investigated the striatal dopamine release in 6 patients with advanced PD under effective bilateral STN-DBS with positron emission tomography (PET) of the reversible dopamine-D2/3-receptor ligand [(11)C]raclopride (RACLO). Although STN-DBS proved to be a highly effective treatment in these subjects, we found no significant difference of the striatal RACLO binding between the STN-DBS-on and -off condition. The changes of radioligand binding did not correlate with the patients' improvement in clinical rating scales or with the stimulation amplitudes. Therefore, our PET data in living parkinsonian humans do not provide evidence for an increased striatal dopamine concentration under effective STN-DBS. We conclude that the modulation of dopaminergic activity does not seem to play a crucial role for the stimulation's mechanisms of action in parkinsonian humans.