Introducing a gatekeeping system for amyloid status assessment in mild cognitive impairment.

BACKGROUND: In patients with mild cognitive impairment (MCI), enhanced cerebral amyloid-ß plaque burden is a high-risk factor to develop dementia with Alzheimer's disease (AD). Not all patients have immediate access to the assessment of amyloid status (A-status) via gold standard methods. It may therefore be of interest to find suitable biomarkers to preselect patients benefitting most from additional workup of the A-status. In this study, we propose a machine learning-based gatekeeping system for the prediction of A-status on the grounds of pre-existing information on APOE-genotype 18F-FDG PET, age, and sex. METHODS: Three hundred and forty-two MCI patients were used to train different machine learning classifiers to predict A-status majority classes among APOE-ε4 non-carriers (APOE4-nc; majority class: amyloid negative (Aß-)) and carriers (APOE4-c; majority class: amyloid positive (Aß +)) from 18F-FDG-PET, age, and sex. Classifiers were tested on two different datasets. Finally, frequencies of progression to dementia were compared between gold standard and predicted A-status. RESULTS: Aß- in APOE4-nc and Aß + in APOE4-c were predicted with a precision of 87% and a recall of 79% and 51%, respectively. Predicted A-status and gold standard A-status were at least equally indicative of risk of progression to dementia. CONCLUSION: We developed an algorithm allowing approximation of A-status in MCI with good reliability using APOE-genotype, 18F-FDG PET, age, and sex information. The algorithm could enable better estimation of individual risk for developing AD based on existing biomarker information, and support efficient selection of patients who would benefit most from further etiological clarification. Further potential utility in clinical routine and clinical trials is discussed.

[Tauopathies : From molecule to therapy]. / Tauopathien : Vom Molekül zur Therapie.

BACKGROUND: The microtubule-associated tau protein is the defining denominator of a group of neurodegenerative diseases termed tauopathies. OBJECTIVE: Provide a timely state of the art review on recent scientific advances in the field of tauopathies. MATERIAL AND METHODS: Systematic review of the literature from the past 10 years. RESULTS: Tau proteins are increasingly being recognized as a highly variable protein, underlying and defining a spectrum of molecularly defined diseases, with a clinical spectrum ranging from dementia to hypokinetic movement disorders. Genetic variation at the tau locus can trigger disease or modify disease risk. Tau protein alterations can damage nerve cells and propagate pathologies through the brain. Thus, tau proteins may serve both as a serological and imaging biomarker. Tau proteins also provide a broad spectrum of rational therapeutic interventions to prevent disease progression. This knowledge has led to modern clinical trials. CONCLUSION: The field of tauopathies is in a state of dynamic and rapid progress, requiring close interdisciplinary collaboration.

[Hemichorea with Contralateral High Signal Intensity Putaminal Lesion on T1-Weighted Images in Non-Ketotic Hyperglycemia]. / Hemichorea mit T1-hyperintenser Signalalteration im kontralateralen Putamen bei nichtketotischer Hyperglykämie.

A 64-year-old diabetic female patient presented with involuntary unilateral hyperkinetic movements of the left limbs. Cranial MRI showed a contralateral high signal intensity putaminal lesion on T1-weighted images without any signal changes in the T2-weighted images. This finding is characteristic for hemichorea-hemiballism associated with insufficiently treated diabetes mellitus. Additionally, proton MR spectroscopy was performed and revealed a decreased N-acetylaspartate/creatine and N-acetylaspartate/choline ratio, indicating neuronal damage of the contralateral putamen.

The olfactory bulb volume in patients with idiopathic Parkinson's disease.

BACKGROUND AND PURPOSE: This study addresses the question of whether the neuropathological findings on the olfactory bulb (OB) in idiopathic Parkinson's disease (IPD) correspond to a detectable change in volume of the OB. Additionally, the relationship between OB volume and residual olfactory function, clinical disease characteristics and age are investigated. METHODS: Fifty-two IPD patients were investigated and compared to 31 healthy age-matched controls. All participants were scanned using a 3 T magnetic resonance imaging MRI scanner including a T2 DRIVE sequence in coronal slices through the OB. The OB volumes were measured via manual segmentation of the OB. Olfactory testing was carried out using the Sniffin' Sticks test battery. RESULTS: The OB volume in the IPD group was 42.1 mm³ (SD ± 11.6) for the right and 41.5 mm³ (SD ± 11.7) for the left OB and showed no difference from the controls. Additionally, there were no significant correlations between OB volume and disease characteristics such as disease duration or Unified Parkinson's Disease Rating Scale motor score. Likewise, patients' residual smell function did not correlate with their OB volume. In contrast, controls indicated a correlation between smell function and OB volume. CONCLUSION: The study shows that high resolution MRI does not show a detectable volume loss of the OB in PD patients. It is concluded that OB measurement using in vivo high resolution MRI at 3 T is not helpful to identify IPD.

Human face processing is tuned to sexual age preferences.

Human faces can motivate nurturing behaviour or sexual behaviour when adults see a child or an adult face, respectively. This suggests that face processing is tuned to detecting age cues of sexual maturity to stimulate the appropriate reproductive behaviour: either caretaking or mating. In paedophilia, sexual attraction is directed to sexually immature children. Therefore, we hypothesized that brain networks that normally are tuned to mature faces of the preferred gender show an abnormal tuning to sexual immature faces in paedophilia. Here, we use functional magnetic resonance imaging (fMRI) to test directly for the existence of a network which is tuned to face cues of sexual maturity. During fMRI, participants sexually attracted to either adults or children were exposed to various face images. In individuals attracted to adults, adult faces activated several brain regions significantly more than child faces. These brain regions comprised areas known to be implicated in face processing, and sexual processing, including occipital areas, the ventrolateral prefrontal cortex and, subcortically, the putamen and nucleus caudatus. The same regions were activated in paedophiles, but with a reversed preferential response pattern.

[Repetitive impulse-associated behavioral disorders in Parkinson's disease]. / Repetitive impulsassoziierte Verhaltensstörungen beim Morbus Parkinson.

Parkinson's disease (PD) is associated with a number of behavioral disorders which may cause considerable social, professional or financial problems. Impulse control disorders (ICDs), such as pathological gambling, binge eating, compulsive shopping and hypersexuality occur in approximately 13-14% of PD patients. Further behavioral disorders are the dopamine dysregulation syndrome (DDS), a substance dependence characterized by craving for dopaminergic substances and punding (prolonged repetitive activities which are not goal-oriented).Treatment-related risk factors are dopamine agonists for ICDs and a high total dopaminergic dose for DDS and punding. Shared risk factors are young age at onset, impulsive personality traits, depression and possibly dyskinesia. At the neuronal level these behavioral disorders seem to be associated with changes in the reward system and dysfunction of the orbitofrontal cortex. The evidence level for management strategies is at present insufficient. For ICDs current clinical practice consists of discontinuation or reduction of dopamine agonists.

Drug-induced deactivation of inhibitory networks predicts pathological gambling in PD.

OBJECTIVE: Some patients with Parkinson disease (PD) develop pathological gambling when treated with dopamine agonists (DAs). However, little is known about DA-induced changes in neuronal networks that may underpin this drug-induced change in behavior in vulnerable individuals. In this case-control study, we aimed to investigate DA-induced changes in brain activity that may differentiate patients with PD with DA-induced pathological gambling (gamblers) from patients with PD without such a history (controls). METHODS: Following overnight withdrawal of antiparkinsonian medication, patients were studied with H2(15)O PET before and after administration of DA (3 mg apomorphine) to measure changes in regional cerebral blood flow as an index of regional brain activity during a card selection game with probabilistic feedback. RESULTS: We observed that the direction of DA-related activity change in brain areas that are implicated in impulse control and response inhibition (lateral orbitofrontal cortex, rostral cingulate zone, amygdala, external pallidum) distinguished gamblers from controls. DA significantly increased activity in these areas in controls, while gamblers showed a significant DA-induced reduction of activity. CONCLUSIONS: We propose that in vulnerable patients with PD, DAs produce an abnormal neuronal pattern that resembles those found in nonparkinsonian pathological gambling and drug addiction. DA-induced disruption of inhibitory key functions--outcome monitoring (rostral cingulate zone), acquisition and retention of negative action-outcome associations (amygdala and lateral orbitofrontal cortex)--together with restricted access of those areas to executive control (external pallidum)--may well explain loss of impulse control and response inhibition in vulnerable patients with PD, thereby fostering the development of pathological gambling.

Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study.

Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson's disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson's disease patients with impulse control disorders. We describe results of a [(11)C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson's disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson's disease patients may provide a model into the pathophysiology of this disorder.

Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype.

OBJECTIVE: To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements. METHODS: Nonmanifesting individuals carrying a single heterozygous Parkin (n = 13) or PINK1 (n = 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During fMRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous Parkin and PINK1 mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally implicated in the control of complex motor sequences. We expected this overactivity to be independent of the underlying genotype. RESULTS: Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a Parkin or PINK1 mutation. CONCLUSION: Mutations in different genes linked to recessively inherited Parkinson disease are associated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a "generic" compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit.

Morphometric fingerprint of asymptomatic Parkin and PINK1 mutation carriers in the basal ganglia.

BACKGROUND: Mutations in the Parkin and PINK1 genes can cause parkinsonism. Since asymptomatic carriers of a single mutant allele of the Parkin or PINK1 gene display a presynaptic dopaminergic dysfunction in the striatum, they provide a unique in vivo model to study structural and functional reorganization in response to latent nigrostriatal dysfunction. We hypothesized that subclinical nigrostriatal neurodegeneration caused by these mutations would induce morphologic changes in the dysfunctional striatal gray matter. METHODS: In asymptomatic carriers of a heterozygous Parkin (n = 13) or PINK1 (n = 10) mutation and 23 age-and sex-matched individuals without a mutation, we applied observer independent region-of-interest and voxel-based morphometry to high-resolution structural MRIs. RESULTS: Relative to controls without a mutation, Parkin and PINK1 mutation carriers displayed a bilateral increase in gray matter volume in the putamen and the internal globus pallidus. In 8 of the 13 Parkin mutation carriers, the presynaptic dopaminergic function was studied with (18)F-DOPA PET. The metabolic-morphometric regression analysis revealed that the linear decrease in individual presynaptic striatal (18)F-DOPA uptake was linked to a reciprocal decrease in the striatal gray matter volume in the putamen bilaterally and in the left caudate nucleus. CONCLUSIONS: The alternative causes of the increased striatal gray matter volume may be either due to excessive levels of neuronal activity caused by chronic dopaminergic dysfunction or due to long-term adaptation to chronic nigrostriatal dysfunction actively compensating for the dopaminergic denervation. In any case, the results indicate that a genetically driven regional dysfunction may be imprinted in the structure of the dysfunctional brain region, for example in the striatum.

Motor reorganization in asymptomatic carriers of a single mutant Parkin allele: a human model for presymptomatic parkinsonism.

Mutations in the Parkin gene are the most common known single cause of early-onset parkinsonism. It has been shown that asymptomatic carriers with a single mutant allele have latent presynaptic dopaminergic dysfunction in the striatum. Here we used functional MRI to map movement-related neuronal activity during internally selected or externally determined finger movements in 12 asymptomatic carriers of a Parkin mutation and 12 healthy non-carriers. Mean response times were 63 ms shorter during internally selected movements than during externally guided movements (P = 0.003). There were no differences in mean response times between groups (P > 0.2). Compared with externally determined movements, the internal selection of movements led to a stronger activation of rostral motor areas, including the rostral cingulate motor area (rCMA), rostral supplementary motor area, medial and dorsolateral prefrontal cortices. The genotype had a significant impact on movement-related activation patterns. Asymptomatic carriers showed a stronger increase in movement-related activity in the right rCMA and left dorsal premotor cortex, but only if movements relied on internal cues. In addition, synaptic activity in the rCMA had a stronger influence on activity in the basal ganglia in the context of internally selected movements in asymptomatic carriers relative to non-carriers. We infer that this reorganization of striatocortical motor loops reflects a compensatory effort to overcome latent nigrostriatal dysfunction.

Motor excitability in a patient with a somatosensory cortex lesion.

OBJECTIVE: We report a patient with an ischemic lesion in right somatosensory cortex who developed dystonic posturing and pseudo-athetotic involuntary left-sided finger movements during voluntary muscle contractions. METHODS: Motor excitability was assessed using transcranial magnetic stimulation techniques and electrical peripheral nerve stimulation. Results obtained from abductor digiti minimi muscles of both hands were compared. RESULTS: On the affected side, silent period duration and intracortical inhibition were reduced, indicating a loss of inhibitory properties. Intracortical facilitation was enhanced. Stimulus-response curves showed a smaller increase of motor evoked potential amplitudes when recorded during muscle relaxation, but not during voluntary muscle activation. CONCLUSIONS: The results suggest that, under normal conditions, somatosensory cortex modifies inhibitory as well as excitatory properties in the motor system.

Right lateralized motor cortex activation during volitional blinking.

Using H2 15O positron emission tomography in 6 healthy volunteers, we found that self-initiated and externally cued blinking activated the right primary motor cortex and supplementary motor area (SMA). The left dorsolateral prefrontal cortex (DLPFC) and the rostral SMA showed greater activation during the self-initiated task compared to the externally cued task. This study confirms the hypothesis of right hemispheric lateralization of volitional blinking derived from observations in stroke patients. Furthermore, it underscores the role of DLPFC and rostral SMA in self-initiated movements, which has been found in similar experiments with hand movements.