Biology subjects

Kaasinen, V.

Publications and source records attributed to Kaasinen, V..

15 recordsLinked to original sources

bioRxiv2026

Stools and stool-derived extracellular vesicles from patients with Parkinson`s disease show alpha-4 synuclein seeding activity

BackgroundParkinsons disease (PD) is a neurodegenerative disorder for which there is currently no cure or reliable biomarker for early detection or for evaluating the effectiveness of potential treatments. PD pathology is driven by misfolding and subsequent accumulation of alpha-synuclein (Syn) protein into pathological aggregates within neurons and glial cells. Seed amplification assay (SAA) is a highly sensitive and specific diagnostic tool developed to detect pathological Syn species in the cerebrospinal fluid (CSF) of PD patients. However, Syn aggregates are present in multiple tissues and biosamples, including stools. In this study, we aimed to investigate the potential diagnostic value of SAA using stool samples from PD patients and healthy controls (HC). MethodsStool samples from PD patients (n=45) and healthy controls (n=35) were analysed for the presence of Syn species using slot blot assays with a panel of six Syn antibodies, and ELISA assays. Samples were subjected to SAA, and the end-point products (SAA EP) were characterised using transmission electron microscopy (TEM). Extracellular vesicles (EVs) were isolated from the subset of samples (n=5 per group) using size exclusion chromatography and characterized by TEM. The seeding activity of isolated EVs was evaluated using SAA, followed by TEM analysis of SAA EP. ResultsProtein extracts from both PD and HC stool samples revealed pathological Syn species in the slot blot assay using the phosphorylated Syn antibody, pS129 and conformation-specific antibodies, MJFR-14 and 5G4. ELISA showed significantly elevated total Syn levels in PD samples compared to HC, although no differences in aggregated Syn levels were detected. In stool protein extracts, SAA demonstrated 55.6% sensitivity and 60% specificity. When applied to stool-derived EVs from PD patients and controls, sensitivity increased to 100%, while specificity remained at 60%. Notably, SAA applied to stool-derived EVs pre-incubated with recombinant monomeric Syn achieved 100% sensitivity and 100% specificity. ConclusionThese findings suggest that SAA applied to EVs isolated from stool samples, particularly after pre-incubation with recombinant monomeric Syn, may serve as a valuable, non-invasive screening tool for the diagnosis of PD.

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bioRxiv2025

Striatal dopamine synthesis capacity in Parkinson's disease: Effects of age, sex, and body mass index in a large fluorodopa PET cohort

BACKGROUNDIn Parkinsons disease (PD), the degeneration of nigrostriatal dopaminergic neurons leads to motor symptoms. Positron emission tomography (PET) using radioligand [18F]fluorodopa detects reduced striatal dopamine synthesis capacity in PD patients. Demographic factors such as sex and BMI are also associated with dopamine synthesis capacity. The combined contribution of demographic and clinical effects however remains elusive. It also remains unresolved how the dopamine synthesis capacity is correlated between striatal subregions and how the dopamine synthesis capacity and dopamine receptor function across striatal regions are associated with each other in PD patients and healthy controls. MATERIAL, AIMS, AND METHODSFor this retrospective register-based study, we used baseline [18F]fluorodopa PET data acquired at the Turku PET Centre between the years 1988-2016 with three different scanners (Ecat 931, GE Advance, HRRT). The data included scans of 350 adult human subjects, including 132 healthy controls (65 males and 67 females), and 218 PD patients (134 males and 84 females). The primary aim was to simultaneously investigate the effects of PD, age, sex and BMI on regional dopamine synthesis capacity (influx rate constant Kiref quantified with Patlak) using Bayesian linear regression. Secondary aims were to assess interregional correlations of dopamine synthesis capacity, and the association between regional presynaptic dopamine synthesis and postsynaptic dopamine type 2 receptor (D2R) availability in subjects who also had a proximal [11C]raclopride PET scan. RESULTSWe found modest support for age-dependent decline in dopamine synthesis capacity, increased capacity for higher BMIs, and for higher capacity in females versus males. These effects were smaller than the effect of PD status. Dopamine synthesis capacity across regions was correlated in both patients and controls. Support for positive correlation between the synthesis capacity and the D2R was observed in caudate nucleus. CONCLUSIONSPD and demographic effects are independently associated with the striatal dopamine synthesis capacity. The capacity is reduced by PD, decreased through age (particularly after the age of around 50), higher in females versus males, and weakly increased in higher BMIs. Synthesis capacity is correlated between the striatal and thalamic regions in both PD patients and controls. The dopamine synthesis capacity was positively correlated with the D2R availability in caudate. Scanner affects the estimates of dopamine synthesis capacity measured with [18F]fluorodopa PET, and it is preferrable to adjust for such variation in the data.

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bioRxiv2023

Seasonal variation in D2/3 dopamine receptor availability in the human brain

Brain functional and physiological plasticity is essential to combat dynamic environmental challenges. The rhythmic in vivo dopamine signaling pathway, which regulates emotion, reward and learning, shows seasonal patterns with higher capacity of dopamine synthesis and lower number of dopamine transporters during dark seasons. However, seasonal variation of the dopamine receptor signaling remains to be characterized. Here, based on historical database of healthy human brain [11C]raclopride PET scans (n = 291, 224 males and 67 females), we investigated the seasonal patterns of D2/3 dopamine receptor signaling. We found that daylength at the time of scanning was negatively correlated with availability of this type of receptors in the striatum. Likely, seasonally varying D2/3 receptor signaling also underlies the seasonality of mood, feeding, and motivational processes. Significance of the studyBrain in vivo neurotransmitter signaling demonstrates seasonal patterns. The dopamine D2/3 receptor, with both pre- and postsynaptic expressions, has been targeted by major antipsychotic and antiparkinsonian pharmaceuticals. The current study, based on a large dataset of healthy brain PET images quantifying these receptors, shows that dark seasons are associated with increased receptor availability in the striatum. Considering the previous findings of increased dopamine synthesis and lowered number of transporters, findings may suggest elevated presynaptic control of dopamine release and increased dopamine receptor sensitivity during dark seasons. The rhythmic D2/3 receptor availability may be a mechanism underlying seasonality in mood, feeding, and motivational processes.

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bioRxiv2023

Alterations in type 2 dopamine receptors across neuropsychiatric conditions: A large-scale PET cohort

Aberrant dopaminergic function is linked with motor, psychotic, and affective symptoms, but studies have typically compared a single patient group with healthy controls. Here, we investigated the variation in striatal (caudate nucleus, nucleus accumbens, and putamen) and thalamic type 2 dopamine receptor (D2R) availability using [11C]raclopride positron emission tomography (PET) data from a large sample of 437 humans including healthy controls and subjects with Parkinsons disease (PD), antipsychotic-naive schizophrenia, severe violent behavior, pathological gambling, depression, and overweight. We analyzed regional group differences in D2R availability using Bayesian mixed effects modeling. Subjects with PD showed clearest decline in D2R availability. Healthy controls and patients with PD showed high interregional correlation of D2R availability, while this pattern was weaker in schizophrenia, severe violent behavior, and depression. Subjects with pathological gambling or overweight did not show clear changes in either the regional receptor availability or the interregional correlation. We conclude that the dopaminergic changes in neuropsychiatric conditions might not only affect the overall receptor availability but also the connectivity between the regions. The region-specific receptor availability more profoundly links to the motor symptoms, while the between-region connectivity might be disrupted in affective symptoms. HighlightsWe compared human striatal and thalamic type 2 dopamine receptor (D2R) availability between healthy controls, and subjects with Parkinsons disease (PD), antipsychotic-naive schizophrenia, severe violent behavior, pathological gambling, depression, and overweight. We present the mean brain maps of group specific D2R availabilities in NeuroVault (https://neurovault.org; https://identifiers.org/neurovault.collection:12799). Dopamine type 2 receptor availability is lowered in PD in caudate nucleus, nucleus accumbens and thalamus. Antipsychotic-naive schizophrenia, severe violent behavior, and depression were associated with decreased connectivity between the striatal and thalamic D2R availability. Altered regional D2R availability in the striatum and thalamus is linked with motor disorders, while lowered regional connectivity in D2R might relate to affective disturbance.

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bioRxiv2022

Regulators of proteostasis are translationally repressed in fibroblasts from sporadic and LRRK2-G2019S Parkinson's patients

Parkinsons disease (PD) is characterized by heterogeneous motor and non-motor symptoms. The majority of PD cases are sporadic, whereas the leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is the most common monogenic cause of familial PD and symptomatically indistinguishable from the sporadic form. Deficits in protein synthesis have been reported in PD. However, it is not known which proteins are affected or if there are synthesis differences between patients with sporadic and LRRK2 G2019S PD. Here we used non-canonical amino acid labeling and mass-spectrometry based proteomics to perform a quantitative comparison of nascent proteins in fibroblasts from sporadic and G2019S mutation PD patients compared to healthy individuals. We found that several proteins were under-represented among nascent proteins in cells from PD patients. Among these were regulators endo-lysosomal sorting, mRNA processing and translation itself. We further validated which of these proteins were dysregulated at the static proteome level using targeted proteomics. Key downregulated proteins included the autophagy regulator ATG9A and translational stability regulator YTHDF3. Notably, 68% of the identified proteins were downregulated in both sporadic and LRRK2-G2019S forms of PD. We identify translational repression of key regulators of proteostasis in patient fibroblasts that are common to both sporadic and LRRK2-G2019S PD.

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bioRxiv2021

Age and sex dependent variability of type 2 dopamine receptors in the human brain: A large-scale PET cohort

BACKGROUNDThe dopamine system contributes to a multitude of functions ranging from reward and motivation to learning and movement control, making it a key component in goal-directed behavior. Altered dopaminergic function is observed in neurological and psychiatric conditions. Numerous factors have been proposed to influence dopamine function, but due to small sample sizes and heterogeneous data analysis methods in previous studies their specific and joint contributions remain unresolved. METHODSIn this cross-sectional register-based study we investigated how age, sex, body mass index (BMI), as well as cerebral hemisphere and regional volume influence striatal type 2 dopamine receptor (D2R) availability in the human brain. We analyzed a large historical dataset (n=156, 120 males and 36 females) of [11C]raclopride PET scans performed between 2004 and 2018. RESULTSStriatal D2R availability decreased through age for both sexes and was higher in females versus males throughout age. BMI and striatal D2R availability were weakly associated. There was no consistent lateralization of striatal D2R. The observed effects were independent of regional volumes. These results were validated using two different spatial normalization methods, and the age and sex effects also replicated in an independent sample (n=135). CONCLUSIONSD2R density is dependent on age and sex, which may contribute to the vulnerability of neurological and psychiatric conditions involving altering D2R expression.

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bioRxiv2020

Cerebral μ-opioid and CB1-receptor systems have distinct roles in human feeding behavior

Eating behavior varies greatly between healthy individuals, but the neurobiological basis of these trait-like differences in feeding remains unknown. Central {micro}-opioid receptors (MOR) and cannabinoid CB1-receptors (CB1R) regulate energy balance via multiple neural pathways, promoting food intake and reward. Because obesity and eating disorders have been associated with alterations in the brains opioid and endocannabinoid signaling, the variation in MOR and CB1R system function could potentially underlie distinct eating behavior phenotypes. In this retrospective positron emission tomography (PET) study, we analyzed [11C]carfentanil PET scans of MORs from 92 healthy subjects (70 males and 22 females), and [18F]FMPEP-d2 scans of CB1Rs from 35 subjects (all males, all also included in the [11C]carfentanil sample). Eating styles were measured with the Dutch Eating Behavior Questionnaire (DEBQ). We found that lower cerebral MOR availability was associated with increased external eating - individuals with low MORs reported being more likely to eat in response to environments palatable food cues. CB1R availability was associated with multiple eating behavior traits. We conclude that although MORs and CB1Rs overlap anatomically and functionally in the brain, they have distinct roles in mediating individual feeding patterns.

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bioRxiv2020

Seasonal variation in brain mu-opioid receptor availability

Seasonal rhythms influence mood and sociability. The brain -opioid receptor (MOR) system modulates a multitude of seasonally varying socioemotional functions, but its seasonal variation remains elusive with no previously reported in vivo evidence. Here, we studied the seasonal effects on brain MOR availability via analysing a dataset (n=204) of [11C]carfentanil positron emission tomography (PET) scans of healthy volunteers. We found that seasonally varying daylength had an inverted U-shaped functional relationship with brain MOR availability. Brain regions sensitive to daylength spanned the socio-emotional brain circuits, where MOR availability formed a spring-like peak. Causal effect of daylength on brain MOR availability was further verified by a post hoc experiment with repeated PET imaging of rats (n=9) under seasonal photoperiodic simulation. Therefore, the in vivo brain MOR availability in normal humans shows significant seasonal variation, which aligns with expected seasonal variation in mood and suicidality.

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bioRxiv2020

Resting state EEG as a biomarker of Parkinson's disease: Influence of measurement conditions

Resting state electroencephalographic (EEG) recording could provide cost-effective means to aid in the detection of neurological disorders such as Parkinsons disease (PD). We examined how many electrodes are needed for classification of PD based on EEG, which electrode locations provide most value for classification, and whether data recorded eyes open or closed yield comparable results. We used a nested cross-validated classifier which included a budget-based search algorithm for selecting the optimal electrodes for classification. By iterating over variable budgets, we show that with eyes open recording, only 10 electrodes, localized over motor and occipital areas enable relatively accurate classification (AUC = .82) between PD patients (N=20) and age-matched healthy control participants (N=20). Classification accuracy only slightly increased when all 64 electrodes were included (AUC = .85). With the data recorded eyes closed, classification was not statistically significantly above chance even with full set of 64 electrodes (AUC = .55). These results show that classification based on small number of EEG electrodes is a promising tool for classifying PD, but measurement conditions and electrode locations can have a significant effect on classifier performance.

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bioRxiv2020

Protein synthesis is suppressed in sporadic and familial Parkinson's Disease by LRRK2

Gain of function LRRK2-G2019S is the most common mutation associated with both familial and sporadic Parkinsons disease. It is expected therefore that understanding the cellular function of LRRK2 will provide much needed insight on the pathological mechanism of sporadic Parkinsons, which is the most common form. Here we show that constitutive LRRK2 activity represses nascent protein synthesis in rodent neurons. Specifically, enzymatic inhibition of LRRK2, gene silencing or gene knockout of Lrrk2 increase translation. In the rotenone model of Parkinsons, LRRK2 activity increases, leading to repression of translation and dopaminergic neuron atrophy both of which are prevented by LRRK2 inhibition. This is accompanied by altered phosphorylation of eIF2-S52({uparrow}), eIF2s2-S2({downarrow}) and eEF2-T57({uparrow}) in striatum/substantia nigra in a direction that signifies inhibition of protein synthesis. Significantly, LRRK2 is activated and translation is 40% reduced in Parkinsons patient fibroblasts (G2019S and sporadic) and LRRK2 inhibition restores normal translation. In contrast, translation is unchanged in cells from multiple system atrophy patients, implying disease specificity. These findings suggest that LRRK2-dependent repression of translation may be a proximal function of LRRK2 in Parkinsons pathology.

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bioRxiv2020

Cerebral grey matter density is associated with neuroreceptor and neurotransporter availability: A combined PET and MRI study

Positron emission tomography (PET) can be used for in vivo measurement of specific neuroreceptors and transporters using radioligands, while voxel-based morphometric analysis of magnetic resonance images allows automated estimation of local grey matter densities. However, it is not known how regional neuroreceptor or transporter densities are reflected in grey matter densities. Here, we analyzed brain scans retrospectively from 325 subjects and compared grey matter density estimates with three different neuroreceptors and transporter availabilities. {micro}-opioid receptors (MORs) were measured with [11C]carfentanil (162 scans), dopamine D2 receptors with [11C]raclopride (91 scans) and serotonin transporters (SERT) with [11C]MADAM (72 scans). The PET data were modelled with simplified reference tissue model. Voxel-wise correlations between binding potential and grey matter density images were computed. Regional binding of all the used radiotracers was associated with grey matter density in region and ligand-specific manner independently of subjects age or sex. These data show that grey matter density and MOR and D2R neuroreceptor / SERT availability are correlated, with effect sizes (r2) ranging from 0.04 to 0.69. This suggests that future studies comparing PET outcome measure different groups (such as patients and controls) should take grey matter density differences between the groups into account.

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bioRxiv2019

Reduced speaking-induced suppression of auditory evoked-potentials in early Parkinson’s disease suggests deficits in monitoring self-produced speech

ObjectiveSpeech deficits are common in Parkinsons disease, and behavioural findings suggest that the deficits may be due to impaired monitoring of self-produced speech. The neural mechanisms of speech deficits are not well understood. We examined a well-documented electrophysiological correlate of speech self-monitoring in patients with Parkinsons disease and control participants. MethodsWe measured evoked electroencephalographic responses to self-produced and passively heard sounds (/a/ phonemes) in age-matched controls (N=18), and Parkinsons disease patients who had minor speech impairment, but reported subjectively experiencing no speech deficits (N=17). ResultsDuring speaking, auditory evoked activity 100 ms after phonation (N1 wave) was less suppressed in Parkinsons disease than controls when compared to the activity evoked by passively heard phonemes. This difference between the groups was driven by increased amplitudes to self-produced phonemes, and reduced amplitudes passively heard phonemes in Parkinsons disease. ConclusionsThe finding indicates that auditory evoked activity is abnormally modulated during speech in Parkinsons patients who do not subjectively notice speech impairment. This mechanism could play a role in producing speech deficits in as the disease progresses.

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bioRxiv2019

Interindividual variability and lateralization of μ-opioid receptors in the human brain

The brains {micro}-opioid receptors (MORs) are involved in analgesia, reward and mood regulation. Several neuropsychiatric diseases have been associated with dysfunctional MOR system, and there is also considerable variation in receptor density among healthy individuals. Sex, age, body mass and smoking have been proposed to influence the MOR system, but due to small sample sizes the magnitude of their influence remains inconclusive. Here we quantified in vivo MOR availability in the brains of 204 individuals with no neurologic or psychiatric disorders using positron emission tomography (PET) with tracer [11C]carfentanil. We then used Bayesian hierarchical modeling to estimate the effects of sex, age, body mass index (BMI) and smoking on [11C]carfentanil binding potential. We also examined hemispheric lateralization of MOR availability. Age had regionally specific effects on MOR availability, with age-dependent increase in frontotemporal areas but decrease in amygdala, thalamus, and nucleus accumbens. The age-dependent increase was stronger in males. MOR availability was globally lowered in smokers but independent of BMI. Finally, MOR availability was higher in the right versus the left hemisphere. The presently observed variation in MOR availability may explain why some individuals are prone to develop MOR-linked pathological states, such as chronic pain or psychiatric disorders.

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bioRxiv2018

Altered orbitofrontal sulcogyral patterns in gambling disorder: a multicenter study

Gambling disorder is a serious psychiatric condition characterized by decision-making and reward processing impairments that are associated with dysfunctional brain activity in the orbitofrontal cortex (OFC). However, it remains unclear whether OFC functional abnormalities in gambling disorder are accompanied by structural abnormalities. We addressed this question by examining the organization of sulci and gyri in the OFC. This organization is in place very early and stable across life, such that OFC sulcogyral patterns (classified into Type I, II and III) can be regarded as potential pre-morbid markers of pathological conditions. We gathered structural brain data from nine existing studies, reaching a total of 165 individuals with gambling disorder and 159 healthy controls. Our results, supported by both frequentist and Bayesian statistics, show that the distribution of OFC sulcogyral patterns is skewed in individuals with gambling disorder, with an increased prevalence of Type II pattern compared with healthy controls. Examination of gambling severity did not reveal any significant relationship between OFC sulcogyral patterns and disease severity. Altogether, our results provide evidence for a skewed distribution of OFC sulcogyral patterns in gambling disorder, and suggest that pattern Type II might represent a pre-morbid structural brain marker of the disease. It will be important to investigate more closely the functional implications of these structural abnormalities in future work.

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bioRxiv2018

Impairment in updating spatial representations in Parkinson’s disease correlates with dopaminergic deficiency

Movement in Parkinsons disease (PD) is fragmented, and the patients depend on visual information in their behavior. This suggests that the patients may have deficits in internally monitoring their own movements. Internal monitoring of movements is assumed to rely on corollary discharge signals that enable the brain to predict the sensory consequences of actions. We studied early-stage PD patients (N=14), and age-matched healthy control participants (N=14) to examine whether PD patients reveal deficits in updating their sensory representations after eye movements. The participants performed a double-saccade task where, in order to accurately fixate a second target, the participant must correct for the displacement caused by the first saccade. In line with previous reports, the patients had difficulties in fixating the second target when the eye movement was performed without visual guidance. Furthermore, the patients had difficulties in taking into account the error in the first saccade when making a saccade towards the second target, especially when eye movements were made towards the side with dominant motor symptoms. Across PD patients, the impairments in saccadic eye movements correlated with the integrity of the dopaminergic system as measured with [123I]FP-CIT SPECT: Patients with lower striatal (caudate, anterior putamen and posterior putamen) dopamine transporter binding made larger errors in saccades. This effect was strongest when patients made memory-guided saccades towards the second target. Our results provide tentative evidence that the motor deficits in PD may be partly accounted by deficits in internal monitoring of movements.

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