Publications by authors named "Juha O Rinne"

206 Publications

Increased risk for dementia in neurofibromatosis type 1.

Genet Med 2021 Jul 13. Epub 2021 Jul 13.

Institute of Biomedicine, University of Turku, Turku, Finland.

Purpose: To determine the risk for dementia in neurofibromatosis type 1 (NF1) using a Finnish nationwide cohort of individuals with NF1, and data from national registries.

Methods: A Finnish cohort of 1,349 individuals with confirmed NF1 according to the US National Institutes of Health (NIH) diagnostic criteria was compared with a control cohort of 13,870 individuals matched for age, sex, and area of residence. Dementia-related hospital visits were retrieved from the Finnish Care Register for Health Care using International Classification of Diseases, 10th revision (ICD-10) diagnosis codes G30 and F00-F03. Purchases of antidementia drugs were queried with Anatomical Therapeutic Chemical (ATC) classification code N06D from the drug reimbursement register maintained by the Social Insurance Institution of Finland. The follow-up spanned 1998-2014.

Results: Totals of 16 and 165 individuals with at least two dementia-related diagnoses or drug purchases were identified in the NF1 and control cohorts, respectively. The hazard ratio for dementia in NF1 was 1.67 (95% confidence interval [CI] 1.00-2.80, P = 0.050). In an analysis stratified by the type of dementia, the risk for Alzheimer disease was increased in NF1 compared to controls with a hazard ratio of 2.88 (95% CI 1.47-5.66, P = 0.002).

Conclusion: Dementia and especially Alzheimer disease are previously unrecognized neurological complications of NF1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01261-3DOI Listing
July 2021

(S)-[F]THK5117 brain uptake is associated with Aβ plaques and MAO-B enzyme in a mouse model of Alzheimer's disease.

Neuropharmacology 2021 Jun 30;196:108676. Epub 2021 Jun 30.

Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland; Medicity Research Laboratory, University of Turku, Tykistökatu 6 A, FI-20520, Turku, Finland. Electronic address:

The mouse model of beta-amyloid (Aβ) deposition, APP/PS1-21, exhibits high brain uptake of the tau-tracer (S)-[F]THK5117, although no neurofibrillary tangles are present in this mouse model. For this reason we investigated (S)-[F]THK5117 off-target binding to Aβ plaques and MAO-B enzyme in APP/PS1-21 transgenic (TG) mouse model of Aβ deposition. APP/PS1-21 TG and wild-type (WT) control mice in four different age groups (2-26 months) were imaged antemortem by positron emission tomography with (S)-[F]THK5117, and then brain autoradiography. Additional animals were used for immunohistochemical staining and MAO-B enzyme blocking study with deprenyl pre-treatment. Regional standardized uptake value ratios for the cerebellum revealed a significant temporal increase in (S)-[F]THK5117 uptake in aged TG, but not WT, brain. Immunohistochemical staining revealed a similar increase in Aβ plaques but not endogenous hyper-phosphorylated tau or MAO-B enzyme, and ex vivo autography showed that uptake of (S)-[F]THK5117 co-localized with the amyloid pathology. Deprenyl hydrochloride pre-treatment reduced the binding of (S)-[F]THK5117 in the neocortex, hippocampus, and thalamus. This study's findings suggest that increased (S)-[F]THK5117 binding in aging APP/PS1-21 TG mice is mainly due to increasing Aβ deposition, and to a lesser extent binding to MAO-B enzyme, but not hyper-phosphorylated tau.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2021.108676DOI Listing
June 2021

Prodromal neuroinflammatory, cholinergic and metabolite dysfunction detected by PET and MRS in the TgF344-AD transgenic rat model of AD: a collaborative multi-modal study.

Theranostics 2021 3;11(14):6644-6667. Epub 2021 May 3.

Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK.

Mouse models of Alzheimer's disease (AD) are valuable but do not fully recapitulate human AD pathology, such as spontaneous Tau fibril accumulation and neuronal loss, necessitating the development of new AD models. The transgenic (TG) TgF344-AD rat has been reported to develop age-dependent AD features including neuronal loss and neurofibrillary tangles, despite only expressing and mutations, suggesting an improved modelling of AD hallmarks. Alterations in neuronal networks as well as learning performance and cognition tasks have been reported in this model, but none have combined a longitudinal, multimodal approach across multiple centres, which mimics the approaches commonly taken in clinical studies. We therefore aimed to further characterise the progression of AD-like pathology and cognition in the TgF344-AD rat from young-adults (6 months (m)) to mid- (12 m) and advanced-stage (18 m, 25 m) of the disease. TgF344-AD rats and wild-type (WT) littermates were imaged at 6 m, 12 m and 18 m with [F]DPA-714 (TSPO, neuroinflammation), [F]Florbetaben (Aβ) and [F]ASEM (α7-nicotinic acetylcholine receptor) and with magnetic resonance spectroscopy (MRS) and with (S)-[F]THK5117 (Tau) at 15 and 25 m. Behaviour tests were also performed at 6 m, 12 m and 18 m. Immunohistochemistry (CD11b, GFAP, Aβ, NeuN, NeuroChrom) and Tau (S)-[F]THK5117 autoradiography, immunohistochemistry and Western blot were also performed. [F]DPA-714 positron emission tomography (PET) showed an increase in neuroinflammation in TG vs wildtype animals from 12 m in the hippocampus (+11%), and at the advanced-stage AD in the hippocampus (+12%), the thalamus (+11%) and frontal cortex (+14%). This finding coincided with strong increases in brain microgliosis (CD11b) and astrogliosis (GFAP) at these time-points as assessed by immunohistochemistry. [F]ASEM PET revealed an age-dependent increase uptake in the striatum and in WT only, similar to that observed with this tracer in humans, resulting in TG being significantly lower than WT by 18 m. [F]Florbetaben PET scanning detected Aβ accumulation at 18 m, and (S)-[F]THK5117 PET revealed subsequent Tau accumulation at 25m in hippocampal and cortical regions. Aβ plaques were low but detectable by immunohistochemistry from 6 m, increasing further at 12 and 18 m with Tau-positive neurons adjacent to Aβ plaques at 18 m. NeuroChrom (a pan neuronal marker) immunohistochemistry revealed a loss of neuronal staining at the Aβ plaques locations, while NeuN labelling revealed an age-dependent decrease in hippocampal neuron number in both genotypes. Behavioural assessment using the novel object recognition task revealed that both WT & TgF344-AD animals discriminated the novel from familiar object at 3 m and 6 m of age. However, low levels of exploration observed in both genotypes at later time-points resulted in neither genotype successfully completing the task. Deficits in social interaction were only observed at 3 m in the TgF344-AD animals. By MRS, we showed a decrease in neuronal marker N-acetyl-aspartate in the hippocampus at 18 m (-18% vs age-matched WT, and -31% vs 6 m TG) and increased Taurine in the cortex of TG (+35% vs age-matched WT, and +55% vs 6 m TG). This multi-centre multi-modal study demonstrates, for the first time, alterations in brain metabolites, cholinergic receptors and neuroinflammation in this model, validated by robust approaches. Our data confirm that, unlike mouse models, the TgF344-AD express Tau pathology that can be detected via PET, albeit later than by techniques, and is a useful model to assess and longitudinally monitor early neurotransmission dysfunction and neuroinflammation in AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.56059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171096PMC
May 2021

Effects of White Matter Hyperintensities on Verbal Fluency in Healthy Older Adults and MCI/AD.

Front Aging Neurosci 2021 6;13:614809. Epub 2021 May 6.

Department of Psychology, Åbo Akademi University, Turku, Finland.

Background: White matter hyperintensities (WMHs) are markers for cerebrovascular pathology, which are frequently seen in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Verbal fluency is often impaired especially in AD, but little research has been conducted concerning the specific effects of WMH on verbal fluency in MCI and AD.

Objective: Our aim was to examine the relationship between WMH and verbal fluency in healthy old age and pathological aging (MCI/AD) using quantified MRI data.

Methods: Measures for semantic and phonemic fluency as well as quantified MRI imaging data from a sample of 42 cognitively healthy older adults and 44 patients with MCI/AD (total = 86) were utilized. Analyses were performed both using the total sample that contained seven left-handed/ambidextrous participants, as well with a sample containing only right-handed participants ( = 79) in order to guard against possible confounding effects regarding language lateralization.

Results: After controlling for age and education and adjusting for multiple correction, WMH in the bilateral frontal and parieto-occipital areas as well as the right temporal area were associated with semantic fluency in cognitively healthy and MCI/AD patients but only in the models containing solely right-handed participants.

Conclusion: The results indicate that white matter pathology in both frontal and parieto-occipital cerebral areas may have associations with impaired semantic fluency in right-handed older adults. However, elevated levels of WMH do not seem to be associated with cumulative effects on verbal fluency impairment in patients with MCI or AD. Further studies on the subject are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnagi.2021.614809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134546PMC
May 2021

Brain Glucose Metabolism in Health, Obesity, and Cognitive Decline-Does Insulin Have Anything to Do with It? A Narrative Review.

J Clin Med 2021 Apr 6;10(7). Epub 2021 Apr 6.

Turku PET Centre, University of Turku and Turku University Hospital, 20520 Turku, Finland.

Imaging brain glucose metabolism with fluorine-labelled fluorodeoxyglucose ([F]-FDG) positron emission tomography (PET) has long been utilized to aid the diagnosis of memory disorders, in particular in differentiating Alzheimer's disease (AD) from other neurological conditions causing cognitive decline. The interest for studying brain glucose metabolism in the context of metabolic disorders has arisen more recently. Obesity and type 2 diabetes-two diseases characterized by systemic insulin resistance-are associated with an increased risk for AD. Along with the well-defined patterns of fasting [F]-FDG-PET changes that occur in AD, recent evidence has shown alterations in fasting and insulin-stimulated brain glucose metabolism also in obesity and systemic insulin resistance. Thus, it is important to clarify whether changes in brain glucose metabolism are just an epiphenomenon of the pathophysiology of the metabolic and neurologic disorders, or a crucial determinant of their pathophysiologic cascade. In this review, we discuss the current knowledge regarding alterations in brain glucose metabolism, studied with [F]-FDG-PET from metabolic disorders to AD, with a special focus on how manipulation of insulin levels affects brain glucose metabolism in health and in systemic insulin resistance. A better understanding of alterations in brain glucose metabolism in health, obesity, and neurodegeneration, and the relationships between insulin resistance and central nervous system glucose metabolism may be an important step for the battle against metabolic and cognitive disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10071532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038699PMC
April 2021

Effect of dopaminergic medication on adenosine 2A receptor availability in patients with Parkinson's disease.

Parkinsonism Relat Disord 2021 May 29;86:40-44. Epub 2021 Mar 29.

Turku PET Centre, University of Turku, Turku, Finland; Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland.

Objective: To assess the necessity of withdrawing dopaminergic medication in Parkinson's disease (PD) patients for accurate estimation of adenosine 2A receptor (AR) availability using [C]TMSX PET imaging. This was accomplished by studying the short-term effect of the cessation of dopaminergic medication on AR availability in non-dyskinetic patients with PD treated with dopaminergic medication.

Methods: Eight PD patients (age 67.9 ± 5.6 years; 6 men, 2 women) without dyskinesia were enrolled in this study. AR availability was measured using PET imaging with a [7-methyl-C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([C]TMSX) radioligand after a short term cessation of dopaminergic medication (12hrs for levodopa, 24hrs for dopamine agonists and MAO-B inhibitors). Repeated PET imaging was performed while the patients were back 'on' their regular dopaminergic medication (median 13 days after first imaging). Conventional MRI was acquired for anatomical reference. Specific binding of [C]TMSX was quantified as distribution volume ratios (DVR) for caudate, pallidum and putamen using Logan graphical method with clustered gray matter reference region.

Results: No significant differences were observed for the DVRs in all three striatal regions between 'on' and 'off' medication states. Strong correlations were also observed between the two states. Statistical equivalence was found in pallidum (TOST equivalence test, p = 0.045) and putamen (TOST equivalence test, p = 0.022), but not in caudate DVR (TOST equivalence test, p = 0.201) between the two medication states.

Conclusions: Our results show that dopaminergic medication has no significant short-term effect on the availability of A receptors in putamen and pallidum of patients with PD. However, relatively poor repeatability was demonstrated in the caudate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2021.03.030DOI Listing
May 2021

Systemic cross-talk between brain, gut, and peripheral tissues in glucose homeostasis: effects of exercise training (CROSSYS). Exercise training intervention in monozygotic twins discordant for body weight.

BMC Sports Sci Med Rehabil 2021 Feb 24;13(1):16. Epub 2021 Feb 24.

Turku PET Centre, University of Turku, P.O. Box 52, FIN-20521, Turku, Finland.

Background: Obesity and physical inactivity are major global public health concerns, both of which increase the risk of insulin resistance and type 2 diabetes. Regulation of glucose homeostasis involves cross-talk between the central nervous system, peripheral tissues, and gut microbiota, and is affected by genetics. Systemic cross-talk between brain, gut, and peripheral tissues in glucose homeostasis: effects of exercise training (CROSSYS) aims to gain new systems-level understanding of the central metabolism in human body, and how exercise training affects this cross-talk.

Methods: CROSSYS is an exercise training intervention, in which participants are monozygotic twins from pairs discordant for body mass index (BMI) and within a pair at least the other is overweight. Twins are recruited from three population-based longitudinal Finnish twin studies, including twins born in 1983-1987, 1975-1979, and 1945-1958. The participants undergo 6-month-long exercise intervention period, exercising four times a week (including endurance, strength, and high-intensity training). Before and after the exercise intervention, comprehensive measurements are performed in Turku PET Centre, Turku, Finland. The measurements include: two positron emission tomography studies (insulin-stimulated whole-body and tissue-specific glucose uptake and neuroinflammation), magnetic resonance imaging (brain morphology and function, quantification of body fat masses and organ volumes), magnetic resonance spectroscopy (quantification of fat within heart, pancreas, liver and tibialis anterior muscle), echocardiography, skeletal muscle and adipose tissue biopsies, a neuropsychological test battery as well as biosamples from blood, urine and stool. The participants also perform a maximal exercise capacity test and tests of muscular strength.

Discussion: This study addresses the major public health problems related to modern lifestyle, obesity, and physical inactivity. An eminent strength of this project is the possibility to study monozygotic twin pairs that share the genome at the sequence level but are discordant for BMI that is a risk factor for metabolic impairments such as insulin resistance. Thus, this exercise training intervention elucidates the effects of obesity on metabolism and whether regular exercise training is able to reverse obesity-related impairments in metabolism in the absence of the confounding effects of genetic factors.

Trial Registration: ClinicalTrials.gov , NCT03730610 . Prospectively registered 5 November 2018.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13102-021-00241-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905681PMC
February 2021

Association of Early β-Amyloid Accumulation and Neuroinflammation Measured With [C]PBR28 in Elderly Individuals Without Dementia.

Neurology 2021 03 29;96(12):e1608-e1619. Epub 2021 Jan 29.

From the Turku PET Centre (S.T., L.L.E., J.T., S.H., J.J., P.M., J.O.R.) and Department of Biostatistics (E.L.), University of Turku; Kuopio City Home Care (S.T.), Rehabilitation and Medical Services for Elderly, Kuopio, Finland; Amsterdam Alzheimer Center (L.L.E.), Amsterdam UMC, the Netherlands; Department of Radiation Sciences (J.J.), Umeå University, Sweden; City of Turku (H.L.), Welfare Division, Turku City Hospital, Turku, Finland; Department of Medicine (H.L.), University of Turku, Turku University Hospital, Finland; Department of Psychiatry and Neurochemistry (K.B., H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory (K.B., H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (H.Z.), London; National Institute for Health and Welfare (A.J.); Department of Geriatrics (M.V.), Turku City Hospital; University of Turku (M.V.), Finland; Division of Clinical Geriatrics (M.V.), NVS, Karolinska Institutet, Stockholm, Sweden; and Division of Clinical Neurosciences (J.O.R.), Turku University Hospital, Finland.

Objective: To examine whether early β-amyloid (Aβ) accumulation and metabolic risk factors are associated with neuroinflammation in elderly individuals without dementia.

Methods: We examined 54 volunteers (mean age 70.0 years, 56% women, 51% ɛ4 carriers) with the translocator protein (TSPO) tracer [C]PBR28 to assess neuroinflammation and with [C] Pittsburgh compound B (PiB) to assess cerebral Aβ accumulation. [C]PBR28 and [C]PiB standardized uptake value ratios (SUVRs) were quantified in 6 regions of interests by using the cerebellar cortex as a pseudo-reference and reference region, respectively. Fasting venous glucose, insulin, and high-sensitivity C-reactive protein (hs-CRP) values were determined. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. A subset of individuals (n = 11) underwent CSF sampling, and Aβ, Aβ, total tau, phospho-tau, soluble TREM2, and YKL-40 levels were measured.

Results: Among the whole study group, no significant association was found between [C]PiB and [C]PBR28 SUVR composite scores (slope 0.02, = 0.30). However, higher [C]PiB binding was associated with higher [C]PBR28 binding among amyloid-negative ([C]PiB composite score ≤1.5) (TSPO genotype-, age- and sex-adjusted slope 0.26, = 0.008) but not among amyloid-positive (slope -0.004, = 0.88) participants. Higher CSF soluble TREM2 ( = 0.72, = 0.01) and YKL-40 ( = 0.63, = 0.04) concentrations were associated with a higher [C]PBR28 composite score. Higher body mass index, HOMA-IR, and hs-CRP were associated with higher [C]PBR28 binding in brain regions where Aβ accumulation is first detected in Alzheimer disease.

Conclusions: While there was no association between amyloid and neuroinflammation in the overall study group, neuroinflammation was associated with amyloid among the subgroup at early stages of amyloid pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000011612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032368PMC
March 2021

Seasonal Variation in the Brain μ-Opioid Receptor Availability.

J Neurosci 2021 02 23;41(6):1265-1273. Epub 2020 Dec 23.

Turku PET Centre, University of Turku, FIN-20520 Turku, Finland.

Seasonal rhythms influence mood and sociability. The brain μ-opioid receptor (MOR) system modulates a multitude of seasonally varying socioemotional functions, but its seasonal variation remains elusive with no previously reported evidence. Here, we first conducted a cross-sectional study with previously acquired human [C]carfentanil PET imaging data (132 male and 72 female healthy subjects) to test whether there is seasonal variation in MOR availability. We then investigated experimentally whether seasonal variation in daylength causally influences brain MOR availability in rats. Rats (six male and three female rats) underwent daylength cycle simulating seasonal changes; control animals (two male and one female rats) were kept under constant daylength. Animals were scanned repeatedly with [C]carfentanil PET imaging. Seasonally varying daylength had an inverted U-shaped functional relationship with brain MOR availability in humans. Brain regions sensitive to daylength spanned the socioemotional brain circuits, where MOR availability peaked during spring. In rats, MOR availabilities in the brain neocortex, thalamus, and striatum peaked at intermediate daylength. Varying daylength also affected the weight gain and stress hormone levels. We conclude that cerebral MOR availability in humans and rats shows significant seasonal variation, which is predominately associated with seasonal photoperiodic variation. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior. Seasonal rhythms influence emotion and sociability. The central μ-opioid receptor (MOR) system modulates numerous seasonally varying socioemotional functions, but its seasonal variation remains elusive. Here we used positron emission tomography to show that MOR levels in both human and rat brains show daylength-dependent seasonal variation. The highest MOR availability was observed at intermediate daylengths. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.2380-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888218PMC
February 2021

Application of the PET ligand [C]ORM-13070 to examine receptor occupancy by the α-adrenoceptor antagonist ORM-12741: translational validation of target engagement in rat and human brain.

EJNMMI Res 2020 Dec 9;10(1):152. Epub 2020 Dec 9.

Orion Corporation, Orion Pharma, Research and Development, Tengströminkatu 8, 20380, Espoo, Finland.

Background: Availability of the α-adrenoceptor (α-AR) positron emission tomography (PET) tracer, [C]ORM-13070, and the α-AR antagonist ORM-12741 allows probing of the roles of this G-protein coupled receptor subtype in brain function, both in healthy humans and in patients with various brain disorders. This translational study employed [C]ORM-13070 autoradiography and PET to determine α-AR occupancy by ORM-12741 in rat and human brain, respectively.

Results: ORM-12741 has high affinity (K: 0.08 nM) and potent antagonist activity (K: 0.04 nM) as well as selectivity (K estimates for the human α-AR and α-AR were 8.3 nM and 0.8 nM, respectively) for the human α-AR subtype. [C]ORM-13070 had highest uptake in the basal ganglia of rat and human brain. Pretreatment with ORM-12741 inhibited [C]ORM-13070 binding in rat striatum in a time- and dose-dependent manner at 10 and 50 µg/kg (s.c.) with an EC estimate of 1.42 ng/mL in rat plasma, corresponding to protein-free drug concentration of 0.23 nM. In the living human brain, time- and dose-related α-AR occupancy was detected with EC estimates of 24 ng/mL and 31 ng/mL for the caudate nucleus and putamen, respectively, corresponding to protein-free concentrations in plasma of 0.07 nM and 0.1 nM. Modelling-based maximum α-AR occupancy estimates were 63% and 52% in the caudate nucleus and the putamen, respectively.

Conclusions: ORM-12741 is a selective α-AR antagonist which penetrates the rat and human brain to occupy α-ARs in a manner consistent with its receptor pharmacology. Trial registration number and date of registration: ClinicalTrial.cov NCT00829907. Registered 11 December 2008. https://clinicaltrials.gov/ .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13550-020-00741-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726058PMC
December 2020

Middle-age dementia risk scores and old-age cognition: a quasi-experimental population-based twin study with over 20-year follow-up.

J Neurol Neurosurg Psychiatry 2021 Mar 5;92(3):323-330. Epub 2020 Nov 5.

Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Sciences, HiLIFE, University of Helsinki, Helsinki, Finland.

Background: Middle-age risk scores predict cognitive impairment, but it is not known if these associations are evident when controlling for shared genetic and environmental factors. Using two risk scores, self-report educational-occupational score and Cardiovascular Risk Factors, Aging and Dementia (CAIDE), we investigated if twins with higher middle-age dementia risk have poorer old-age cognition compared with their co-twins with lower risk.

Methods: We used a population-based older Finnish Twin Cohort study with middle-age questionnaire data (n=15 169, mean age=52.0 years, SD=11.8) and old-age cognition measured via telephone interview (mean age=74.1, SD=4.1, n=4302). Between-family and within-family linear regression analyses were performed.

Results: In between-family analyses (N=2359), higher educational-occupational score was related to better cognition (B=0.76, 95% CI 0.69 to 0.83) and higher CAIDE score was associated with poorer cognition (B=-0.73, 95% CI -0.82 to -0.65). Within twin-pair differences in educational-occupational score were significantly related to within twin-pair differences in cognition in dizygotic (DZ) pairs (B=0.78, 95% CI 0.25 to 1.31; N=338) but not in monozygotic (MZ) pairs (B=0.12, 95% CI -0.44 to 0.68; N=221). Within twin-pair differences in CAIDE score were not related to within twin-pair differences in cognition: DZ B=-0.38 (95% CI -0.90 to 0.14, N=343) and MZ B=-0.05 (95% CI -0.59 to 0.49; N=226).

Conclusion: Middle-age dementia risk scores predicted old-age cognition, but within twin-pair analyses gave little support for associations independent of shared environmental and genetic factors. Understanding genetic underpinnings of risk score-cognition associations is important for early detection of dementia and designing intervention trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2020-324009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892379PMC
March 2021

Disentangling the Role of Working Memory in Parkinson's Disease.

Front Aging Neurosci 2020 25;12:572037. Epub 2020 Sep 25.

Department of Psychology, Åbo Akademi University, Turku, Finland.

Working memory (WM) represents a core cognitive function with a major striatal contribution, and thus WM deficits, commonly observed in Parkinson's disease (PD), could also relate to many other problems in PD patients. Our online study aimed to determine the subdomains of WM that are particularly affected in PD and to clarify the links between WM and everyday cognitive deficits, other executive functions, psychiatric and PD symptoms, as well as early cognitive impairment. Fifty-two mild-to-moderate PD patients and 54 healthy controls performed seven WM tasks tapping selective updating, continuous monitoring, or maintenance of currently active information. Self-ratings of everyday cognition, depression, and apathy symptoms, as well as screenings of global cognitive impairment, were also collected. The data were analyzed using structural equation modeling. Of the three WM domains, only selective updating was directly predictive of PD group membership. More widespread WM deficits were observed only in relation to global cognitive impairment in PD patients. Self-rated everyday cognition or psychiatric symptoms were not linked to WM performance but correlated with each other. Our findings suggest that WM has a rather limited role in the clinical manifestation of PD. Nevertheless, due to its elementary link to striatal function, the updating component of WM could be a candidate for a cognitive marker of PD also in patients who are otherwise cognitively well-preserved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnagi.2020.572037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544957PMC
September 2020

Association of neuroinflammation with episodic memory: a [C]PBR28 PET study in cognitively discordant twin pairs.

Brain Commun 2020 14;2(1):fcaa024. Epub 2020 Apr 14.

Turku PET Centre, University of Turku, Turku 20521, Finland.

Alzheimer's disease is associated with chronic response of innate immune system, referred as neuroinflammation. PET radioligands binding to the 18 kDa translocator protein are potential biomarkers of neuroinflammation. Translocator protein PET studies in mild cognitive impairment and Alzheimer's disease have indicated controversial results, possibly reflecting interindividual variation and heterogeneity of study populations. We controlled for genetic and environmental effects by studying twin pairs discordant for episodic memory performance. Episodic memory impairment is a well-known cognitive hallmark of early Alzheimer's disease process. Eleven same-sex twin pairs (four monozygotic pairs, six female pairs, age 72-77 years) underwent [C]-acetyl--(2-methoxybenzyl)-2-phenoxy-5-pyridinamine ([C]PBR28) PET imaging, structural magnetic resonance imaging and neuropsychological testing in 2014-17. Main PET outcome was the volume-weighted average standardized uptake value of cortical regions vulnerable to Alzheimer's disease pathology. Ten pairs were discordant for episodic memory performance. In the eight pairs with identical translocator protein genotype, twins with poorer episodic memory had ∼20% higher cortical [C]PBR28 binding compared with their better-performing co-twins (mean intra-pair difference 0.21 standardized uptake value, 95% confidence interval 0.05-0.37,  = 0.017). The result remained the same when including all discordant pairs and controlling for translocator protein genotype. Increased translocator protein PET signal suggests that increased microglial activation is associated with poorer episodic memory performance. Twins with worse episodic memory performance compared with their co-twins had on average 20% higher uptake of the neuroinflammatory marker translocator protein PET tracer [C]PBR28. The findings support a negative association between neuroinflammation and episodic memory and the use of translocator protein positron emission tomography as a useful indicator of Alzheimer's disease process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/braincomms/fcaa024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425350PMC
April 2020

White Matter Changes on Diffusion Tensor Imaging in the FINGER Randomized Controlled Trial.

J Alzheimers Dis 2020 ;78(1):75-86

Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland.

Background: Early pathological changes in white matter microstructure can be studied using the diffusion tensor imaging (DTI). It is not only important to study these subtle pathological changes leading to cognitive decline, but also to ascertain how an intervention would impact the white matter microstructure and cognition in persons at-risk of dementia.

Objectives: To study the impact of a multidomain lifestyle intervention on white matter and cognitive changes during the 2-year Finnish Geriatric Intervention Study to prevent Cognitive Impairment and Disability (FINGER), a randomized controlled trial in at-risk older individuals (age 60-77 years) from the general population.

Methods: This exploratory study consisted of a subsample of 60 FINGER participants. Participants were randomized to either a multidomain intervention (diet, exercise, cognitive training, and vascular risk management, n = 34) or control group (general health advice, n = 26). All underwent baseline and 2-year brain DTI. Changes in fractional anisotropy (FA), diffusivity along domain (F1) and non-domain (F2) diffusion orientations, mean diffusivity (MD), axial diffusivity (AxD), radial diffusivity (RD), and their correlations with cognitive changes during the 2-year multidomain intervention were analyzed.

Results: FA decreased, and cognition improved more in the intervention group compared to the control group (p < 0.05), with no significant intergroup differences for changes in F1, F2, MD, AxD, or RD. The cognitive changes were significantly positively related to FA change, and negatively related to RD change in the control group, but not in the intervention group.

Conclusion: The 2-year multidomain FINGER intervention may modulate white matter microstructural alterations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-200423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683078PMC
January 2020

Detecting Amyloid Positivity in Elderly With Increased Risk of Cognitive Decline.

Front Aging Neurosci 2020 30;12:228. Epub 2020 Jul 30.

Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland.

The importance of early interventions in Alzheimer's disease (AD) emphasizes the need to accurately and efficiently identify at-risk individuals. Although many dementia prediction models have been developed, there are fewer studies focusing on detection of brain pathology. We developed a model for identification of amyloid-PET positivity using data on demographics, vascular factors, cognition, genotype, and structural MRI, including regional brain volumes, cortical thickness and a visual medial temporal lobe atrophy (MTA) rating. We also analyzed the relative importance of different factors when added to the overall model. The model used baseline data from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) exploratory PET sub-study. Participants were at risk for dementia, but without dementia or cognitive impairment. Their mean age was 71 years. Participants underwent a brain 3T MRI and PiB-PET imaging. PiB images were visually determined as positive or negative. Cognition was measured using a modified version of the Neuropsychological Test Battery. Body mass index (BMI) and hypertension were used as cardiovascular risk factors in the model. Demographic factors included age, gender and years of education. The model was built using the Disease State Index (DSI) machine learning algorithm. Of the 48 participants, 20 (42%) were rated as Aβ positive. Compared with the Aβ negative group, the Aβ positive group had a higher proportion of ε4 carriers (53 vs. 14%), lower executive functioning, lower brain volumes, and higher visual MTA rating. AUC [95% CI] for the complete model was 0.78 [0.65-0.91]. MRI was the most effective factor, especially brain volumes and visual MTA rating but not cortical thickness. was nearly as effective as MRI in improving detection of amyloid positivity. The model with the best performance (AUC 0.82 [0.71-0.93]) was achieved by combining and MRI. Our findings suggest that combining demographic data, vascular risk factors, cognitive performance, genotype, and brain MRI measures can help identify Aβ positivity. Detecting amyloid positivity could reduce invasive and costly assessments during the screening process in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnagi.2020.00228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406705PMC
July 2020

Association of Peripheral Insulin Resistance and Other Markers of Type 2 Diabetes Mellitus with Brain Amyloid Deposition in Healthy Individuals at Risk of Dementia.

J Alzheimers Dis 2020 ;76(4):1243-1248

Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland.

We explored the association of type 2 diabetes related blood markers with brain amyloid accumulation on PiB-PET scans in 41 participants from the FINGER PET sub-study. We built logistic regression models for brain amyloid status with12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOEɛ4 carrier status. Lower levels of insulin, insulin resistance index (HOMA-IR), C-peptide, and plasminogen activator (PAI-1) were associated with amyloid positive status, although the results were not significant after adjusting for multiple testing. None of the models found evidence for associations between amyloid status and fasting glucose or HbA1c.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-200145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504982PMC
June 2021

White Matter Hyperintensities and Cognitive Impairment in Healthy and Pathological Aging: A Quantified Brain MRI Study.

Dement Geriatr Cogn Disord 2019 25;48(5-6):297-307. Epub 2020 Mar 25.

Åbo Akademi University, Turku, Finland.

Background: Brain changes involving the white matter (WM), often an indication of cerebrovascular pathology, are frequently seen in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). Few studies have examined possible cognitive domain- or group-specific cognitive effects of WM pathology in old age, MCI, and AD.

Objective: Our purpose was to examine the relationship between WM hyperintensities (WMH), a typical marker for WM pathology, and cognitive functioning in healthy old age and pathological aging using quantified MRI data.

Methods: We utilized multidomain neuropsychological data and quantified MRI data from a sample of 42 cognitively healthy older adults and 44 patients with MCI/AD (total n = 86).

Results: After controlling for age and education, WMH in the temporal and parieto-occipital lobes was associated with impairments in processing speed and parieto-occipital pathology with verbal memory impairment in the whole sample. Additionally, temporal WMH was associated with impaired processing speed in the patient group specifically.

Conclusions: WM pathology is strongly associated with impaired processing speed, and our results indicate that these impairments arise from WMH in the temporal and parieto-occipital regions. In MCI and AD patients with temporal WMH, processing speed impairments are especially prominent. The results of this study increase our knowledge of cognitive repercussions stemming from temporal and/or parieto-occipital WM pathology in healthy and pathological aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000506124DOI Listing
July 2020

Insights into disseminated MS brain pathology with multimodal diffusion tensor and PET imaging.

Neurol Neuroimmunol Neuroinflamm 2020 05 2;7(3). Epub 2020 Mar 2.

From the Turku PET Centre (S.B., J.T., M. Matilainen, A.V., M.N., S.S., M.S., M. Mohammadian, V.S., S.L., J.R., J.O.R., E.R., L.A.), University of Turku and Turku University Hospital; Division of Clinical Neurosciences (A.V., M.N., S.S., M.S., S.L., E.R., L.A.), Turku University Hospital; and Department of Medical Physics (V.S.), Division of Medical Imaging, Turku University Hospital, Finland.

Objective: To evaluate in vivo the co-occurrence of microglial activation and microstructural white matter (WM) damage in the MS brain and to examine their association with clinical disability.

Methods: 18-kDa translocator protein (TSPO) brain PET imaging was performed for evaluation of microglial activation by using the radioligand [C](R)-PK11195. TSPO binding was evaluated as the distribution volume ratio (DVR) from dynamic PET images. Diffusion tensor imaging (DTI) and conventional MRI (cMRI) were performed at the same time. Mean fractional anisotropy (FA) and mean (MD), axial, and radial (RD) diffusivities were calculated within the whole normal-appearing WM (NAWM) and segmented NAWM regions appearing normal in cMRI. Fifty-five patients with MS and 15 healthy controls (HCs) were examined.

Results: Microstructural damage was observed in the NAWM of the MS brain. DTI parameters of patients with MS were significantly altered in the NAWM compared with an age- and sex-matched HC group: mean FA was decreased, and MD and RD were increased. These structural abnormalities correlated with increased TSPO binding in the whole NAWM and in the temporal NAWM ( < 0.05 for all correlations; < 0.01 for RD in the temporal NAWM). Both compromised WM integrity and increased microglial activation in the NAWM correlated significantly with higher clinical disability measured with the Expanded Disability Status Scale score.

Conclusions: Widespread structural disruption in the NAWM is linked to neuroinflammation, and both phenomena associate with clinical disability. Multimodal PET and DTI allow in vivo evaluation of widespread MS pathology not visible using cMRI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136049PMC
May 2020

Magia: Robust Automated Image Processing and Kinetic Modeling Toolbox for PET Neuroinformatics.

Front Neuroinform 2020 4;14. Epub 2020 Feb 4.

Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland.

Processing of positron emission tomography (PET) data typically involves manual work, causing inter-operator variance. Here we introduce the Magia toolbox that enables processing of brain PET data with minimal user intervention. We investigated the accuracy of Magia with four tracers: [C]carfentanil, [C]raclopride, [C]MADAM, and [C]PiB. We used data from 30 control subjects for each tracer. Five operators manually delineated reference regions for each subject. The data were processed using Magia using the manually and automatically generated reference regions. We first assessed inter-operator variance resulting from the manual delineation of reference regions. We then compared the differences between the manually and automatically produced reference regions and the subsequently obtained binding potentials and standardized-uptake-value-ratios. The results show that manually produced reference regions can be remarkably different from each other, leading to substantial differences also in outcome measures. While the Magia-derived reference regions were anatomically different from the manual ones, Magia produced outcome measures highly consistent with the average of the manually obtained estimates. For [C]carfentanil and [C]PiB there was no bias, while for [C]raclopride and [C]MADAM Magia produced 3-5% higher binding potentials. Based on these results and considering the high inter-operator variance of the manual method, we conclude that Magia can be reliably used to process brain PET data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fninf.2020.00003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012016PMC
February 2020

Accuracy of Imputation for Apolipoprotein E ε Alleles in Genome-Wide Genotyping Data.

JAMA Netw Open 2020 01 3;3(1):e1919960. Epub 2020 Jan 3.

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2019.19960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991323PMC
January 2020

Midlife Insulin Resistance as a Predictor for Late-Life Cognitive Function and Cerebrovascular Lesions.

J Alzheimers Dis 2019 ;72(1):215-228

Turku PET Centre, University of Turku, Finland.

Background: Type 2 diabetes (T2DM) increases the risk for Alzheimer's disease (AD) but not for AD neuropathology. The association between T2DM and AD is assumed to be mediated through vascular mechanisms. However, insulin resistance (IR), the hallmark of T2DM, has been shown to associate with AD neuropathology and cognitive decline.

Objective: To evaluate if midlife IR predicts late-life cognitive performance and cerebrovascular lesions (white matter hyperintensities and total vascular burden), and whether cerebrovascular lesions and brain amyloid load are associated with cognitive functioning.

Methods: This exposure-to-control follow-up study examined 60 volunteers without dementia (mean age 70.9 years) with neurocognitive testing, brain 3T-MRI and amyloid-PET imaging. The volunteers were recruited from the Finnish Health 2000 survey (n = 6062) to attend follow-up examinations in 2014-2016 according to their insulin sensitivity in 2000 and their APOE genotype. The exposure group (n = 30) had IR in 2000 and the 30 controls had normal insulin sensitivity. There were 15 APOEɛ4 carriers per group. Statistical analyses were performed with multivariable linear models.

Results: At follow-up the IR+group performed worse on executive functions (p = 0.02) and processing speed (p = 0.007) than the IR- group. The groups did not differ in cerebrovascular lesions. No associations were found between cerebrovascular lesions and neurocognitive test scores. Brain amyloid deposition associated with slower processing speed.

Conclusion: Midlife IR predicted poorer executive functions and slower processing speed, but not cerebrovascular lesions. Brain amyloid deposition was associated with slower processing speed. The association between midlife IR and late-life cognition might not be mediated through cerebrovascular lesions measured here.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-190691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839606PMC
November 2020

Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer's disease.

Clin Epigenetics 2019 09 2;11(1):130. Epub 2019 Sep 2.

Turku Bioscience Centre, University of Turku and Åbo Akademi University, FIN-20520, Turku, Finland.

Background: Alzheimer's disease results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. Environmental and lifestyle factors largely modulate the disease risk and may influence the pathogenesis through epigenetic mechanisms, such as DNA methylation. As environmental and lifestyle factors may affect multiple tissues of the body, we hypothesized that the disease-associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs.

Results: Comparison of 23 disease discordant Finnish twin pairs with reduced representation bisulfite sequencing revealed peripheral blood DNA methylation differences in 11 genomic regions with at least 15.0% median methylation difference and FDR adjusted p value ≤ 0.05. Several of the affected genes are primarily associated with neuronal functions and pathologies and do not display disease-associated differences in gene expression in blood. The DNA methylation mark in ADARB2 gene was found to be differentially methylated also in the anterior hippocampus, including entorhinal cortex, of non-twin cases and controls. Targeted bisulfite pyrosequencing of the DNA methylation mark in ADARB2 gene in 62 Finnish and Swedish twin pairs revealed that, in addition to the disease status, DNA methylation of this region is influenced by gender, age, zygosity, APOE genotype, and smoking. Further analysis of 120 Swedish twin pairs indicated that this specific DNA methylation mark is not predictive for Alzheimer's disease and becomes differentially methylated after disease onset.

Conclusions: DNA methylation differences can be detected in the peripheral blood of twin pairs discordant for Alzheimer's disease. These DNA methylation signatures may have value as disease markers and provide insights into the molecular mechanisms of pathogenesis. We found no evidence that the DNA methylation marks would be associated with gene expression in blood. Further studies are needed to elucidate the potential importance of the associated genes in neuronal functions and to validate the prognostic or diagnostic value of the individual marks or marker panels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-019-0729-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721173PMC
September 2019

Prevalence and correlates of dementia and mild cognitive impairment classified with different versions of the modified Telephone Interview for Cognitive Status (TICS-m).

Int J Geriatr Psychiatry 2019 12 5;34(12):1883-1891. Epub 2019 Sep 5.

Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.

Objectives: The modified Telephone Interview for Cognitive Status (TICS-m) is an efficient and cost-effective screening instrument of dementia, but there is less support for its utility in the detection of mild cognitive impairment (MCI). We undertook a comprehensive evaluation of the utility of different TICS-m versions with or without an education-adjusted scoring method to classify dementia and MCI in a large population-based sample.

Methods: Cross-sectional assessment of cognition (TICS-m), depressive symptoms (CES-D), and apolipoprotein E (APOE) ε4 status was performed on 1772 older adults (aged 71-78 y, education 5-16 y, 50% female) from the population-based older Finnish Twin Cohort. TICS-m classification methods with and without education adjustment were used to classify individuals with normal cognition, MCI, or dementia.

Results: The prevalence of dementia and MCI varied between education-adjusted (dementia = 3.7%, MCI = 9.3%) and unadjusted classifications (dementia = 8.5%-11%, MCI = 22.3%-41.3%). APOE ε4 status was associated with dementia irrespective of education adjustment, but with MCI only when education adjustment was used. Regardless of the version, poorer continuous TICS-m scores were associated with higher age, lower education, more depressive symptoms, male sex, and being an APOE ε4 carrier.

Conclusions: We showed that demographic factors, APOE ε4 status, and depressive symptoms were similarly related to continuous TICS-m scores and dementia classifications with different versions. However, education-adjusted classification resulted in a lower prevalence of dementia and MCI and in a higher proportion of APOE ε4 allele carriers among those identified as having MCI. Our results support the use of education-adjusted classification especially in the context of MCI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gps.5205DOI Listing
December 2019

Domain-specific cognitive effects of white matter pathology in old age, mild cognitive impairment and Alzheimer's disease.

Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 2020 05 14;27(3):453-470. Epub 2019 Jun 14.

Department of Psychology, Åbo Akademi University, Turku, Finland.

Concomitant white matter (WM) brain pathology is often present in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Cognitive effects of WM pathology on cognition in normal and pathological aging have been studied, but very little is known about possible group-specific effects in old age, MCI and AD. The purpose of the current study was to examine the relationship between WM pathology and cognitive functioning in four cognitive domains in old age, MCI and AD. The study utilized multi-domain neuropsychological data and visually rated MRI imaging data from a sample of 56 healthy older adults, 40 patients with MCI and 52 patients with AD ( = 148). After controlling for age and education, main effects of frontal WM pathology (especially in the left hemisphere) were found for cognitive performances in two domains, whereas a main effect of parieto-occipital WM pathology was only found for processing speed. In addition, with regard to processing speed, an interaction between group and WM changes was found: Patients with AD that had moderate or severe left frontal WM pathology were considerably slower than patients with AD that had milder cerebrovascular pathology. Frontal WM pathology, especially in the left hemisphere, seems to affect cognitive functions in many domains in all three groups. The results of the study increase our knowledge of cognitive repercussions stemming from frontal and/or parieto-occipital WM pathology in AD. Clinicians should be aware that patients with AD with prominent frontal cerebrovascular pathology can have considerably slowed cognitive processing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13825585.2019.1628916DOI Listing
May 2020

Comparison of high and low molar activity TSPO tracer [F]F-DPA in a mouse model of Alzheimer's disease.

J Cereb Blood Flow Metab 2020 05 29;40(5):1012-1020. Epub 2019 May 29.

Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku and Turku University Central Hospital, Turku, Finland.

[F]F-DPA, a novel translocator protein 18 kDa (TSPO)-specific radioligand for imaging neuroinflammation, has to date been synthesized with low to moderate molar activities (A's). In certain cases, low A can skew the estimation of specific binding. The high proportion of the non-radioactive component can reduce the apparent-specific binding by competitively binding to receptors. We developed a nucleophilic synthesis of [F]F-DPA resulting in high A (990 ± 150 GBq/µmol) and performed in vivo comparison with low A (9.0 ± 2.9 GBq/µmol) [F]F-DPA in the same APP/PS1-21 and wild-type mice (injected masses: 0.34 ± 0.13 µg/kg and 38 ± 15 µg/kg, respectively). The high level of microgliosis in the APP/PS1-21 mouse model enables good differentiation between diseased and healthy animals and serves better to distinguish the effect of differing A on specific binding. The differing injected masses affect the washout profile and shape of the time-activity curves. Ratios of standardized uptake values obtained with high and low A [F]F-DPA demonstrate that there is a 1.5-fold higher uptake of radioactivity in the brains of APP/PS1-21 animals when imaging is carried out with high A [F]F-DPA. The differences between APP/PS1-21 and wild-type animals showed higher significance when high A was used.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0271678X19853117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181084PMC
May 2020

Effect of genotype and age on cerebral [F]FDG uptake varies between transgenic APP-PS1 and Tg2576 mouse models of Alzheimer's disease.

Sci Rep 2019 04 5;9(1):5700. Epub 2019 Apr 5.

MediCity Research Laboratory, University of Turku, Tykistökatu 6 A, FI-20520, Turku, Finland.

Back-translation of clinical imaging biomarkers of Alzheimer's disease (AD), such as alterations in cerebral glucose metabolism detected by [F]FDG positron emission tomography (PET), would be valuable for preclinical studies evaluating new disease-modifying drugs for AD. However, previous confounding results have been difficult to interpret due to differences in mouse models and imaging protocols between studies. We used an equivalent study design and [F]FDG µPET imaging protocol to compare changes in cerebral glucose metabolism in commercial transgenic APP-PS1 (n = 12), Tg2576 (n = 15), and wild-type mice (n = 15 and 9). Dynamic [F]FDG scans were performed in young (6 months) and aged (12 or 17 months) mice and the results verified by ex vivo methods (i.e., tissue counting, digital autoradiography, and beta-amyloid and Iba-1 immunohistochemistry). [F]FDG uptake exhibited significant regional differences between genotypes (TG < WT) and ages (6 months <12 months) in the APP-PS1 model, whereas similar differences were not present in Tg2576 mice. In both models, only weak correlations were detected between regional beta-amyloid deposition or microgliosis and [F]FDG uptake. By using equivalent methodology, this study demonstrated differences in cerebral glucose metabolism dysfunction detected with [F]FDG PET between two widely used commercial AD mouse models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-42074-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450965PMC
April 2019

[11C]PIB PET Is Associated with the Brain Biopsy Amyloid-β Load in Subjects Examined for Normal Pressure Hydrocephalus.

J Alzheimers Dis 2019 ;67(4):1343-1351

Institute of Clinical Medicine, Neurosurgery, University of Eastern Finland, Kuopio, Finland.

Background: Idiopathic normal pressure hydrocephalus (iNPH) is frequently associated with concomitant amyloid-β (Aβ) pathology.

Objective: To compare the [11C]PIB PET uptake in the patients with suspected iNPH to Aβ and hyperphosphorylated-tau (HPτ) in the right frontal cortical biopsy, the cerebrospinal fluid (CSF) Aβ, the response to a CSF shunt, and the final clinical diagnosis of Alzheimer's disease (AD).

Methods: Patients (n = 21) from Kuopio NPH Registry (http://www.uef.fi/nph) with intraventricular pressure monitoring, immunostaining for Aβ and HPτ in the right frontal cortical biopsies, and a Mini-Mental State Examination and a Clinical Dementia Rating underwent [11C]PIB PET. Aβ, total tau, and Pτ181 were measured by ELISA from the ventricular (n = 15) and the lumbar (n = 9) CSF. Response to the shunt was seen in 13 out of the 15 shunted patients. AD was diagnosed in 8 patients during a median follow-up of 6 years (mean 7.3±2.4 years, range 3-1).

Results: [11C]PIB uptake in the right frontal cortex (ρ= 0.60, p < 0.01) and the combined neocortical [11C]PIB uptake score (ρ= 0.61, p < 0.01) were associated with a higher Aβ load in the right frontal cortical biopsy. Excluding one (1/15) outlier, [11C]PIB uptake was also associated with the ventricular CSF Aβ (ρ= -0.58, p = 0.03).

Conclusions: The findings show that [11C]PIB PET can reliably detect simultaneous amyloid pathology among the iNPH patients. Further studies will show whether amyloid PET could predict a clinical response to the shunt operation. In addition, the presence of Aβ pathology in the patients with iNPH might also warrant treatment with current AD drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-180645DOI Listing
May 2020

Cognitive Effects of White Matter Pathology in Normal and Pathological Aging.

J Alzheimers Dis 2019 ;67(2):489-493

Department of Psychology, Åbo Akademi University, Finland.

We examined whether cerebrovascular white matter pathology is related to cognition as measured by the compound score of CERAD neuropsychological battery in cognitively normal older adults, patients with mild cognitive impairment, and patients with Alzheimer's disease (total n = 149), controlling for age and education. Trend-level effects of white matter pathology on cognition were only observed in patients with Alzheimer's disease (p = 0.062, η2  = 0.052), patients with severe frontal white matter pathology performed notably worse than those with milder pathology. This indicates that frontal cerebrovascular pathology may have an additive negative effect on cognition in Alzheimer's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-180554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484248PMC
March 2020

[F]F-DPA for the detection of activated microglia in a mouse model of Alzheimer's disease.

Nucl Med Biol 2018 12 26;67:1-9. Epub 2018 Sep 26.

PET Preclinical Imaging Laboratory, Turku PET Centre, University of Turku, Finland; MediCity Research Laboratory, University of Turku, Finland.

Introduction: Neuroinflammation is associated with several neurological disorders, including Alzheimer's disease (AD). The translocator protein 18 kDa (TSPO), due to its overexpression during microglial activation and relatively low levels in the brain under normal neurophysiological conditions, is commonly used as an in vivo biomarker for neuroinflammation. Reported here is the preclinical evaluation of [F]F-DPA, a promising new TSPO-specific radioligand, as a tool for the detection of activated microglia at different ages in the APP/PS1-21 mouse model of AD and a blocking study to determine the specificity of the tracer.

Methods: [F]F-DPA was synthesised by the previously reported electrophilic F-fluorination methodology. In vivo PET and ex vivo brain autoradiography were used to observe the tracer distribution in the brains of APP/PS1-21 and wildtype mice at different ages (4.5-24 months). The biodistribution and degree of metabolism of [F]F-DPA were analysed and the specificity of [F]F-DPA for its target was determined by pre-treatment with PK11195.

Results: The in vivo PET imaging and ex vivo brain autoradiography data showed that [F]F-DPA uptake in the brains of the transgenic animals increased with age, however, there was a drop in the tracer uptake at 19 mo. Despite the slight increase in [F]F-DPA uptake with age in healthy animal brains, significant differences between wildtype and transgenic animals were seen in vivo at 9 months and ex vivo already at 4.5 months. The specificity study demonstrated that PK11195 can be used to significantly block [F]F-DPA uptake in all the brain regions studied.

Conclusions: In vivo time activity curves plateaued at approximately 20-40 min suggesting that this is the optimal imaging time. Significant differences in vivo are seen at 9 and 12 mo. Due to the higher resolution, ex vivo autoradiography with [F]F-DPA can be used to visualise activated microglia at an early stage of AD pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nucmedbio.2018.09.001DOI Listing
December 2018

Immediate verbal recall and familial dementia risk: population-based study of over 4000 twins.

J Neurol Neurosurg Psychiatry 2019 01 12;90(1):90-97. Epub 2018 Oct 12.

Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.

Objective: To investigate the effect of familial risk for dementia on verbal learning by comparing cognitively healthy twins who had demented co-twins with cognitively healthy twins who had cognitively healthy co-twins.

Methods: 4367 twins aged ≥65 years including 1375 twin pairs (533 monozygotic (MZ), 823 dizygotic (DZ) and 19 unknown zygosity pairs) from a population-based Finnish Twin Cohort participated in a cross-sectional telephone assessment for dementia and in a single free recall trial of a 10-item word list.

Results: Cognitively healthy twins with demented co-twins (n=101 pairs) recalled less words than cognitively healthy twins with cognitively healthy co-twins (n=770 pairs) after adjusting for age, sex and education, B=- 0.44, 95%  CI (-0.73 to -0.14), p=0.003. The effect size was similar in MZ (n=31) twins (3.88 vs 4.29 words, B=-0.41, 95%  CI (-0.96 to 0.13)) and DZ (n=66) twins (3.70 vs 4.17 words, B=-0.47, 95%  CI (-0.84 to -0.10)). The heritability estimate of immediate recall (IR) was 0.37, 95%  CI (0.21 to 0.43).

Conclusions: The results demonstrate that familial risk for dementia is reflected in the IR performance of cognitively healthy older persons. The finding of poorer IR performance in non-affected siblings compared with the general population, together with substantial heritability of IR, supports IR as a useful endophenotype for molecular genetic studies of dementia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2018-319122DOI Listing
January 2019
-->