Browsing by Subject "ALS"
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(2015)This review focuses on neurotrophic factors, especially CDNF, and Amyotropic lateral sclerosis (ALS). This review finds out which neurotrophic factors have been studied in clinical trials of ALS and what kind of results have been got. Neurotrophic factors are important for development and function of neurons because they prevent apoptosis of neurons. They also play role in differentiation, development and migration of neurons. It is also known that many of the neurotrophic factors have protective and restorative properties. ALS is a rare neurodegenerative disease which causes the destruction of motor neurons and leads to death in three years. The disease degenerate the upper and lower motor neurons. Symptoms are muscle weakness, muscle atrophy, cramps and problems with swallowing. At the moment there is no cure for ALS so it is important to study neurotrophic factors that could prevent the progression of the disease and perhaps to protect or repair destroyed motor neurons. This is why it is important to study potential of CDNF in ALS. The experimental part consists of three different parts. The purpose of the first part study was to determine the distribution of CDNF after intraventricular delivery at different time points. CDNF was labeled with 125I (125I-CDNF). The distribution was determined by gammacounter and autoradiography. To determine the stability of the injected 125-I CDNF we performed SDS-PAGE. The second part studied the diffusion volume of CDNF after intraventricular injection with seven wild type mice. After stereotaxic surgery CDNF-immunohistochemistry staining from coronal sections was done. The last experimental part studied the effect of single intracerebral injection of CDNF on motivation, locomotor activity, anxiety and depression with male and female mice. Light-dark box, open field, rotarod, forced swim test (FST), elevated plus maze and fear conditioning were carried out with male mice. After behavioural tests mice were sacrified for HPLC-analysis. Light-dark box and IntelliCage were carried out with female mice before c-fos staining. Gammacounter and autoradiography shows that 125I-CDNF distributes widely after intracerebroventricular injection. It spread throughout to the brain and also all the way to the spinal cord after one and three hours from injection. After 24 hours 125I-CDNF was cleared so the CDNF signal was very weak. SDS-PAGE showed the stability of radioactive CDNF. CDNF increased locomotor activity and decreased anxiety in male mice. But a statistically significant difference appeared in forced swim test and fear conditioning test. HPLC-analysis supported these results partly. CDNF also increased motivation of female mice in IntelliCage experiment. C-fos staining was observed in CDNF group and PBS group so quantitative analysis should be done from these sections so that reliable conclusions could be done. However, because CDNF distributed to spinal cord and it showed some effect on locomotor activity, motivation and depression it might be potential for ALS disease.
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(2021)Amyotrofinen lateraaliskleroosi (ALS) on etenevä, kuolemaan johtava, neurodegeneratiivinen sairaus, jolle tyypillistä on raaja-alkuinen lihasheikkous, lihasjäykkyys ja atrofia. Noin 25-30% potilaista sairastaa bulbaarialkuista tautia, jolle tyypillistä on puheentuoton ja nielemisen häiriöt. Taudin esiintyvyys Euroopassa on 4.1-8.2 tapausta 100 000 henkilövuotta kohden. Tämän tutkimuksen tavoitteena oli selvittää ensisijaisesti korva-, nenä- ja kurkkutaudeille hakeutuvien ALS-potilaiden ja erityisesti bulbaarista tautia sairastavien potilaiden tyypillinen oirekirjo, mahdollinen läheteviive ja taudin kulku sekä nielemisfunktiotutkimusten käyttökelpoisuus ja hoidon tulokset. Toissijainen tavoite oli selvittää parenteraalisen ravitsemuksen ja trakeostomian esiintyvyys koko potilasryhmässä. Tutkimusta varten kerättiin kaikki Helsingin ja Uudenmaan sairaanhoitopiirin diagnosoidut ALS-potilaat vuosilta 2010–2014, joita oli yhteensä 327, ja näistä 110 bulbaari-ALS-potilaita. Kaikista potilaista selvitettiin sukupuoli, taudin tyyppi ja kesto, tehdyt toimenpiteet, ja lisäksi bulbaarialkuista tautia sairastavilta nielemisfunktiotutkimuksiin, hengitys- ja nielemisoireiden alkuun, ensimmäiseen hoitokontaktiin, erikoislääkärikontaktiin sekä ensimmäiseen neurologikontaktiin liittyvää dataa. Aineisto analysoitiin käyttäen vakiintuneita tilastollisia menetelmiä. Tutkimuksessa selvisi, että korva-, nenä- ja kurkkutaudeille tyypillisesti hakeudutaan bulbaarialkuisen taudin tyyppioireiden takia. ALS-potilaiden hoitotulokset eivät merkittävästi riipu siitä, mille erikoisalalle potilas ensimmäisenä lähetetään. Lisäksi taudin insidenssi, hoitotulokset ja tehtyjen toimenpiteiden kumulatiivinen insidenssi vastaa kirjallisuuskatsauksessa ilmeneviä eurooppalaisia lukuja. Tutkimuksemme perusteella parenteraalinen ravitsemus näyttää parantavan bulbaarialkuista tautia sairastavan elinajan ennustetta, mutta hieman yllättäen huonontavan raaja-alkuista tautia sairastavan potilaan elinajan ennustetta. Tutkimus selkeyttää korva-, nenä- ja kurkkutautilääkäreille hakeutuvien potilaiden oirekuvaa ja selvittää ALS:n hoidon tilaa ja tuloksia Suomessa.
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(2020)Amyotrophic lateral sclerosis (ALS) is a rare fatal neurodegenerative disease in which both the upper and lower motor neurons degenerate. Pathological features of the disease include misfolded proteins and accumulations in the central nervous system. The molecular mechanisms of the disease include neuroinflammation, glutamate induced excitotoxicity, and endoplasmic reticulum stress (ER-stress). Numerous genetic defects have been identified in the background of ALS, the most common mutations are in the C9ORF72, SOD1, TDP43 and FUS genes. For each gene mutation, it is important to develop a reliable animal model of ALS for studying pathology and testing new therapies. The most common and most recently found gene mutation, the C9ORF72 repeat expansion mutation, does not yet have an established animal disesase model. The molecular mechanisms of the disease include neuroinflammation, glutamate induced excitotoxicity, and endoplasmic reticulum stress (ER- stress). There is no drug treatment to cure or slow ALS, so the need for new drug therapies that affect the course of the disease is significant. Cerebral dopamine neurotrophic factor (CDNF) protects and restores dopamine neurons and controls ER-stress in preclinical models of Parkinson’s disease. CDNF has also been shown to improve motor coordination as well as protect spinal cord neurons from cell destruction in ALS genetic SOD1- G93A mouse and TDP-43M337 animal models. The purpose of this master's thesis study was to characterize the changes related to neurodegeneration and neuroinflammation in the new C9ORF72-500 disease model and study ER stress of the SOD1-93A disease model and the effect of CDNF on ER stress in SOD1-model and on inflammation in C9-model. In the first sub-study, brain sections from C9ORF72 transgenic and wild-type mice at different time points were subjected to six different immunohistological stainings. The results were compared at each time point (30, 70 and 170) between the wild type and the transgenic group. In another sub-study, spinal cord sections from CDNF snd vehicle treated SOD1- G93A mice were subjected to immunofluorescence staining, after which the intensity of their ER stress marker, GRP78, was analyzed using a confocal microscope. GFAP stained brain sections from CDNF and vehicle treated C9ORF72 mice were analyzed using microscope and imaging analyses. The results of the first sub-study showed neuroinflammation at 24 weeks timepoint in the transgenic group compared to wild-type mice. Pathological features of C9-ALS, various protein accumulations, were observed only in the transgenic group, mainly at 24 weeks. No neuronal loss was observed in this study. The obtained results support the previously published research results and support the reliability of the studied disease model. In the second sub-study ER stress levels were higher in SOD1-mice compared to wild-type mice. Single intracerebroventrical CDNF injection reduced ER stress in SOD1-G93A transgenic mice almost to the same level as ER stress in wild-type mice. CDNF treatment also showed a tendency for reducing inflammation in hippocampus and motor cortex of C9ORF72 mice. The results confirm the pathological role of ER stress in ALS and show that CDNF reduces ER stress when administered as early in the disease as possible, when neuronal damage begins to occur but does not yet lead to neuronal destruction. CDNF appears to be a promising drug candidate for the treatment of ALS and should therefore be further investigated.
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(2021)Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motoneuron disease. ALS is characterized by a progressive loss of upper and lower motoneurons, resulting in muscle atrophy, paralysis and ultimately in death. Approximately 30,000 people die of ALS annually. There is no cure for ALS, and only two drugs - riluzole and edavarone - have been approved for the treatment of the disease. The complex pathology of ALS contributes to the lack of effective treatments. Several cellular pathologies have been suggested to contribute to the pathogenesis, including ER stress, disruption of calcium homeostasis, oxidative stress and excitotoxicity. Here we describe the cytoprotective effects of C-terminal fragments of the novel proteins with neurotrophic factor properties MANF (mesencephalic astrocyte-derived neurotrophic factor) and CDNF (cerebral dopamine neurotrophic factor) on a toxin model of ALS in vitro. Unlike the classical neurotrophic factors, MANF and CDNF are predominantly localized to the endoplasmic reticulum (ER) and have been shown to alleviate ER stress by keeping the unfolded protein response (UPR) transducers inactive. ER stress is a major component in many neurodegenerative diseases, including ALS, and is a promising therapeutic target for MANF and CDNF. However, the potential of these proteins in ALS treatment remains to be insufficiently described. We used differentiated motoneuron-like NSC-34 cells treated with a range of toxins, modelling different cellular pathologies linked to ALS. After the toxin addition, we treated the cells with MANF and CDNF variants and riluzole and measured the cell viability. The toxin panel consists of tunicamycin, ionomycin and staurosporine. Tunicamycin causes cell death by activating proapoptotic branches of the UPR. Ionomycin is an ionophore and depletes the ER of calcium, thus inducing both UPR-dependent and UPR-independent apoptosis. Less is known about the mechanisms of staurosporine, but it has been shown to induce caspase-3-dependent apoptosis, increase intracellular calcium levels and cause oxidative stress. We hypothesized that both MANF and CDNF variants protect the cells against UPR-dependent apoptosis but not against UPR-independent cell death. We show that MANF and CDNF variants protect the cells against apoptosis induced by tunicamycin, ionomycin and staurosporine. Interestingly, the protein variants mediated the highest protection against ionomycin-induced stress, and they exhibited mild protective effects against staurosporine as well. These findings suggest that MANF and CDNF variants might have a role in maintaining intracellular calcium homeostasis. However, it is possible that staurosporine induces ER stress as well, which would explain the protection conferred by the protein variant. We report that the CDNF variant mediates higher protection at lower concentrations compared to the MANF variant in every toxin assay, whereas the MANF variant mediates higher protection at the highest tested concentration compared to the CDNF variant. We also show that the CDNF variant-mediated protection against staurosporine-induced stress peaked at lower concentrations, and the highest concentration provided distinctively lower, yet significant effect. These data lead us to hypothesize that the protein variants may have a slightly different mode of action, and that they might provide an additive effect when administered simultaneously. We tested a combination of MANF and CDNF variants in cells treated with tunicamycin, ionomycin and staurosporine. However, the combination treatment did not increase the viability more than MANF and CDNF variants independently did. The results answered our questions as well as raised new ones. In the future, the putative calcium-regulating effects of the protein variants should be investigated. The UPR-modifying effects of the drug candidates and toxins need to be assessed by quantifying changes in the UPR marker mRNA and protein expression levels. If it is revealed that the variants have a different mode of action, the possible additive protective effects must be assessed. Finally, a wider toxin panel is needed to fully explore the potential of MANF and CDNF variants in ALS treatment. This study demonstrates the potential of MANF and CDNF variants in protecting motoneurons against several pathological pathways contributing to ALS pathology. However, the mechanisms of action of the variants need further investigation to fully understood their therapeutic potential.
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(2021)Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motoneuron disease. ALS is characterized by a progressive loss of upper and lower motoneurons, resulting in muscle atrophy, paralysis and ultimately in death. Approximately 30,000 people die of ALS annually. There is no cure for ALS, and only two drugs - riluzole and edavarone - have been approved for the treatment of the disease. The complex pathology of ALS contributes to the lack of effective treatments. Several cellular pathologies have been suggested to contribute to the pathogenesis, including ER stress, disruption of calcium homeostasis, oxidative stress and excitotoxicity. Here we describe the cytoprotective effects of C-terminal fragments of the novel proteins with neurotrophic factor properties MANF (mesencephalic astrocyte-derived neurotrophic factor) and CDNF (cerebral dopamine neurotrophic factor) on a toxin model of ALS in vitro. Unlike the classical neurotrophic factors, MANF and CDNF are predominantly localized to the endoplasmic reticulum (ER) and have been shown to alleviate ER stress by keeping the unfolded protein response (UPR) transducers inactive. ER stress is a major component in many neurodegenerative diseases, including ALS, and is a promising therapeutic target for MANF and CDNF. However, the potential of these proteins in ALS treatment remains to be insufficiently described. We used differentiated motoneuron-like NSC-34 cells treated with a range of toxins, modelling different cellular pathologies linked to ALS. After the toxin addition, we treated the cells with MANF and CDNF variants and riluzole and measured the cell viability. The toxin panel consists of tunicamycin, ionomycin and staurosporine. Tunicamycin causes cell death by activating proapoptotic branches of the UPR. Ionomycin is an ionophore and depletes the ER of calcium, thus inducing both UPR-dependent and UPR-independent apoptosis. Less is known about the mechanisms of staurosporine, but it has been shown to induce caspase-3-dependent apoptosis, increase intracellular calcium levels and cause oxidative stress. We hypothesized that both MANF and CDNF variants protect the cells against UPR-dependent apoptosis but not against UPR-independent cell death. We show that MANF and CDNF variants protect the cells against apoptosis induced by tunicamycin, ionomycin and staurosporine. Interestingly, the protein variants mediated the highest protection against ionomycin-induced stress, and they exhibited mild protective effects against staurosporine as well. These findings suggest that MANF and CDNF variants might have a role in maintaining intracellular calcium homeostasis. However, it is possible that staurosporine induces ER stress as well, which would explain the protection conferred by the protein variant. We report that the CDNF variant mediates higher protection at lower concentrations compared to the MANF variant in every toxin assay, whereas the MANF variant mediates higher protection at the highest tested concentration compared to the CDNF variant. We also show that the CDNF variant-mediated protection against staurosporine-induced stress peaked at lower concentrations, and the highest concentration provided distinctively lower, yet significant effect. These data lead us to hypothesize that the protein variants may have a slightly different mode of action, and that they might provide an additive effect when administered simultaneously. We tested a combination of MANF and CDNF variants in cells treated with tunicamycin, ionomycin and staurosporine. However, the combination treatment did not increase the viability more than MANF and CDNF variants independently did. The results answered our questions as well as raised new ones. In the future, the putative calcium-regulating effects of the protein variants should be investigated. The UPR-modifying effects of the drug candidates and toxins need to be assessed by quantifying changes in the UPR marker mRNA and protein expression levels. If it is revealed that the variants have a different mode of action, the possible additive protective effects must be assessed. Finally, a wider toxin panel is needed to fully explore the potential of MANF and CDNF variants in ALS treatment. This study demonstrates the potential of MANF and CDNF variants in protecting motoneurons against several pathological pathways contributing to ALS pathology. However, the mechanisms of action of the variants need further investigation to fully understood their therapeutic potential.
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(2023)Human induced pluripotent stem cells (hiPSCs) are derived from adult differentiated somatic cells and reprogrammed to an embryonic-like state. Pluripotent stem cells can be differentiated into almost any somatic cell type by using directed differentiation methods, but the differentiation efficiency often varies depending on the cell type. hiPSCs and cells differentiated from them can be used as a disease model carrying the patient’s phenotype and genotype. Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease where both upper and lower motor neurons degenerate, leading to paralysis. There is no curative treatment for ALS, and it leads to the death of the patient in 3 to 5 years on average from the first symptoms. The most common genetic cause of familial ALS is a hexanucleotide repeat expansion in C9orf72-gene. ALS pathology is strongly linked to endoplasmic reticulum (ER) stress, which affects cell homeostasis and proteostasis, and leads to apoptosis when prolonged. The primary aim of this research is to characterize the differentiation of four hiPSCs lines towards lower motor neurons and to study the neuroprotective effects of cerebral dopamine neurotrophic factor (CDNF) and CDNF-derived peptide on ER stress and cell viability. This experiment used two control cell lines from two healthy donors and two patient cell lines from two different ALS patients carrying the C9orf72-mutation. To evaluate the efficiency of the differentiation towards motor neurons, molecular markers for pluripotent and neural progenitor cells as well as for maturated motor neurons were analyzed. Relative gene expression levels were measured from weekly time points with qPCR. Immunocytochemical (ICC) antibody staining was performed during differentiation. Endogenic CDNF levels were analyzed from differentiating cells at weekly time points and the effect of CDNF on Thapsigargin (TG) -induced ER stress in motor neurons was analyzed. In addition, cell viability was analyzed in TG-CDNF treatment. All pluripotent and progenitor markers were downregulated in differentiated cells, and the expression of the mature motor neuron markers was upregulated. Mature motor neuron markers were also expressed at the protein level. The endogenous CDNF levels were highest at the progenitor cell stage. The ER stress response was upregulated in TG-treated cells, and there were no differences between treatments against ER stress. Furthermore, TG and growth factor treatments differentially affected the viability of the control and patient cell lines. Treatment decreased viability in control cell lines and increased viability in patient cell lines. Pluripotent stem cells were successfully differentiated toward motor neurons. The differentiation was performed twice, and the results were similar on both individual biological repeats. Analysis of endogenous CDNF expression levels was performed for the first time on hiPSCs lines. In this study, CDNF or its derivate didn’t reduce ER stress but it influenced cell viability, especially in patient cell lines with growth factor treatment. In the future, TG-treatment could be optimized regarding timing and growth factor treatment, or the toxin could be changed to another ER-stress inducing toxin. In addition, the C9orf72 pathology should be identified in order to use differentiated motor neurons as a pre-clinical disease model.
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(2023)Human induced pluripotent stem cells (hiPSCs) are derived from adult differentiated somatic cells and reprogrammed to an embryonic-like state. Pluripotent stem cells can be differentiated into almost any somatic cell type by using directed differentiation methods, but the differentiation efficiency often varies depending on the cell type. hiPSCs and cells differentiated from them can be used as a disease model carrying the patient’s phenotype and genotype. Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease where both upper and lower motor neurons degenerate, leading to paralysis. There is no curative treatment for ALS, and it leads to the death of the patient in 3 to 5 years on average from the first symptoms. The most common genetic cause of familial ALS is a hexanucleotide repeat expansion in C9orf72-gene. ALS pathology is strongly linked to endoplasmic reticulum (ER) stress, which affects cell homeostasis and proteostasis, and leads to apoptosis when prolonged. The primary aim of this research is to characterize the differentiation of four hiPSCs lines towards lower motor neurons and to study the neuroprotective effects of cerebral dopamine neurotrophic factor (CDNF) and CDNF-derived peptide on ER stress and cell viability. This experiment used two control cell lines from two healthy donors and two patient cell lines from two different ALS patients carrying the C9orf72-mutation. To evaluate the efficiency of the differentiation towards motor neurons, molecular markers for pluripotent and neural progenitor cells as well as for maturated motor neurons were analyzed. Relative gene expression levels were measured from weekly time points with qPCR. Immunocytochemical (ICC) antibody staining was performed during differentiation. Endogenic CDNF levels were analyzed from differentiating cells at weekly time points and the effect of CDNF on Thapsigargin (TG) -induced ER stress in motor neurons was analyzed. In addition, cell viability was analyzed in TG-CDNF treatment. All pluripotent and progenitor markers were downregulated in differentiated cells, and the expression of the mature motor neuron markers was upregulated. Mature motor neuron markers were also expressed at the protein level. The endogenous CDNF levels were highest at the progenitor cell stage. The ER stress response was upregulated in TG-treated cells, and there were no differences between treatments against ER stress. Furthermore, TG and growth factor treatments differentially affected the viability of the control and patient cell lines. Treatment decreased viability in control cell lines and increased viability in patient cell lines. Pluripotent stem cells were successfully differentiated toward motor neurons. The differentiation was performed twice, and the results were similar on both individual biological repeats. Analysis of endogenous CDNF expression levels was performed for the first time on hiPSCs lines. In this study, CDNF or its derivate didn’t reduce ER stress but it influenced cell viability, especially in patient cell lines with growth factor treatment. In the future, TG-treatment could be optimized regarding timing and growth factor treatment, or the toxin could be changed to another ER-stress inducing toxin. In addition, the C9orf72 pathology should be identified in order to use differentiated motor neurons as a pre-clinical disease model.
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(2017)Transactive DNA Response Element Binding Protein 43 (TDP-43) is a RNA binding protein participating in gene expression on a transcriptional level. It is localized in the cell nucleus. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons. In most ALS patients TDP-43 becomes localized into the cytoplasm of neurons and glia cells. The TDP-43 rat ALS model provide insight in ALS disease progression and molecular mechanisms. This animal model has been characterized previously in the literature. Cerebral Dopamine Growth Factor (CDNF) is a neuroprotective and restorative protein in rat animal model of Parkinson's disease. CDNF may have an impact on disease progression in ALS. One of the goals in this work was to recharacterize the TDP-43 rat ALS model and to try repeat published data. The other aim of this work was to treat TDP-43 rats with intraventricular chronic infusion of CDNF, and to compare symptom progression with TDP-43 rats treated with phosphate buffered saline. Behavioral assays were done trice a week and when rats reached endpoint, spinal cords were removed. Motor neuron counting and detection of stress granule formation were investigated in spinal cords with immunohistochemistry. Also, the volume of CDNF diffusion in rat brain after chronic intraventricular CDNF infusion was investigated with immunohistochemistry. In the characterization part, symptom progression was repeated in a similar manner as it has been reported previously. CDNF treatment could not stop the symptom progression nor slow down the progression of symptoms in TDP-43 rats. Motor neuron counting revealed a heavy loss of motor neurons in the lumbal part of the spinal cord in both treatment groups. Diffusion of CDNF was very poor in the rat brain. Higher doses of CDNF and proper administration depth in the brain or route of administration should be reconsidered in the future.
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(2015)Endoplasmic reticulum stress (ER-stress) is the result of accumulation of unfolded and misfolded proteins in the ER. The unfolded proteins activate the unfolded protein response (UPR), which seeks to reduce the protein load in the ER and reduces ER-stress. When ER-stress is prolonged, the UPR will activate apoptosis. Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disease that affects lower and higher motorneurons. The cause of ALS is unknown but ER-stress is known to play a role in the disease progression. CDNF is a new neurotrophic factor, which is known to play a role in protein folding in the ER. CDNF is neuroprotective and neurorestorative in animal models of Parkinson's disease. Thus, CDNF is a potential new drug candidate for treating ALS. The aim of this work was to examine the effect of CDNF on disease state and life span in transgenic SOD1(G93A)-mice. CDNF or PBS was injected into the mouse's ventricle in stereotaxic surgery when the mice were about 90 days old. Clinical status and motor coordination was monitored twice a week throughout the study. The mice were dissected when they reached the end point that was set for the study. Deepfrozen gastrocnemius muscles were stained with antibodies, to examine the integrity of the neuromuscular junctions (NMJ). Quantitative PCR (qPCR) was executed on deepfrozen spinal cord and motor cortex samples to measure the expression of ER-stress genes. The results showed that CDNF improves motor coordination and delays disease progression in SOD1 female mice. The NMJs were notably more damaged in SOD1 mice than in wild type mice, but CDNF did not have any significant effect on NMJ integrity. ER-stress could be observed in the spinal cord and motor cortex of SOD1 mice and CDNF decreased ER-stress in the motor cortex. CDNF did not decrease ER-stress in the spinal cord where the expression of apoptosis related genes was increased. Thus, CDNF is a potential new drug candidate for treating ALS and it should be studied further.
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(2019)Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease in which both upper and lower motor neurons degenerate gradually. The disease leads to a total paralysis of almost all skeletal muscles and to death within 3-5 years after onset. At the moment there are two disease modifying medicines available, riluzole and edaravone. Neither is able to cure the disease or even to stop or remarkably slow down its progression. Endoplasmic reticulum (ER) stress has been proposed as one of the pathophysiological mechanisms underlying ALS. During ER stress misfolded of unfolded proteins accumulate in ER lumen. As a defense mechanism, the cell launches unfolded protein response (UPR). UPR response aims to reduce the protein load in ER and restore cell’s normal functions. If the damage is already beyond repair, UPR signal cascades lead to programmed cell death. Neurotrophic factors (NTFs) regulate the growth of nervous tissue and participate in repairing processed. Many of the known NTFs have first seemed promising in the preclinical models of ALS but however failed in clinical trials. Cerebral dopamine neurotrophic factor (CDNF) differs drastically both in structure and function from conventional NTFs. CDNF has seen to relieve ER stress and improve motor behavior in the animal models of Parkinsons’s disease. Recently CDNF entered clinical trials in Parkinson’s patients. Since ER stress is believed to be present not only in ALS but also in Parkinson’s disease and other neurodegenerative diseases, it might have an effect in treating ALS patients. SOD1-G93A is a well-established animal model of ALS in which the animals show typical motor impairments comparable to human disease. In this study we used a novel mouse line obtained from crossing traditional SOD1-G93A model and CDNF knock out models. The study aimed to evaluate the effect of endogenic CDNF loss in survival, onset of symptoms, motor behavioral and spinal motor neuron degeneration in the new line. ER-stress and autophagy marker levels were studied with quantitative polymerase chain reaction (CNDF) and western blotting techniques. Spinal motor neuron loss was examined by anti-choline acetyltransferase antibody (ChAT) stainings. SOD1-G93A CDNF knock out animals were observed to have more severe motor impairments in the early stages of the disease compared to the traditional SOD1-G93A mice. In addition, the degeneration of spinal motor neurons appeared to be more severe in the new line. There were no statistically significant differences in ER stress between the genotypes although a trend of increased ER stress was observed. Endogenous CDNF loss had no effect on the healthy animals. The results suggest that CNDF is a potential treatment for ALS and it might have only little side effect since it does not seen to affect healthy tissue. In medical usage, CDNF might be most effective when administered immediately after disease onset. However, this might be difficult because of the challenges in ALS diagnosis.
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C-MANF:n farmakokineettiset ominaisuudet ja vaikutukset ALS:n geneettisessä SOD1-G93A-hiirimallissa (2021)Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder caused by degeneration of motor neurons in brain and spinal cord. The degeneration of motor neurons leads to muscle atrophy and paralysis. Currently there is no cure for ALS. Available drugs for ALS can lengthen the survival time by a couple of months. Several factors involve the pathophysiology of ALS, such as endoplasmic reticulum stress and neuroinflammation. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a protein which has shown neuroprotective effects on animal models of Parkinson disease and brain ischemia. C-terminal fragment of MANF can cross the blood-brain barrier, allowing it to be administered subcutaneously instead of injected directly into the brain. The experimental part consists of two parts. The aim of the first part was to study the pharmacokinetic properties of next generation MANF (C-MANF). The aim of the second part was to elucidate the effect of twice a week administered subcutaneous injection of C-MANF in genetic SOD1-G93A mouse model and its neuroprotective effects by assessing protection of lumbar motor neurons. Pharmacokinetic properties of C-MANF were determined in wild type mice after a single subcutaneous injection of C-MANF at different time points by using indirect ELISA assay. The effects of C-MANF in SOD1-G93A mouse model were assessed by subcutaneous injection of either C-MANF or PBS twice a week and by monitoring clinical score and motor behavior of mice from 10 weeks of age to clinical endpoint. Hematoxylin eosin staining was used to study neuroprotective effects of C-MANF. C-MANF administered subcutaneously is absorbed into the blood circulation and the highest serum concentration of C-MANF is after 60 minutes of dosing. Subcutaneously injected C-MANF also crosses the blood-brain barrier and reach the brain in 120 minutes. C-MANF did not preserve motor function or ameliorated ALS symptoms in SOD1-G93A mouse model. In this study C-MANF did not increase the survival of SOD1-G93A mice. C-MANF did not significantly protect motor neurons from degeneration even though there was a slight trend between the groups. No beneficial effects were observed with C-MANF in SOD1-G93A mouse model and therefore the dose and frequency of administration of C-MANF were not optimal. Subcutaneously injected C-MANF provides a safer dosing option for neurodegenerative disorders.
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C-MANF:n farmakokineettiset ominaisuudet ja vaikutukset ALS:n geneettisessä SOD1-G93A-hiirimallissa (2021)Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder caused by degeneration of motor neurons in brain and spinal cord. The degeneration of motor neurons leads to muscle atrophy and paralysis. Currently there is no cure for ALS. Available drugs for ALS can lengthen the survival time by a couple of months. Several factors involve the pathophysiology of ALS, such as endoplasmic reticulum stress and neuroinflammation. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a protein which has shown neuroprotective effects on animal models of Parkinson disease and brain ischemia. C-terminal fragment of MANF can cross the blood-brain barrier, allowing it to be administered subcutaneously instead of injected directly into the brain. The experimental part consists of two parts. The aim of the first part was to study the pharmacokinetic properties of next generation MANF (C-MANF). The aim of the second part was to elucidate the effect of twice a week administered subcutaneous injection of C-MANF in genetic SOD1-G93A mouse model and its neuroprotective effects by assessing protection of lumbar motor neurons. Pharmacokinetic properties of C-MANF were determined in wild type mice after a single subcutaneous injection of C-MANF at different time points by using indirect ELISA assay. The effects of C-MANF in SOD1-G93A mouse model were assessed by subcutaneous injection of either C-MANF or PBS twice a week and by monitoring clinical score and motor behavior of mice from 10 weeks of age to clinical endpoint. Hematoxylin eosin staining was used to study neuroprotective effects of C-MANF. C-MANF administered subcutaneously is absorbed into the blood circulation and the highest serum concentration of C-MANF is after 60 minutes of dosing. Subcutaneously injected C-MANF also crosses the blood-brain barrier and reach the brain in 120 minutes. C-MANF did not preserve motor function or ameliorated ALS symptoms in SOD1-G93A mouse model. In this study C-MANF did not increase the survival of SOD1-G93A mice. C-MANF did not significantly protect motor neurons from degeneration even though there was a slight trend between the groups. No beneficial effects were observed with C-MANF in SOD1-G93A mouse model and therefore the dose and frequency of administration of C-MANF were not optimal. Subcutaneously injected C-MANF provides a safer dosing option for neurodegenerative disorders.
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(2015)Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease affecting motor neurons. It finally leads to the malfunction of the respiratory muscles and death after 1-3 years of diagnosis. Sporadic cases of ALS cover 90-95% of all patients and familial 5-10% respectively. The onset of the disease is usually between age of 40 and 60 and the worldwide incidence is considered to be 1-2/100000. Currently discovered cerebral dopamine neurotrophic factor, CDNF, has showed neuroprotective effects on Parkinson's disease model. What is more, it is known that CDNF is expressed in the muscles of mice and one of its' main functions is to protect cells from ER-stress, one of the pathological mechanisms in ALS. Hence, it is rational to study the effects of CDNF in ALS mouse model. Treatment options are needed, since there is only one approved treatment for ALS, anti-glutaminergic rilutzole. The aim of this study was to find out whether CDNF shows neuroprotective effects in SOD1-mice e.g. by measuring the changes in motor function with different behavioral tests. More over, the distribution of CDNF after intrathecal ventricle injection was studied using immunohistochemical and radioactive labeling methods. The hypothesis was that CDNF is distributed through the cerebrospinal fluid into the spinal cord and muscles in the limbs and shows neuroprotective effects in this SOD1 mouse model.
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(2012)Site index and site type are methods for describing a habitat’s highest annual production of tree (m3/ha/a). Site index is based on the growth of trees’ dominant height, and site type on the existence of plant communities in a habitat. This research examined whether site type can be estimated with site index derived by airborne laser scanning (ALS). ALS is a remote sensing method by which trees’ characteristics are predicted based on the height distribution and density values of laser pulses. Data were gathered from Syöte, Northern Ostrobothnia. Arbonaut Oy provided the ALS-data, and Metsähallitus provided age and habitat data of microstands. Site type, trees’ ages and dominant heights were also measured by field surveying. Experimental data from plots were generalized to microstand data. There were 208 experimental plots that were generalized to 39 microstands. Site indexes for experimental plots and microstands were calculated to index age 100 years with Vuokila and Väliaho’s (1980) growth models for dominant height and with Schumacher’s (1939) guide curve. Site indexes were converted to site types with Vuokila and Väliaho’s (1980) conversion diagram and then compared to site types of the field surveys. The accuracy of the site indexes was evaluated with an error matrix. Accuracy of age and dominant height was evaluated with a paired t-test. Variation of index aged dominant height inside a site type was examined with root mean square error (RMSE). The effect of the proportions of tree species on the site index was analyzed with a correlation coefficient. The percentage of properly classified site types was 57 % at best when using Schumacher’s (1939) guide curve and two site types (rich and poor). With Vuokila and Väliaho’s (1980) growth models for dominant height the best percentage of correctly classified site types was 46 %. The variation (RMSE) of index aged dominant height as an average in all site types was 3,2 m. The maximum variation of index aged dominant height in one site type was 6 m. This indicated that the dependency between site index and site type was poor with this data. The proportions of tree species did not have a significant effect on site index. Based on this study, predicting site types with ALS does not work. One problem is the absence of very rich site types. There are also many sources of error: SutiGIS’ (position knowledge system) age data, prescribed burning, possible fertilization of stands, and the problems of fitting site index and site type. Vuokila and Väliaho’s (1980) growth models for dominant height were made in the 1980s, so they do not acknowledge the increased growth of present-day trees. Site index cannot reliably predict the site type, but site index gives valuable extra information about the trees for example when evaluating the value of forest estates.
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(2010)Leaf and needle biomasses are key factors in forest health. Insects that feed on needles cause growth losses and tree mortality. Insect outbreaks in Finnish forests have increased rapidly during the last decade and due to climate change the damages are expected to become more serious. There is a need for cost-efficient methods for inventorying these outbreaks. Remote sensing is a promising means for estimating forests and damages. The purpose of this study is to investigate the usability of airborne laser scanning in estimating Scots pine defoliation caused by the common pine sawfly (Diprion pini L.). The study area is situated in Ilomantsi district, eastern Finland. Study materials included high-pulse airborne laser scannings from July and October 2008. Reference data consisted of 90 circular field plots measured in May-June 2009. Defoliation percentage on these field plots was estimated visually. The study was made on plot-level and methods used were linear regression, unsupervised classification, Maximum likelihood method, and stepwise linear regression. Field plots were divided in defoliation classes in two different ways: When divided in two classes the defoliation percentages used were 0–20 % and 20–100 % and when divided in four classes 0–10 %, 10–20 %, 20–30 % and 30–100 %. The results varied depending on method and laser scanning. In the first laser scanning the best results were obtained with stepwise linear regression. The kappa value was 0,47 when using two classes and 0,37 when divided in four classes. In the second laser scanning the best results were obtained with Maximum likelihood. The kappa values were 0,42 and 0,37, correspondingly. The feature that explained defoliation best was vegetation index (pulses reflected from height > 2m / all pulses). There was no significant difference in the results between the two laser scannings so the seasonal change in defoliation could not be detected in this study.
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(2015)Metsäkanalintujen elinympäristövaatimukset tunnetaan Suomessa hyvin ja elinympäristöihin kiinnitetään yhä enemmän huomiota osana metsän- ja luonnonhoidon toimia. Metso (Tetrao urogallus) ja pyy (Tetrastes bonasia) ovat elinympäris-töjen valinnassaan melko tarkkoja ja lajien välillä on selkeitä eroja. Elinympäristöjen ennakkotarkasteluun ei tällä hetkellä ole olemassa monipuolisia metsäsuunnittelun työkaluja ja lentolaserkeilauksella kerättyä aineistoa ei ole käytetty metsä-kanalintujen elinympäristötutkimuksiin Suomessa. Tässä kvalitatiivisessa tutkimuksessa selvitettiin Maanmittauslaitoksen vuonna 2012 keräämän lentolaserkeilausai-neiston soveltuvuutta potentiaalisten metso- ja pyyelinympäristöjen ohjaamattomaan luokitukseen. Aineiston pulssitiheys oli 0,74–0,8 / m2. Tutkimusalueena oli noin 1 200 hehtaaria Metsähallituksen omistamaa metsätalousmetsää Hämeenlinnan Evolla. Tutkimusalue jaettiin 16 x 16 metrin soluihin. Laserkeilausaineistosta laskettiin viisi elinympäristöä kuvaavaa lisäpiirrettä: latvuspeitto CC, alikasvostunnus US, puuston korkeusosuuden tiheystunnus k60_den, korkeusosuuden keski-hajonta H60_stdv sekä pituustunnus H_max. Menetelmänä käytettiin solukohtaista ohjaamatonta luokitusta (K-means), joka jakoi solut 43 luokkaan. Edelleen kohdennettuun maasto-otantaan valittiin 16 luokkaa. Säteeltään kiinteitä 9 metrin ympyräkoealoja mitattiin alueelta kaikkiaan 168 kpl, joista selkeitä pyykohteita ja vähintään arvosanalla 8 arvioituja metsokohteita oli molempia 12 kpl. Ohjaamaton luokitus ei nostanut esiin yhtä tai useampaa potentiaalisia kohteita kuvaavaa luokkaa, vaan potentiaalisten kohteiden lisäksi luokissa oli paljon ei-potentiaalisia soluja. Vähintään arvosanalla 8 arvioitujen metsokohteiden lisäpiirteet täyttäviä kohteita oli suhteellisesti eniten luokissa 3, 7 ja 8 osuuksilla 40,4 %, 35,6 % ja 31,8 %. Vastaavasti pyylle osuudet luokissa 4, 18 ja 20 olivat 38,4 %, 28,5 % ja 23,8 % minimiarvosanalla 6. Tutkimusalue sisältää arvioitujen kohteiden lisäpiirteiden perusteella hyviä elinympäristöjä metsolle (Arvosana ≥ 8) 15,0 % ja pyylle (Arvosana ≥ 6) 9,2 % sen pinta-alasta. Korkeimman arvosanan kohteiden lisäpiirteiden arvojen herkkyysanalyysissä alueet olivat vastaavasti 8,5 % ja 14,4 % kunkin lisäpiirteen ± 30 % marginaaleilla. Arvosanarajoite toimi loogisesti eli lisäpiirteiden vaihteluväli kapeni arvosanan kasvaessa. Tuloksena saadut poten-tiaaliset solut olivat toisiinsa erittäin kytkeytyneitä molemmissa analyyseissä vaikka käytetty menetelmä oli täysin riip-pumaton solujen sijainnista toistensa suhteen. Pyyhavainnot olivat potentiaalisuutta kuvaavalla solulla neljässä ja hyvin lähellä potentiaalisuutta kuvaavaa solua kahdessa havainnossa kuudesta, kun lisäpiirteiltään potentiaaliset solut valittiin arvosanoihin perustuen. Käytetyn aineiston kyky kuvata tässä tutkimuksessa määritettyjä potentiaalisia kohteita on siis lupaava. Aineiston kykyä tulee kuitenkin edelleen testata ennen kuin luotettavia metsäsuunnittelun työkaluja voidaan soveltaa operatiiviseen käyttöön.
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(2020)Urban trees and forests are important for human well-being and the diversity of urban nature. Urban forests maintain biodiversity, improve air quality and offer aesthetic and recreational value. The urban trees have also some negative effects. Trees in bad condition can cause harm or danger to humans property. Dense and shady urban forests may cause feelings of insecurity and tree pollen can cause health problems. The urban trees require intensive management and their condition must be constantly monitored. Maximizing the benefits of urban trees and minimizing disadvantages requires detailed data on urban trees. For this reason, many municipalities and cities maintain a tree register with accurate information on individual city trees. Traditionally, data on urban trees have been collected and updated by field surveys, which is laborious and expensive. New laser scanning methods that produce accurate three-dimensional information offer the opportunity to automatically update the tree register. Interest in utilizing them in urban tree mapping and monitoring has been growing rapidly in recent years. This thesis studied ALS-based individual tree detection methods in urban tree mapping. The aim of this study was to determine whether the accuracy of the automatically generated canopy map from ALS-data could be improved by a semi-automatic method. Initially, a detailed canopy map of trees was produced by automated method. Tree candidates were deliniated from the surface model by utilizing watershed segmentation. The canopy segmentation produced by the automated method was visually modified and incorrectly delimited canopy segments were corrected. This resulted in a semi-automatically produced canopy map. The results of the automatic and semi-automatic canopy segmentation method were compared by determining the detection accuracy of the trees and the modeling accuracy of the tree diameter. The results were compared with the number and the diameter of trees measured in the field. Non-parametric random forest method and the nearest neighbor (kNN) method were used in the diameter modeling process. The study area consisted of nine Helsinki hospital areas with a total area of 47,2 ha. There were 4365 trees and 37 different tree species measured in the field. The automatic method produced 6860 trees and the semi-automatic method produced 3500 trees. Thus, the automatic method produced an overestimation of 57.2% and the semi-automatic method produced an underestimation of 19.5 % compared to the reference trees. The largest overestimation by the automatic method was in the Koskela study area (221.6 %) and the smallest underestimation was produced by the semi-automatic method in the Suursuo study area (75.5 %). 63 % of the canopy segments produced by the automatic method were commission errors and 33% of the canopy segments produced by semi-automatic method were commission errors. With the automatic method, the absolute RMSE of the diameter prediction was 12,84 cm and 10,99 cm with semi-automatic method. The diameter predictions of the whole data were 6 % more accurate with the semi-automatic method. The results of the study showed that the accuracy of the automatically generated canopy map from the laser scanning data can be improved by the semi-automatic method. Tree mapping accuracy improved in terms of both tree detection accuracy and diameter modeling accuracy. Based on the results of the study, it can be stated that the semi-automatic method is useful especially in parkland areas, but in densely wooded forest areas there is still issues to solve make this method practical. The benefits of a semi-automated method should be assessed by comparing the workload with the results. Based on this study, the semi-automatic individual tree detection method used in this work could be useful in the operational mapping and monitoring of urban trees.
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(2020)Urban trees and forests are important for human well-being and the diversity of urban nature. Urban forests maintain biodiversity, improve air quality and offer aesthetic and recreational value. The urban trees have also some negative effects. Trees in bad condition can cause harm or danger to humans property. Dense and shady urban forests may cause feelings of insecurity and tree pollen can cause health problems. The urban trees require intensive management and their condition must be constantly monitored. Maximizing the benefits of urban trees and minimizing disadvantages requires detailed data on urban trees. For this reason, many municipalities and cities maintain a tree register with accurate information on individual city trees. Traditionally, data on urban trees have been collected and updated by field surveys, which is laborious and expensive. New laser scanning methods that produce accurate three-dimensional information offer the opportunity to automatically update the tree register. Interest in utilizing them in urban tree mapping and monitoring has been growing rapidly in recent years. This thesis studied ALS-based individual tree detection methods in urban tree mapping. The aim of this study was to determine whether the accuracy of the automatically generated canopy map from ALS-data could be improved by a semi-automatic method. Initially, a detailed canopy map of trees was produced by automated method. Tree candidates were deliniated from the surface model by utilizing watershed segmentation. The canopy segmentation produced by the automated method was visually modified and incorrectly delimited canopy segments were corrected. This resulted in a semi-automatically produced canopy map. The results of the automatic and semi-automatic canopy segmentation method were compared by determining the detection accuracy of the trees and the modeling accuracy of the tree diameter. The results were compared with the number and the diameter of trees measured in the field. Non-parametric random forest method and the nearest neighbor (kNN) method were used in the diameter modeling process. The study area consisted of nine Helsinki hospital areas with a total area of 47,2 ha. There were 4365 trees and 37 different tree species measured in the field. The automatic method produced 6860 trees and the semi-automatic method produced 3500 trees. Thus, the automatic method produced an overestimation of 57.2% and the semi-automatic method produced an underestimation of 19.5 % compared to the reference trees. The largest overestimation by the automatic method was in the Koskela study area (221.6 %) and the smallest underestimation was produced by the semi-automatic method in the Suursuo study area (75.5 %). 63 % of the canopy segments produced by the automatic method were commission errors and 33% of the canopy segments produced by semi-automatic method were commission errors. With the automatic method, the absolute RMSE of the diameter prediction was 12,84 cm and 10,99 cm with semi-automatic method. The diameter predictions of the whole data were 6 % more accurate with the semi-automatic method. The results of the study showed that the accuracy of the automatically generated canopy map from the laser scanning data can be improved by the semi-automatic method. Tree mapping accuracy improved in terms of both tree detection accuracy and diameter modeling accuracy. Based on the results of the study, it can be stated that the semi-automatic method is useful especially in parkland areas, but in densely wooded forest areas there is still issues to solve make this method practical. The benefits of a semi-automated method should be assessed by comparing the workload with the results. Based on this study, the semi-automatic individual tree detection method used in this work could be useful in the operational mapping and monitoring of urban trees.
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(2020)Single Photon LiDAR (Light Detection and Ranging) is a novel and promising technology that can make laser scanning faster and cheaper. Compared to typical linear mode LiDARs (LML), SPL (Single Photon LiDAR) can be operated from higher altitude which means wider bandwidth on ground and a larger scanning area at once. Due to capability of SPL systems to create denser point clouds than current typical LML systems, the flight altitude can be higher in SPL which means quick remote sensing data collations abilities over large areas. Additionally, SPL can penetrate thin clouds and fog which gives airborne ALS better time frame as flight can be operated earlier in the morning than with LML. To the best of authors knowledge, this is pioneering research in Finland to analyse the applicability of SPL in Finnish forests and compare it with LML dataset. This thesis focuses on applying and comparing two LiDAR systems (SPL and LML) for extracting individual tree level (ITD) forest inventorying attributes and generating canopy height models in mature forests. Results were validated over 49 field measured plots, located in southern boreal forest. Additionally, the suitability of two crown segmentation methods (local maxima and watershed) were tested in both datasets. Watershed segmentation method yielded more accurate results for tree density and height estimation in both LML and SPL datasets. Tree density was underestimated by 4.7% (rRMSE: 32.3%) for all species. Comparing tree density estimation in different species, it was most accurate in deciduous plots (rRMSE: 17.0%, rBias: -9.5). Tree height estimation with SPL was highly correlated (R 2=0.93) with field-measured height and reliability accurate with underestimation of 3.4% (rRMSE of 7.0%). Comparing the tree height estimation in different species, it was most accurate between pine plots (rRMSE: 1.1%, rBias: 4.9%). In this research, SPL represented reliable and usable point cloud data for forest remote sensing and quality similar to LML. As expected, SPL had more deviation and higher bias compared to LML in tree density but yielded more accurate results for height estimations. Further studies with more accurate geolocated plots and individual tree maps are required. The hypothesis, the applicability of SPL data for forest inventorying and extracting tree density and tree height in mature forests, is valid.
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(2020)Single Photon LiDAR (Light Detection and Ranging) is a novel and promising technology that can make laser scanning faster and cheaper. Compared to typical linear mode LiDARs (LML), SPL (Single Photon LiDAR) can be operated from higher altitude which means wider bandwidth on ground and a larger scanning area at once. Due to capability of SPL systems to create denser point clouds than current typical LML systems, the flight altitude can be higher in SPL which means quick remote sensing data collations abilities over large areas. Additionally, SPL can penetrate thin clouds and fog which gives airborne ALS better time frame as flight can be operated earlier in the morning than with LML. To the best of authors knowledge, this is pioneering research in Finland to analyse the applicability of SPL in Finnish forests and compare it with LML dataset. This thesis focuses on applying and comparing two LiDAR systems (SPL and LML) for extracting individual tree level (ITD) forest inventorying attributes and generating canopy height models in mature forests. Results were validated over 49 field measured plots, located in southern boreal forest. Additionally, the suitability of two crown segmentation methods (local maxima and watershed) were tested in both datasets. Watershed segmentation method yielded more accurate results for tree density and height estimation in both LML and SPL datasets. Tree density was underestimated by 4.7% (rRMSE: 32.3%) for all species. Comparing tree density estimation in different species, it was most accurate in deciduous plots (rRMSE: 17.0%, rBias: -9.5). Tree height estimation with SPL was highly correlated (R 2=0.93) with field-measured height and reliability accurate with underestimation of 3.4% (rRMSE of 7.0%). Comparing the tree height estimation in different species, it was most accurate between pine plots (rRMSE: 1.1%, rBias: 4.9%). In this research, SPL represented reliable and usable point cloud data for forest remote sensing and quality similar to LML. As expected, SPL had more deviation and higher bias compared to LML in tree density but yielded more accurate results for height estimations. Further studies with more accurate geolocated plots and individual tree maps are required. The hypothesis, the applicability of SPL data for forest inventorying and extracting tree density and tree height in mature forests, is valid.
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