Authors: Zhao, Chuansheng | Könönen, Mervi | Vanninen, Ritva | Pitkänen, Kauko | Hiekkala, Sinikka | Jolkkonen, Jukka
Article Type: Research Article
Abstract: Recent advances in basic research have revealed the complex structural plasticity associated with the spontaneous motor recovery after stroke. Various rehabilitative interventions seem to act through the same repair mechanisms to further enhance recovery processes. In this review, we first summarize the current understanding on brain plasticity and repair after stroke. We then outline experimental approaches for studying stroke rehabilitation in rodents and review current rehabilitative practices in stroke patients. Although experimental approaches are valuable in providing details regarding mechanisms and proof-of-concept data, relatively modest treatment effects in stroke patients highlight the translational gap. Further studies will be needed to …find optimal treatment paradigms through emerging knowledge of brain repair, whilst appreciating the important differences between rodent and patient studies that complicate the translation of experimental data. Show more
Keywords: Stroke, brain plasticity, recovery, rehabilitation, translational research
DOI: 10.3233/RNN-180814
Citation: Restorative Neurology and Neuroscience, vol. 36, no. 4, pp. 519-533, 2018
Authors: Hartikainen, Päivi | Räsänen, Janne | Julkunen, Valtteri | Niskanen, Eini | Hallikainen, Merja | Kivipelto, Miia | Vanninen, Ritva | Remes, Anne M. | Soininen, Hilkka
Article Type: Research Article
Abstract: Cortical thickness analysis has been proposed as a potential diagnostic measure in memory disorders. In this retrospective study, we compared the cortical thickness values of 24 patients with frontotemporal dementia (FTD) to those of 25 healthy controls, 45 symptomatic subjects with stable mild cognitive impairment (S-MCI), 15 subjects with progressive mild cognitive impairment (P-MCI), and 36 patients with Alzheimer's disease (AD). The patterns of regions of thinning in FTD when compared to controls and also S-MCI patients showed similar trends; thinning of the bilateral frontal poles and bilateral medial temporal lobe structures, especially the anterior part of the gingulum, the …uncus, and parahippocampal gyri. Cortical thinning in FTD was also found on the boundary regions of parietal and occipital lobes. In the P-MCI group compared to FTD, the trend of thinning in small distinct areas of the parietal and occipital lobes was observed. The FTD and AD groups did not differ statistically, but we found trends toward thinning in FTD of the left cingulate gyrus, and the left occipitotemporal gyri, and in AD of the inferior parietal, occipitoparietal, and the pericalcarine regions, more in the right hemisphere. In FTD, increased slowness in the executive test (Trail-Making A) correlated with the thinner cortex, whereas the language tests showed the lower scores, the thinner cortex in the left hemisphere. Cortical thickness might be a tool for detecting subtle changes in brain atrophy in screening of dementia prior to the development of diffuse or lobar atrophies. Show more
Keywords: Alzheimer's disease, cortical thickness analysis, frontotemporal dementia, magnetic resonance imaging, mild cognitive impairment
DOI: 10.3233/JAD-2012-112060
Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 857-874, 2012
Authors: Kaipainen, Aku | Jääskeläinen, Olli | Liu, Yawu | Haapalinna, Fanni | Nykänen, Niko | Vanninen, Ritva | Koivisto, Anne M. | Julkunen, Valtteri | Remes, Anne M. | Herukka, Sanna-Kaisa
Article Type: Research Article
Abstract: Background: Cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) biomarkers of neurodegenerative diseases are relatively sensitive and specific in highly curated research cohorts, but proper validation for clinical use is mostly missing. Objective: We studied these biomarkers in a novel memory clinic cohort with a variety of different neurodegenerative diseases. Methods: This study consisted of 191 patients with subjective or objective cognitive impairment who underwent neurological, CSF biomarker (Aβ42 , p-tau, and tau) and T1-weighted MRI examinations at Kuopio University Hospital. We assessed CSF and imaging biomarkers, including structural MRI focused on volumetric and cortical thickness analyses, across groups stratified …based on different clinical diagnoses, including Alzheimer’s disease (AD), frontotemporal dementia, dementia with Lewy bodies, Parkinson’s disease, vascular dementia, and mild cognitive impairment (MCI), and subjects with no evidence of neurodegenerative disease underlying the cognitive symptoms. Imaging biomarkers were also studied by profiling subjects according to the novel amyloid, tau, and, neurodegeneration (AT(N)) classification. Results: Numerous imaging variables differed by clinical diagnosis, including hippocampal, amygdalar and inferior lateral ventricular volumes and entorhinal, lingual, inferior parietal and isthmus cingulate cortical thicknesses, at a false discovery rate (FDR)-corrected threshold for significance (analysis of covariance; p < 0.005). In volumetric comparisons by AT(N) profile, hippocampal volume significantly differed (p < 0.001) between patients with normal AD biomarkers and patients with amyloid pathology. Conclusion: Our analysis suggests that CSF and MRI biomarkers function well also in clinical practice across multiple clinical diagnostic groups in addition to AD, MCI, and cognitively normal groups. Show more
Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, diagnostic imaging, magnetic resonance imaging, neurodegenerative diseases, tau proteins
DOI: 10.3233/JAD-200175
Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 751-765, 2020
Authors: Muñoz-Ruiz, Miguel Ángel | Hartikainen, Päivi | Hall, Anette | Mattila, Jussi | Koikkalainen, Juha | Herukka, Sanna-Kaisa | Julkunen, Valtteri | Vanninen, Ritva | Liu, Yawu | Lötjönen, Jyrki | Soininen, Hilkka
Article Type: Research Article
Abstract: Background: Disease State Index and Disease State Fingerprint represent a novel tool which collates data information from different sources, helping the clinician in the diagnosis and follow-up of dementia diseases. It has been demonstrated that it is applicable in the diagnosis of Alzheimer’s disease (AD). Objective: We applied this novel tool to classify frontotemporal dementia (FTD) cases in comparison with controls, AD, and mild cognitive impairment (MCI) subjects. Methods: Thirty seven patients with FTD, 35 patients with AD, 26 control subjects, and 64 subjects with MCI were included in the study. The Disease State Index encompassed data from cognitive performance …assessed by Mini-Mental State Examination, cerebrospinal fluid biomarkers, MRI volumetric and morphometric parameters as well as APOE genotype. Results: We applied the Disease State Index for comparisons at the group level. The data showed that FTD patients could be differentiated with a high accuracy, sensitivity, and specificity from controls (0.84, 0.84, 0.83) and from MCI (0.79, 0.78, 0.80). However, the correct accuracy was lower in the FTD versus AD comparison (0.69, 0.70, 0.71). In addition, we demonstrated the use of Disease State Fingerprint by comparing one particular FTD case with control, AD, and MCI population data. Conclusion: The results suggest that the Disease State Fingerprint and the underlying Disease State Index are particularly useful in differentiating between normal status and disease in patients with dementia, but it may also help to distinguish between the two dementia diseases, FTD and AD. Show more
Keywords: Alzheimer's disease, cognition, frontotemporal dementia, memory, mild cognitive impairment
DOI: 10.3233/JAD-122260
Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 727-739, 2013
High Risk of Dementia in Ventricular Enlargement with Normal Pressure Hydrocephalus Related Symptoms
Authors: Koivisto, Anne M. | Kurki, Mitja I. | Alafuzoff, Irina | Sutela, Anna | Rummukainen, Jaana | Savolainen, Sakari | Vanninen, Ritva | Jääskeläinen, Juha E. | Soininen, Hilkka | Leinonen, Ville
Article Type: Research Article
Abstract: Background: Differential diagnosis of ventricular enlargement with normal pressure hydrocephalus (NPH) related symptoms is challenging. Patients with enlarged ventricles often manifest cognitive deterioration but their long-term outcome is not well known. Objectives: We aim to evaluate long-term cognitive outcome in patients with enlarged ventricles and clinically suspected NPH. Methods: A neurologist and a neurosurgeon clinically evaluated 468 patients with enlarged ventricles and suspected NPH using radiological methods, intraventricular pressure monitoring, and frontal cortical brain biopsy. The neurologist confirmed final diagnoses after a median follow-up interval of 4.8 years. Results: Altogether, 232 patients (50%) with enlarged ventricles did not fulfill the …criteria for shunt surgery. The incidence of dementia among patients with enlarged ventricles, and at least one NPH-related symptom with adequate follow-up data (n = 446) was high, varying from 77 (iNPH, shunt responders) to 141/1000 person-years (non-shunted patients with enlarged ventricles). At the end of the follow-up, 59% of all these patients were demented. The demented population comprised 73% of non-shunted patients with enlarged ventricles, 63% of shunted iNPH patients that did not respond to treatment, and 46% of iNPH patients that were initially responsive to shunting. The most common cause of dementia was Alzheimer’s disease (n = 94, 36%), followed by vascular dementia (n = 68, 26%). Conclusions: One-half of patients with enlarged ventricles and clinically suspected NPH were not shunted after intraventricular pressure monitoring. Dementia caused by various neurodegenerative diseases was frequently seen in patients with ventricular enlargement. Thus, careful diagnostic evaluation in collaboration with neurologists and neurosurgeons is emphasized. Show more
Keywords: Alzheimer’s disease, cognition, dementia, memory, normal pressure hydrocephalus, prognosis, vascular dementia, ventricular enlargement
DOI: 10.3233/JAD-150909
Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 497-507, 2016
Authors: Julkunen, Valtteri | Niskanen, Eini | Koikkalainen, Juha | Herukka, Sanna-Kaisa | Pihlajamäki, Maija | Hallikainen, Merja | Kivipelto, Miia | Muehlboeck, Sebastian | Evans, Alan C. | Vanninen, Ritva | Soininen, Hilkka
Article Type: Research Article
Abstract: In this study, we analyzed differences in cortical thickness (CTH) between healthy controls (HC), subjects with stable mild cognitive impairment (S-MCI), progressive MCI (P-MCI), and Alzheimer's disease (AD), and assessed correlations between CHT and clinical disease severity, education, and apolipoprotein E4 (APOE) genotype. Automated CTH analysis was applied to baseline high-resolution structural MR images of 145 subjects with a maximum follow-up time of 7.4 years pooled from population-based study databases held in the University of Kuopio. Statistical differences in CTH between study groups and significant correlations between CTH and clinical and demographic factors were assessed and displayed on a cortical …surface model. Compared to HC group (n =26), the AD (n = 21) group displayed significantly reduced CTH in several areas of frontal and temporal cortices of the right hemisphere. Higher education and lower MMSE scores were correlated with reduced CTH in the AD group, whereas no significant correlation was found between CDR-SB scores or APOE genotype and CTH. The P-MCI group demonstrated significantly reduced CTH compared to S-MCI in frontal, temporal and parietal cortices even after statistically adjusting for all confounding variables. Ultimately, analysis of CTH can be used to detect cortical thinning in subjects with progressive MCI several years before conversion and clinical diagnosis of AD dementia, irrespective of their cognitive performance, education level, or APOE genotype. Show more
Keywords: Alzheimer's disease, apolipoprotein E, cortical thickness, magnetic resonance imaging, mild cognitive impairment
DOI: 10.3233/JAD-2010-100114
Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1141-1151, 2010
Authors: Huovinen, Joel | Helisalmi, Seppo | Paananen, Jussi | Laiterä, Tiina | Kojoukhova, Maria | Sutela, Anna | Vanninen, Ritva | Laitinen, Marjo | Rauramaa, Tuomas | Koivisto, Anne M. | Remes, Anne M. | Soininen, Hilkka | Kurki, Mitja | Haapasalo, Annakaisa | Jääskeläinen, Juha E. | Hiltunen, Mikko | Leinonen, Ville
Article Type: Research Article
Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is a late onset, surgically treated progressive brain disease caused by impaired cerebrospinal fluid dynamics and subsequent ventriculomegaly. Comorbid Alzheimer’s disease (AD) seems to be frequent in iNPH. Objective: We aim to evaluate the role of AD-related polymorphisms in iNPH. Methods: Overall 188 shunt-operated iNPH patients and 688 controls without diagnosed neurodegenerative disease were included into analysis. Twenty-three single-nucleotide polymorphisms (SNPs FRMD4A [rs7081208_A, rs2446581_A, rs17314229_T], CR1, BIN, CD2AP, CLU, MS4A6A, MS4A4E, PICALM, ABCA7, CD33, INPP5D, HLA_DRB5, EPHA1, PTK2B, CELF1, SORL1, FERMT2, SLC24A, DSG2, CASS4, and NME8 ) adjusted to APOE were analyzed between groups …by using binary logistic regression analysis. Neuroradiological characteristics and AD-related changes in the right frontal cortical brain biopsies were available for further analysis. Results: Logistic regression analysis adjusted to age, gender, and other SNPs indicated allelic variation of NME8 between iNPH patients and non-demented controls (p = 0.014). The allelic variation of NME8 was not related to the neuropathological changes in the brain biopsies of iNPH patients. However, periventricular white matter changes (p = 0.017) were more frequent in the iNPH patients with the AA-genotype, an identified risk factor of AD. Conclusions: Our findings increase the evidence that iNPH is characterized by genetic and pathophysiological mechanisms independent from AD. Considering that NME8 plays a role in the ciliary function and displays SNP-related diversity in white matter changes, the mechanisms of NME8 in iNPH and other neurodegenerative processes are worth further study. Show more
Keywords: Alzheimer’s disease, genetics, idiopathic normal pressure hydrocephalus, pathology, radiology
DOI: 10.3233/JAD-170583
Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1077-1085, 2017
Authors: Stephen, Ruth | Liu, Yawu | Ngandu, Tiia | Rinne, Juha O. | Kemppainen, Nina | Parkkola, Riitta | Laatikainen, Tiina | Paajanen, Teemu | Hänninen, Tuomo | Strandberg, Timo | Antikainen, Riitta | Tuomilehto, Jaakko | Keinänen Kiukaanniemi, Sirkka | Vanninen, Ritva | Helisalmi, Seppo | Levälahti, Esko | Kivipelto, Miia | Soininen, Hilkka | Solomon, Alina
Article Type: Research Article
Abstract: Background: CAIDE Dementia Risk Score is the first validated tool for estimating dementia risk based on a midlife risk profile. Objectives: This observational study investigated longitudinal associations of CAIDE Dementia Risk Score with brain MRI, amyloid burden evaluated with PIB-PET, and detailed cognition measures. Methods: FINGER participants were at-risk elderly without dementia. CAIDE Risk Score was calculated using data from previous national surveys (mean age 52.4 years). In connection to baseline FINGER visit (on average 17.6 years later, mean age 70.1 years), 132 participants underwent MRI scans, and 48 underwent PIB-PET scans. All 1,260 participants were cognitively assessed (Neuropsychological Test …Battery, NTB). Neuroimaging assessments included brain cortical thickness and volumes (Freesurfer 5.0.3), visually rated medial temporal atrophy (MTA), white matter lesions (WML), and amyloid accumulation. Results: Higher CAIDE Dementia Risk Score was related to more pronounced deep WML (OR 1.22, 95% CI 1.05–1.43), lower total gray matter (β-coefficient –0.29, p = 0.001) and hippocampal volume (β-coefficient –0.28, p = 0.003), lower cortical thickness (β-coefficient –0.19, p = 0.042), and poorer cognition (β-coefficients –0.31 for total NTB score, –0.25 for executive functioning, –0.33 for processing speed, and –0.20 for memory, all p < 0.001). Higher CAIDE Dementia Risk Score including APOE genotype was additionally related to more pronounced MTA (OR 1.15, 95% CI 1.00–1.30). No associations were found with periventricular WML or amyloid accumulation. Conclusions: The CAIDE Dementia Risk Score was related to indicators of cerebrovascular changes and neurodegeneration on MRI, and cognition. The lack of association with brain amyloid accumulation needs to be verified in studies with larger sample sizes. Show more
Keywords: Aging, cognition, dementia, neuroimaging
DOI: 10.3233/JAD-170092
Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 695-705, 2017
Authors: Ylä-Herttuala, Salla | Hakulinen, Mikko | Poutiainen, Pekka | Laitinen, Tiina M. | Koivisto, Anne M. | Remes, Anne M. | Hallikainen, Merja | Lehtola, Juha-Matti | Saari, Toni | Korhonen, Ville | Könönen, Mervi | Vanninen, Ritva | Mussalo, Hanna | Laitinen, Tomi | Mervaala, Esa
Article Type: Research Article
Abstract: Background: The suggested association between severe obstructive sleep apnea (OSA) and risk of Alzheimer’s disease (AD) needs further study. Only few recent reports exist on associations between brain amyloid-β (Aβ) burden and severe OSA in middle-aged patients. Objective: Examine the possible presence of cortical Aβ accumulation in middle-aged patients with severe OSA. Methods: We performed detailed multimodal neuroimaging in 19 cognitive intact patients (mean 44.2 years) with severe OSA (Apnea-Hypopnea Index >30 h–1 ). Known etiological factors for possible Aβ accumulation were used as exclusion criteria. Aβ uptake was studied with [11 C]-PiB-PET, glucose metabolism with [18 F]-FDG-PET, and structural imaging …with 3.0T MRI. Results: When analyzed individually, in [11 C]-PiB-PET a substantial number (∼32%) of the patients exhibited statistically significant evidence of increased cortical Aβ uptake based on elevated regional Z-score values, mostly seen bilaterally in the precuneus and posterior cingulum regions. Cortical glucose hypometabolism in [18 F]-FDG-PET was seen in two patients. MRI did not show structural changes suggestive of AD-related pathology. Conclusion: Increased [11 C]-PiB uptake was seen in middle-aged cognitively intact patients with severe OSA. These findings are similar to those described in cognitive unimpaired older OSA patients. The changes in cortical Aβ uptake suggest that severe OSA itself may predispose to alterations related to AD already in middle-age. Aβ clearance may be compromised without simultaneous evidence of metabolic or structural alterations. The results emphasize the importance of early diagnostics and proper treatment of severe OSA in cognitively intact middle-aged subjects, possibly diminishing the individual risk for later cognitive dysfunction. Show more
Keywords: Alzheimer’s disease, amyloid, PET, sleep apnea
DOI: 10.3233/JAD-200736
Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 153-161, 2021
Authors: Reijs, Babette L.R. | Vos, Stephanie J.B. | Soininen, Hilkka | Lötjonen, Jyrki | Koikkalainen, Juha | Pikkarainen, Maria | Hall, Anette | Vanninen, Ritva | Liu, Yawu | Herukka, Sanna-Kaisa | Freund-Levi, Yvonne | Frisoni, Giovanni B. | Frölich, Lutz | Nobili, Flavio | Rikkert, Marcel Olde | Spiru, Luiza | Tsolaki, Magda | Wallin, Åsa K. | Scheltens, Philip | Verhey, Frans | Visser, Pieter Jelle
Article Type: Research Article
Abstract: Background: Lifestyle factors have been associated with the risk of dementia, but the association with Alzheimer’s disease (AD) remains unclear. Objective: To examine the association between later life lifestyle factors and AD biomarkers (i.e., amyloid-β 1–42 (Aβ42 ) and tau in cerebrospinal fluid (CSF), and hippocampal volume) in individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). In addition, to examine the effect of later life lifestyle factors on developing AD-type dementia in individuals with MCI. Methods: We selected individuals with SCD (n = 111) and MCI (n = 353) from the DESCRIPA and Kuopio Longitudinal MCI studies. CSF Aβ42 …and tau concentrations were assessed with ELISA assay and hippocampal volume with multi-atlas segmentation. Lifestyle was assessed by clinical interview at baseline for: social activity, physical activity, cognitive activity, smoking, alcohol consumption, and sleep. We performed logistic and Cox regression analyses adjusted for study site, age, gender, education, and diagnosis. Prediction for AD-type dementia was performed in individuals with MCI only. Results: Later life lifestyle factors were not associated with AD biomarkers or with conversion to AD-type dementia. AD biomarkers were strongly associated with conversion to AD-type dementia, but these relations were not modulated by lifestyle factors. Apolipoprotein E (APOE) genotype did not influence the results. Conclusions: Later life lifestyle factors had no impact on key AD biomarkers in individuals with SCD and MCI or on conversion to AD-type dementia in MCI. Show more
Keywords: Alcohol consumption, Alzheimer’s disease, amyloid-β (1–42), cerebrospinal fluid, cognitive reserve, exercise, hippocampus, lifestyle, mild cognitive impairment
DOI: 10.3233/JAD-170039
Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1387-1395, 2017