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2018
A report from the 8th Kuopio Alzheimer Symposium
Haapasalo, Annakaisa
Future Medicine Ltd
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http://dx.doi.org/10.2217/nmt-2018-0029
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Conference report 1
A report from the 8th Kuopio Alzheimer Symposium 2
Annakaisa Haapasalo1* and Mikko Hiltunen2 3
1A.I. Virtanen Institute for Molecular Sciences and2Institute of Biomedicine, University of Eastern 4
Finland, Kuopio, Finland.
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*Corresponding author:
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Annakaisa Haapasalo, PhD 8
Associate Professor in Molecular Neurodegeneration 9
A.I. Virtanen Institute for Molecular Sciences 10
University of Eastern Finland 11
Neulaniementie 2 12
70211 Kuopio, Finland 13
Tel: +358 40 355 2768 14
E-mail: annakaisa.haapasalo@uef.fi 15
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Running title: Report from 8th Kuopio AD symposium 17
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Abstract 21
The international Kuopio Alzheimer Symposium was organized by the University of Eastern Finland 22
in Kuopio, Finland on June 6-8, 2018 for the 8th time. Approximately 300 researchers in the fields of 23
neuroscience and neurology from 12 different countries around the world gathered to Kuopio to hear 24
and discuss about the latest insights into the mechanisms and comorbidities and novel approaches 25
for diagnosis, prediction, prevention and therapies of Alzheimer s disease (AD) and other 26
neurodegenerative diseases. The two-day international program on June 7-8 included a keynote 27
session, five oral scientific sessions, and a poster session. The international symposium was 28
preceded by a “Memory Day” on June 6, held in Finnish and targeted to Finnish health care 29
professionals, including doctors, psychologists, and nurses, who work daily with patients suffering 30
from neurodegenerative diseases.
31
The 8th Kuopio Alzheimer Symposium hosted 25 talks by international leading scientists and 32
49 poster presentations given by PhD students, postdocs and other researchers. The themes in the 33
symposium covered novel advances related to disease mechanisms, model systems and 34
translational medicine applications, biomarker studies, brain imaging, technology-supported 35
diagnosis and care, population-based prevention studies, co-morbidities, and clinical treatment 36
studies.
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Alzheimer’s disease (AD), the most common cause of dementia in the elderly, and other 38
neurodegenerative diseases generate a growing global health challenge as the portion of the aging 39
population in the societies continuously increases worldwide [1]. Aging is the most important risk 40
factor for dementing brain diseases. On the other hand, some neurodegenerative disorders, such as 41
frontotemporal lobar degeneration (FTLD), whose main clinical subtype is frontotemporal dementia 42
(FTD), typically have an earlier onset age than AD. Therefore, they may affect people already at 43
working-age [2]. Management of neurodegenerative diseases and their comorbidities, such as 44
cardiovascular diseases, high blood pressure, type 2 diabetes (T2D), or brain traumas, which are 45
other major risk factors for neurodegenerative diseases, becomes increasingly important and has 46
been recognized as a health care priority internationally and nationally in different countries [1,3]. A 47
general consensus is that identification of the patients or even individuals with an increased risk of 48
having a neurodegenerative disease as early as possible is key to successful treatment and 49
prevention of AD and other neurodegenerative disorders. Combining data from biomarker and brain 50
imaging studies with information of the individual’s genetic background will likely be applied in the 51
risk assessment, early diagnosis, prevention, and choosing appropriate treatment options for 52
neurodegenerative diseases at personalized level in the future. However, early identification and 53
intervention are complicated by the current lack of suitable specific and sensitive biomarkers, which 54
could be used in the diagnosis or prediction of the diverse neurodegenerative diseases. The currently 55
available treatments offer only relief to the symptoms (e.g. behavioral or psychiatric symptoms) and 56
support for the neuronal function, but so far, no disease-modifying therapies that would be able to 57
decelerate or halt the disease progression exist for treating the patients suffering from 58
neurodegenerative diseases. One likely reason for this is that the molecular disease mechanisms 59
underpinning neurodegeneration are highly complex and not yet well understood. Thus, novel model 60
systems, including those directly derived from the patients themselves, are needed to decipher 61
disease mechanisms and aid the discovery of novel biomarker candidates and therapeutic targets.
62
Also, preventive measures that could be applied globally are essential in the management of 63
neurodegenerative diseases in the future. These complex and challenging topics were covered in 64
the presentations of the 8th Kuopio Alzheimer Symposium. Here, we provide a summary of the oral 65
presentations of the symposium.
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67
Keynote lectures 68
In 2018, 112 drugs are in the development pipeline for AD. Of these, 23 agents (in 25 trials) 69
are in phase I, 63 agents (in 75 clinical trials) in phase II, and 26 agents (in 35 trials) in phase III [4].
70
Sixty three percent are disease-modifying drugs, 22 % are symptomatic cognitive enhancers and 12 71
% address neuropsychiatric or behavioral symptoms [4]. Despite the large number of trials, many 72
initially promising clinical trials have been discontinued because of the lack of efficacy or adverse 73
side effects over the last decades. Prof. Hilkka Soininen from the University of Eastern Finland, 74
Kuopio, Finland, underlined in her keynote lecture on “Highlights of clinical Alzheimer research” that 75
development of treatments and prevention are major challenges in AD research. Therefore, it is 76
essential to focus on earlier start of the treatment of the patients so that a patient with the right 77
diagnosis gets the right drug at the right time. By using biomarker data, AD can be diagnosed earlier.
78
Furthermore, participants could be recruited into drug trials in an earlier phase of the disease, which 79
is important when investigating effects of disease-modifying treatments. Large international 80
consortium studies related to brain imaging, biomarker and genetics have produced an ample 81
amount data. The temporal sequence of disease progression in AD, suggested also by previous 82
brain imaging and biomarker studies, was recently confirmed by Dominantly Inherited Alzheimer 83
Network (DIAN), reporting that in AD familial mutation carriers, -amyloid (A ) starts accumulating 84
over two decades before the symptoms, followed by brain metabolism decline six years later, and 85
brain atrophy about five years before symptoms [5]. Therefore, international consortia aiming at 86
better understanding of the early stages of AD and testing interventions that are targeted to AD 87
prevention before the clinical symptoms occur are extremely important. Prof. Soininen summarized 88
that key issues in the successful drug development and treatment of AD patients in the future are 89
the need for disease-modifying drugs, new drug targets and proper target validation, targets 90
suggested by epidemiological studies that have been confirmed in randomized control trials (RCTs) 91
and use of combination therapies.
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The other keynote lecture was given by Prof. Daniel M. Michaelson from Rabin Institute of 93
Neurobiology, Tel Aviv University, Israel, on “Converging approaches to the development of anti- 94
APOE4 therapy”. Apolipoprotein E4 (APOE 4) is the strongest genetic risk factor for AD, increasing 95
the risk of AD by approximately four-fold [6]. Prof. Michaelson suggested thatAPOE 4, if combined 96
with a “second hit”, such as aging, head injury, A , tau, or synaptic stress, is harmful to the neurons 97
and causes synaptotoxic effects. Using the CRISPR-Cas9 gene editing technology to specifically 98
target APOE 4 in mice and crossing these targeted replacement (TR) mice with -synuclein- 99
deficient mice, Prof. Michaelson and colleagues found that the mice displayed decreased levels of 100
specific synaptic markers and increased levels of A 42, hyperphosphorylated tau and the astrocyte 101
marker glial fibrillary acidic protein (GFAP), corroborating their “second hit” hypothesis. The mice 102
also showed cognitive deficits in behavioral tests. Prof. Michaelson’s team has also used theAPOE 103
4 TR mice to investigate the effects of immunization therapy using specific anti-ApoE4 monoclonal 104
antibodies and treatments targeting lipidation, as they had earlier found that ApoE4 protein is 105
hypolipidated. Repetitive immunization of young ApoE4 TR mice resulted in the accumulation of 106
ApoE-antibody complexes in the brain and the reversal of the A 42, tau, and synaptic pathological 107
alterations and cognitive deficits. Moreover, treatment of young APOE4-TR mice with CS-6253, a 108
brain-penetrant agonist of the lipidation protein ATP-binding cassette transporter (ABCA1), reversed 109
the hypolipidation of ApoE4 and counteracted the APOE4-driven brain and cognitive impairments.
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Altogether, Prof. Michaelson’s team has identified potential new APOE4-related therapeutic 111
approaches, which might show translational potential also in AD patients.
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I Scientific session - Translational research of neurodegeneration in Alzheimer’s disease and 113
other neurodegenerative diseases 114
Patients with different neurodegenerative diseases are neuropathologically characterized by 115
accumulation of protein aggregates in the affected brain areas [7]. Dr. Vesa Kiviniemi from University 116
of Oulu, Finland, presented insights into enhancing brain clearance of aggregated proteins through 117
the recently discovered glymphatic system [8]. Recent findings suggest that dysfunction of the 118
glymphatic system leads to a slow accumulation of proteins and neurodegeneration. While the 119
glymphatic system and factors affecting clearance in brain are under intensive debate, research 120
elucidating these factors may hold great potential for identification of novel therapeutic approaches.
121
Normally, glymphatic system pulsation is at least partially driven by the heart to clear up the brain, 122
but in AD brain, the glymphatic system pulsation shows an impairment. This finding is supported by 123
e.g. novel brain magnetic resonance imaging (MRI) signal analyses and advances in optoelectronic 124
imaging enabling the monitoring of dynamic free water changes in the human brain. Studies in AD 125
mouse models indicate that increasing of blood-brain barrier (BBB) permeability with focused 126
ultrasound (FUS) can facilitate the removal of the accumulated proteins from the brain and reverse 127
memory loss. The research team of Dr. Kiviniemi now uses advanced optoelectronic brain monitoring 128
to measure the status of glymphatic brain system at various manipulations of BBB. They aim at 129
investigating tailored techniques for BBB opening to reveal the role of BBB permeability in brain 130
clearance and allow optimization of therapies targeted to brain areas with insufficient clearance.
131
Technological advances allowing the use of skin fibroblasts or blood cells to generate induced 132
pluripotent stem cells (iPSC) and further neurons or other brain cells, such as astrocytes or microglia, 133
from the patients have revolutionized the field of modeling different neurological diseases and offer 134
excellent options to screen new biomarker and drug candidates [9-12]. Prof. Jari Koistinaho from the 135
University of Eastern Finland, Kuopio, and University of Helsinki, Finland, described utilization of the 136
iPSC technology to generate astrocytes from AD patients harboring the exon 9 deletion in thePSEN1 137
gene (PSEN1 E9). He showed that the PSEN1 E9 mutant astrocytes, which manifest key 138
hallmarks of AD pathology including increased A production, altered cytokine release and 139
dysregulated calcium homeostasis, also show impaired mitochondrial metabolism and glutathione 140
and lactate secretion concomitantly with increased reactive oxygen species production after 141
neuroinflammatory stimulation. When co-cultured in 3D cultures together with neurons from a healthy 142
donor, these mutant astrocytes, but not the gene-corrected isogenic control astrocytes generated 143
using CRISPR/Cas9 technology from the same PSEN1 E9 mutation-carrying patients, led to 144
impairments of synaptic responses in the neurons. These data provide novel insights into the 145
important and previously poorly known contribution of astrocytes to AD pathology in humans.
146
Drug development against AD has faced many drawbacks as many drug trials have been 147
stopped because of the lack of efficacy or adverse side effects, such as liver toxicity. Although 148
treatment of patients with already established dementia has been unsuccessful, stopping A 149
deposition by -secretase ( -site amyloid precursor protein cleaving enzyme, BACE1) inhibition 150
appears a promising treatment strategy for AD. Dr. Ulf Neumann form Novartis Institute for 151
Biomedical Research, Basel, Switzerland, said that the current hypothesis is that BACE1 inhibition 152
treatment (or other A -targeting therapies) needs to be started at the early phases of A deposition, 153
before the onset of significant neurodegeneration. He introduced the BACE1 inhibitor CNP520, 154
which had undergone previous careful pharmacokinetic, metabolism, and long-term toxicological 155
profiling. Clinical phase I and phase IIa studies in healthy elderly volunteers established its safety, 156
tolerability, and active dose range. The phase I studies showed a dose- and time-dependent 157
reduction of cerebrospinal fluid (CSF) A 42 by CNP520 and its activity was unchanged by theAPOE 158
genotype. Therefore, the profile of CNP520 supports its use in prevention studies of AD. Currently, 159
clinical phase II/III studies are ongoing, which test CNP520 effects in a cognitively healthy population 160
with enhanced risk to develop AD. Participants were included based on their age, APOE 4 161
genotype, and for those carrying a singleAPOE 4 allele, elevated brain amyloid. The dose selection 162
for CNP520 in long-term clinical trials aims at avoiding full enzyme inhibition, good safety margins, 163
and good separation of exposure and effect.
164
Prof. Dieter Edbauer from German Center for Neurodegenerative Diseases (DZNE), Munich, 165
Germany, discussed the early role of dipeptide repeat (DPR) proteins in C9orf72 hexanucleotide 166
repeat expansion-associated amyotrophic lateral sclerosis (ALS)/FTD. This repeat expansion is the 167
most common genetic cause of ALS and FTD [13,14]. His team has previously shown that the 168
expanded repeat RNA is translated in all reading frames into five DPR proteins by an unconventional 169
mechanism, but it is still unclear how toxicity of the repeat RNA and the DPR proteins are driving 170
neurodegeneration in patients. The C9orf72 repeat expansion carriers show brain atrophy and 171
deficits in neuropsychological tests already 20 years before disease onset [15] and the DPR proteins 172
can be detected in the CSF of presymptomatic C9orf72 expansion carriers many years prior to 173
disease onset [16]. To elucidate the potential early role of DPR proteins in ALS/FTD, Prof. Edbauer’s 174
group has generated cellular and animal models expressing the DPR proteins individually. They 175
showed that mice overexpressing the neurotoxic poly-glycine-alanine (poly-GA), the most abundant 176
DPR species in patient brains, display progressive brain poly-GA protein and phosphorylated TDP- 177
43 pathology and progressive motor deficits and gait abnormalities. Mice expressing poly-GA at high 178
levels showed regional neurodegeneration that was preceded by microglial activation. Using 179
cryoelectron tomography, the Edbauer team found that poly-GA protein aggregates sequestered 180
large amounts of proteasomes, which are essential components of the protein degradation 181
machinery in cells, and inhibit their function, leading to stalled protein degradation. All in all, the data 182
indicate that early DPR expression contributes to the prodromal symptoms and disease progression 183
of C9orf72 hexanucleotide repeat expansion-carrying patients and one potential underlying 184
mechanism driving neurodegeneration could be compromised proteasomal protein degradation, 185
leading to toxic protein accumulation in the brain.
186
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II Scientific session - New developments in diagnostic and predictive biomarkers in 188
Alzheimer’s disease and other neurodegenerative diseases 189
Dr. Marylene Simon from Roche Diagnostics GmbH, Penzberg, Germany and Roche 190
Diagnostics International, Rotkreuz, Switzerland opened the session by discussing automated CSF 191
biomarker assays in AD management. She described a study where CSF samples collected from 192
patients with mild cognitive impairment (MCI), subjective cognitive decline, and AD from the Swedish 193
BioFINDER and theAlzheimer’s Disease Neuroimaging Initiative (ADNI) cohort were analyzed using 194
the Roche Elecsys® A 42 immunoassay. The results were compared to positron emission 195
tomography (PET) brain A imaging data to test the potential of the CSF biomarker status to predict 196
clinical progression, measured by the change in the Clinical Dementia Rating Sum of Boxes (CDR- 197
SB) score from baseline to 24 months. They found that CSF biomarker data from the Elecsys®
198
immunoassay analyses and A PET imaging showed high concordance. Moreover, biomarker 199
positive and negative groups showed significantly different progression rates over the 24-month 200
follow-up. These findings suggest that the Elecsys® CSF biomarker assays show potential in the 201
diagnosis and prediction of patients with suspected AD or MCI.
202
Tau pathology is a hallmark of several neurodegenerative diseases and CSF tau and 203
phosphorylated tau levels, in addition to those of total tau and A 42, are used as clinical biomarkers 204
for AD and other neurodegenerative diseases [17]. Assoc. Prof. Kina Höglund from University of 205
Gothenburg, Sweden, presented novel CSF tau fragments as potential candidate biomarkers for 206
tauopathies, including AD. Her team hypothesizes that secreted tau fragments may reflect disease- 207
specific proteolytic cleavages of tau. They have developed a technique where CSF samples are 208
immunoprecipitated using specific antibodies against tau followed by mass spectrometry (MS) 209
analysis. They also have generated end-specific tau antibodies and developed enzyme-linked 210
immunosorbent assay (ELISA) or single molecule array (Simoa) assays using these antibodies. For 211
each tau fragment, the clinical relevance in CSF studies was evaluated by comparing the levels 212
between AD and other tauopathies to healthy controls and correlating the data to tau PET brain 213
imaging. The research team found that amino-terminal tau fragments of 20-25 kDa in size provided 214
the best separation between AD patients and controls. Specific fragments were found increased in 215
the CSF of AD patients as compared to the controls and these fragments were enriched in the tau 216
neurofibrillary tangles (NFTs) in the brain. Interestingly, patients with progressive supranuclear palsy 217
(PSP), another tauopathy and a rare form of FTLD, showed decreased levels of these fragments.
218
Future studies will reveal whether these fragments prove to be useful biomarkers in the clinics.
219
Prof. Martin Ingelsson from Uppsala University, Sweden, discussed improved discrimination 220
between healthy control subjects and patients with cognitive decline. His group applied ELISA and 221
MS-based shotgun proteomics to investigate the classical biomarkers and the CSF proteome in 222
patients with AD, FTD, or mild cognitive impairment (MCI; some of which converted to AD during 223
follow-up) and in non-demented control subjects. They observed that 12 MS-based biomarkers can 224
slightly improve identification of AD patients. Furthermore, combination of ELISA and MS-based 225
assays allowed a good identification of FTD patients. Prof. Ingelsson concluded that their findings 226
suggest that the addition of new biomarkers in a model-based approach can improve the value of 227
analyzing CSF to distinguish control subjects from patients with cognitive decline.
228
Prof. Pieter Jelle Visser from Maastrich University, The Netherlands, introduced the EMIF-AD 229
Multimodal Biomarker Discovery Study for identifying diagnostic and predictive markers for AD in 230
the predementia stage. In this study, the diagnostic and prognostic value of proteins in CSF and 231
plasma, brain atrophy patterns on MRI and genetic markers are tested. Existing samples and brain 232
scans from altogether 1200 A -positive and negative individuals with normal cognition, mild cognitive 233
impairment (MCI) or mild dementia from 11 existing European cohort studies central proteomic, 234
metabolomic, genomic, epigenomic and imaging analyses. The average follow-up was 2.3 years.
235
Prof. Visser concluded that by combining already existing data and samples, it is feasible to perform 236
large-scale multimodal biomarker discovery analyses. Also, including CSF and possibly plasma 237
analyses of recently introduced new biomarkers, whose levels are altered in AD patients including 238
neurofilament light chain (NFL), neurogranin, and YKL40, a chitinase-like glycoprotein associated 239
with inflammation and tissue remodeling, might show potential diagnostic value in the future.
240 241
III Scientific session - New technologies in neurodegenerative diseases, including imaging, 242
disease models and neuroinformatics 243
Insulin resistance (IR) is suggested to be a risk factor for AD and cognitive decline [18].
244
Previous studies have also shown that cardiovascular risk factors, such as increased cholesterol or 245
blood pressure, are associated with AD and cognitive decline later in life [19]. However, association 246
among midlife IR and late-life cognitive performance, cerebrovascular lesions, and brain A 247
accumulation is unclear. Dr. Laura Ekblad from Turku PET Center, Finland, discussed about PET 248
imaging of individuals who did not have dementia but had an increased homeostatic model 249
assessment of IR (HOMA-IR) score at midlife. Sixty individuals, of whom half had elevated HOMA- 250
IR score (HOMA-IR+) at midlife and the other half normal HOMA-IR score (HOMA-IR-), underwent 251
neuropsychological testing, MRI, and PET imaging using the A -binding Pittsburgh compound B 252
(PiB). In both groups, 50% of the individuals carried the APOE 4 allele. In the HOMA-IR+ group, 253
60% of the individuals and in the HOMA-IR- group, 33% of the individuals showed positive PiB-PET 254
imaging results. Concomitantly, the HOMA-IR+ group displayed lower executive function and 255
processing speed in the neuropsychological tests. Moreover, in the HOMA-IR+ group, theAPOE 4 256
carriers showed enhanced PiB binding in the PET imaging. Dr. Ekblad summarized that their findings 257
now show that midlife IR is an independent risk factor for brain A accumulation and decreased 258
cognitive function in elderly individuals, who do not have dementia. An unexpected observation was 259
that individuals with IR did not have more cerebrovascular lesions than those without IR.
260
Dr. Jyrki Lötjönen from Combinostics Ltd, Tampere, Finland, described thePredictND project 261
developing tools for helping the clinical diagnosis of patients with neurodegenerative diseases.
262
These tools aid clinicians in interpreting different types of data coming from multiple sources 263
(biomarkers, brain imaging etc.) in a systematic and objective manner to support disease diagnosis 264
and prediction. ThePredictND project developed a clinical decision support tool including two main 265
components. The image quantification module provides a set of imaging biomarkers from MRI 266
images. The decision support module compares all the patient’s data to data originating from a large 267
number of previously diagnosed patients and evaluates their similarity to those of the different 268
etiologies (AD, FTD, dementia with Lewy bodies, vascular dementia, or cognitively normal 269
individuals) or to patients known to progress to dementia. Approximately 800 patients from four 270
memory clinics (Amsterdam, Copenhagen, Kuopio and Perugia) and from different studies with 271
retrospective data underwent a prospective study usingPredictND. Although statistically significant 272
difference was not observed in diagnostic accuracy, the tool improved the confidence of clinicians in 273
decision making. Multiple studies using PredictND showed that automatically computed imaging 274
biomarkers combined with other data provide valuable information both for differential diagnostics 275
and prediction of disease progression. The project has demonstrated that clinical decision support 276
systems based on modern machine learning techniques can be useful in helping to interpret patient 277
data in clinical practice.
278
Examples of low-cost tests for decision support in neurodegenerative disease were given by 279
Dr. Mark van Gils from VTT Technical Research Center of Finland. His team has compared the 280
relationship ofMuistikko web-based cognitive test battery, computer games, and gait analysis with 281
standard neuropsychological assessments used in clinical practice. Dr van Gil’s team developed a 282
global cognitive score (GCS) based on age, sex, Mini Mental State Examination (MMSE) test, and 283
different other cognitive tests. Then, they developed regression models to estimate GCS from 284
Muistikko and computer game features. For the gait analysis, time and frequency features from 3D- 285
accelerometry were studied and correspondence analysis with established cognitive measures was 286
performed. The results of the study including over 300 patients from memory clinics in Amsterdam, 287
Copenhagen, Kuopio and Perugia indicated that both Muistikko test and game-based features 288
showed a good correspondence with the GCS, and gait-related features, such as speed, variance 289
and regularity, correlated with different levels of cognitive impairment. The study by Dr. van Gils and 290
colleagues indicated that low-cost measurements, which can be easily done during everyday living, 291
are able to provide valuable information related to cognitive impairment. These kinds of 292
measurements that can be done in informal settings may offer a valuable, low-cost addition to the 293
existing set of tools to support decision making and evaluation of risk of cognitive decline in the 294
management of dementing diseases.
295
The last two talks of the session moved from diagnostic tools to new developments in disease 296
modeling systems. Assist. Prof. Doo Yeon Kim from Massachusetts General Hospital and Harvard 297
Medical School, Charlestown, MA, USA, described novel biological model systems to help in the 298
dissection of molecular disease mechanisms and drug development in AD. His team has recently 299
developed a 3D “Alzheimer’s on a dish” human neural culture model that recapitulates robust AD- 300
like A aggregation and hyperphosphorylated tau NFT accumulation [20]. From the original set up, 301
they have now developed the model further by creating a sophisticated 3D culture model based on 302
the co-culture of human neuronal precursor cells, astrocytes, and microglia in microfluidic devices, 303
allowing them to include the previously missing AD-related neuroinflammatory elements into the 304
model. This new model system has now been utilized in the dissection pathogenic mechanistic 305
cascades that mediate A -induced tau phosphorylation. Assist. Prof. Kim also described an 306
exploratory high-throughput AD drug screening project using the 3D model. Here, primary screening 307
of a drug library of almost 2500 compounds containing all the US Food and Drug Administration 308
(FDA)-approved drugs was performed. The screening yielded 39 hits that strongly decreased 309
accumulation of insoluble hyperphosphorylated tau with or without affecting A accumulation. The 310
Kim research group has now shown that the 3D human model system recapitulating the key 311
pathological features of AD, A accumulation an NFT formation, can be utilized to screen e.g. - 312
secretase modulators (GSMs), FDA-approved drugs for their repurposing, or testing the potency of 313
hit molecules fromin silico drug screenings in alleviating these pathologies.
314
Prof. Tiago Outeiro from University Medical Center Goettingen, Germany, described cell- 315
based systems to model Parkinson’s disease (PD, [21]) -related -synuclein pathologies. -synuclein 316
is a synaptic protein, which is misfolded and undergoes aggregation in PD brains. Prof. Outeiro’s 317
group uses novel imaging approaches and has developed tissue-clearing and expansion microscopy 318
(ExM) techniques to overcome the detection limit of normal light microscopy. Using these novel 319
imaging approaches, it is possible to achieve 10-12 times better resolution and nanoscale precision 320
of the target cells or tissues. By using these techniques, they have revealed novel interactions of - 321
synuclein. These techniques will be useful in understanding the underlying mechanisms and protein 322
features and interactions that result in protein misfolding and subsequent aggregation in different 323
neurodegenerative diseases characterized by protein aggregation, including PD.
324 325
IV Scientific session - Co-morbidities of neurodegenerative diseases 326
The fourth session was opened by Prof. Wiesje van der Flier, from VU University Medical 327
Center, The Netherlands, who said that the advances in diagnosis of AD using MRI, CSF biomarkers, 328
and PET A -imaging are among the biggest successes in AD research, but often the diagnosis is 329
made only in the late stages of the disease. She underlined that a better and earlier diagnosis would 330
be very beneficial so that the patients could receive help quicker and more effectively. Alzheimer’s 331
biomarkers in daily practice (ABIDE) is a Dutch project, which aims to improve AD diagnosis in 332
memory clinics by promoting effective application of MRI, CSF biomarker, and PET data for 333
diagnosis of MCI and AD, e.g. by using thePredictND clinical decision support system, and taking 334
into account patients’ perspective and wishes on their use. Focus groups comprising patients, 335
caregivers and professionals provide support for the notion that decisions on diagnostic testing 336
should be made in a setting of shared decision making. Patients and caregivers also stress that they 337
would value more specific information on what the results of the diagnostic tests mean for them. In 338
the ABIDE project, individualized risk models that allow estimation of probabilities of progression 339
from MCI to dementia, taking patients’ characteristics into account, have been developed. The risk 340
models will be integrated in an easy-to-use app, called the ADappt, which aims to improve doctor- 341
patient communication and provide support for the diagnostic conversation. Prof. van der Flier 342
concluded that with the development of new diagnostic tests, we enter an era allowing translation of 343
the scientific findings to daily clinical practice. Thus, tools supporting the diagnostic process may 344
catalyze quicker and more effective diagnosis.
345
Dr. Alina Solomon from the University of Eastern Finland, Kuopio, Finland, talked about the 346
urgent need for developing tools to help to quantify dementia risk and prevention potential in clinical 347
trials. The currently available dementia risk scores can be based on only non-modifiable risk factors, 348
such as age or genetic background, only modifiable risk factors, such as lifestyle-related factors or 349
vascular, metabolic or other manageable comorbidities, or combinations of these. All these different 350
types of risk scores have been previously used in dementia prevention trials testing pharmacological 351
or non-pharmacological interventions with varying results. Thus far, the most successful intervention 352
model has been based on modifiable lifestyle factors. In this model, multidomain interventions 353
targeting real-life multifactorial risk profiles instead of a single risk factor have been carried out. So 354
far, only a few studies have attempted to bridge the gap between prediction and prevention of 355
dementia. Validated prediction tools are essential in both clinical trials and everyday clinical practice 356
to aid identification individuals, who are at risk of developing dementia, and to direct them to the 357
interventions that will be the most beneficial for them. Dr. Solomon concluded that development of 358
prediction tools that can estimate the individual’s dementia risk, but also his or her prevention 359
potential is important.
360
Different comorbidities of neurodegenerative diseases were also discussed in the session.
361
Profs. Ville Leinonen from Kuopio University Hospital and Oulu University Hospital, Finland, and 362
Etsuro Mori from Osaka University, Japan, described in their presentations the normal pressure 363
hydrocephalus (NPH), a disease which is characterized by enlarged ventricles, gait difficulty and 364
urinary incontinence [22]. A subset of the patients respond well to shunt treatment and their clinical 365
symptoms are relieved. NPH often co-occurs with AD and some NPH patients show molecular 366
comorbid features to AD, such as A pathology in brain. Patients with enlarged ventricles often show 367
cognitive deterioration, but the final specific diagnosis may vary. Some NPH patients may develop 368
other co-occurring neurodegenerative diseases later in life. Prof. Leinonen described that the Kuopio 369
NPH registry contains of more than 900 patients with enlarged ventricles and a diagnosis of possible 370
idiopathic NPH (iNPH). Long-term follow-up indicated that 73% of non-shunted patients with 371
enlarged ventricles, 63% shunted iNPH patients who did not respond to treatment, and 46% iNPH 372
patients who were initially responsive to shunting developed dementia. Based on the registry data, 373
Prof. Leinonen’s team was able to make an estimation of the long-term cognitive outcome of shunted 374
iNPH patients. Approximately 25% of the patients is estimated to remain cognitively intact, 25% to 375
suffer mild cognitive impairment, 20% to have AD dementia, 20% vascular dementia, 10% NPH- 376
related dementia, and occasional cases to have some other neurodegenerative disease. Prof.
377
Leinonen concluded that the fact that dementia, caused by various neurodegenerative diseases, 378
occurred frequently in patients with ventricular enlargement emphasizes the need for a careful and 379
collaborative diagnostic evaluation by neurologists and neurosurgeons. Moreover, the shunted iNPH 380
patients should undergo clinical follow-up to test for shunt patency in the case of cognitive 381
deterioration.
382
Prof. Etsuro Mori corroborated in his talk that the only effective treatment for iNPH is CSF 383
diversion with ventriculo-peritonal (VP) or lumbar subarachnoid space-peritoneal (LP) shunt. He 384
introduced the SINPHONI-2 study, carried out in Japan, which is an RCT comparing shunt and 385
conservative therapy. The SINPHONI-2 study has clearly demonstrated the benefits of LP shunt.
386
However, iNPH patients are often misdiagnosed and inadequately treated. It has been recognized 387
that a characteristic deformity termed disproportionately enlarged subarachnoid space 388
hydrocephalus (DESH), which is apparent on MRI or computer tomography (CT) scans, is a valuable 389
biomarker for differential diagnosis of iNPH and AD and for predicting the efficacy of shunting. Then 390
again, iNPH and AD often co-occur, and the co-occurring AD may diminish the effect of shunting.
391
Thus, it needs to be evaluated if shunting is beneficial for patients with comorbid AD and iNPH. On 392
the other hand, the efficacy of the shunt therapy may be larger than that of any currently available 393
drugs for treating AD in these patients. Prof. Mori also mentioned that iNPH therapy that may 394
alleviate dementia might give useful cues for developing treatments for AD.
395
One of the important risk factors for AD and dementia, as shown by many epidemiological 396
studies, is T2D [18]. Several studies have provided evidence for insulin resistance in the brains of 397
AD patients, but the common molecular mechanisms linking AD and T2D are still largely unknown.
398
Prof. Mikko Hiltunen from the University of Eastern Finland, Kuopio, Finland, and his team have 399
utilized large population-based cohorts to identify such links. They have used the METabolic 400
Syndrome In Men (METSIM) and the Finnish Geriatric Intervention Study to Prevent Cognitive 401
Impairment and Disability (FINGER) cohorts to correlate AD-associated genetic factors to 402
parameters related to cardiovascular health and metabolism. It has previously been shown that 403
carriers of theA673T variant of amyloid precursor protein geneAPP scored better in cognitive tests 404
and displayed less age-related cognitive decline over time, suggesting that this genetic variation is 405
protective against AD [23]. Prof. Hiltunen and his team identified carriers of theAPP-A673T variant 406
from the METSIM cohort and showed that they had 30% lower levels of A 40 and A 42 in the plasma 407
as compared to the controls. The mechanism explaining the decreased levels of A in theA673T 408
variant carriers is that it makes APP a less favorable substrate for BACE1, leading to reduced BACE1 409
cleavage of APP and subsequently decreased A production. The APP-A673T variant carriers did 410
not show any adverse changes in the metabolic or cardiovascular parameters, which is encouraging 411
from the point of view of designing A -reducing therapies, such as BACE1 inhibition, against AD.
412
Using the METSIM and FINGER cohorts, the Hiltunen team moved on to assess peripheral effects 413
of APOE 4 and found a strong association with decreased levels of plasma high-sensitivity C- 414
reactive protein (hs-CRP). Also, reduced hs-CRP and plasma A 42 levels showed an association 415
independently of the APOE status, suggesting that A might possess anti-inflammatory effects as 416
suggested by some previous studies. Finally, to interrogate the mechanistic link between AD and 417
insulin signaling, Prof. Hiltunen and his group used transgenic APP/PS1 AD model mice and their 418
wild-type littermates that underwent intranasal insulin treatment. The intranasal insulin administration 419
was found to specifically activate signaling of Akt2, a protein kinase, which belongs to the PI3K/Akt 420
pathway downstream of the insulin receptor, in the hippocampus of wild-type mice, but not in 421
APP/PS1 mice, suggesting that brain insulin signaling may be compromised in AD. Altogether, the 422
data from Prof. Hiltunen and colleagues suggest that large population-based cohorts are suitable for 423
assessing the cardiovascular and metabolic effects of AD-associated genetic variants and 424
emphasize the disadvantageous link between AD-associated genetic components and insulin 425
signaling in the brain.
426 427
V Scientific session - Prevention and therapies of neurodegenerative diseases 428
The topic of the last session of the symposium dealt with the latest advances in prevention 429
studies and therapies of neurodegenerative diseases and dementia. Prof. Miia Kivipelto from 430
Karolinska Institute, Stockholm, Sweden and University of Eastern Finland, Kuopio, Finland, 431
discussed about multidomain interventions to prevent dementia. Mounting evidence indicates that 432
multidomain lifestyle interventions, which simultaneously target several risk factors and 433
mechanisms, possess large potential to prevent or postpone late-life cognitive impairment and 434
dementia. The FINGER study is the first large trial indicating that a multidomain lifestyle intervention 435
can prevent cognitive impairment in the elderly [24] and it represents a pragmatic model for dementia 436
prevention. In another ongoing project,Multimodal preventive trials for Alzheimer Disease: towards 437
multinational strategies (MIND-AD), the FINGER intervention model is tested in patients who have 438
prodromal AD and lifestyle or vascular risk factors. Furthermore, prompted by the positive results of 439
the FINGER study, similar studies have been started in different populations and settings in Europe, 440
USA, China, Singapore, and Australia. To promote synergy across these trials and optimize the 441
efforts towards dementia prevention, the World-Wide FINGERS Initiative (WW-FINGERS) was 442
recently launched. WW-FINGERS is an interdisciplinary network aiming at sharing experiences and 443
data and planning joint initiatives focusing on dementia prevention. It is expected that WW-FINGERS 444
will facilitate synergistic use of data from different countries and enable rapid implementation of 445
knowledge and definition of effective and feasible prevention programs for diverse populations 446
globally.
447
Prof. Ingmar Skoog from the University of Gothenburg, Sweden, discussed the implications of 448
prevention and treatment related to preclinical AD. Previous studies suggest that midlife vascular 449
risk factors, such as high blood pressure and/or cholesterol, T2D, atrial fibrillation and myocardial 450
infarction, and lifestyle-related factors, including leisure intellectual and physical activities, 451
cardiovascular fitness, and dietary habits, influence the risk of late-life AD. Also, proneness to stress, 452
number of adverse life events, neurotic personality, and lower education at midlife increase the risk 453
of AD later in life. Although several longitudinal population-based studies have reported that midlife 454
high blood pressure and body mass index (BMI) are linked to AD, these start to decline 5-10 years 455
before disease onset, possibly because of AD-related brain changes that may influence the 456
regulation of blood pressure. These changes in the brain are present more than two decades before 457
the clinical onset of the disease as shown by brain imaging and neurochemical studies. This idea is 458
supported by the findings that 23% of cognitively normal 70-year-olds showed pathological A 42 459
levels, 33% pathological tau and 10% pathological phospho-tau levels in the CSF. In total, 46% these 460
cognitively normal individuals displayed at least one pathological CSF AD marker. Prof. Skoog 461
emphasized that, based on these findings, the association between AD biomarkers and risk factors 462
needs to be clarified. This information can then be used to evaluate when the suitable prevention 463
measures and treatment need to be initiated.
464
Prof. Christopher Chen from the National University of Singapore presented Asian 465
perspectives for the prevention and therapy of neurodegenerative diseases. He referred to a recent 466
report from the Lancet Commission on Dementia Prevention, Intervention and Care [25], which listed 467
nine potentially modifiable risk factors for dementia and calculated for them a weighted population 468
attributable fraction (PAF), an estimate of the proportion of cases of dementia that could be avoided 469
if exposure to individual risk factors were eliminated, supporting the idea of launching multidomain 470
lifestyle interventions globally. Prof. Chen introduced a pilotSINgapore GERiatric intervention study 471
to reduce physical frailty and cognitive decline(SINGER) as part of the WW-FINGERS initiative. The 472
SINGER study was designed to establish the most appropriate multidomain lifestyle interventions 473
for Singaporean seniors, optimize recruitment procedures, and provide a strong basis for a proposed 474
two-year RCT. He also introduced novel Asian therapeutic approaches to AD, including traditional 475
Chinese medicines. For example, the ongoing Alzheimer’s disease THErapy with NEuroaid 476
(ATHENE) study, which is a randomized, double-blind and placebo-controlled trial, assesses the 477
safety and efficacy of Neuroaid II, a natural product combining several active ingredients including 478
herbal extracts, in patients with mild to moderate AD stable on acetylcholinesterase inhibitors 479
(AChEI) or memantine. Studies in cellular and animal models of brain injury have indicated that 480
Neuroaid II has neuroprotective and neuroproliferative properties and may modulate APP processing 481
and tau hyperphosphorylation. Moreover, it has shown beneficial effects on cognitive function in AD 482
patients with better tolerability and safety profile than standard AChEIs.
483
Dr. Tiia Ngandu from National Institute for Health and Welfare (THL), Finland, talked about 484
adherence to multidomain preventive interventions and shared experiences from real-life 485
implementation of these interventions. She said that multimodal lifestyle interventions can be 486
demanding for the participants. However, the participants must adequately adhere to the trial 487
protocol in order to achieve lifestyle changes that will provide cognitive benefit. Currently, there is 488
no golden standard for defining good or poor adherence to the intervention and not much is known 489
about the adherence to non-pharmacological interventions. In practice, adherence and intervention 490
outcome likely show a dose-response relation. Recent results from European lifestyle trials have 491
identified potential determinants of adherence to the interventions and characteristics of the 492
intervention and the participant may influence adherence. The positive results of the lifestyle 493
intervention trials in dementia prevention now call for actions to implement the prevention activities 494
into real-life settings. Dr. Ngandu mentioned that here, identification of target groups for the 495
interventions, identification of the facilitators and obstacles for achieving and maintaining healthy 496
lifestyle changes, and close collaboration with the key stakeholders responsible for the 497
implementation activities are essential.
498
Prof. Nenad Bogdanovic from Karolinska University Hospital, Stockholm, Sweden, discussed 499
about therapeutic strategies against AD, which would be much needed for the treatment of patients 500
with AD and other neurodegenerative diseases. The currently approved drugs in the clinical use for 501
mild-to-severe AD or moderately severe-to-severe AD are the AChEIs donepezil, galantamine, and 502
rivastigmine, and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine. Prof.
503
Bogdanovic summarized that the current drug studies have largely depended on the amyloid 504
cascade hypothesis targeting A , but also tau and small molecules are being investigated. The 505
diagnostic groups in the drug trials comprise patients at different phases of the disease, including at- 506
risk populations (in prevention studies) and preclinical or pre-symptomatic AD, prodromal AD, or 507
mild-to-moderate AD. In these studies, the amyloid pathway is targeted using vaccination and 508
antibodies against A or and inhibitors or modulators of -secretase and -secretase. Prof.
509
Bogdanovic mentioned that even though the link between A deposition and tau pathology remains 510
elusive, the downregulation of tau-related toxicity might provide clinical benefit. It is widely 511
acknowledged that a large problem in developing drugs against AD is the multifactorial nature of 512
dementia and the fact that the elderly individuals often have other comorbidities, including concurrent 513
vascular dementia and different types of neurodegenerative lesions. As the successful treatment 514
against AD is still waiting to be discovered, Prof. Bogdanovic said that meanwhile the current 515
treatment options could be improved by e.g. individualization and adjustment of current AChEI- 516
related therapy to age, gender andAPOE genotype.
517
Prof. Anders Wimo from Karolinska Institute, Stockholm, Sweden, concluded the symposium 518
by discussing health economic aspects of dementia prevention. The significantly positive results of 519
the FINGER multidomain lifestyle intervention study related to cognition and function in the elderly 520
have generated hope that such prevention programs would be able to impact the future numbers of 521
people with dementia. However, the long-term effects or long-term cost effectiveness of these 522
studies are still unknown. Prof. Wimo’s team has used the FINGER study to perform health economic 523
simulation with a comprehensive sensitivity analysis. They also compared prevention simulations 524
and the simulations for potential cost effectiveness of hypothetical disease-modifying treatments for 525
AD. In these studies, they have identified the number needed to treat (NNT) in a prevention program 526
like FINGER and its related costs to avoid one case of dementia, as well as the incremental cost- 527
effectiveness ratio with QALYs (quality adjusted life years) as the outcome. In all the simulations, 528
the prevention was proven cost-effective, implicating that primary dementia prevention is potentially 529
cost-saving or cost-effective. These results suggest that dementia prevention programs may be able 530
to affect the number of people suffering from dementia and be economically beneficial in the future.
531
In summary, the 8th Kuopio Alzheimer symposium provided a comprehensive overview of the 532
latest advances and future directions of the research into AD and other neurodegenerative diseases.
533
The program comprised oral and poster presentations related to the molecular and cellular 534
mechanisms of neurodegeneration, novel, sophisticated model systems and their translational 535
potential, identification of new predictive and diagnostic biomarker candidates, new technologies and 536
tools for decision support, insights into comorbidities with other diseases, and global efforts in the 537
prevention and treatment of AD and other neurodegenerative diseases. This research altogether 538
aims at better understanding of the mechanisms of neurodegeneration and at developing efficacious 539
methods for early identification, diagnosis, and treatment of patients with neurodegenerative 540
diseases or even identification of individuals at increased risk of dementia for prevention and 541
therapeutic studies. Ultimately, the knowledge gained from these studies is expected to lead to the 542
discovery of optimal, timely, and individualized prevention and treatment options to help 543
management of neurodegenerative diseases worldwide.
544
The program and abstracts of the 8th Kuopio Alzheimer symposium can be found at the 545
symposium website [26].
546
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http://www.uef.fi/documents/250078/302440/2018+-+8th+Kuopio+Alzheimer+Symposium+- 601
+Abstract+book.pdf/0455c9c1-45ac-409d-b137-7d7f68672555.
602
