Day 1 :
Keynote Forum
Barbara F. Fisher
United Psychological Services, USA
Keynote: The Road to Prevention: Diagnosing Early Cognitive Decline and Targeting Deficits with the Implementation of Cognitive Training
Time : 09:30-10:10
Biography:
Barbara Fisher is a neuropsychologist with board certification in behavioral sleep medicine. She has been involved in dementia evaluation for over twenty years. She is the author of four books on Attention Deficit Disorder and co-morbid disorders, lead author on a publication on twenty years of ADHD evaluation, articles and ongoing abstracts on cognitive rehabilitation for dementia and head injury and participating author on publications on sleep and ADHD. Dr. Fisher is the clinical director for United Psychological Services, a private clinic which specializes in diagnosis and treatment of dementia amongst other specializations. Cognitive training has been provided at United Psychological Services for the last fifteen years at United Psychological Services; targeting dementia for the last ten years; publishing ongoing research over the last three years. The cognitive training program is unique with over 200 tasks to choose from that is individually designed based upon neuropsychological test results.
Abstract:
Neuropsychological evaluation identifies neurocognitive deficits to aid in the diagnosis of the specific type of dementia that carries a different intervention and/or treatment plan. Predominantly frontal (executive reasoning) deficits will tend to be more suggestive of frontal lobe dementia or disease; frontal and temporal deficits (memory and the impact of executive reasoning deficits) of cardiovascular disease; visual perceptual, executive reasoning deficits and psychiatric signs of Lewy body dementia; while rather clear signs of highly impaired memory (for retrieval and recognition) as well as visual spatial issues will tend to reflect the true Alzheimer’s dementia. Cognitive decline associated with neurological diseases depends upon the brain areas affected; for example, Multiple Sclerosis (impacts memory and attention, processing information quickly and efficiently) Parkinson’s disease (executive reasoning, as well as attention and memory) while Huntington’s has a predilection for executive reasoning deficits and motoric response. rnUse of neuropsychological evaluation and diagnosing the specific deficit areas has allowed us to develop a very specific cognitive training regimen which has shown positive findings when comparing testing prior to and following treatment intervention. Specificity of the cognitive training has been a primary variable for improved functioning following treatment. At our facility all of the brain enhancing activities have been systematically studied and labeled for the effect they are expected to have in remediating brain function; memory (short and long term, retrieval and recognition, visual and verbal) executive reasoning processes (selective attention, integration, perseveration, sequential analysis, cognitive flexibility) language (word retrieval) and visual perceptual. The key to the most effective and efficacious outcome in our research has been early diagnosis and treatment.rnWe are on an outreach effort for neurocognitive evaluation of individuals with any type of illness (physical or psychiatric) in their sixties and everyone in their seventies. Outreach is currently ongoing to the primary care physician to query about memory difficulties and executive reasoning symptoms. In the USA, dementia is known as one of the most expensive medical conditions; costs are currently in the billions and projected to the trillions for the future. rnThe answer is early diagnosis and education of the general population of the increased risk of dementia when there is avoidance of memory problems. Fear and avoidance of dementia is enormous and pervasive; affecting the caregiver, spouse, as well as the children. Waiting until a basic dementia assessment or mini-mental status is failed or for the problem to be exacerbated and outwardly obvious, results in more severe diagnosis and complications. Our research and work with the aging population over the last ten years reveals the benefit of early diagnosis and the intervention of cognitive training/rehabilitation upon brain function in helping to remediate the effects of dementia. Case studies will be provided to illustrate the significant neurocognitive changes that occurred from cognitive rehabilitation which transferred to improved emotional and daily living skills.
Keynote Forum
Guosong Liu
Neurocentria, USA
Keynote: Efficacy and safety of MMFS-01, a synapse density enhancer, for reversing age-related cognitive decline: a randomized, double-blind, placebo-controlled trial
Time : 10:10-10:50
Biography:
Guosong Liu received his PhD in Physiological Sciences from the University of California, Los Angeles in 1990. He completed post-doctoral scientific training at Stanford University and then went on to a faculty position at Massachusetts Institute of Technology. Liu continued a vigorous scientific research program at Tsinghua University, and leads and oversee as CEO the multiple clinical development programs of Neurocentria. Dr. Liu is a world renowned expert in synaptic physiology, learning, and memory. His research focuses primarily on discovering principles that regulate synapse density in the brain under physiological and pathological conditions and developing novel strategies for treating neurodegeneration and preventing brain atrophy.
Abstract:
Background: Age-related cognitive decline is a major problem in elderly, affecting quality of life. Pre-clinical studies show that MMFS-01, a synapse density enhancer, is effective at reversing cognitive decline in aging rodents.rnObjective: Since brain atrophy during aging is strongly associated with both cognitive decline and sleep disorder, we evaluated the efficacy of MMFS-01 in its ability to reverse cognitive decline and improve sleep.rnMethods: We conducted a randomized, double-blind, placebo-controlled, parallel designed trial in elderly subjects (age 50-70) with complaints of memory impairment, sleep disorder, and anxiety. Subjects were treated with MMFS-01 (n=23) or placebo (n=21) for 12 weeks and cognitive ability, sleep quality, and emotion were evaluated. Overall cognitive ability was determined by a composite score of tests in four major cognitive domains.rnResults: With MMFS-01 treatment, overall cognitive ability improved significantly relative to placebo (p=0.002; Cohen\'s d=0.92). Age-related cognitive fluctuation was also reduced. Although the study population had more severe executive function deficits than age-matched controls, MMFS-01 treatment nearly restored impaired executive function, demonstrating that MMFS-01 was clinically significant. Sleep quality and anxiety were improved in MMFS-01 treatment group; however, similar degrees of improvement were also observed in the placebo control group. rnConclusions: The current study demonstrates the potential of MMFS-01 for treating age-related cognitive decline in elderly.rn
Keynote Forum
Tohru Hasegawa
Saga Woman Junior College, Japan
Keynote: Alzheimer’s cognitive impairment can be recovered by decreasing homocysteic acid in blood
Time : 11:10-12:00
Biography:
Tohru Hasegawa got his PhD degree from Okayama Medical School at 1980. He was Associate Professor of Saga Medical School from 1981 to 2000, and he was a Professor of Saga Woman Junior College from 2000 to 2011. He is a Professor Emeritus of Saga Woman Junior College from 2011. He investigated the pathogenic process of Alzheimer’s disease and he found that homocysteic acid in blood is one of pathogens of AD.
Abstract:
Recent big two clinical trials of amyloid beta treatment for Alzheimer’s disease are all failed to recover the cognitive impairment, it has forced us to reconsider the central hypothesis of amyloid pathogen for Alzheimer’s disease. We recently published that human Alzheimer’s patients showed the strong relationship between Mini Mental State Examination (MMSE) scores and blood homocysteic acid (HA) level. 6 AD patients (all female: age 77, 82, 86, 87, 91, 91) were given green tea powder 1g at every meal for 2 months. Their blood HA level and MMSE score were measured before and after taking green tea powder. The relationship between blood HA level change and MMSE score change was investigated. The strong statistically significant negative relationship between blood HA level change and MMSE score change: r=-0.96, p=0.00018, n=6. From our observation, it showed that blood HA level change induced MMSE score change, that is, Alzheimer’s cognitive ability was controlled by blood HA level. Now we can present that some healthy food, that is named HBF, can recovered 100% Alzheimer’s cognitive impairment by the decreasing the homocysteic acid in a peripheral blood. Now we have made a relative large open trial of AD patients. 91 patients were enrolled. Their cognitive recovery was measured by NM scale (New Clinical Scale for Rating of Mental States). All patients who took HBF showed the recovery of their behaviors. From this open-trial of HBF, (1) Alzheimer’s cognitive impairment could be recovered at even end stage. (2) Alzheimer’s disease is induced by homocysteic acid.
- Causes, Prevention and Management of Dementia
Chair
Barbara C Fisher
United Psychological Services, USA
Co-Chair
Guosong liu
Neurocentria, Inc., USA
Session Introduction
Caron Leid
Aspen University, Canada
Title: Alzheimer’s- What they forget to tell you
Time : 12:00-12:30
Biography:
Caron Leid, Author of Alzheimer’s: What they forget to tell you and founder of R&R Inc., is a dedicated mother and passionate student. Caron pursues her passion for education by completing her MBA and currently pursuing her Doctorate in Education. Her book has been featured on Amazon, Barnes & Noble and international book stores. Caron received her undergraduate degree from University of Windsor, majoring in Psychology and minoring in Sociology. Her career and passion surrounded educating others and believes in the pay it forward principle. As the primary caregiver to her mother, Caron hopes that her story can inspire people that struggle with Alzheimer’s disease and the various aspect surrounding the disease that you may not have the ability to read in a book.
Abstract:
Although more and more people are being affected by Alzheimer’s disease, there is not enough information surrounding the true daily struggle of the disease. Due to that reason, I felt there was a huge gap for those in the sandwich generation. My mother was diagnosed with Atypical Alzheimer’s disease at the age of 57. The book which I wrote is a journey to assist others with resources and the struggle of living with the disease, from a raw perspective.
Bettina Von Kampen
Asia University, Taiwan
Title: Adapting the Tinetti tool for balance and gait for person with dementia
Time : 12:30-13:00
Biography:
Alison Douglas is affiliated with St Joseph’s Healthcare Hamilton in the Senior Mental Health Behavioral Unit. She is also affiliated with McMaster University Department of Psychiatry and Behavioral Neurosciences and is the Editor-in-Chief of the journal Physical and Occupational Therapy in Geriatrics.
Abstract:
Background: A recent review of the literature reveals an absence of standardized measures to assess mobility in persons with advanced dementia. Persons with moderate to severe dementia have significant difficulty adhering to instructions. The aim of the study was to develop a standardized measure of gait and balance for use with persons with dementia. We chose to modify the ‘Tinetti Assessment Tool for Balance and Gait’ because many of the items are based on observation. Modification of test items requires analysis of reliability prior to establishing validity. Objective: To determine the inter-rater and test-retest reliability of ‘Tinetti Assessment Tool for Balance and Gait-Dementia’ Methods: Inter-rater reliability: Participants were observed and scored simultaneously by two raters familiar with the written instructions (physiotherapy, occupational therapy or nursing staff). Test-retest reliability: The test was re-administered after 10 to 30 minutes. Results: A total of n=20 participants were recruited and included. The mean age of participants was 75 with the majority being female (n=11, 55%). All were diagnosed with dementia or cognitive impairment. Secondary diagnoses include heart disease, diabetes and Parkinson’s disease. The mean cognitive assessment (SMMSE) score was 8.5/30 (n=12). Inter-rater reliability of the total score was high (r=0.90) as was test-retest reliability (r=0.92). Discussion: These results are comparable to established reliability of the original Tinetti tool (r>0.8). The results indicate that the modified measure has sufficient reliability to commence validity testing. Developing a measure that assesses functional changes in this population is important for determining the impact of mobilization and least restraint programs for people with dementia in long term care. Further study will establish validity of the cut score for predicting falls risk.
Biography:
Atul Sunny Luthra is presently an Associate Clinical Professor at McMaster University, Hamilton, Ontario, in the faculty of health sciences, Department of Behavioural Neuroscience. He is also affi liated as a research scientist with the Research Institute for Aging, Schlegel, and University of Waterloo, Ontario. He is currently working as medical coordinator in the Program for Older Adults at Homewood Health Centre, Guelph, Ontario. He is affi liated in the same capacity with the St. Peter’s site of Hamilton Health Science, Hamilton, Ontario. His clinical and research focus is on developing safe pharmacological and affordable nonpharmacological treatment interventions for behaviors in moderate to advanced dementia.
Abstract:
Objectives: There is vast heterogeneity in use of terminology and classification of behaviors in dementia with no universally accepted classification system. Methods: Criteria proposed by Davis, Buckwalter and Burgio (1997) were identified as the basis for classification of behaviors in dementia. A review of the literature was done to identify the “Specification of the Theoretical Construct†(STC) to justify aggregation of similar behavioral symptoms into clinically meaningful categories. Results: STC identified for these behavioral categories are those based in theories on information processing (TIP). Two behavioral categories emanating from pathological changes in TIP are: Disorganized Behaviors (DOB), and Misidentification Behaviors (MiB). Discussion: DOB is the result of an alteration in the physiological status of the patient. This result in changes in arousal and attentiveness and this, in turn, leads to impairment of the sequential organization of information processing thereby giving way to fragmentation of the process at many different levels of the brain. MiB are the result of a specific breakdown in two specific steps of TIP; schema identification and pattern recognition. This result in the failure of the usual pairing of old and new information with an altered sense of relatedness between self and persons, places, objects and events. Keywords: Dementia, Behavioral Symptoms, Classification, Information Processing, Disorganized Behaviors, Misidentification Behaviors
Atul Sunny Luthra
Homewood Health, Canada
Title: Classification of Behaviors in Dementias Based on Principles of Compliance and Aggression
Biography:
Atul Sunny Luthra is presently an associate clinical professor at McMaster University, Hamilton, Ontario, in the faculty of health sciences, Department of Behavioral Neuroscience. He is also affiliated as a research scientist with the Research Institute for Aging, Schlegel, and University of Waterloo, Ontario. He is currently working as medical coordinator in the Program for Older Adults at Homewood Health Centre, Guelph, Ontario. He is affiliated in the same capacity with the St. Peter's site of Hamilton Health Science, Hamilton, Ontario. His clinical and research focus is on developing safe pharmacological and affordable non-pharmacological treatment interventions for behaviors in moderate to advanced dementia.
Abstract:
Objectives: There is vastheterogeneityin use of terminology and classification of behaviors in dementia with no universallyaccepted classification system. Methods: Criteria proposed by Davis, Buckwalter and Burgio(1997) were identified as the basis for classification ofbehaviors in dementia. A review of literature was done with a view to Identify the “Specification of the Theoretical Construct†(STC) to justify aggregation of similar Behavioral symptoms into clinically meaningful categories. Results: STC identified for these behavioral categories are theories on compliance and aggression. Behavioral categories emanating from this construct are; Oppositional Behaviors (OB) and Physically Aggressive Behaviors (PAB). Discussion: OB is the result of non-compliance to the directions being given bythe care provider. Thetypes of OBaredetermined bythe level of developmental sophistication or converselybythe degreeof cognitive impairment in patients with dementia. PABarethe result ofperceived impediment bythe patient in goal attainment. This results in the emergenceof negative emotions. These emotions are ‘out of proportion’ to the stimulus. The purpose of this behaviour is to warn the care provider of the noxious nature of their involvement in the present situation.
- Workshop
Location: Saloon D
Session Introduction
Simon Chiu
University Western Ontario, Canada
Title: Exploring the kaleiodoscopic oasis of epigenetics-based diet, brain games and physical exercises in cognitive aging and Alzheimer dementia: Evidence, promises and challenges
Biography:
Simon CHIU graduated from McMaster University , Hamilton Ontario PhD program in neurosciences and has became qualifi ed in Medicine from University of Toronto MD. He is board certifi ed with the Canadian Royal College of Physicians and Surgeons in psychiatry (FRCP) and the American Board of Neurology and Psychiatry :sub-specialty qualifi cations in addiction psychiatry and geriatric psychiatry. Currently as the Associate Professor of psychiatry at University of Western Ontario London Ontario he has been active in research on neuro-psychopharmacology of CNS disorders, focusing on novel drug targets for neurodegenerative and neuropsychiatric disorders. . He has completed funded studies of epigenetics-based nutraceuticals and drug candidates :Ginsana-115 (Sirtunin modulator), Liposomal curcumin (HDAC inhibitor), Zembrin extract (PDE-4/serotonin modulator of epigenetics network and the emerging role of epigenetics diet in Alzheimer diseases. He published more than 70 peer-reviewed papers, abstracts/presentation.
Abstract:
Background: Recently, increased interest has been expressed in developing diverse strategies to optimize cognitive aging and to modify the onset and course of Alzheimer’s dementia (AD). Th e interaction of Gene and Environment in modulating cognitive decline is best understood within the framework of Epigenetics. Epigenetics refers to heritable changes in gene expression and remodeling of chromatins and dependent of alterations in DNA sequence, and comprise of three key components; DNA methylation, histone modifi cations (acetylation and deacetylation) and non-coding microRNA. Epigenetics targets play major role in reprogramming of neural networks and neural repair. Epigenetics can turn genes “On†and “Off †depending upon the milieu. Th ere is emerging evidence supports the model of dysregulation in epigenomics in age-related cognitive decline and AD. A large number of studies have shown that nutrition factors: diets, dietary and herbal supplements, functional foods, are capable of regulating the epigenetic states and targets in reversing abnormal gene activation or silencing. Physical exercises and e-delivered brain games likewise can change various domains in aging and in AD through the epigenetics signatures. We review the translational and clinical evidence in support of the benefi cial eff ects of dietary phytochemicals from diverse dietary sources; grapes, chocolates, green and black coff ee, soya beans and fava beans, curry extract, peanuts, garlic and ginger and seafood products have positive impact on epigenomics in facilitating translational and transcriptional events involved in memory, attention and executive functions. Th e fi ndings from the studies on DASH and Mediterranean diets reinforce the relevance of epigenetic diet menu, along with the proposed Epigenetics diet for cognitive aging platform. We will also discuss the multi-faceted actions of herbal supplements :Panax Ginseng , and Curcumin from Curry extract, and Zembrin extract from South African plant Sceletiumtortuosum. and diet menu in enhancing vascularneuronal coupling and to reduce metabolic and vascular risks in aging. Epigenetics targets are also sensitive to environmental stimuli and processing. Hence physical exercises and e-delivered cognitive challenge tasks like puzzles, video games. Th e evidence is mounting in terms of the putative positive eff ects in reprogramming neural circuitry for cognition and reactivating neurogenesis in the hippocampus. We conclude that epigenomics-driven lifestyle measures and diet interventionsare promising in cognitive aging on the progression of AD. We anticipate in the near future we will have epigenetics-based dietary and exercise and e-stimulation can prevent AD and optimize cognitive aging and will be translated intoevidence-based practice guidelines forgeriatric care. We believe that biotechnology caneventuallytransform bioactive factors to CNS drug candidates for AD treatment and prevention. Objectives: At conclusion of this session, the participant should be able to understand how cognition can be regulated through dietary interventions targeting Epigenomics in aging & Alzheimer dementia (AD). To evaluate the benefi t-to-risk ratio and evidence of clinical cognitive studies of specialized diets, dietary supplements and functional foods in preventing cognitive decline in aging and in AD. To gain insights into the benefi ts of aerobic exercise and e-delivered video games in reprogramming gene expression and neural circuits involved in cognitive aging and in modifying the course of AD. To identify fi scal and systemic issues involved in translating new research fi ndings on brain foods, exercise and e-delivered brain exercise to evidence-based practice in geriatric are to understand how epigenomics may shed light on the link of nutrition, cognition and AD and has the potential to transform bioactive phytochemicals to promising drugs for treating and preventing AD.
- Alzheimers Disease Diagnosis and Imaging
Chair
Toshimitsu Musha
University of Tsukuba, Japan
Co-Chair
Tohru Hasegawa
Saga Woman Junior College, Japan
Session Introduction
Toshimitsu Musha
University of Tsukuba, Japan
Title: New System NAT(Neuronal Activity Topography) for Assisting Differential Diagnosis of Dementia
Biography:
Toshimitsu Musha was born in 1931 in Tokyo, Japan. He received the Graduation and PhD degrees from the Department of Physics, the University of Tokyo in 1954, and 1964. He was with the Electrical Communications Lab of NTT(1954-1965), the Research Lab of Electronics, Mass. Inst. of Technology (USA), as a Fulbright exchange scholar(1964-1965). In 1966-1992 he was Professor of Tokyo Institute of Technology, and founded a series of the international symposia (ICNF). He summarized his work as “Theoretical background of 1/f fluctuations of energy partition among harmonic oscillators in equilibrium†(International Journal of Physical Sciences Vol. 7(43)
Abstract:
The EEG signals are recorded for five minutes with 21 electrodes and analyzed via the Internet. From the normalized power spectrum of each of the recorded signals, the normalized power spectrum NPSj,m is derived referring to signal channel j and frequency bin mf0 where m is an integer and f0 (=1.56Hz) which equals an inverse of the signal segment length 0.64 sec. A pair of markers, sNAT and vNAT which have 210 sub-markers each, is derived for characterizing EEG power partitions across the 10 frequency bins and power ratios between the adjacent frequency bins, respectively. The likelihood between the template markers and a pair of markers of an unknown subject derives information of differential diagnosis concerning several dementias. The NAT pattern of a patient gives us information about the local cerebral impairment. Severity of the impairment can be on a differential-likelihood diagram, and this diagram enables detection of dementia in the early stage. VCI and DLB can be separated from the normal control (NL) at 90ï¾95%, and AD from NL at 80%. Moreover, improvement of impaired cerebral activities can be numerically monitored after a proper intervention. NAT will serve to prevent the increase of demented senior population wherever the internet system is available.
Jens Wiltfang
Georg August University Gottingen, Germany
Title: Predictive molecular diagnosis of Alzheimer’s Dementia: Towards new clinical models for preventive treatment
Biography:
Jeans Wiltfang is a graduate from the Faculty of Medicine of Hannover where he obtained a PhD in Psychiatry. He is the Director of the Department of Psychiatry and Psychotherapy at the University Medical Center Gottingen (UMG). He is a neurologist and psychiatrist with wide experience in the fi eld of neurodegenerative diseases. His activity includes the clinical characterization of patients with dementia and research on the biomarker discovery and validation. In particular his main expertise is on the fi eld of cerebrospinal fl uid and blood biomarkers for early diagnosis of neurodegenerative diseases, with special interest on Alzheimer’s disease and Parkinson’s disease.
Abstract:
There is an unmet need for fi rst preventive, that is disease-modifying, treatments of Alzheimer´s dementia (AD). However, preventive treatment calls for predictive diagnosis since novel preventive treatment options can only be off ered if patients are identifi ed during preclinical stages of the incipient AD. Per defi nition, a preclinical stage can not be detected by clinical tools and accordingly, patients at high risk for later AD have to be identifi ed by biomarker guided predictive diagnostics. Th e presentation will demonstrate that patients with preclinical AD can meanwhile be identifi ed within the clinically heterogenous cohort of Mild Cognitive Impairment (MCI) with positive and negative predictive values of at least 90% by a multiparameter biomarker approach relying on CSF dementia biomarkers, MRI volumetry and/or F18-Amyloid-PET. In view of a prevalence of approximately 20% of preclinical AD within the MCI risk cohort the latter predictive values are clinically signifi cant. Morevover, it will be critically discussed in how far fi rst blood-based assays may support the identifi cation of preclinical AD. Finally, the presentation will exemplify that novel diagnostic targets may indicate promising novel therapeutic targets.
Matthias L Schroeter
Max Planck Institute for Human Cognitive and Brain Sciences, Germany
Title: Predicting frontotemporal lobar degeneration with meta-analyses, pattern classification and multimodal imaging
Biography:
Matthias Schroeter studied Medicine and Philosophy in Berlin/Germany, Vellore/India and Jerusalem/Israel. He has completed his MD from Humboldt University Berlin/Charité and his PhD from Technical University Berlin. He is consultant for psychiatry and professor for Cognitive Neuropsychiatry at Leipzig University and Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig, Germany. He has published more than 100 papers in reputed journals.
Abstract:
Recently, new diagnostic criteria including imaging biomarkers have been proposed for frontotemporal lobar degeneration (FTLD) in particular for its behavioural variant and language subtypes. Th ese imaging criteria shall enable individual diagnosis. New imaging criteria were validated by conducting quantitative anatomical likelihood estimate meta-analyses according to the QUOROM/PRISMA statement across studies published in the literature. Th ese meta-analyses identify the neural correlates for each of the FTLD subtypes and underline disease-specifi city of the imaging criteria. Analyses were conducted separately for atrophy measured with magnetic resonance imaging (MRI) and glucose metabolism measured with [F18] fl uorodeoxyglucose positron emission tomography (FDG-PET). Both imaging methods revealed specifi c regional patterns. Results might open the road to method-specifi c imaging criteria as already suggested for Alzheimer’s disease. If new imaging criteria are valid they shall enable early individual diagnosis in single patients. To prove the potential for individual diagnosis we investigated whether FTLD might be diagnosed with cutting edge pattern classifi cation algorithms in multimodal imaging data. Support vector machine classifi cation (SVM) with multimodal imaging data (MRI & FDG-PET) enabled early individual detection of FTLD and discrimination between FTLD and Alzheimer’s disease. Limiting SVM classifi cation regionally to meta-analytically identifi ed disease networks even improved discrimination accuracy. Analyses were also reliable in multi-centric data. In conclusion, our results support and refi ne the application of imaging criteria and suggest that pattern classifi cation algorithms enable early individual diagnosis and diff erential diagnosis of FTLD sub types, a precondition for early intervention strategies.