IHC-RORS9 Improving medical services in neurology and psychiatry

  1. Study Overview

This study, titled IHC “Improved health care in neurology and psychiatry – longer life“, is a 18-month prospective, observational, non-interventional study in patients with mild cognitive impairment (MCI) following ischemic strokes. The current trends in worldwide population ageing have drawn our attention not only to the quality of life in the elderly but also to the regression time towards old age-related dementia and other diseases connected to elderliness.

During the last century, particularly in the 90’s, MCI has been described as a stage of memory disorders that went beyond normal ageing, characterised by no negative impact upon other cognitive area and by an almost intact preservation of daily routines. More recently, the MCI concept has been widened once with the clinical observation that no all patients with memory diseases will eventually develop Alzheimer’s Disease (AD) or other dementias. Both the aetiology and the heterogeneous evolution of MCI are also described in the speciality literature. This study aims to observe the evolution of memory / cognitive disorders in patients with MCI following ischemic strokes.

Ischemic stroke is the most important cause of mortality and long-term incapacity for work in Europe, and implicitly in Romania. Consequently, ischemic strokes have a considerable social and economic impact. 75-80% of all strokes are ischemic, occurring after a focal vascular occlusion. Finding the exact aetiology of ischemic strokes contributes to the implementation of the proper therapy. Atherosclerosis is the main cause of ischemic strokes (30%). While CT scans and MRI scans allow an efficient and early differentiation between ischemic and hemorrhagic strokes, vascular imaging tests (such as extra / transcranial colour-coded Doppler ultrasound, digital subtraction angiography (DSA), CT angiography and/or MR angiography) provide valuable information on the permeability of cervical and intracranial arteries (stenosis, occlusions). 

Vascular cognitive impairment is part of a heterogeneous group of cognitive disorders that all share a vascular cause. Dementia is one of the major causes of invalidity and dependence among the elderly worldwide. It is one of the diseases with significant negative impact not only upon patients, but also upon patients’ families and caregivers. Dementia is characterised by a clinical syndrome represented by an overall cognitive impairment involving a considerable decline compared to the previous level of functionality and which gathers up a wide range of neurological and psychological symptoms. The cognitive functions that are basically affected by dementia are: memory, attention, temporal and spatial orientation, computation, written and spoken language, gnosis, praxis, learning skills, thinking and reasoning. Pathophysiological mechanisms of vascular cognitive impairment are still being investigated globally. Nowadays, the most plausible causes for vascular cognitive impairment are large-vessels disease correlated to small-vessels disease (including subcortical ischemic lacunar strokes, leucoaraiozis and athrophy).    

Objectives of this project are described below:

1.) To identify patients with ischemic strokes and to outline the vascular risk factors and the hemodynamic and structural changes determined by such factors at the level of carotidal and / or vertebrobasilar arterial systems and the encephalon, which are correlated with cognitive impairment;

2.) To choose the battery of tests required to examine patients with ischemic strokes (NIHSS, Barthel Index, the modified Rankin scale) and vascular cognitive impairment (MMSE, MoCA, CDR, Delayed Recall Test- Rey Test, Hamilton rating scale for depression, FAQ, CGI) and to use such tests for early screening of cognitive impairment;

3.) To identify the stage from which patients with ischemic strokes and vascular cognitive impairment may be included in a relevant therapeutic management programme.

  1. National and international situation at the level of both the field and the theme proposed

Ischemic strokes represent the third leading cause of mortality worldwide, after cardiovascular diseases and cancer. More 700 thousands ischemic strokes that lead to over 150 thousands deaths are identified in USA on an annual basis. Over 125.000 new episodes of ischemic strokes occur in France every year. The incidence of ischemic strokes increases exponentially with ages, affecting less than 1 in 1000 persons aged over 50 years and over 20 in 1000 persons aged over  80 years, every year. Ischemic strokes are seen as the leading cause of mortality and long-term incapacity for work in Europe, and implicitly in Romania, having at the same time a considerable social and economic impact. 75-80% of all strokes are ischemic, occurring after a focal vascular occlusion which causes the stoppage of oxygen and glucose supply to the corresponding encephalic area, which, in its turn, brings the disruption of all metabolic processes that usually take place in that particular area. Although the aetiology of ischemic strokes is heterogeneous, there are three main causes (atherosclerosis, cerebral lacunae and heart embolisms) which account for 2/3 of all cases (atherosclerosis is the main case in 30% of cases).

Statistics reveal that 0,5% of world population (i.e. 35.6 millions) was affected by dementia in 2010; according to scientists’ estimates, this percentage will double by 2030 and by 2050, it will increase by three times. The same statistics report alarming data: 7.7 million new cases of dementia every year; a new case emerges every 4 second; 7.1 years - the estimated median survival from Alzheimer dementia’s onset to death; 3.9 years - the estimated median survival from vascular dementia’s onset to death; US $ 600 billion – annual costs incurred at the global level, equivalent to the budget of the 21st global economy, between Poland and Saudi Arabia; £ 23 billion incurred in UK, equal to the budget assigned for treating cancer (£ 12 billion), cardiovascular diseases (£ 8 billion) and strokes (£ 5 billion). On the other hand, the funds assigned for researches in the field of dementia are significantly lower than those allocated for researches targeting other diseases: from every million pounds assigned to cover the costs generated by diseases, only £ 5.000 are allocated for the study of dementia, almost £ 130.000 – for cancer, £ 75.000 – for cardiovascular diseases, £ 9.000 for strokes. It is obvious that more financial resources should be assigned for the researches conducted in the field of dementia. Accurate identification of all pathophysiological mechanisms will guarantee not only a proper treatment scheme, but also the control of this phenomenon which unfortunately has an exponential growth.



  1. Objectives of this study

A total of 100 patients are estimated to enrol in this study. The leading target group of our study will be the patients with ischemic strokes from the Romanian-Serbian border area, particularly those living in Timis, Caras-Severin and Mehedinti Counties (in Romania). Ischemic strokes have a greater impact on the elderly. The risk of having a stroke nearly doubles every 10 years after the age of 50 years. Although men are at higher risk of stroke, the overall number of women who actually suffer a stroke is higher because women usually live longer than men and therefore they are more prone to be affected by strokes. The average age of occurrence of ischemic stroke is 70 years in men and 75 years in women. However in Romania and Serbia, ischemic strokes occur earlier, between ages of 60 and 65 years. Our project is intended to bring its contribution not only to the improvement of the quality of life of this category of patients, by implementing new protocols that guarantee quicker and more accurate diagnosis of cognitive impairment in patients with ischemic strokes, but also to a better communication between the medical experts in both countries.

Several factors such as the socio-economic status, the geographic location, the lifestyle and the daily habits of the inhabitation from the Romanian-Serbian border area determine similar medical issues.

The protocols and techniques employed during the implementation of this project will also be used afterwards in all three institutions involved (University of Medicine and Pharmacy of Timisoara, the hospitals of Varset and Smederevo). Moreover, we will disseminate the results of this project to other similar establishments in Romania and Serbia. Another reason that supports the cross-border approach facilitated by this study is the fact that Romania, as an EU member state for several years, has access to certain cutting-edge medical technologies. After the completion of this project, students, residents and PhD students will be involved in order to acquire new practical and theoretical insights.

The main objective of this study consists in the identification of patients with ischemic strokes as well as in outlining both the vascular risk factors and the encephalic and hemodynamic structural changes these factors cause at the level of carotid and/or vertebrobasilar arterial levels, and which are best correlated with vascular cognitive impairment. During this 18-months study we will dynamically assess the primary neurological profile (motor deficit, objective sensory impairments, etc.) using the following scales: NIHSS, mRS, Barthel Index, on the one hand, and, on the other hand, all cognitive functions, employing the scales listed as follows: MMSE, MoCA, CDR, Delayed Recall Test- Rey Test, Hamilton rating scale for depression, FAQ, CGI.

Secondary objectives:

- To identify and underline several reliable, non-invasive and cost-friendly diagnosis methods that may be included in the standard battery tests for early screening of vascular cognitive impairment;

- To clearly determine the stage from which the patients with cognitive impairments may be included in a relevant therapeutic management programme.

Working hypotheses:

- Cognitive status depends on the normal function of both cerebral hemispheres which, in their turn, rely upon the cerebral blood flow which is highly influenced by the condition of the encephalic arterial system. According to the literature, the ageing process and the risk factors may be directly involved in the occurrence of cognitive impairment; 

- A series of reliable, quick and cost-friendly paraclinical methods may reveal essential data regarding the structural and hemodynamic parameters of both the endocranial arteries and the arteries from the bottom of the neck (head and neck CT/MR angiography scans and extra / transcranial colour-coded Doppler ultrasounds).


Inclusion criteria:

- Female or male subjects over the age of 50 years;

- Memory disorders, ideally validated by a caregiver;

- Clinical analysis (particularly neurological analyses – rating scales used to assess focal neurological deficits, etc.) and imaging analysis (CT / MRI, transcranial colour-coded Doppler ultrasound scans);

- Examination of cognitive functions using various tests (MMSE, MoCA, clinical dementia rating scale (CDR), Rey Test, Hamilton rating scale for depression);

- In spite of the fact that the general cognitive function is basically preserved (CDR ≤ 0,5, MMSE ≥ 24), the patient shows signs of impairment of one or more cognitive fields, including memory;

- Mostly intact functional activities (normal FAQ scores);

- Subjects able to communicate (no Wernicke’s aphasia; no global aphasia);

- No signs of dementia (patients do not meet the DSM-IV criteria related to dementia);

- The patients or the patients’ legal caregivers must understand the purpose of this study and consequently sign the informed consent prior to carrying out any other study-related procedure and prior to collection of any study-related data). 


Exclusion criteria:

- Diagnosis of a dependence syndrome (alcohol or drugs);

- Severe cardiovascular, respiratory, neurological, renal, hepatic, endocrinological, haematological comorbidities and basically any other unbalanced somatic diseases; 

- History of malignity;

- Simultaneous participation in other studies.

  1. Scientific presentation of project

Classification of ischemic strokes:

  1. atherothrombotic cerebral infarction (20%);
  2. cardioembolic cerebral infarction (20%);
  3. lacunar stroke (25%);
  4. rare causes (arterial dissections, arteritis, vasospasms, prothrombotic state: protein S deficiency, protein C deficiency; antiphospholipid antibody syndrome, etc.) (5%);
  5. cryptogenic stroke (30%);


  1. Atherothrombotic cerebral infarction.

This type of cerebral infarction comes as a consequence of atherosclerosis of either the extracranial arteries or the large intracranial arteries.

There are two main ways by means of which atherosclerosis may precipitate the occurrence of cerebral infarction:

  • either as a consequence of the growth and progression of atheromatous plaque with the simultaneous occurrence of thrombosis and secondary injury of vascular lumen;
  • or as a result of thromboembolism or fragmentation of plaque (arterio-arterial embolisms), including at the level of the aortic arch;

These patients report more frequently histories of transient ischemic attacks (TIA) and/or carotid bruits.

Clinical diagnosis of atherothrombotic cerebral infarction is based on the accurate identification of certain arterial stenosis or occlusions occurred due to the atherosclerotic processes, with one or more localisations. Atheromatous plaques are basically formed in certain areas of the cerebral arterial system, at the level of junctions and bifurcations characterized by swirling blood flows and vortices, such as: initial or final segments of the internal carotid artery (ICA), left subclavian pre-ostial artery. Atheromas are frequently formed in the initial segment of the middle cerebral artery (MCA), at the level of junction of vertebral arteries (VA) or at the level of bifurcation of the basilar artery (BA). White platelet thrombi are initially formed at the level of the atheromatous plaques. These white thrombi are known for their tendency to migrate causing the embolisation of arteries which usually occurs downstream (a short-term process characterized by a subsequent disaggregation of the emboli). Ulceration of atheromatous plaques causes the formation of larger and more adherent parietal thrombi. Sometime these red thrombi migrate as well, causing a long-term embolisation of downstream arteries which results in embolic strokes. Typically the parietal thrombi continue to further develop in situ, causing the complete occlusion of that particular artery and ultimately inducing the atherothrombotic cerebral infarction.


b.) Cardioembolic cerebral infarction

Typically, this type of infarction occurs unexpectedly, causing a sudden onset of focal neurological deficit that may progress. To accurately diagnose this infarction we need to clinically and/or paraclinically prove the cardiogenic source of the cerebral embolism. The most frequent cardiac diseases that may generate cerebral embolisms are: paroxysmal or permanent atrial fibrillation, atrial flutter, acute/chronic myocardial infarction (MI), cardiac failure and mitral and aortic valvulopathies. In relation to the paradoxical embolisms via the patent foramen ovale (resulted from cardiopathies with right-to-left shunts), the peripheral venous thrombosis is usually the source of embolus. Cardioembolic cerebral infarctions are essentially multiple infarcts, they may be associated with renal, mesenteric infarctions or with acute upper or lower limb ischemias. Sometimes CT scans may detect hemorrhagic infarctions.


c.) Lacunar stroke (Small-vessel stroke)

Although it is a morphopathological term, lacunar infarction is widely used in practice to indicate a category of minor lesions such as infarctions occurred due to occlusion of small penetrating arteries.

These arteries branch off almost at right angles from the main cerebral arteries and irrigate the white matter and the deep grey matter of both cerebral hemispheres and brain trunk. As they have few lateral connections, the thrombotic or embolic occlusion occurred at these levels causes infarcts in their limited distribution areas. Over time, the infarct takes the shape of a cyst filled with fluid. The infarction area is surrounded by normal tissue. The morphopathological substrate of cerebral lacunae is represented by the microangiopathy of intraparenchymal cerebral vessels, a process that usually occurs in hypertensive and/or diabetic patients.

CT scans indicate lesions smaller than <1,5 cm.

The clinical picture corresponds to the profile of multi-lacunar brain infarction or the Binswanger’s arteriosclerotic encephalopathy. Cerebral “lacunae” are frequently asymptomatic.

Vascular dementia

Vascular dementia is represented by a heterogeneous group of diseases. Its progression/reversibility depends on several factors such as: the root causes that led to dementia, the pharmacologic treatment scheme and the psychological support provided to the patient. The variety of symptoms shown by patients with vascular dementia reflects the heterogeneity of pathophysiological processes as well as the number, size and the various locations of lesions. There has been reported that structural changes visible in CT / MRI scans are more complex in patients with the most risk factors.

Also, studies conducted over time have shown that the most common causes of vascular dementia are chiefly represented by: periventricular subcortical lacunar ischemic lesions, temporal lobe atrophy, vascular calcifications (a marker of endocranial atherosclerosis), etc. Vascular dementia is characterised by functional deactivation of cortex due to a certain number of cortical and subcortical lesions. The resulting disease profile is, in its turn, characterized by subcortical vascular dementia. This type of dementia is probably the most common and homogeneous type of vascular dementi

The latest developments in the field of cerebral imaging technology are very useful to get an in-depth understanding of the association between dementia and the cerebrovascular disease.

The specific diagnosis and the pathophysiological importance of vascular lesions identified via imaging investigations validate the observations according to which that a large number of different (pathogenetic and morphological) combinations are in fact the basis of the clinical polymorphism of cerebrovascular diseases. Thus, the patient may experience changes in brain structures and active risk factors without any alterations in terms of his/her personality and affectivity and without presenting any cognitive decline, yet.

Vascular dementia is more common in men, especially prior to the age of 75 years, with gender difference decreasing after this age. Up to 75 years of age, the higher the age of the subjects, the more they are associated with a greater number of vascular lesions. After the age of 75 years, and in relation to the existing lesions, the role of vascular risk factors decreases and the age becomes a critical factor. The risk factors for vascular dementia have been extrapolated from vascular diseases, a valuable indication being that the evolution of any cognitive impairment is progressive. This progressive evolution suggests that ischemic strokes actually initiate the development of dementia. The occurrence of extra/intracranial stenosis, as a consequence of vascular risk factors, may cause cerebral ischemic injuries and, implicitly, may trigger vascular dementia.

Neuropsychological tests are exact and precise tools to assess the clinical development and the cognitive impairment associated with vascular dementia (e.g. the higher the number of risk factors, the lower the MMSE score).

The suspicious of a probable diagnosis for vascular dementia may justify the performance of a cerebral CT / MRI scan, even if the patient experiences no cognitive decline that may be quantified using the standard neuropsychological tests (MMSE, Rey test, Hamilton scale, etc.). Vascular dementia is a form of dementia that, in some cases, can be prevented. Early stages of the disease (mild cognitive impairment-MCI) offer the opportunity to prevent, as much as possible, the development of dementia at various risk groups. Significant risk factors are: age, hypertension, diabetes, hyperlipidemia, etc.



Study methods

A total number of 4 visits will be conducted during the 18-months period assigned for this study. The first visit (known as the baseline visit) will be conducted at the time the patients enrol in this study, after having signed the relevant informed consents. The remaining three visits will be conducted every 6 months (+/- 2 weeks).

The following data will be collected during the evaluation of patients included in this study:

  • Patients’ demographic details and medical histories, including any concomitant treatment schemes, medication, etc.;
  • Overall clinical examination, targeting all patients’ systems;
  • Exhaustive neurological examinations, documented by the application of several neurological rating scales (NIHSS, mRS, Barthel Index);
  • Evaluation of cognitive functions will consist in the assessment of patients’ short-term and long-term memory, attention, capacity to concentrate and focus, orientation, praxis, language and execution functions. There will be applied relevant tests to assess patients’ cognitive functions as well as specific rating scales to evaluation depression which may mimic dementia or may be associated to a certain type of dementia. Consequently, the following tests and scales will be employed: M.M.S.E. (Mini Mental State Examination), MoCA (Montreal Cognitive Assessment), CDR (Clinical Dementia Rating Scale), Rey’s test (Delayed recall test), Hamilton rating scale for depression, FAQ (Functional activity questionnaire) and CGI (Clinical global impression scale). The evaluation of cognitive functions by means of relevant neuropsychological tests is highly important for the diagnosis of MCI or dementia. The neuropsychological evaluation in conjunction with a thoroughgoing anamnesis and a complete clinical examination are extremely useful to differentiate cortical dementia (where memory loss, language and praxis impairment are predominant) from subcortical dementia (characterised by bradyphrenia and behavioural disorders involving structural alterations of personality).
  • Structural neuroimaging investigations, such as encephalon CT / MRI scans are absolutely necessary. CT scans of the brain are very useful to exclude other cerebral pathologies, such as tumours, subdural hematomas, may be excluded, to determine the exact type of stroke (ischemic or hemorrhagic stroke) and also to diagnose the exact type of dementia (for example, in the case of vascular dementia, CT scans highlight not only the vascular lesions but also their exact types: lacunar strokes, strategic infarcts, etc.). MRI scans allow an accurate differentiation of the exact type of ischemic stroke (large-vessel disease vs. small-vessel disease), the specific area of the brain tissue which has been irreversible affected by infarction as well as the area of the brain tissue that has been functionally altered but which may be rescue (the penumbra ischemic area with “tissue at risk”). On the other hand, CT angiograms or MRA scans highlight a possible stenosis or occlusion of an extra / intracranial arterial trunk.
  • Extra / transcranial colour-coded Doppler ultrasound provides relevant information about the permeability of cervical and cerebral vessels, outlining any possible stenosis or occlusions as well as the impairment of the cerebrovascular reserve (the arteriolar and capillary microcirculation) which may be associated with cognitive impairment.

Statistic analysis

Brief summary statistics (number, mean, standard deviation, median, minimal and maximal values) or frequencies of the data that has been collected will be presented. The comparisons between the values recorded on the date of enrolment in this study and the data recorded after 6, 12, and 18 months will be made using the Wilcoxon signed rank test or the Friedman’s ANOVA test. The Stata software (ver. 15) will be used to conduct the relevant statistic evaluation.

Project relevance

The relevance of this study results not only from its scientific objectives (as described above) but also from the following aspects:

  • enhancement of material and informational logistics in order to provide the relevant training and instruction of experts able to involve in proper multidisciplinary research activities;
  • exploration of a primary area of clinical medicine and applicative research related to the study of cognitive impairments in patients with cerebrovascular pathology (ischemic strokes);
  • collaboration with foreign research and healthcare centres and facilities (from Serbia) in connection to the theme approached herein;
  • transfer of the findings and knowledge acquired in the field of applicative research to clinical medicine.

The main expected outcome of this project will be not only the identification and definition of a reliable algorithm to quickly diagnose the patients with vascular cognitive impairment occurred after ischemic strokes but also to determine the exact stage from which the patients with cognitive impairments may be included in relevant therapeutic management programmes. These measures will improve the quality of life of such patients and at the same time will reduce the already existing gaps compared to the EU patients.

By the end of this project we will have gathered up a valuable database that may be useful to students, registrars, senior house officers, specialist and consultant physicians as well as to doctoral students and the teaching staff to initiate and conduct related medical studies. The results we obtained under this project will not directly lead to profit but, after implementing the algorithm identified and formulated thanks to this study, the time required to set a diagnosis will be considerably reduced and more important, the quality of life of these patients will be improved.

Dissemination of the results of this study during conferences and publication thereof at the national level will help creating new theoretical databases intended to significantly contribute to the training of highly qualified experts in this multidisciplinary field of activity. Sharing the results of this project on the occasion of various international symposiums will allow a better understanding and an in-depth knowledge of the activity and preoccupations of our healthcare professionals.

Taking into consideration the technical aspect of this project, i.e. the medical expertise, our project team chose to use a dual approach in terms of promoting the project activities and outcomes. Therefore, the project will be presented in a particular way to the neurologists and psychiatrists who did not join the three teams who were directly involved in this study, and in a completely different manner to the wide public (including without limitation to patients and their relatives, the risk groups within the wide population and the healthy people).

On the one hand, by organizing symposiums, workshops, round tables, seminars, etc., we will create the opportunity to inform our peers from other healthcare institutions in the Romanian-Serbian cross-border area, about the achievements of our project team, giving them the possibility to use and continue the activities started under our project in their own healthcare institutions for the benefit of their patients. This will create opportunities for new partnerships and new projects in other regions. By using the electronic health co-operation platform, we will be able to transfer the results and findings of our research, and, at the same time, we may also involve other medical and research institutions, facilitating thus a close and direct co-operation with our team

On the other hand, a coherent campaign focused on the clear and concise information of the wide public on the risks of stroke and dementia will include the preparation and distribution of brochures and flyers, particularly in rural areas, accompanied by a relevant awareness campaign in mass-media


Project Director,

Dragos Catalin Jianu, MD, PhD

Professor of Neurology

Senior consultant neurologist

Certificate in Neurovascular Ultrasound




IHC-RORS9 “Improved healthcare in neurology and psychiatry - longer life” (May 2017 – May 2019)


Visit 1

Visit 2

Visit 3

Visit 4




6 months+/- 14 days

12 months +/- 14 days

18 months +/- 14 days

Informed consent



Demographic data



Eligibility criteria



Medical history – Vital signs (pulse, BP)





Medical examination – Concomitant pathology





Neurological examination  (NIHSS/mRS/ Barthel Index)





Laboratory data








Brain structural imaging (CT/MRI )



Extra and Transcranial Doppler or Trans-cranial color-coded duplex sonography





Amnestic MCI/ MCI diagnosis

















Delayed recall test (Rey probe)









Hamilton Depression Scale




CGI Improvement scale




BP = Blood pressure, CT= Computer Tomography, MRI = Magnetic Resonance Imaging, MMSE= Mini Mental State Examination, MoCA = Montreal Cognitive Assessment, CDR = Clinical Dementia Rating – Scale, FAQ = Functional Activities Questionnaire, CGI – Clinical Global Impresion



Mai multe despre Formular Consimtamant Informat.