View/Download PDF

Translate this page into:
Notice: Please configure GTranslate from WP-Admin -> Settings -> GTranslate to see it in action.

Original Article
2021
:12;
172
doi:
10.25259/SNI_48_2021

Intracranial pressure waveform changes in Alzheimer’s disease and mild cognitive impairment

Department of Nursing, Nursing Postgraduate Program, Federal University of São Carlos, São Carlos, São Paulo, Brazil.
Department of Medicine, UNIFENAS, Alfenas, Minas Gerais, Brazil.
Department of Neurosurgery, Atenas Medical School, Passos, Minas Gerais, Brazil.
Brain4care, São Carlos, São Paulo, Brazil.
Department of Medicine, Nursing Postgraduate Program, Federal University of São Carlos, São Carlos, São Paulo, Brazil.
Corresponding author: Francisco Assis Carvalho Vale, Department of Medicine, Nursing Postgraduate Program, Federal University of São Carlos, São Carlos - 13565-905, São Paulo, Brazil. facvale@gmail.com
Licence

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Ribeiro EB, Cobos LD, Rabelo NN, Frigieri G, Vale FAC. Intracranial pressure wave form changes in Alzheimer’s disease and mild cognitive impairment. Surg Neurol Int 2021;12:172.

Abstract

Background:

Alzheimer’s disease (AD) is known to cause an enormous impairment to the quality of life and impact in the health system; meanwhile, studies show that in the coming years, the number of affected individuals will continue to grow. It is also believed that amnestic mild cognitive impairment (MCI) could represent an early symptomatic form of AD, which precedes dementia.

Methods:

The present study aimed to evaluate the intracranial pressure (ICP) through a noninvasive method in patients with AD and MCI, seeking for differences when compared to healthy elderlies. This is a cross-sectional, correlational, and observational study of a quantitative character, carried out in a Brazilian city, with patients from the ANEC of the UFSCar.

Results:

It was found a statistically significant difference between the ICP morphology when analyzing the results in patients with AD and MCI, compared to healthy volunteers. It is known that dementias means a progressive disorder that leads to the loss of independency and function of the patient, although, it is believed that it can be found early ICP alterations in these patients. Nevertheless, considering this is an unprecedent study, it was not possible to compare results with previous studies and literatures. However, the study has a limitation related to the sample size; an expansion of it could possibility lead to different findings.

Conclusion:

The findings through the ICP measurement could indicate an early diagnosis, which would lead to an early treatment and an improvement in the quality of life of patients with AD. Thus, further investigation and widening studies are encouraged.

Keywords

Altered intracranial pressure
Alzheimer’s disease
Alzheimer’s early diagnosis
Mild cognitive impairment
Noninvasive intracranial pressure monitor

INTRODUCTION

Alzheimer’s disease (AD) causes an enormous loss of quality of life of elderly people and impacts the health systems, and in the coming years the number of people with this disease will increase all over the world. However, even when the patients report symptoms and present objective cognitive losses, the dementia may not be discovered. Studies demonstrates that up to 75% of patients with dementia and near 97% of those with mild cognitive impairment (MCI) may not be diagnosed.[18] It is believed that the amnestic subtype of MCI (aMCI) could represent an early symptomatic form of AD, which precedes dementia.[28]

The concept of MCI was developed by Petersen et al., 1999,[29] and has as diagnosis criteria: memory complaint, subjective or referred by an informant, objective impairment of memory, normal general cognitive functions, preserved daily living activities, and absence of dementia.[30]

The prevalence of MCI was estimated in 36.7% in individuals with over 50 years,[7] and it is believed that the aMCI may correspond to a symptomatic phase of AD that precedes the dementia.[28] This hypothesis gains more relevance as it receives support from genomic image findings[20] that confirm this relation between MCI and AD.[18,20]

Dementia is characterized by cognitive decline and behavioral changes in a sufficient intensity and duration to interfere with the person’s occupational and social functioning, involving at least two domains, one of which must be memory.[23] With the population aging, dementia has become one of the most relevant health problems worldwide; the United Nations estimated 35.6 million people with dementia in 2010, a number that will almost double to 65.7 million in 2030 and to 115.4 million in 2050 and is projected that this increase in the occurrence of dementias will have a major global economic impact.[2,32]

Furthermore, for the first time, a successful experimental therapy in blocking the formation of oligomers involved in the etiopathogenesis of AD was achieved in an animal model.[14] This experimental therapy introduces the perspective of developing a successful way to prevent disease progression through the manipulation of immunomodulators, such as transforming growth factor beta-1, which has been proved to be an effective modulator of the astrocytes activities, implicated in the disease etiology.

Regarding the use of the noninvasive method of measuring the intracranial pressure (ICP) through the brain4care monitor and sensor under conditions that would not be indicated an invasive measurement, findings of important clinical relevance were observed in case studies in infectious diseases such as cryptococcal meningitis in an human immunodeficiency virus-immunosuppressed patient[6] and even in chronic renal patients.[4] In both cases, a pathologic ICP patterns (P2 > P1) was present, which could indicate an useful clinical marker of conditions that usually would not have their ICP measured due to invasive standard procedures.

In the light of the new discoveries of a potential immunomodulatory therapy that is effective to prevent the progression of AD, and of the new technology, created by researchers from São Carlos, Brazil, with has proven sensitivity to evaluate a parameter that was lightly explored in many clinical and neurological conditions. Both associated, brought up the question: Is there an influence on the values and morphology obtained from the measurement of ICP in patients with AD or MCI, which associated with clinical and proteomic markers under development may constitute new tools in the early identification of AD?

The present study aimed to evaluate the ICP through a noninvasive method in patients with AD and MCI, seeking for differences when compared to elderly individuals without the conditions. Therefore, monitoring the ICP in elderly patients with AD and MCI through the noninvasive method and analyzing possible statistic associating the ICP with the clinical conditions studied, when compared to the control group, compose the specific objectives in this study.

MATERIALS AND METHODS

Ethical aspects

All ethical precautions were adopted. The study was forwarded to the Federal University of São Carlos (UFSCar) Research Ethics Committee and the predicted evaluations only started after its approval by the Committee.

All assessments were carried out after signing the term of informed consent form Termo de Consentimento Livre e Esclarecido (TCLE), also approved by the Ethics Committee. The evaluations took place in an outpatient setting, where participants were invited to participate in the study. When they agreed, they participated in the evaluations after the medical consultation. In the case of patients with AD, it was necessary for the caregiver to indicate their consent together with the patient and for both to sign the consent form.

Study design

This is a cross-sectional, correlational, observational study of a quantitative character, carried out in a city in the interior of São Paulo, with people who are assisted at the Cognitive-Behavioral Neurology Clinic of the UFSCar.

Place of study

The sample of this study was composed of elderly people diagnosed with AD, family members of the same, and/ or caregivers and elderly people without a diagnosis of dementia. All subjects are followed up at the Cognitive-behavioral Neurology Outpatient Clinic at UFSCar (ANEC), which is located in the city of São Carlos, State of São Paulo, Brazil.

ANEC is a specialized neurological medical clinic, which serves people with cognitive and behavioral disorders associated with neurological and nonneurological diseases, especially dementias, among other neurological diseases.

Sampling method

The sample was composed by participants aged 55 years or older, being in total 32 participants. They were divided in two groups, resulting in 20 volunteers with AD, clinically identified by scoring in the memory complaints scale (MCS A and B), mini-mental state exam (MMSE), and clinical dementia rating (CDR); and 12 volunteers whom did not presented clinical alterations in the tests (MCS, MMSE, and CDR) composing the control group. For data analysis, the subjects were paired by gender, education, and age.

The inclusion criteria included the agreement to participate in the study, expressed through the subject’s signature in the informed consent form term (TCLE). The AD Group was composed by individuals that had been diagnosed (probable diagnosis) with AD and/or had the diagnosis confirmed by the ANEC team, being followed up on the same equipment and having a family caregiver; and the control group was composed by elderly people whom did not have any type of neurological disease and/or dementia.

The exclusion criteria were based on mental illness or disorders, or untreated systemic diseases; and untreated hearing and/or visual deficits that preclude cognitive tests. Both exclusion criteria prevent the inadequate volunteers from participating in the study, considering that their participation may compromise the study’s result.

The MCS (A and B) was validated to the Brazilian population in the year of 2012 by Vale et al.,[39] being a useful tool in the screening of individuals with memory complaints. The CDR is a rating that aims to stratify the clinical severity of dementia, its influence in the patient’s daily functions, autonomy and quality of life, created in 1993 by Morris,[25] and translated by Macedo, 2005,[21] becoming valid for the Brazilian population in 2006.[22] The MMSE in its turn is one of the most validated and useful tests in clinical practice and research for the detection and measurement of cognitive impairment, created in 1975 by Folstein et al.,[16] and validated to the Brazilian reality in 2003 by Brucki et al.[8]

ICP collection method

As the patient arrived in the outpatient clinic consult, it was applied the neuropsychological tests (MCS, MMSE, and CDR), to evaluate if the patient fitted in the study. The ICP was measured through the noninvasive brain4care monitor and sensor, by trained professionals, with the patient sited, with its hands lied on their knees, and as still as possible, during 5 min, in this condition. The device consists of a headband with a monitor that captures form alterations in the patients skull caused by the ICP and transmits the data to an electronic device. In case of any complications, such as agitation and movements, the professionals would calm the patients and re-evaluate the ICP.

RESULTS

The casuistry was composed mostly by women. It was analyzed the CDR, memory, fluency, language, spatial reference, numerical level, the ICP morphology (P1 and P2), the emerge time of the ICP waves (characterized by T1 and T2), the Pfeffer scale, the quality of life scale, age, educational level, the MMES, the Addenbrooke’s Cognitive Examination and the attention and orientation of the volunteers [Table 1].

Table 1:: Frequency and socio-demographic data of the samples in the present study.

[Table 1] shows the patients classified according to the CDR and the sample of the volunteers nominal variables (gender).

As shown in [Table 2], the variables of the difference between the emerge time of P1 and P2 (T2/T1) and the difference between the amplitude of P1 and P2 (P2/P1) were observed in the group of patients with AD. In both measures (P2/P1 and T2/T1), the values suggested differences in the groups’ ICP, with higher rates in the group of patients with AD. In [Figure 1], it is possible to graphically visualize the PIC measurements between the groups.

Table 2:: Descriptive statistics of the study variables according to the ICP.
Figure 1:: Graphical visualization of PIC measurements between groups of people with and without Alzheimer’s disease.

A statistically significant difference between the ICP morphology when analyzing the results in patients with AD and MCI, compared to the volunteers whom did not have the conditions was found, as the results show.

DISCUSSION

Population ageing

At present, in Brazil, we are experiencing an increase in the percentage of the population with 65-years-old or over; with the population ageing, dementia has become one of the most relevant public health issue worldwide, affecting almost 7% of the people in this age group. Among the different types, the dementia caused by AD is the most frequent, corresponding to almost 60% of the cases.[2]

In 2013, the Brazilian Institute of Geography and Statist Instituto Brasileiro de Geografia e Estatística (IBGE) verified that in the period from 2001 to 2011 there was an increase in the number of elderly, the numbers revealed a modification from 15.5 million to 24.85 million people. According to the IBGE data (2013), Brazil presents one of the most intense and accelerated process of population ageing, known as demographic transition; in 2010, 10.7% of the Brazilian population had 60 or more years old and only in São Carlos, and 8.96% of the population has over 65-years-old. That said, the latest estimation points out that in Brazil, the number of people with dementia is near 1 million.[10]

AD dementia

Dementias stand out due to two factors, their high prevalence, affecting about 7% of the population over 65 years,[35] and its already high socioeconomic cost.[34] A Brazilian population study showed a dementia incidence of 13.8/1,000 person-years and a prevalence of 7.1% in people aged 65 and over.[26] AD is the leading cause of dementia, responsible for more than half of the cases; it is a disease with grand socioeconomic impact and in the last decades it has been defined as one of the main public health issues worldwide.[6]

A Brazilian population study showed that de AD was the cause in 55.1% cases of dementia, number which rises to 69.5% if the cases of association with cerebrovascular disease are included.[26] The AD is a chronic nontransmissible, neurodegenerative, and progressive disease, and it is characterized by deterioration of cognitive functions, neuropsychiatric symptoms, and impairment in activities of daily living.

The cerebral pathology in AD is characterized macroscopically by cortical atrophy predominantly in the medial temporal regions, and microscopically by extensive neuronal losses, neurofibrillary tangles, and senile plaques.[19] Age is the most relevant risk factor, the pathology affects 5–10% of the population in the age range of 65-years-old and 50% of those with over 85.[13] The incidence of dementia syndromes also increases in adult and elderly populations with Diabetes Mellitus, Hypertension and Dyslipidemia,[5] conditions known to be prevalent in the Brazilian population.

Current epidemiological estimates of AD indicate that more than 20 million people worldwide are affected by this disease, with 4.6 million new cases per year, due to global demographic development, an increase in the number of cases is expected for 2030 for approximately 36 million people with AD.[3]

The fast and accurate diagnosis of the dementia has a grand value in the multidisciplinary therapeutic approach, since it allows early monitoring and interventions[12,15] with a positive influence for the patient to slow the progression of the disease and implement adaptations that preserve the quality of life of the demented patient.[6] Therefore, it is extremely worrying that even when the patients report symptoms and have objective cognitive losses, dementia it may not be diagnosed; it is known that up to 75% of patients with dementia may not be diagnosed by the primary care physician as having cognitive impairment and up to 97% of patients with MCI do not have this problem identified.[18]

The training of health teams with the implementation of screening algorithms for the dementia syndromes diagnosis in the most affected populations proved to be an effective method of improving the identification of this condition in the populations of third world countries,[31] the training is fundamental and one of the limitations to ensure adequate care for this population is the construction of instruments that facilitate the identification of dementia syndromes and neurodegenerative processes of great importance to increase the access of this population to the specialized healthcare they need.

ICP

At present, the gold standard for ICP monitoring requires intracerebral introduction into one of the ventricles, guided by sensors, catheters permeated with fluid or optic fibers connected to a transducer and connected to a monitor at the patient’s bedside that allows continuous measurements of the ICP and drainage of the cerebrospinal fluid (CSF), when it is necessary.[37] The invasive method, inherent to the most validated techniques makes the measurement indicated only in some cases, since it involves risks that must be considered.

According to studies cited by Prodan et al., 2010,[33] the most common complication of the catheters installation procedure is the infection (2–22%) with its risk increased if the measuring catheter remains for more than 5 days installed, the complication is followed by bleeding and obstruction (1–6%). Several methods have been developed for direct or indirect measurement of ICP with different values of sensitivity and specificity. A device for noninvasive measurement of ICP should ideally be accessible and inexpensive, easily available, operable in emergency situations, risk-free, independent of operators, reliable, and accurate.[36]

In this context, the team of the Professor Dr. Sérgio Mascarenhas and Dr. Gustavo Henrique Frigieri Vilela, from the São Carlos’ Institute of Physics of the University of São Paulo, developed a new noninvasive method for measuring ICP that consists of an external system of chips that transmits, through the mechanic sensor brain4care, the reflection of the retraction and expansion of the skullcap. Transmitting this data in real time through specialized algorithms, it is able to translate these electrical signals of cranial deformation to a monitor, in the form of a curve in numerical value, mirroring the ICP in real time, which can be used as a source of diagnostic information by health professionals.

This system has already been patented[27] and it is in the process of propagation and dissemination among the medical-scientific community.[1] The method is based on proof of the Invalidity of the Monro-Kellie Doctrine, which determines that the cranial case would be completely inelastic;[24] the instrument was validated in experimental models and is currently being studied with humans, being able to monitor with good sensitivity and in accordance with the invasive measures used as parameters for comparison of ICP.[9]

Dementia and ICP

The Grading of Recommendations, Assessment, Development and Evaluating method considers clinical application on the evaluation of CSFs biomarkers such as amyloid-β1–42, tau, and phosphorylated tau in the diagnosis and evaluation of patients whom present dementia, the analysis of this CSF biomarkers could indicate and early diagnosis. Relating to AD, reduced levels of amyloid-β1–42 and elevated levels of tau and phosphorylated tau were found in correlation to the disease.[38] It is known that spontaneous, secondary or idiopathic hydrocephalus could lead to a, possibly reversible, dementia state, characterized by an insidious start, typically followed by ataxia and urinary incontinence.[17] That stated, it is possible to hypothesize that the CSF density and volume could also present alterations in patients whom present dementia, in a reverse sequel, presenting altered ICP as an early marker for dementias such as AD.

Many morphology alterations in dementias, such as AD, consist of brain atrophies, which lead to an enlargement of the ventricles and a wider flow of CSF inside the skull, resulting in altered ICP. It is also stated that many patients whom present dementia could develop communicating hydrocephalus, leaded by the alterations in the ventricles proportions.[11]

Dementias, such as AD, are already degenerative pathologies, an alteration in the ICP or even an hydrocephalus state could lead to a more rapidly and progressive state of the cognitive dysfunction. This could mean an early loss of independency and function to the patient.

Limitations

This study was conducted with volunteers from the Cognitive-Behavioral Neurology Outpatient Clinic (ANEC) at UFSCar, São Carlos, Brazil; which resulted in a sample of 20 AD patients and 12 healthy volunteers (control group), being in its total majority, composed by women (68.75%).

The patients were awake and sited during the ICP measurement; it is believed that if they were in their sleep and/or lied down, the results could have expressed a larger difference between the groups studied.

The quality of the patients sleep was also evaluated, although it was based in a self-referred scale, where the patient would grade their sleep quality, or a scale based on the caretaker’s perception.

The sample is considered to be limited, which may not reflect the results in a widening field and may not be enough to conclude a direct correlation between the ICP and the early diagnoses of AD.

CONCLUSION

In this study, it was found a statistically significant difference between the ICP of individuals with AD and the control group, whom do not have the condition; these findings could indicate an early diagnosis to AD patients; however, considering it is an unprecedent study, it is not possible to compare the findings with the previous studies and literatures. Considering the limitations of the study, the results serve as a basis for further research, aimed at validating a possible useful, inexpensive, and noninvasive marker for a chronic neurodegenerative condition.

Acknowledgments

E. Ribeiro and F. Vale designed the study and collected the data, L. Cobos, N. Rabelo and G. Frigeri were responsible to write the article under the supervision of the first two authors.

Declaration of patient consent

Patient’s consent not required as patients identity is not disclosed or compromised.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

REFERENCES

  1. , , , , , . Brain trauma foundation guidelines for intracranial pressure monitoring: Compliance and effect on outcome. World J Surg. 2017;41:1543-9.
    [Google Scholar]
  2. . Alzheimer’s disease facts and figures. Alzheimers Dement. 2017;13:325-73.
    [Google Scholar]
  3. , , , , , . Alzheimer’s disease. Lancet. 2011;377:1019-31.
    [Google Scholar]
  4. . Avaliação Laboratorial e Monitorização Não Invasiva da PIC em Pacientes Submetidos a Hemodiálise. Dissertação de Mestrado em Ciências Farmacêuticas UEPG;.
    [Google Scholar]
  5. , , , , , . Systematic evaluation of the associations between environmental risk factors and dementia: An umbrella review of systematic reviews and meta-analyses. Alzheimers Dement. 2017;13:406-18.
    [Google Scholar]
  6. , , , , , , . Non-invasive intracranial pressure monitoring for HIV-associated cryptococcal meningitis. Braz J Med Biol Res. 2017;50:e6392.
    [Google Scholar]
  7. , , , , , , . Mild cognitive impairment in a community sample: The Sydney memory and ageing study. Alzheimers Dement. 2013;9:310-7.
    [Google Scholar]
  8. , , , , . Sugestões para o uso do mini-exame do estado mental no brasil. Arq Neuropsiquiatr. 2003;61:777-81.
    [Google Scholar]
  9. , , , , , , . Validation of a new noninvasive intracranial pressure monitoring method by direct comparison with an invasive technique. Acta Neurochir Suppl. 2016;122:93-6.
    [Google Scholar]
  10. . Available from: http://www.censo2010.ibge.gov.br [Last accessed on 2020 Sep 07]
  11. , , . Intracranial pressure in patients with dementia and communicating hydrocephalus. J Neurosurg. 1974;40:376-80.
    [Google Scholar]
  12. . The decreasing prevalence of reversible dementias: An updated meta-analysis. Arch Intern Med. 2003;163:2219-29.
    [Google Scholar]
  13. , , , , , , . Target risk factors for dementia prevention: A systematic review and Delphi consensus study on the evidence from observational studies. Int J Geriatr Psychiatry. 2015;30:234-46.
    [Google Scholar]
  14. , , , , , , . Astrocyte transforming growth factor beta 1 protects synapses against aβ oligomers in Alzheimer’s disease model. J Neurosci. 2017;37:6797-809.
    [Google Scholar]
  15. , , , , , . Improving Prognostic Prediction from Mild Cognitive Impairment to Alzheimer’s Disease Using Genetic Algorithms. Berlin: Springer; .
    [Google Scholar]
  16. , , . “Mini-mental state”: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-98.
    [Google Scholar]
  17. , , , . The several faces of dementia syndrome: How to diagnose clinically? Sci Med. 2010;20:185-93.
    [Google Scholar]
  18. , . Evaluating dementia screening tests methodologic standards to rate their performance. Neurology. 1999;52:224-4.
    [Google Scholar]
  19. . Molecular mechanisms in the pathogenesis of Alzheimer’s disease and tauopathies-prion-like seeded aggregation and phosphorylation. Biomol Multidiscip Digital. 2016;6:24.
    [Google Scholar]
  20. , . Amyloid-β deposition and long-term progression in mild cognitive impairment due to Alzheimer’s disease defined with amyloid pet imaging. J Alzheimers Dis. 2017;57:765-73.
    [Google Scholar]
  21. . Arquitetura da Informação: Aspectos Epistemológicos, Científicos e Práticos. In: Dissertação (Dissertação de Mestrado) Universidade de Brasília. .
    [Google Scholar]
  22. , , , , , , . Aplicação da Versão Brasileira da Escala de Avaliação Clínica da Demência (Clinical Dementia rating-CDR) em amostras de pacientes com demência. Arq NeuroPsiquiatr. 2006;64:180-3.
    [Google Scholar]
  23. . Manual Diagnóstico e Estatístico de Transtornos Mentais DSM-5/American Psychiatric Association; Tradução. Revisão Técnica: Aristides Volpato Cordioli. (5th ed). Porto Alegre: Artmed; .
    [Google Scholar]
  24. , , , , , , . The new ICP minimally invasive method shows that the Monro-Kellie doctrine is not valid. Acta Neurochir Suppl. 2012;114:117-20.
    [Google Scholar]
  25. . The Clinical Dementia Rating (CDR): Current Version and Scoring Rules Neurology. Philadelphia, PA: Lippincott Williams and Wilkins; .
    [Google Scholar]
  26. , , , , , , . Incidence of dementia in a community-dwelling Brazilian population. Alzheimer Dis Assoc Disord. 2004;18:241-6.
    [Google Scholar]
  27. , . Non-invasive Intracranial Pressure System. Google Patents US Patent, No. 13/621,635.
    [Google Scholar]
  28. , , , , , . Mild cognitive impairment: A concept in evolution. J Intern Med. 2014;275:214-28.
    [Google Scholar]
  29. , , , , , . Mild cognitive impairment: Clinical characterization and outcome. Arch Neurol Am Med Assoc. 1999;56:303-8.
    [Google Scholar]
  30. , , , , , . Practice parameter: Early detection of dementia: Mild cognitive impairment (an evidence-based review) report of the quality standards subcommittee of the American academy of neurology. Neurology. 2001;56:1133-42.
    [Google Scholar]
  31. , , , , . Dementia diagnosis in developing countries: A cross-cultural validation study. Lancet. 2003;361:909-17.
    [Google Scholar]
  32. , , , , . World Alzheimer Report 2016: Improving Healthcare for People Living with Dementia: Coverage, Quality and Costs now and in the Future. Alzheimer’s Disease International;
    [Google Scholar]
  33. , , , . Lower coated-platelet levels are associated with early hemorrhagic transformation in patients with non-lacunar brain infarction. J Thromb Haemost. 2010;8:1185-90.
    [Google Scholar]
  34. , , , , , . Prevalence, costs, and treatment of Alzheimer’s disease and related dementia: A managed care perspective. Am J Manag. 2001;7:809-20.
    [Google Scholar]
  35. , . The dementias. Lancet. 2002;360:1759-66.
    [Google Scholar]
  36. , , , , , . Non-invasive assessment of intracranial pressure. Acta Neurol Scand. 2016;134:4-21.
    [Google Scholar]
  37. , , , . Basic concepts about brain pathophysiology and intracranial pressure monitoring. Neurología. 2015;30:16-22.
    [Google Scholar]
  38. , , , , , , . Recommendations for CSF AD biomarkers in the diagnostic evaluation of dementia. Alzheimers Dement. 2017;13:274-84.
    [Google Scholar]
  39. , , . Memory complaint scale (MCS) Proposed tool for active systematic search. Dement Neuropsychol. 2012;6:212-8.
    [Google Scholar]
Show Sections