Alzheimer’s disease is a chronic neurodegenerative disease characterized by a long clinically asymptomatic phase, in which silent changes occur within the brain, and a symptomatic phase with the cognitive deterioration that inevitably evolves into dementia. The structural changes in the central nervous system are the formation of extracellular amyloid plaques, mainly composed of β-amyloid 1-42 protein, and intracellular neurofibrillary tangles of tau and p-tau. Amyloid plaques and tau tangles represent the distinctive histological markers of AD associated with the degeneration process leading to cognitive impairment. Identifying these mechanisms early, when cognitive function is not yet severely com promised, allows to improve the clinical course and, above all, the search for new personalized therapies. Clinically, the clinical onset of AD may occur by manifesting amnestic symptoms, such as the classic memory disorder, while atypical forms prevail in alterations of other cognitive domains, such as language, behavior, or movement.

Considerable evidence has shown that the use of biomarkers of neurodegeneration, β-amyloid 1-42 (Aβ42), β-amyloid 1-40 (Aβ40), T-tau, and p-tau protein, offers a significant added value to the diagnosis of AD. The CSF levels of these proteins allow investigating in vivo the pathological processes that characterize the disease and support the decision- making pathway by increasing the level of certainty in the clinical diagnosis.

According to the amyloid hypothesis, in AD the altered metabolism of Aβ42 causes an increase in the content of this protein due to the imbalance between its production and proper removal. Aβ42 forms soluble intermediates, the so- called “oligomers,” which are highly toxic to neurons and synapses and progressively aggregate to form insoluble protofibrils and fibrils, which precipitate in plaques. This sequestering process is reflected in the CSF by a reduction in Aβ42 content, typical of AD pathology (Table 1). Aβ42 levels in AD patients are below 800–900 pg/mL, with wide variability in the values adopted among centers, due to different analytical issues.

Table1. Cerebrospinal fluid (CSF) biomarkers in Alzheimer’s disease

However, there is considerable interindividual variability in physiological levels of total β-amyloid in subjects who may be hyper- or hypoproducers. These differences in global β-amyloid levels may affect the diagnostic accuracy of Aβ42, with falsely positive results (low Aβ42 levels) in non-AD individuals or falsely negative results (normal Aβ42 levels) in AD subjects. The assessment of Aβ40 content, whose levels do not vary during AD, thus allows investigating whether the reduction of Aβ42 is due to a real accumulation in the tissue or whether a physiological overproduction of total Aβ may hide the reduction of Aβ42 due to sequestration in plaques. Indeed, the use of the Aβ42/Aβ40 ratio improves the accuracy of Aβ42, especially in individuals with high total Aβ content. Aβ42/Aβ40 values below 0.055 distinguish patients with AD, whereas normal values may exclude the likelihood of cognitive impairment due to AD-type dementia.

Tau is a microtubule-associated protein and is involved in maintaining the stability of the cytoskeleton. The formation of neurofibrillary tangles composed of tau is one of the histological features of AD, along with hyperphosphorylation of tau at numerous phosphorylation sites. Following neuronal death, tau is released into the CSF with increased measurable levels. The increase in tau and p-tau is an index of neurodegeneration characteristic of AD pathology and is a helpful tool to assess the extent of neuronal damage and phosphorylation status. In patients with AD pathology, CSF T-tau levels are increased, with values above 350–400 pg/ mL; in parallel, the content of phosphorylated tau exceeds the cutoff of 61–70 pg/mL (Table 39.1). Changes in tau levels can be nonspecific and are also observed in other forms of dementia or pathologies due to acute neuronal damage (e.g., ischemia). On the contrary, the process of hyperphosphorylation of tau represents a peculiar mechanism in Alzheimer’s disease. Therefore, the evaluation of p-tau content represents a useful biochemical marker for the differential diagnosis, with high specificity, especially in cases of differential diagnosis between Alzheimer’s disease and dementia with Lewy bodies.

Recently, several studies have demonstrated the diagnostic usefulness of CSF biomarkers even in the early stages of the disease, when silent pathological changes in the brain begin. In these stages, which are asymptomatic or characterized by mild symptoms, evaluating possible variations of measurable biomarkers in the CSF allows for identifying subjects at risk of developing Alzheimer’s dementia. The redefinition of the concept of Alzheimer’s disease and mild cognitive impairment (MCI) has considerably modified the diagnostic criteria of dementia, including the evaluation of biomarkers as an early in vivo index of AD. The reduction of Aβ42 is the first marker that is altered by the effect of aggregate formation, while the combination with t-tau and p-tau allows for predicting the progression of MCI toward AD dementia (prodromal AD). Moreover, even in asymptomatic individuals without cognitive impairment, biomarkers can identify preclinical stages of a neurodegenerative process that may evolve into cognitive impairment and dementia. Finally, biomarkers have a high negative predictive value and, in the elderly population, can be used to exclude a form of AD dementia.

Recently, the comprehensive panel of CSF markers, consisting of Aβ42, Aβ40, T-tau, and p-tau, has been included in the recommendations of the Alzheimer’s Association and the National Institute on Aging (NIA), an agency of the US National Institutes of Health (NIH), for the diagnosis of AD and MCI, together with the assessment of topographic markers by neuroimaging (PET and MRI). The analysis of markers allows for assessing the probability of AD pathology through indicators associated with the pathogenetic mechanisms of the disease. In Italy, their use in clinical practice is limited to a few centers, mainly specialized in memory dis orders, but a greater diffusion is desirable to promote early diagnosis.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشؤون الطبية يقدم الخدمات الصحية والعلاجية لزائري مدينة سامراء

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المجمَع العلمي ووفد وزارة التربية يبحثان سبل التعاون المشترك

قسم الشؤون الفكرية يصدر العدد 192 من مجلة الرياحين للأطفال

المزيد

الآخبار الصحية

ثورة طبية.. الذكاء الاصطناعي يكشف سرطان الكلى في وقت قياسي

لتعزيز الطاقة والتغلب على التعب.. عليك بـ7 طرق بسيطة

لتحسين الهضم والتحكم في الشهية.. ما أفضل وقت لتناول التمر؟

خبراء يكشفون تأثير الاستحمام في الظلام على جودة النوم !

المزيد

الآخبار التكنلوجية

إزالة ثاني أكسيد الكربون من الغلاف الجوي.. ما دور المحيطات والبحار؟

نظائر الهيليوم مقياس لاكتشاف رواسب الذهب.. كيف ذلك؟

الصين تطلق أول ناقلة نفط خام ذكية في العالم تعمل بالميثانول

الزمن على المريخ أسرع من الأرض.. دراسة علمية تكشف الفوارق

المزيد

مواضيع ذات صلة

Frontotemporal and Vascular Dementias

Human Prion Diseases

Diabetes treatments

Preeclampsia and Eclampsia

Gestational Diabetes

Clinical Manifestations of Aging and Hematopoiesis

Reactions of Blood Vessels in Acute Inflammation

Cellular Aging

Pathologic Calcification

Acute Lymphoblastic Leukemia

Myelodysplastic Syndromes

Intracellular Accumulations : Pigments