The clinical diagnosis of AD and the different forms of dementia is complicated by the manifestation of often over lapping clinical symptoms and by comorbidity, which is very frequent, especially in elderly individuals. The use of bio markers helps the identification of pathological mechanisms responsible for cognitive deficits and guides the diagnosis, especially in doubtful cases. Indeed, in most forms of non AD dementia, such as vascular dementia (VaD) and frontotemporal dementia (FTD), CSF biomarkers levels are normal, and their evaluation excludes the suspicion of Alzheimer’s disease, directing the diagnosis toward a form of dementia with a different etiology.
Frontotemporal dementias are a heterogeneous group of syndromes characterized by cognitive impairment, which clinically manifests with behavioral or language disorders, symptoms also common in atypical AD forms. Normal levels of Aβ42 and tau characterize the CSF profile of patients with FTD even in those forms where the formation of tau protein inclusions is involved in degeneration processes. This profile excludes a suspicion of presenile AD and distinguishes mixed forms of dementia, where increased tau and decreased Aβ42 may indicate comorbidity between FTD and AD (Table 1).
Table1. Cerebrospinal fluid (CSF) biomarkers in frontotemporal dementias
Some genetic forms of FTD are due to a mutation in the gene for progranulin, a growth factor with neurotrophic properties, which causes a reduction in protein levels in the blood (normal values between 100 and 250 ng/mL). Therefore, the measurement of serum progranulin levels allows to identify carriers of the mutation, even asymptomatic ones, to be subjected to in-depth genetic investigation to highlight the presence of the mutated gene. However, normal progranulin values cannot exclude the presence of FTD of other origin and do not distinguish subjects with FTD from controls.
Often vascular events in different brain areas can cause neuronal damage and cognitive impairment (vascular cognitive impairment, VCI) that manifest themselves with different symptoms depending on the area or areas involved and do not necessarily evolve toward a form of dementia. Therefore, the clinical and pathological phenotype and the neuroimaging may be heterogeneous and coexist with other pathologies, particularly AD, leading to mixed dementia (MD). CSF analysis of biomarkers allows for investigating the probable cause of cognitive impairment and distinguishing VCI, VaD, AD, and MD (Table 2). Given the complexity of clinical and pathological pictures, which determines the difficulty in defining appropriate control groups, and the possible co-presence in VCI of neuropathological changes associated with age or AD, the results of studies on the usefulness of biomarkers have often been conflicting. Most studies agree that the CSF profile in patients with VCI is characterized by increased tau and nor mal levels of Aβ42 and p-tau (Table 2). Normal levels of Aβ42 allow us to distinguish VaD or VCI from AD or AD-like dementias with secondary vascular events. The presence of even clinically silent vascular damage in AD patients does not alter their CSF profile. While patients with AD and AD associated with vascular damage have a similar profile (reduced Aβ42, increased tau and p-tau), VCI patients without AD have a CSF profile similar to controls, sometimes associated with an increase only in T-tau protein.
Table2. Cerebrospinal fluid (CSF) biomarkers in vascular dementias
Finally, the reduction of Aβ42 and the increase of tau allow the distinction between mixed dementias, permitting the correct classification of 85–89% of cases with VCI, AD, and mixed dementia.
