Ruolo dei biomarcatori come criterio di supporto nella diagnostica delle demenze ad esordio precoce

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1 Ruolo dei biomarcatori come criterio di supporto nella diagnostica delle demenze ad esordio precoce ALESSANDRO MARTORANA UOC NEUROLOGIA-CENTRO ALZHEIMER POLICLINICO TOR VERGATA-UNIVERSITÀ DI ROMA TOR VERGATA

2 Early Onset Dementia (EOD) EOD often refers to dementia becoming clinically manifest before age 65. The chronological age cut-off is however arbitrarily determined. EODs pose several challenges for the clinician that may confound accurate diagnosis. Numerically the most important causes of dementia are degenerative in nature at all ages, but the reversible causes are relatively more prevalent in the young. Those with EOD face different challenges to those with onset later in life. It has been difficult to quantify this disease burden. Telles Vieira Clin Pract & Epidemiol Ment Health; Kelley et al., 2008 Arch. Neurol.

3 EODs subtypes There are two types of dementia with early onset: (i) presenile dementias (EODs) (ii) senile dementias with early onset. Most patients who develop dementia before 65 years of age have Alzheimer's disease (AD). The remainder are likely to have vascular dementia (VaD), fronto-temporal dementia spectrum (FTDs), head injury, alcohol intoxication, or metabolic disorder. EODs, caused by FTDs, progressive supranuclear palsy, and corticobasal degeneration, usually occur in patients of presenile and are rarely seen in patients of senile age. Miyoshi et al., 2009 Psichogeriatrics

4 EODs: general concepts Epidemiological data for prevalence rates for EOD are sparse. EOD remains a rare condition with low case numbers. Assimilation and comparison of results from existing studies is difficult due to methodological heterogeneity. Comorbidities such as cerebrovascular/metabolic risk factors are rarer in the young and are less likely to contribute to the pathogenic cascade in comparison with LOAD. EODs are an heterogeneous group of cognitive disorders, poorly understood, as the main focus of dementia is based on older populations, thus EOD are more underdiagnosed, mis-understood, and inadequately treated, with limited services and resources in many countries Lambert et al., 2014 Eur. J. Neurol

5 Early-Onset Alzheimer s Disease Early Onset Alzheimer s Disease (EOAD) accounts for %. Most of them are familial cases (APP, PSEN1 and PSEN2). EOAD is considered an homogeneous clinico-pathological condition with respect to late onset AD (LOAD). EOAD and LOAD share the same pathologic burden. Neuropsychological profile may differ from LOAD in many cases. Mendez 2012 Arc. Med. Res. ;Bouwman et al., 2008 Neurobiol. Dis.

6 Early-Onset Alzheimer s Disease EOAD may present with non-amnestic symptoms, causing diagnostic delay, often overlaps with FTD presentation. Focal presentation may occur in several cases. Such presentations represents a serious challenge for clinicians. Indeed, a large group of AD with focal presentation were for 7% bvftd, 44% PPA, 10 % svppa, and in 50 % showed Extrapyramidal signs. Such differentiation of AD and FTD spectrum disorders pones serious diagnostic challenge for clinicians. 30% of autopsy cases showed AD pathology in FTD individuals. The non-amnestic AD subtypes have also a more aggressive rate of progression with shorter duration of disease. Irwnin et al, 2014 Front Aging Neurosci. ; Bouwman et al., 2008 Neurobiol. Dis.

7 Fronto-Temporal Degeneration Syndromes FTDs represents the second most common form of EOD after AD. FTDs are divided in two main neuropathological subtypes: FTD-TAU comprises: Pick s disease, CBD, PSP, FTD with parkinsonism linked to chromosome 17, unclassifiable FTDs. FTD-TDP-43 comprises: 4 subtypes (A-D) based on the morphology and distribution of lesions. Others subtypes: FTD-fus; FTD-UPS; FTD-ni. Snowden et al., 2011 Brain

8 Fronto-Temporal Degeneration Syndromes FTDs clinically can be subdivided in two main subtypes: bvftd (behavioural variant) FTD with language disorders: Primary Progressive Aphasia (PPA). PPA is distinct in: -logopenic variant (lvppa) -semantic variant (svppa) -non fluent agrammatic (nappa) Snowden et al., 2011 Brain

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10 CerebroSpinal Fluid (CSF)biomarkers There is a good correlation between CSF biomarkers and pathological findings in AD patients (good sensitivity and specificity). Cerebrospinal fluid (CSF) biomarkers have the potential to optimize diagnostic accuracy and detect disease earlier in the case of illness and possibly in presymptomatic phases. Such as prior to structural changes of neurodegeneration seen on imaging. Blennow et al., 2014 Alzheimer s and Dementia

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13 How to use CSF Biomarkers Unfortunately, most of the available studies have been performed in Late-Onset AD. IN LOAD: low levels of Aβ1-42 and high levels of t-tau and P-Tau are considered a typical pattern for AD. Aβ 1-42 < 500 pg/ml t-tau > 450 pg/ml p-tau > 75 pg/ml to improve diagnostic accuracy use Aβ1-42/p-Tau ratio: Aβ1-42/p-Tau ratio 6,43 non AD pattern; < 6,43 AD pattern. Balasa et al., 2014 JAD; Rosen et al., 2013 Mol. Neurodeg.

14 CSF biomarkers in EOAD The evidence that EOAD overlap with FTD presentation, making diagnoses uncertain, indicate that CSF biomarkers analysis is mandatory in all these cases. Since asymptomatic individual at older age seem to have lower CSF Aβ1-42 and higher t-tau and p-tau levels, it is suggested that CSF biomarker might have higher discriminative value in young rather than in older individuals with suspected AD. Few well conducted studies on CSF biomarkers in EOAD are still available however.

15 Masellis et al., Alzheimer s Res Ther. 2013

16 CSF biomarkers in non-ad EOD CSF biomarkers showed low diagnostic accuracy for FTDs. Plasma and CSF biomarkers are under study (TDP-43 and/or Progranulin levels). CSF biomarkers analysis is not indicated for FTDs and/or DLBs cases. In cases of dementia due to causes other than degenerative available CSF biomarkers are not helpful for diagnostic purposes.

17 Masellis et al., Alzheimer s Res Ther. 2013

18 Masellis et al., Alzheimer s Res Ther. 2013

19 CONCLUSIONS The use of CSF biomarkers in clinical practice improve accuracy, particularly in early phases of disease, and have also prognostic value, although only in AD cases. Due to overlap presention in degenerative EOD, CSF analysis is mandatory to reduce diagnostic delay and also to reach a differential diagnosis. In cases of EOD due to infectious disease, metabolic and /or neoplastic pathologies CSF biomarkers are not helpful.

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