New Insights into Biological Markers of Frontotemporal Lobar Degeneration Spectrum

Abstract

In the last decade, there has been enormous progress in our understanding of Frontotemporal Lobar Degeneration (FTLD). Published clinicopathological series have clearly demonstrated an overlap between the clinical syndromes subsumed under the term frontotemporal dementia and the Progressive Supranuclear Palsy (PSP), and the Corticobasal Degeneration (CBD) syndrome. From a neuropathological point of view, two broad pathological subdivisions of FTLD are currently recognized: a) tau-positive pathology due to the accumulation of various forms of the microtubule-associated protein tau, that encompasses FTLD with Pick bodies, PSP and CBD, and b) tau-negative pathology, mainly characterized by ubiquitin/TDP-43-immunoreactive inclusions and in some cases due to Progranulin mutations. Several biological markers in cerebrospinal fluid and in blood have been evaluated to identify monogenic forms of FTLD and to differentiate either FTLD spectrum disorders or FTLD from other neurodegenerative disorders. The proposed biomarkers are primarily related to the mechanisms underlying the accumulation of the abnormal proteins in FTLD such as Tau, TDP-43 and Progranulin. These biomarkers may support the accurate diagnosis of the specific diseases causing FTLD, can be useful in assessing efficacy during pharmacological trials, and may help in identifying new molecular targets for treatment approaches. In this review, we summarise the most recent findings on biological markers and their usefulness in clinical practice for the diagnosis and management of FTLD.

Cerebrospinal Fluid Tau in Frontotemporal Lobar Degeneration: Clinical, Neuroimaging, and Prognostic Correlates

“…In FTLD, reports of CSF tau levels have been widely variable [6][7][8], but the meaning of such a finding needs to be further elucidated. The results of the present work suggest that CSF tau might be considered a marker of neurodegeneration, and higher levels of tau protein in CSF might be associated with increased vulnerability of specific brain areas, thus leading to defined neuropsychological deficits and brain atrophy pattern as compared to patients with lower CSF tau.…”

“…Despite clear-cut neuroimaging features, affecting frontal and temporal lobes [3], no diagnostic biological markers are available yet. Several studies have evaluated the usefulness of cerebrospinal fluid (CSF) total tau and phospho-tau levels in patients with FTLD, but with contrasting findings [4][5][6][7][8]. Indeed, while it has been widely demonstrated that CSF tau, phospho-tau, and amyloid-␤ (A␤) markers are reliable tools to identify Alzheimer's disease in the preclinical stages [9][10][11], in FTLD, the results have been highly variable.…”

“…Indeed, while it has been widely demonstrated that CSF tau, phospho-tau, and amyloid-␤ (A␤) markers are reliable tools to identify Alzheimer's disease in the preclinical stages [9][10][11], in FTLD, the results have been highly variable. Some studies have shown statistically increase of CSF tau, whereas others have shown unremarkable levels [4][5][6][7][8].…”

The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis

“…Hexanucleotide repeat expansions (GGGGCC) in a non-coding region of C9orf72 are the most common genetic abnormality in both ALS and FTD, which is responsible for approximately 40% of familial ALS, 5–10% of sporadic ALS, 40% of familial FTD, and 4–21% of sporadic FTD [ 13 , 14 , 15 ]. Mutations in the genes encoding the TAR-DNA binding protein (TDP-43) ( TARDBP ), fused in sarcoma (FUS) ( FUS ), TANK-binding kinase-1 ( TBK-1 ), Ubiquilin 2 ( UBQLN2 ), optineurin ( OPTN ), and Cyclin F ( CCNF ), are also present in both ALS and FTD patients [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. In contrast, mutations in other genes are present in ALS only, including SOD1 and VAPB, encoding superoxide dismutase 1 and VAMP (vesicle-associated membrane protein)-associated protein B and C, respectively [ 32 ].…”

Biomarkers in biological fluids for dementia with Lewy bodies

“…Thus, one current major problem is the overlapping neuropathology and the as yet incompletely understood molecular constituents of the pathological changes. It is expected that in the next years many more neuropathological entities will be identified and characterized at the molecular level, which will also influence our thinking of clinical phenotyping and the selection of biomarker candidates in the future [ 25 ].…”