Table 1.
Diagnostic accuracy of international criteria for chronic neurodegenerative diseases.
| Clinical syndroms | Accuracy of diagnostic criteria* | Estimated prevalence (N/100,000) | Primary pathology | Main genes mutations | Pathophysiological biomarkers | Topographic/Phenotypic biomarkers (typical brain regions of atrophy or hypometabolism) | Candidate pathophysiological biomarkers |
|---|---|---|---|---|---|---|---|
| AD | Sensitivity 81% Specificity 71% [4,32] | 5000 | Amyloid Plaques, NFTs (3R/4R tau) | PSEN1 PSEN2 APP |
Reduced CSF Aβ42 (Aβ42:Aβ40) Increased CSF p-tau and t-tau Increased tracer retention on amyloid PET Increased tracer retention on tau PET |
MRI/FDG-PET: Medial temporal lobe atrophy (hippocampi, entorhinal cortex, amygdala). Hypometabolism in bilateral temporal parietal regions Note: Structural (FDG-PET, DTI) and Functional (fMRI) techniques identify atypical AD phenotypes (fvAD, IvAD, PCA) depending on cerebral areas and networks involved |
Aβ42, Aβ40, Aβ42: Aβ40 (blood) B-Amyloid retina scanning |
| CAA | Sensitivity highly variable Specificity 87.5–100% [71] |
Unknown, suspected high prevalence | Amyloid deposits (mostly Aβ40 peptide) in leptomeningeal/cortical/cerebellar arteries wall and smooth muscle cells | APP CST3 |
NA | MRI: cortical, cortico-subcortical microbleeds, cortical superficial siderosis (T2*MRI), small vessels disease (centrum semiovale), lobar (or cerebellar) hemorrhages | Aβ42, Aβ40, Aβ42: Aβ40 (blood) |
| PD | Sensitivity 91% Specificity 98% [17,76,77] |
1500 | A-synuclein in LBs (mainly midbrain/pons) | SNCA LRRK2 PARK2 PINK1 DJ1 |
NA | SPECT: Nigrostriatal dopaminergic degeneration | Transcranial sonography CSF α-syn (Protein misfolding amplification assays) |
| DLB | Sensitivity 83% Specificity 95% [105,106] |
1000 | A-synuclein in LBs (diffuse in brain) | SNCA LRRK2 |
NA | SPECT: Nigrostriatal dopaminergic degeneration FDG-PET: hypometabolism on occipital regions and sparing of PCC. MIBG myocardial scintigraphy: Low uptake |
Transcranial sonography CSF α-syn (Protein misfolding amplification assays) |
|
bvFTD ~ 60% of FTD |
Sensitivity of 85% Specificity of 95% [142] |
11 (all FTD) | TDP-43 B (50%) 3R tau (40%) FUS (5–10%) |
C90RF72 MAPT GRN Heritability (40–45%) |
NA | MRI/FDG-PET: Frontal and/or anterior temporal atrophy/hypometabolism (frontoinsular region is especially indicative of frontotemporal dementia) | Progranulin (blood) CSF Poly(GP) |
|
PPA nfvPPA ~ 25% of FTD |
NA | 11 (all FTD) 5 |
4R tau | GRN C90RF72 Heritability (5%) |
NA | MRI/FDG-PET: Left posterior frontoinsular atrophy/hypometabolism | Progranulin (blood) CSF Poly(GP) |
| svPPA ~20% of FTD | NA | 4 | TDP-43 C | GRN C90RF72 Heritability (< 1%) |
NA | MRI/FDG-PET: Anterior temporal lobe atrophy/hypometabolism | Progranulin (blood) CSF Poly(GP) |
| PSP | Sensitivity 87.9% Specificity 85.7% [110,111] |
5 | 4R tau (tufted astrocytes) | MAPT | NA | SPECT: Nigrostriatal dopaminergic degeneration MRI/FDG-PET: Midbrain atrophy/hypometabolism |
NA |
| CBD | Unreliable accuracy [123,124] |
Unknown | 4R tau (astrocytic plaques) | NA | NA | (MRI/FDG-PET not included in diagnostic criteria: Asymmetric frontoparietal atrophy) | NA |
| ALS | Sensitivity 57% Specificity 99% [224] | 3 | TDP-43 SOD1 (2%) | C9ORF72 TARDBP FUS SOD1 |
NA | Electrophysiological tests (low motor neuron degeneration) | NFL (blood): massive increase T2*MRI (cortical primary motor hypointensities) |
| MSA | Accuracy 79% [128,129] | 5 | A-synuclein (oligodendrocytes cytoplasmic inclusion) | COQ2 | NA | SPECT: Nigrostriatal dopaminergic degeneration MRI/FDG-PET: Atrophy of putamen, middle cerebellar peduncle, pons, or cerebellum. Hypometabolism in putamen, brainstem, or cerebellum Orthostatic hypotension |
NA |
with postmortem validation as reference standard
Abbreviations: Aβ40= Amyloid-Beta 40; Aβ42= Amyloid-Beta 42; AD= Alzheimer’s Disease; ALS= Amyotrophic Lateral Sclerosis; APP= Amyloid protein precursor; α-syn= alpha-synuclein; BRI-2= type II Transmembrane Protein gene; bvFTD= behavioral variant Frontotemporal Dementia; CAA= Cerebral Amyloid Angiopathy; CBD= Corticobasal Degeneration; C9ORF72= Chromosome 9 Open Reading Frame 72; DLB= Dementia with Lewy Bodies; COQ2= OH-benzoate Polyprenyltransferase gene; CST3= (Cystatin C gene); DJ1= Protein deglycase DJ-1 gene, also known as Parkinson Protein 7 (PARK7) DTI= Diffusion Tensor Imaging; fvAD= frontal variant of Alzheimer’s Disease; FTD= Frontotemporal Dementia; FUS= Fused in Sarcoma DNA-binding protein; GRN= Progranulin (Granulin Precursor); LBs= Lewy bodies; LRRK2= Leucine-Rich Repeat Kinase 2; lvAD= logopenic variant of Alzheimer’s Disease; MAPT= Microtubule Associated Protein Tau; MSA= Multiple System Atrophy; NfL= Neurofilament Light Chain; NFTs= Neurofibrillary Tangles; nfv-PPA= non-fluent variant Primary Progressive Aphasia; PARK2= Parkinson Protein 2 (Parkin) gene; PCA= Posterior Cortical Atrophy; PCC= Posterior Cingulate Cortex; PD= Parkinson’s Disease; PINK1= PTEN Induced Kinase 1 gene; PPA= Primary Progressive Aphasia; PSEN 1= presenilin-1; PSEN 2= presenilin-2; PSP= Progressive Supranuclear Palsy; SNCA= Synuclein Alpha gene; TDP-43= Transactive Response DNA-binding Protein 43 KDa; SOD1= Superoxide Dismutase 1; sv-PPA= semantic-variant Primary Progressive Aphasia.