Table 1.

Clinical and pathological features of main tauopathies and synucleinopathies

Disease	Proteinopathy type	Motor features	Cognitive features	Protein accumulation pattern	Brain atrophy and neuronal degeneration pattern	References
FTD (FTLD-tau)	Primary tauopathy	Parkinsonism with symmetrical bradykinesia, postural rigidity, absence of resting tremor, and minimal or absent response to levodopa. Features can overlap with CBS or PSP.	bvFTD: personality changes, disinhibition, apathy, impulsivity, loss of empathy, hyperorality, compulsive behavior, repetitive movements, ritualistic behaviors, and stereotypy of speech. Deficits in executive tasks with relative sparing of episodic memory and visuospatial skills. PNFA: impaired speech production and non-fluent speech, impaired comprehension of complex sentences. Spared single word comprehension and object knowledge. SD: impaired word comprehension, loss of semantic memory, surface dyslexia or dysgraphia. Spared repetition and speech production.	FTLD-tau pathologic subtypes: AGD - accumulation of 4R tau-containing argyrophilic grains in the medial temporal lobe. GGT - 4R-tau containing globular glial inclusions and neuronal globular or tangle-like inclusions. Pathology can overlap with PSP and CBD.	bvFTD - Bilateral atrophy of the frontal lobes, insula, anterior cingulate, and anterior temporal lobes. PNFA - atrophy of the anterior perisylvian cortex, mostly in the dominant hemisphere. SD - asymmetrical atrophy of the dominant anterior inferior temporal lobe.	23,26,31–33,36,211–214
PSP	Primary tauopathy	Heterogeneous phenotype with many possible variants. Ocular motor dysfunction, dysarthria, postural instability, and bradykinesia / akinesia are common. Can also present as CBS.	Behavioral and/or language impairment similar to subtypes of FTD	Accumulation of 4R-tau NFTs in subcortical structures, especially the subthalamic nucleus, basal ganglia, and brainstem. The NFTs may be associated with 4R-tau positive tufted astrocytes, oligodendroglial coiled bodies, and neuropil threads.	Atrophy of the subthalamic nucleus and brainstem tegmentum, depigmentation of the substantia nigra.	33,79
CBD	Primary tauopathy	CBS: asymmetric levodopa-resistant parkinsonism, dystonia, myoclonus, orobuccal or limb apraxia, alien limb phenomena, cortical sensory deficit. Can present similarly to PD or PSP.	Can present similarly to FTD or AD-like dementia.	Accumulation of 4R-tau positive neuronal inclusions, white and grey matter threads, coiled bodies, and astrocytic plaques. NFTs and corticobasal bodies are seen.	Asymmetric focal cortical atrophy and depigmentation of the substantia nigra.	85,96
PiD	Primary tauopathy	Most commonly presents as bvFTD, but can also present as other types of FTD and CBS.		3R-tau Pick bodies, predominantly in the dentate gyrus and temporal lobes.	Cerebral atrophy predominant in frontal and temporal lobes.
CTE	Primary tauopathy	Usually late in disease: parkinsonism and, in some cases, motor neuron disease.	Irritability, aggressively, impulsivity, depressive symptoms, and memory impairment. Speech abnormalities and dementia can develop later.	Focal deposition of tau-positive NFTs, tangles, threads, and astrocytes that is most pronounced around cortical sulci and penetrating vessels. The medial temporal lobe, basal ganglia, diencephalon, and brainstem can also be involved, especially later in the disease. TDP-43, Aβ, and alpha-synuclein deposition can also be observed.	Generalized atrophy of the cerebral cortex, notably medial temporal lobes, diencephalon, and mamillary bodies.	104,218
PART	Primary tauopathy	Usually not observed.	Can be associated with memory loss in aging. Can also present with progressive decline in episodic and semantic memory, processing speed, and attention. Symptoms are usually milder and progress more slowly than in AD.	Accumulation of 3R and 4R-tau NFTs mostly in the medial temporal lobe, basal forebrain, brainstem, and olfactory bulb and cortex. The NFTs are identical to those of AD, but Aβ deposits are not seen. Symptom severity correlates with NFT burden.	Neocortical and medial temporal lobe atrophy might be observed in some individuals.	106,219,220
AD	Secondary tauopathy	Extrapyramidal symptoms or parkinsonism can be present late in disease but are not common nor predominant.	Short-term memory loss, visuospatial impairment, and executive dysfunction. Language and behavior impairment typically occur later. Can also develop personality changes, loss of empathy, and obsessive / compulsive behaviors.	NFTs and Aβ extracellular neuritic plaques. NFTs accumulate in a stereotypical manner: 1) entorhinal cortex and hippocampus 2) other limbic structures such as the amygdala and thalamus, 3) in neocortex. LBs are also seen in most cases, predominantly in the amygdala.	Predominant atrophy of medial, basal, lateral temporal, and medial parietal lobes.	208–210
PD	Synucleinopathy	Asymmetric and levodopa-responsive parkinsonism. Shuffling, festinating gait. Postural instability and autonomic dysfunction can occur later in disease.	Sleep dysfunction, depression, anxiety, apathy. Dementia occurs late in disease.	Accumulation of misfolded alpha-synuclein into LBs, predominantly in the substancia nigra. NFTs and Aβ plaques can also be identified.	Loss of dopaminergic neurons, predominantly in the ventrolateral area of the substantia nigra pars compacta.	2.135,215
DLB	Synucleinopathy	Parkinsonism (often less levodopa-responsive than PD), dysautonomia.	Dementia, fluctuating cognition, visual hallucinations, RBD, apathy, depression.	LBs predominantly in the brainstem. LBs can also accumulate in limbic structures and in the cerebral cortex, particularly the frontal and temporal lobes. Aβ plaques with or without NFTs can be seen.	Pallor of the substantia nigra, atrophy of the midbrain, hypothalamus, substantia innominate, lateral prefrontal cortex, and left premotor cortex.	3,170,216
MSA	Synucleinopathy	Levodopa-unresponsive parkinsonism (can be responsive to levodopa, especially early in disease), pyramidal signs, cerebellar abnormalities, and autonomic dysfunction. Predominant symptoms depend on subtype: MSA-P (parkinsonism) and MSA-C (cerebellar dysfunction).	Sleep dysfunction, depression, anxiety, attention deficit. Presence of dementia should prompt consideration of alternative diagnosis, such as DLB.	Presence of argyrophilic GCIs that are alpha-synuclein and tau-positive.	Neuronal loss and gliosis in the striatonigral and olivopontocerebellar systems.	4,179,217

Abbreviations: FTD: frontotemporal dementia; FTLD: frontotemporal lobar degeneration; CBS: corticobasal syndrome; PSP: progressive supranuclear palsy; bvFTD: behavioral variant frontotemporal dementia; PNFA: progressive non-fluent aphasia; SD: semantic dementia; AGD: argyrophilic grain disease; GGT: globular glial tauopathy; CBD: corticobasal degeneration; NFTs: neurofibrillary tangles; PD: Parkinson’s disease; AD: Alzheimer’s disease; PiD: Pick’s disease; CTE: chronic traumatic encephalopathy; TDP-43: TAR DNA-binding protein-43; Aβ: amyloid beta; PART: primary age-related tauopathy; LBs: Lewy bodies; DLB: dementia with Lewy bodies; RBD: rapid eye movement sleep behavior disorder; MSA: multiple system atrophy; GCIs: glial cytoplasmic inclusions