SNCA

The aggregation of α-synuclein (αSyn) is thought to play a role in the pathophysiology of PD, although conclusive evidence is lacking regarding whether it is causative or compensatory. Many postmortem studies have revealed αSyn aggregates in the brains of PD patients, forming Lewy bodies (LB).^{Reference Vijiaratnam, Simuni, Bandmann, Morris and Foltynie7} SNCA mutation carriers have diffuse and severe LB pathology in the brainstem and cortex.^{Reference Schneider and Alcalay8} SNCA mutations, which are autosomal dominant, are hypothesized to lead to a gain of function that promotes αSyn accumulation.^{Reference Koros, Simitsi and Stefanis9} This accumulation is thought to disrupt multiple cellular pathways, leading to impairment of protein degradation and clearance, thereby creating a vicious cycle of αSyn aggregation. When toxic αSyn accumulates in presynaptic terminals, it causes synaptic dysfunction, neurodegeneration and cell death, thereby contributing to the clinical presentation of PD. Different types of SNCA mutations induce various molecular effects.^{Reference Serratos, Hernández-Pérez, Campos, Aschner and Santamaría11}

Point mutations and gene multiplications have been reported in SNCA-PD, with the most common point mutation being p.A53T.^{Reference Koros, Simitsi and Stefanis9} Despite marked familial variability, some phenotypic resemblances are observed among p.A53T carriers.^{Reference Ricciardi, Petrucci and Di Giuda12} With 90% penetrance, the disease tends to be more aggressive than idiopathic Parkinson’s disease (iPD), featuring an average onset at 46 years of age, classic iPD motor symptoms that are levodopa-responsive, less common resting tremor and early motor complications.^{Reference Papadimitriou, Antonelou and Miligkos13,Reference Bostantjopoulou, Katsarou, Papadimitriou, Veletza, Hatzigeorgiou and Lees14} Clinicians must assess the premotor phase, as nonmotor features such as olfactory dysfunction and severe orthostatic hypotension (OH) are prominent.^{Reference Papadimitriou, Antonelou and Miligkos13} Dementia typically occurs within 5–7 years of disease progression.^{Reference Bostantjopoulou, Katsarou, Papadimitriou, Veletza, Hatzigeorgiou and Lees14} On dopamine imaging, p.A53T mutation carriers show symmetrical loss of radioligand uptake, distinguishing them from iPD patients.^{Reference Bostantjopoulou, Katsarou, Gerasimou, Costa and Gotzamani-Psarrakou15}

Gene multiplications include triplications and, more commonly, duplications.^{Reference Trinh, Zeldenrust and Huang16} Patients with triplications exhibit 100% penetrance and experience disease onset around 40 years of age, with important nonmotor symptoms, early dementia as a hallmark feature and death approximately 7 years after disease onset.^{Reference Koros, Simitsi and Stefanis9,Reference Ferese, Modugno and Campopiano17} Imaging shows frontoparietal atrophy and severe striatal dopaminergic deficit.^{Reference Olgiati, Thomas and Quadri18} Duplication carriers exhibit highly heterogeneous phenotypes with milder disease and 40%–50% penetrance.^{Reference Koros, Simitsi and Stefanis9} The reduced penetrance and high phenotypic variability can cause one’s clinical presentation to resemble iPD, while another can mimic triplication disease.^{Reference Koros, Simitsi and Stefanis9} Gene multiplications respond adequately to levodopa initially.^{Reference Jia, Fellner and Kumar19}

LRRK2

The LRRK2 gene encodes leucine-rich repeat kinase 2, a synaptic protein involved in vesicular trafficking and endocytosis.^{Reference Piccoli, Condliffe and Bauer20} Mutations in LRRK2 are associated with both autosomal dominant PD and iPD, resulting in increased kinase activity of the LRRK2 protein.^{Reference Jia, Fellner and Kumar19,Reference Di Maio, Hoffman and Rocha21} This toxic gain of function is thought to be associated with neurotoxicity.^{Reference Ye, Robak, Yu, Cykowski and Shulman6} Pathological findings are heterogeneous, including synucleinopathy, tauopathy and pure nigrostriatal degeneration, with the latter being the only consistent feature.^{Reference Koros, Simitsi and Stefanis9}

Overall, LRRK2-PD is the most similar to iPD among the genetic forms of PD, though some differences remain.^{Reference Khan, Jain and Lynch22} LRRK2-PD has a later age of onset (after 50) compared with other genetic forms of PD, with mild, early motor symptoms and a slower disease progression in terms of nonmotor symptoms.^{Reference Koros, Simitsi and Stefanis9,Reference Ahamadi, Mehrotra and Hanan23} One study identified a predominance of lower extremity involvement and a higher prevalence of postural instability and gait impairment.^{Reference Alcalay, Mirelman and Saunders-Pullman24} Patients often maintain their cognitive function for many years and have a lower risk of developing dementia.^{Reference Tolosa, Vila, Klein and Rascol25,Reference Healy, Falchi and O’Sullivan26} However, the most common mutation, Gly2019Ser, is frequently associated with diffuse LB pathology, OH and dementia.^{Reference Kalia, Lang and Hazrati10}

In terms of nonmotor symptoms, olfactory impairment, depression and rapid eye movement (REM) sleep behavior disorder (RBD) are less common.^{Reference Healy, Falchi and O’Sullivan26,Reference Ehrminger, Leu-Semenescu and Cormier27} Autonomic dysfunction is similar to that seen in iPD.^{Reference Gaig, Vilas and Infante28} Due to the low penetrance (25%–80% for the Gly2019Ser mutation)^{Reference Koros, Simitsi and Stefanis9} and less prominent prodromal nonmotor features, assessing the premotor phase can be challenging. However, this phase is critical for developing disease-modifying treatments, as it may represent a window for preventing the disease’s pathophysiological progression. Therefore, further research is needed to identify nonclinical biomarkers for prodromal LRRK2-PD. These patients typically respond similarly to iPD to symptomatic treatments, such as levodopa or deep brain stimulation.^{Reference Tolosa, Vila, Klein and Rascol25}

GBA

Mutations in the GBA gene are also a well-known risk factor for PD. It encodes β-glucocerebrosidase (GCase), a lysosomal protein involved in the degradation of sphingolipids. In human-induced pluripotent stem cells, reduced GCase activity leads to the accumulation of sphingolipid substrates and facilitates αSyn accumulation, leading to deleterious effects on neuronal cells. In turn, αSyn accumulation reduces GCase activity, perpetuating lysosomal dysfunction.^{Reference Mazzulli, Xu and Sun29} GCase activity is decreased in PD patients, both with and without GBA mutations, although it is lower in those with GBA mutations.^{Reference Mullin, Smith and Lee30} Furthermore, reduced GCase activity is thought to hinder mitochondrial energy production and increase oxidative stress.^{Reference Cleeter, Chau and Gluck31} In addition, neuroinflammation and microglial activation have been found in brain regions susceptible to LB in carriers of GBA mutations without PD.^{Reference Mullin, Stokholm and Hughes32} However, it remains unclear whether elevated levels of cytokines in the serum and CSF of PD patients are also present in GBA-PD patients and whether they contribute to disease development. Nonetheless, pathophysiological mechanisms may differ between GBA variants, suggesting that patients could benefit from treatments tailored to their specific variant.^{Reference Senkevich, Rudakou and Gan-Or33}

GBA mutations have typically been associated with Gaucher disease (GD). GBA variants are classified as severe or mild, based on the severity of GD they cause.^{Reference Senkevich, Rudakou and Gan-Or33} Both are associated with a higher risk of PD, with severe variants conferring a higher risk.^{Reference Gan-Or, Amshalom and Kilarski34} In addition, the GBA risk variants p.E326K and p.T369M do not lead to GD but increase the risk of developing PD.^{Reference Senkevich, Rudakou and Gan-Or33} GBA-PD patients have an earlier age of disease onset by 1.7–6 years compared to noncarriers,^{Reference Koros, Simitsi and Stefanis9} with a 10%–30% penetrance.^{Reference Senkevich, Rudakou and Gan-Or33} Despite phenotypic variability, some clinical features can help distinguish mild from severe variant carriers.

Carriers of the severe GBA variant have worse OFF motor symptoms and are more likely to exhibit psychotic symptoms, apathy, OH and severe hyposmia. They also have a higher risk of dementia and death compared to noncarriers. Mild GBA variant carriers are primarily distinguished from the severe variants by a lower risk of dementia, although still higher than in noncarriers. Studies with higher statistical power may find other differences between severe and mild variants.^{Reference Cilia, Tunesi and Marotta35} Compared to noncarriers, p.E326K risk variant carriers show faster motor progression and more prevalent cognitive impairment with faster cognitive decline as measured by MoCA scores, while p.T369M variant carriers show faster disease progression to the third stage of the Hoehn and Yahr scale.^{Reference Senkevich, Rudakou and Gan-Or33}

Although GBA-PD is characterized by more prevalent or severe nonmotor features, motor symptoms are less defined. Some studies show rapid motor progression^{Reference Brockmann, Srulijes and Pflederer36} and more fluctuations,^{Reference Senkevich, Rudakou and Gan-Or37} while others suggest that motor progression is similar to noncarriers.^{Reference Sidransky, Nalls and Aasly38} Interestingly, carriers of both GBA and LRRK2 variants tend to have a milder phenotype than those with GBA variants alone, suggesting that LRRK2 variants may offer a protective effect over GBA variants.^{Reference Senkevich, Rudakou and Gan-Or33} GBA-PD patients generally respond well to levodopa.^{Reference Koros, Simitsi and Stefanis9}

PRKN

Mutations in the PRKN gene can lead to early-onset PD in homozygous or compound heterozygous carriers.^{Reference Koros, Simitsi and Stefanis9} It has an autosomal recessive inheritance pattern, unlike the three previously described genes.^{Reference Senkevich, Rudakou and Gan-Or37} PRKN, along with the PINK1 gene, is responsible for degrading dysfunctional mitochondria in neurons.^{Reference Narendra and Youle39} Mutations in PRKN prevent normal parkin-mediated mitophagy. Because this process is normally initiated by high levels of reactive oxygen species, its dysfunction could lead to an excessive accumulation of these free radicals, resulting in toxicity for dopaminergic neurons.^{Reference Senkevich, Rudakou and Gan-Or37} PRKN also plays a role in innate immunity, and when impaired, neuroinflammatory processes can contribute to dopaminergic neuron death.^{Reference Senkevich, Rudakou and Gan-Or37} Unlike SNCA, LRRK2 and GBA-related PD, neuropathology studies have shown that αSyn accumulation and LB are absent in PRKN-PD. The disease is also thought to be more specific to the substantia nigra and locus coeruleus.^{Reference Senkevich, Rudakou and Gan-Or37}

As with other genetically linked forms of PD, there is marked phenotypic variability in PRKN-PD. Penetrance can be incomplete.^{Reference Koros, Simitsi and Stefanis9} The median age of onset is 31 years, and patients usually present with milder disease.^{Reference Ye, Robak, Yu, Cykowski and Shulman6} Motor features include dystonia in the lower extremities, early gait and balance problems and common motor fluctuations and dyskinesias.^{Reference Khan, Graham and Critchley40} Nonmotor symptoms are less prominent than in iPD, except for psychiatric manifestations such as anxiety, panic attacks, depression and psychosis, which are more frequent. Olfaction and cognition are usually preserved, even after years of disease progression. Patients respond well to levodopa or anticholinergics, even more so than iPD patients.^{Reference Koros, Simitsi and Stefanis9}

Genetic testing is typically reserved for patients with a family history of PD, early disease onset or ethnic risk factors.^{Reference Jia, Fellner and Kumar19} However, this does not align with patients’ and families’ interest in understanding their genetic background.^{Reference Ye, Robak, Yu, Cykowski and Shulman6} A less restrictive approach to genetic testing could help reconcile this gap and expand the pool of patients eligible for clinical trials exploring targeted and disease-modifying treatments. Clinicians must explain the goals, benefits and risks of these tests based on the best available evidence.^{Reference Jia, Fellner and Kumar19} Expanding genetic testing also poses ethical challenges, such as informing healthy individuals that they are carriers of mutations for less-understood diseases with low penetrance.^{Reference Tolosa, Vila, Klein and Rascol25}

Although no medication currently modifies the progression of PD, clinicians can provide tailored symptomatic treatments to alleviate some of the most debilitating symptoms (Table 1).^{Reference Marras, Chaudhuri, Titova and Mestre5,Reference Koros, Simitsi and Stefanis9,Reference Jia, Fellner and Kumar19} Awareness of a patient’s genetic profile can aid in early symptom detection and timely, appropriate care.

Table 1.

Symptomatic treatment can be tailored to the genetic subtypes of PD and their respective phenotypes. Adapted from Marras et al. (2020)^{Reference Marras, Chaudhuri, Titova and Mestre5}

PD = Parkinson’s disease; OH = orthostatic hypotension; DBS = deep brain stimulation; iPD = idiopathic Parkinson’s disease; RBD = REM sleep behavior disorder.

MRI

MRI enables us to investigate specific features in the brains of PD patients and is easily accessible. T1-weighted structural MRI is used to measure cortical and subcortical volumetric changes and atrophy,^{Reference Mitchell, Lehéricy, Chiu, Strafella, Stoessl and Vaillancourt41} which represent axonal degeneration and neuronal cell death found in PD. Interestingly, a relationship has been found between brain connectivity, clinical features and the progression of atrophy in PD.^{Reference Pan, Jiang, Zhang, Zhang, Wang and Cheng42} Many studies have described MRI-based subtypes of PD and found that patterns of cortical atrophy can underpin distinct disease courses (Table 2).^{Reference Pan, Jiang, Zhang, Zhang, Wang and Cheng42–Reference Uribe, Segura and Baggio47} For example, progressive posterior parietal and temporal thinning could be related to semantic fluency deterioration.^{Reference Uribe, Segura and Baggio46} Despite the variations in imaging protocols and methodologies that complicate direct comparisons, widespread cortical thinning on MRI has been associated with more severe cognitive and motor symptoms.^{Reference Pan, Jiang, Zhang, Zhang, Wang and Cheng42–Reference Wang, Cheng and Rolls44,Reference Uribe, Segura and Baggio46,Reference Cao, Pang and Yu48} However, some patients maintain higher function despite brain atrophy, reflecting the brain’s compensatory capacity (brain reserve). Physical activity, known to increase brain volume in older adults, could help patients build brain reserve as a preventive measure.^{Reference Wang, Cheng and Rolls44}

Table 2.

T1-weighted MRI is used to identify PD subtypes based on brain atrophy and its relation to clinical phenotype and disease progression

HC = healthy controls; PD = Parkinson’s disease; RBD = REM sleep behavior disorder.

Specific MRI techniques can be used in clinical trials as outcome measures.^{Reference Mitchell, Lehéricy, Chiu, Strafella, Stoessl and Vaillancourt41} For instance, free-water diffusion MRI, which reflects neurodegeneration and neuroinflammation,^{Reference Mitchell, Lehéricy, Chiu, Strafella, Stoessl and Vaillancourt41} is associated with 4-year disease progression on the Hoehn and Yahr scale.^{Reference Burciu, Ofori and Archer49} Moreover, neuromelanin-sensitive MRI and iron-sensitive MRI can assess specific dopaminergic neuron populations in the substantia nigra and are potential disease progression biomarkers.^{Reference Mitchell, Lehéricy, Chiu, Strafella, Stoessl and Vaillancourt41} Finally, functional MRI, which maps brain connectivity, can help identify patterns of neurodegeneration. Abnormal sensorimotor functional connectivity, found in the supplementary motor area of drug-naïve PD patients and carriers of LRRK2 mutations at the prodromal stage, is partially corrected by levodopa therapy. If these connectivity changes correlate with corticostriatal functional disruption, functional MRI could serve as a tool for predicting symptom development and treatment response.^{Reference Sasikumar and Strafella50} This imaging technique has been used in a multimodal MRI approach to identify new PD subtypes.^{Reference Cao, Pang and Yu48} A diffuse-malignant PD subtype, characterized by reduced spontaneous neuronal activity in the visual cortex and diffuse gray matter (GM) atrophy, showed more severe motor symptoms and cognitive dysfunction compared with the mild subtype. In contrast, the latter presented increased neuronal activity in the frontal, temporal lobes and sensorimotor cortex, mild GM atrophy and less severe motor and cognitive impairment. Given PD’s heterogeneous pathophysiology and clinical presentation, a single imaging modality cannot fully reflect the disease. Thus, objective PD subtyping is likely to benefit from multimodal imaging, as well as genetic and biochemical biomarkers.

Positron emission tomography and single-photon emission computed tomography

Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can be used in PD with tracers that target different neurotransmitters. Reduced uptake of serotonin-specific PET tracers reflects presynaptic serotonergic disruption in cortical and subcortical regions and is associated with PD progression.^{Reference Sasikumar and Strafella50} Serotonergic degeneration has been associated with the severity of several neuropsychiatric symptoms, including apathy, depression and anxiety.^{Reference Maillet, Krack and Lhommée51} Other imaging markers may provide insights into prodromal PD,^{Reference Sasikumar and Strafella50} as patients with idiopathic RBD present with reduced cholinergic markers^{Reference Gersel Stokholm, Iranzo and Østergaard52} and increased microglial activation.^{Reference Stokholm, Iranzo and Østergaard53} Moreover, brain glucose metabolism imaging has been correlated with disease severity^{Reference Zhang, Li and Yuan54} and can help discriminate PD from atypical parkinsonism.^{Reference Sasikumar and Strafella50,Reference Tripathi, Tang and Feigin55}

Dopaminergic PET and SPECT imaging identify striatal presynaptic dopaminergic deficits. Many studies have found a poor correlation between dopaminergic imaging and clinical progression.^{Reference Mitchell, Lehéricy, Chiu, Strafella, Stoessl and Vaillancourt41} Nevertheless, a study described three PD subtypes with differing cognitive prognoses based on cerebral perfusion patterns evaluated by 18F-FP-CIT PET, an imaging marker for nigrostriatal integrity.^{Reference Chung, Kim and Park56} Subtype 1 had preserved cortical uptake, young age at disease onset and better cognitive function. Subtype 2 had decreased uptake in frontal, temporal and parietal regions, with a higher risk of dementia compared to subtype 1. Subtype 3 had extensive decreased uptake, including in the occipital region, with older age at disease onset, poorer cognitive function and risk of dementia higher than subtype 1 but similar to that in subtype 2. Additionally, another study found robust PD subtypes using a combination of clinical, MRI dopamine transporter scan and radiomics imaging features.^{Reference Salmanpour, Shamsaei, Saberi, Hajianfar, Soltanian-Zadeh and Rahmim57} It identified mild, intermediate and severe subtypes in terms of dopaminergic deficit, which correlated both for motor and nonmotor domains, although the intermediate subtype had worse tremors overall.

Phosphodiesterase 10A is an enzyme traceable with 11C-IMA107 PET that modulates dopaminergic striatal pathways. Although not used for subtyping, reduced levels have been linked to longer disease duration and more severe symptoms in PD.^{Reference Sasikumar and Strafella50,Reference Niccolini, Foltynie and Reis Marques58} Consequently, phosphodiesterase 10A may represent a potential target for novel therapies.

Cardiac meta-iodobenzylguanidine scintigraphy

Cardiac meta-iodobenzylguanidine (MIBG) scintigraphy has provided new insights into the pathophysiology of PD. Reduced uptake of myocardial MIBG, associated with cardiac sympathetic denervation, has been documented in PD patients and is thought to reflect the degeneration of the cardiac plexus driven by peripheral LB pathology, possibly via the vagus nerve.^{Reference Pitton Rissardo and Fornari Caprara59} This may point to a distinction between peripheral and central LB deposition. Supporting this distinction is the observation that, in early-stage PD, plasma αSyn levels correlate with cardiac denervation but not with degeneration of nigrostriatal pathways.^{Reference Pitton Rissardo and Fornari Caprara59} MIBG scintigraphy is also used for PD subtyping. Researchers have described three subtypes based on this imaging technique: one that had initial cardiac sympathetic denervation, one with preserved innervation at the initial and follow-up imaging and a converter subtype whose imaging was initially normal but later showed cardiac denervation.^{Reference Yoo, Ryu and Oh60} An increasing degree of asymmetry in nigrostriatal degeneration was found among the groups, with the initially denervated subtype having the most severe and symmetric nigrostriatal degeneration. The authors concluded that these subtypes could reflect distinct origins and patterns of PD pathobiology spread – peripheral, central or converging midway. Furthermore, it was found that converters had preserved memory and that it could be the result of non-dopaminergic compensatory mechanisms such as serotonergic or noradrenergic circuits.^{Reference Yoo, Oh and Ryu61} Moreover, other researchers have found that central serotonergic pathways are linked to cardiac sympathetic innervation, suggesting that these pathways may play a role in cardiac sympathetic dysfunction in PD.^{Reference Pitton Rissardo and Fornari Caprara59}

MIBG scintigraphy can also predict PD phenotypes, mainly in the context of nonmotor symptoms. Regarding autonomic dysfunction, OH was associated with cardiac denervation on MIBG scintigraphy in patients with early and mild disease.^{Reference Kim, Park and Oh62} Other studies have found no association between heart rate variability, sympathetic or parasympathetic function and MIBG scintigraphy in PD.^{Reference Pitton Rissardo and Fornari Caprara59} This imaging technique may be used for risk assessment of syncope, monitoring disease burden and predicting disease progression.^{Reference Pitton Rissardo and Fornari Caprara59} Indeed, subtypes of PD with normal or mild cardiac denervation have a more benign disease course, with less severe cortical atrophy and nigrostriatal damage.^{Reference Tsujikawa, Hasegawa and Yokoi63} Relationships have also been found between cardiac denervation on MIBG scintigraphy and cognitive dysfunction, dysphagia, hyposmia, depression, anxiety and RBD. Interestingly, abnormal cardiac MIBG scintigraphy has been shown to correlate with the incidence of falls and the progression of rigidity and axial motor symptoms.^{Reference Pitton Rissardo and Fornari Caprara59}