Our patient presented with a progressive PD syndrome which started unilaterally with rest tremor, and showed a good response to levodopa with development of classic treatment induced motor complications without the presence of atypical features for PD. The patient fulfilled the accepted criteria used for a clinical diagnosis of PD but, unexpectedly, the histopathology studies disclosed only mild neuronal loss in the SN without α‐synuclein positive LB or Lewy neurites.7
Cases of parkinsonism associated with LRRK2
mutations with histopathological findings similar to those reported here led us to search for a mutation in this gene. Pure nigral degeneration without α‐synuclein positive LB and Lewy neurites was described as the underlying neuropathological substrate in the first PD family linked to the PARK8 locus, the Sagamihara kindred, that later was found to carry the missense mutation I2020T in the LRRK2
Non‐specific nigral degeneration has also been reported in patients with other LRRK2
mutations. In one subject (family D; Western Nebraska; mutation R1441C), the SN showed marked neuronal loss without α‐synuclein inclusions but ubiquitin positive inclusions were observed whereas two other individuals of this kindred presented with LB disease and another had tau positive inclusions.2
In three subjects carrying the mutation Y1699C, non‐specific SN degeneration with ubiquitin positive neuronal inclusions was observed in two cases whereas LB formation was present in one case.2,10
To date, the neuropathology associated with the commonest LRRK2
mutation, G2019S, has been examined in only 14 cases.5,11,12
In 13 cases, LB and Lewy neurites were found and, therefore, some authors have suggested that LRRK2
G2019S may be an α‐synucleinopathy.5,11,12
Our patient, together with another reported case, confirms that the histopathology in patients with the G2019S mutation can be non‐specific nigral degeneration without α‐synuclein positive LB, and indicates that there is no correlation between the type of LRRK2
mutation and the underlying neuropathological changes.12
In addition, tau immunopositive neurofibrillary tangle pathology has been observed recently in a case of parkinsonism with the G2019S mutation.13
In light of this pleomorphic neuropathology associated with different LRRK2
mutations, some authors have hypothesised that the underlying pathogenic mechanism may be an upstream pathway of other proteins implicated in the pathogenesis of neurodegeneration.2
The G2019S mutation has also been observed in a control subject without a personal or family history of neurological or neurodegenerative disease who died at age 68 years. His neuropathological examination did not disclose any neurodegenerative abnormalities.11
The G2019S mutation was also found in a 89‐year‐old patient with neuropathologically confirmed Alzheimer's disease.11
Both cases may reflect the incomplete penetrance of the LRRK2
mutations, which is probably influenced by age and other genetic and environmental factors.
Parkinsonism in the patient reported here showed a benign course for the first 10 years. The rapid worsening of the illness over the last 4 years, with major gait disturbances, could be explained by the development of ischaemic lesions involving the subcortical white matter and basal ganglia. Her initial benign parkinsonism may have been related to the final mild SN neuronal loss found at the pathological examination. Another explanation for this benign course is the absence of α‐synuclein positive LB pathology. Patients with other genetic causes of PD syndrome, such as those with Parkin
gene mutations, may also present with nigral degeneration without α‐synuclein inclusions and frequently have less progressive parkinsonism compared with idiopathic PD patients.14,15
Therefore, it is reasonable to hypothesise that the absence of α‐synuclein positive LB pathology may be a marker of a less aggressive pathogenic process with a slower rate of neuronal loss in the SN.
The presence of Marinesco bodies found in our patient has been described in neurons from other LRRK2
Marinesco bodies are nuclear ubiquitin positive inclusions found in pigmented neurons of the SN nigra that increase in frequency with advancing age. Although no pathological associations have been clearly established, it has recently been suggested that these nuclear inclusions may not represent a benign phenomenon as they are associated with a significant decline in striatal dopaminergic markers.16
Furthermore, pigmented neurons of the SN containing LB more likely present Marinesco bodies than those pigmented neurons without LB, and proteasome dysfunction can lead to similar abnormalities in cultured cells.16
Although their pathological role is still unclear, Marinesco bodies may represent the accumulation or aggregation of ubiquitinated proteins induced by dysfunction of the ubiquitin–proteosome pathway and, consequently, it is possible that they may be involved directly in dopaminergic cell death or, in contrast, may represent an epiphenomenon in response to the risk of neuronal cell death.
Although LB disease is the most frequent autopsy finding in the cases reported in the literature, the present case confirms that clinical PD caused by G2019S mutations can be associated with non‐specific nigral degeneration, without LB, α‐synuclein or any other distinctive inclusion. More extensive series, autopsy and brain bank based, are necessary to clearly define the underlying neuropathology associated with each LRRK2 mutation.