Background Pathological data from autopsies genotyped for PD-related mutations in alpha-synuclein, Parkin, PINK1, DJ1, LRRK2 and glucocerebrosidase have accumulated in recent years. The aim of this review is to systematically review all pathological reports of mutation carriers and to identify pathological patterns and gaps in the currently available data. Methods A systematic review of the English literature using the terms “Parkinson’s disease”, “brain pathology”, “autopsy”, and the specific gene nomenclature, and any combination of the above. Results Most studies included reports of convenience samples, either cases that were pre-identified as mutation carriers before autopsy, or screens of Lewy body brain banks. Nineteen autopsies of alpha-synuclein mutation carriers, 49 of LRRK2 mutation carriers, 9 of Parkin mutation carriers, one of PINK1 mutation carrier and 90 of glucocerebrosidase mutation carriers were identified. Most autopsies of alpha-synuclein, LRRK2 G2019S and glucocerebrosidase mutation carriers demonstrated Lewy body pathology as opposed to Parkin and LRRK2 non-G2019S mutation carriers. However, there was a marked variability in pathological findings even among carriers of identical mutations. Pathological data from DJ1 mutation carriers, non-manifesting mutation carriers (e.g., of LRRK2 mutations), and carriers of a single Parkin mutation were lacking. Discussion In gathering together all studies of PD autopsies with an identified genetic risk, this review highlights the wealth of information generated, as well as shortcomings in the available data. In particular, there is a need for larger, unbiased pathological studies. Differential association of Lewy pathology with specific mutations may reflect heterogeneity in pathogenic mechanisms among the different PD-related genes.

Objective To describe the neuropathologic findings in three LRRK2 G2019S carriers with Parkinson’s disease (PD). Methods We cross referenced a list of 956 PD individuals that had been previously genotyped in clinical studies at Columbia University, with 282 subjects with a parkinsonian syndrome who came to autopsy in our brain bank since 1991. We found three autopsies of G2019S mutation carriers. Pathological analyses of the samples were blind to the genetic findings. We retrospectively reviewed the clinical records of the three patients. Results All three had a clinical and pathological diagnosis of PD. Cognitive impairment was a late feature in two out of three patients. Cortical involvement varied significantly: one had diffuse Lewy Body (LB) pathology, tau inclusions and amyloid pathology consistent with advanced Alzheimer’s disease; one had diffuse cortical LB and one had only brainstem predominant LB pathology. Conclusions Cognitive impairment may be a long term complication in G2019S mutation carriers. However, the extent of cortical involvement is variable. Larger longitudinal follow up of LRRK2 G2019S mutation carriers is required to assess for risk factors for cortical involvement and dementia.

Background/Objectives:The clinical diagnosis of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) remains challenging due to heterogeneity of the diseases.AIMS:Here we compared the clinical features of PSP and MSA to gain insight into their diagnosis and prognosis, particularly the prognostic value of down-gaze palsy latency in PSP progression.Methods:We reviewed clinical features of pathologically confirmed 10 PSP and 13 MSA patients, incidentally matched in age-at-onset, gender, and disease duration, followed at Columbia University Medical Center during 1994–2009.Results:The final antemortem diagnosis was incorrect in 30% of PSP (all lacking down-gaze palsy) and 23% of MSA patients. Falls in the first year of the disease, pyramidal involvement and freezing of gait during the course were similar between PSP and MSA. Ataxia and apraxia were in 50% of the PSP patients. Parkinsonism responsive to levodopa treatment was in 30% of the PSP (all with resting tremor) and 50% of the MSA patients. Dysautonomia in MSA could occur as early as 3 years preceding the motor symptoms, with 46% within the first year of the motor onset, but 15% did not have dysautonomia in life. The latency of down-gaze palsy and urogenital dysfunction and MMSE scores at first visit in PSP, and the latency of falls and wheelchair confinement in MSA were all associated with the disease progression.Conclusions:We confirmed most of the previously published characterizations, and identified for the first time the prognostic value of down-gaze palsy latency in PSP progression.

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