A sample of 25 idiopathic Parkinson's disease subjects and 25 age and education matched elderly healthy control subjects were assessed for their speed of primary memory scanning speed using the Sternberg memory scanning paradigm. In addition, all patients were assessed for cognitive functioning as measured by the Mattis Dementia Rating Scale and the Wechsler Memory Scale. Significant differences were found between Parkinson's disease subjects and control subjects on speed of primary memory scanning, with the parkinsonian subjects performing significantly slower than the control subjects. Increased variability in the measure of memory scanning speed was noted for the parkinsonian subjects as compared to control subjects and different variables associated with increased cognitive disturbances in parkinsonian subjects were investigated as possible sources of this variability. It was found that the majority of variance could be accounted for by the parkinsonian subjects' age of symptom onset. Parkinsonian subjects who developed the disease later in life were significantly slower at primary memory scanning speed than were either parkinsonian subjects who developed the disease earlier in life, or than healthy control subjects. Cognitive variables measuring initiation and perseveration, construction and attention were found to be highly associated with increased primary memory scanning time. The relationship between these cognitive abilities and frontal lobe dysfunction is discussed. Also, the possible relationship between slowing of memory scanning and dopamine depletion is presented.

Thirty-two parkinsonians were compared to 32 age-, sex-, and education-matched healthy controls on measures of depression (Beck Inventory), dementia (Mattis Dementia Rating Scale), and primary and secondary memory components of Free Verbal Recall. Parkinsonians were found to be more depressed, with greater impairment of secondary memory. There were no significant group differences in primary memory or general cognitive functioning. Sub-groups of 41 parkinsonians (including the 32 patients described above) were used to compare the relative contributions of depression, age of onset, and general cognitive decline to the observed secondary memory deficit. Depressed parkinsonians demonstrated more impaired primary memory than did nondepressed parkinsonians, but did not account for the difference in secondary memory. Parkinsonians with later ages of onset demonstrated greater depression and cognitive decline over a shorter length of illness, and parkinsonians with greater cognitive decline performed more poorly on the measure of secondary memory. Comparisons of parkinsonians with predominant unilateral motor symptoms (either right or left) to those with equal bilateral symptoms revealed the bilateral group to be significantly older, with later ages of onset but no difference in length of illness. It is concluded that later age of onset is a critical factor that is more likely to be associated with depression and declines in cognitive functioning than is seen with earlier age of onset. The relationship between age of onset and cognitive decline is not accounted for by age alone, length of illness, nor by the interaction of age with parkinsonian symptoms. Furthermore, the presence of bilateral symptoms may serve as a marker for the cluster of symptoms associated with later ages of symptoms onset.

Parkinson's disease (PD) is an age-related neurodegenerative disease characterized by the selective loss of dopaminergic neurons in the substantia nigra of the brain. The pathogenesis and etiology of PD are unclear. Mitochondrial dysfunction occurs in PD, causing a decrease in complex I activity in postmortem brain, and exacerbating reactive oxygen species production and ATP deficiency contributing to neuronal cell death. Mutation of leucine-rich-repeat kinase 2 (LRRK2) gene is the most common genetic factor identified in both familial and sporadic PD cases. Several mutations in LRRK2 have been linked to PD, in which R1441G is the second commonest mutation after G2019S. LRRK2 protein is ubiquitously expressed in human body, in which a portion is localized to the mitochondria. Mutations of LRRK2 directly or indirectly cause mitochondria dysfunction. Dysfunction of mitochondrial respiratory complexes has been described in skin fibroblasts and skeletal muscle of PD patients. Therefore, these clinically accessible tissues are good for monitoring disease progression. The objectives of this study were to investigate how LRRK2 R1441G mutation affects normal mitochondrial function, and whether this specific LRRK2 mutation potentiates age-dependent deterioration of mitochondrial function. To achieve these aims, colonies of skin fibroblast carrying LRRK2 R1441G mutation or wild-type LRRK2 were derived from a novel LRRK2 R1441G knock-in (KI) mouse model and its wild-type (WT) littermates. Skeletal muscles were dissected from the hind legs of WT and KI mice. The effects of aging and LRRK2 R1441G mutation on mitochondrial function were investigated in vitro using these derived skin fibroblast cultures, and ex vivo using skeletal muscle obtained from young (3-month-old) and aged (18-month-old) WT and KI mice. Reduction-oxidation activities of mitochondrial complex I and complex II in skin fibroblasts and skeletal muscle were measured spectrophotometrically. Intracellular ATP levels in skin fibroblasts were determined by bioluminescent assay. Phase-contrast microscopy showed that aging and LRRK2 R1441G mutation did not affect cell morphology of the derived skin fibroblast cultures. Complex I activity determined in skin fibroblasts and skeletal muscle derived from KI and their WT littermates revealed that, aging caused a significant increase in complex I activity in WT but not KI skin fibroblasts. Conversely, a significant decrease in complex I activity was observed in both WT and KI skeletal muscle, demonstrating an aging effect ex vivo. LRRK2 R1441G mutation did not affect complex I activity in WT and KI skin fibroblasts and skeletal muscle. Moreover, complex II activity in these two tissues was neither affected by aging nor R1441G LRRK2 mutation. Intracellular ATP levels in the skin fibroblast cultures were also unaltered by aging and LRRK2 R1441G mutation. In conclusion, my current findings indicated a significant aging effect on mitochondrial complex I activity ex vivo, supporting the role of age-dependent deterioration of complex I activity in mitochondrial dysfunction of PD. LRRK2 R1441G mutation did not affect complex I and II activities in both skin fibroblasts and skeletal muscle. Also, this mutation did not potentiate the age-dependent deterioration of complex I activities as observed in skin fibroblasts and skeletal muscle of the LRRK2 R1441G knock-in mice. / published_or_final_version / Medicine / Master / Master of Philosophy