Pharmacotherapy and revascularization strategies of peripheral artery disease.

The global epidemiological transition of atherosclerotic vascular diseases is witnessing a rapid redistribution of its burden, shifting from high-income to low- and middle-income countries. With a wide clinical spectrum, spanning from intermittent claudication to more complex critical limb threatening ischemia, nonhealing ulcers, gangrene as well as acute limb ischemia, peripheral artery disease is often faced with the challenges of under-diagnosis and under-treatment despite its high prevalence. The management of peripheral arterial disease in patients with multiple comorbidities presents a formidable challenge and remains a pressing global health concern. In this review, we aim to provide an in-depth overview of the pathophysiology of peripheral artery disease and explore evidence-based management strategies encompassing pharmacological, lifestyle, interventional, and surgical approaches. By addressing these challenges, the review contributes to a better understanding of the evolving landscape of peripheral artery disease, offering insights into effective and holistic management strategies.

Multimodal assessment of nigrosomal degeneration in Parkinson's disease.

BACKGROUND: Approximately forty percent of all dopaminergic neurons in SNpc are located in five dense neuronal clusters, named nigrosomes. T2- or T2*-weighted images are used to delineate the largest nigrosome, named nigrosome-1. In these images, nigrosome-1 is a hyperintense region in the caudal and dorsal portion of the T2- or T2*-weighted substantia nigra. In PD, nigrosome-1 experiences iron accumulation, which leads to a reduction in T2-weighted hyperintensity. Here, we examine neuromelanin-depletion and iron deposition in regions of interest (ROIs) derived from quantitative-voxel based morphometry (qVBM) on neuromelanin-sensitive images and compare the ROIs with nigrosome-1 identified in T2*-weighted images. METHODS: Neuromelanin-sensitive and multi-echo gradient echo imaging data were obtained. R2* was calculated from multi-echo gradient echo imaging data. qVBM analysis was performed on neuromelanin-sensitive images and restricted to SNpc. Mean neuromelanin-sensitive contrast and R2* was measured from the resulting qVBM clusters. Nigrosome-1 was segmented in T2*-weighted images of control subjects and its location was compared to the spatial location of the qVBM clusters. RESULTS: Two bilateral clusters emerged from the qVBM analysis. These clusters showed reduced neuromelanin-sensitive contrast and increased mean R2* in PD as compared to controls. Cluster-1 from the qVBM analysis was in a similar spatial location as nigrosome-1, as seen in T2*-weighted images. CONCLUSION: qVBM cluster-1 shows reduced neuromelanin-sensitive contrast and is in a similar spatial position as nigrosome-1. This region likely corresponds to nigrosome-1 while the second cluster may correspond to nigrosome-2.

Neuropsychiatric Predictors of Cognitive Decline in Parkinson Disease: A Longitudinal Study.

OBJECTIVES: To examine the relationship between anxiety, depression, apathy, and cognitive decline in Parkinson disease (PD). DESIGN: Longitudinal study design to assess whether specific neuropsychiatric, demographic, and clinical features predict future cognitive decline. SETTING: Veterans Affairs San Diego Medical Center and the University of California, San Diego. PARTICIPANTS: PD patients (N = 68) and healthy controls (N = 30). MEASUREMENTS: Participants were administered self-report measures of depression (Geriatric Depression Scale), anxiety (State Trait Anxiety Scale), and apathy (Apathy Scale), and a comprehensive neuropsychological battery assessing attention, language, visuospatial function, verbal and visual learning and memory, and executive function. Participants were tested at baseline and after an approximate 2-year period. RESULTS: Anxiety and depression at baseline were the strongest predictors of longitudinal decline on measures of verbal and visual learning, over and above other clinical and demographic characteristics. However, baseline neuropsychiatric symptoms did not significantly correlate with decline in other cognitive domains. No significant correlations were detected between neuropsychiatric symptoms and cognition in the healthy control group. CONCLUSIONS: These results suggest that anxiety and depression in PD may be risk factors for subsequent declines in learning. Emerging evidence suggests nonmotor symptoms are critical determinants of PD prognosis, and the results of this study highlight the importance of assessment of depression and anxiety early in PD.

The utility of the Mattis Dementia Rating Scale in Parkinson's disease mild cognitive impairment.

BACKGROUND: The Movement Disorders Society (MDS) recently proposed guidelines for diagnosis of mild cognitive impairment in Parkinson's disease (PD-MCI) that includes two assessment levels: abbreviated (Level I) and comprehensive (Level II). The aim of this study was to determine the utility of the Mattis Dementia Rating Scale (MDRS), a recommended Level I test, for detecting Level II PD-MCI diagnosis. METHODS: The study sample included 30 patients diagnosed with PD-MCI based on Level II MDS criteria and 68 PD patients with normal cognition (PD-NC). Receiver operator curve (ROC) analyses were generated to measure the sensitivity and specificity of various MDRS cutoff scores. To examine the utility of the MDRS as a screening tool, the optimal cutoff point was defined as the lowest value providing ≥80% sensitivity. For use of the MDRS as a diagnostic tool, the optimal cutoff point was defined as the highest value providing ≥80% specificity. RESULTS: ROC analyses showed that the optimal MDRS cutoff score for screening purposes and diagnostic purposes were ≤140 and ≤137, respectively. However, an examination of sensitivity/specificity values for the screening cutoff scores suggested that a total score of ≤139 for screening purposes yielded a better balance between sensitivity (77%) and specificity (65%). CONCLUSIONS: In a clinical setting, in which detection of PD-MCI may be important, a total MDRS score of ≤139 can be used to detect PD-MCI. In research and other settings in which diagnostic certainty is more important, a score of ≤137 may be more useful.

Instrumental activities of daily living are impaired in Parkinson's disease patients with mild cognitive impairment.

OBJECTIVE: Although it is well known that Parkinson's disease (PD) with dementia results in functional decline, little is known about the impact of mild cognitive impairment in PD (PD-MCI) on day-to-day functioning. METHOD: Forty-one individuals with PD-MCI, 56 PD patients with normal cognition (PD-NC), and 47 healthy older adults were administered two performance-based measures of instrumental activities of daily living (IADLs) that evaluated medication and financial management. Informants of the PD patients were also administered an IADL questionnaire. RESULTS: There were no significant differences between PD-NC and healthy older adults on the performance-based measures of medication and financial management. However, PD-MCI patients demonstrated significantly lower scores on the performance-based measures of medication and financial management compared with healthy older adults. PD-MCI patients were also impaired compared with PD-NC patients on performance-based medication management, but no difference between these groups was observed for ability to manage finances. Performance-based financial and medication management did not correlate with scores on neuropsychological measures in PD-MCI patients. PD-MCI and PD-NC patients showed comparable scores on the informant-based IADL questionnaire. CONCLUSIONS: Performance-based measures of IADLs, particularly medication management ability, are sensitive to subtle functional declines in PD-MCI. Although impairment in performance-based measures is associated with cognitive status in PD, IADLs may be a separate domain of functioning from cognitive functioning in PD-MCI as these measures did not correlate with performance on the neuropsychological measures. Overall, performance-based assessment of IADLs may add to the clinical evaluation of PD-MCI.

Dissociation of Neural Mechanisms for Intersensory Timing Deficits in Parkinson's Disease.

This study investigated the ability of individuals with Parkinson's disease (PD) to synthesize temporal information across the senses, namely audition and vision. Auditory signals (A) are perceived as lasting longer than visual signals (V) when they are compared together, since attentsion is captured and sustained more easily than for visual information. We used the audiovisual illusion to probe for disturbances in brain networks that govern the resolution of time in two intersensory conditions that putatively differ in their attention demands. PD patients and controls judged the relative duration of successively presented pairs of unimodal (AA, VV) and crossmodal (VA, AV) signals whilst undergoing fMRI. There were four main findings. First, underestimation of time was exaggerated in PD when timing depended on controlled attention (AV), whereas subtle deficits were found when audition dominated and attention was more easily sustained (VA). Second, group differences in regional activation were observed only for the AV-unimodal comparison, where the PD group failed to modulate basal ganglia, anterior insula, and inferior cerebellum activity in accord with the timing condition. Third, the intersensory timing conditions were dissociated by patterns of abnormal functional connectivity. When intersensory timing emphasized controlled attention, patients showed weakened connectivity of the cortico-thalamus-basal ganglia (CTBG) circuit and the anterior insula with widespread cortical regions, yet enhanced cerebellar connectivity. When audition dominated intersensory timing, patients showed enhanced connectivity of CTBG elements, the anterior insula, and the cerebellum with the caudate tail and frontal cortex. Fourth, abnormal connectivity measures showed excellent sensitivity and specificity in accurately classifying subjects. The results demonstrate that intersensory timing deficits in PD were well characterized by context-dependent patterns of functional connectivity within a presumed core timing system (CTBG) and a ventral attention hub (anterior insula), and enhanced cerebellar connectivity irrespective of the hypothesized attention demands of timing.

Predictors of performance-based measures of instrumental activities of daily living in nondemented patients with Parkinson's disease.

Few studies have examined instrumental activities of daily living (iADLs) in nondemented Parkinson's disease (PD), and the majority of these studies have used report-based measures, which can have limited validity. The present study had two main goals: (a) to examine the performance of nondemented PD patients on two performance-based measures of iADLs, which are considered more objective functional measures, and (b) to examine the cognitive, motor, and psychiatric correlates of iADL impairment in PD. Ninety-eight nondemented PD patients and 47 healthy older adults were administered performance-based measures that assess the ability to manage medications (Medication Management Ability Assessment) and finances (University of California, San Diego, UCSD, Performance-based Skills Assessment), the Mattis Dementia Rating Scale to assess global cognitive functioning, the Unified Parkinson's Disease Rating Scale Part III to assess motor symptom severity, and the Geriatric Depression Scale to assess depressive symptoms. Nondemented PD patients demonstrated significantly impaired scores relative to the healthy comparison group on the performance-based measure of financial management, but there were no significant group differences in medication management. Global cognitive functioning, motor severity, and depressive symptoms did not correlate with scores on either of the functional measures, except for a small correlation between depressive symptoms and financial management. The two performance-based measures of iADL functioning did not correlate with one another. These findings suggest that medication and financial management may not be predicted based on global cognitive functioning and that iADLs may not be represented by a single construct. Furthermore, these findings suggest the potential need for a multidimensional approach to assessing iADLs.

White-matter changes correlate with cognitive functioning in Parkinson's disease.

Diffusion tensor imaging (DTI) findings from emerging studies of cortical white-matter integrity in Parkinson's disease (PD) without dementia are inconclusive. When white-matter changes have been found, their relationship to cognitive functioning in PD has not been carefully investigated. To better characterize changes in tissue diffusivity and to understand their functional significance, the present study conducted DTI in 25 PD patients without dementia and 26 controls of similar ages. An automated tract-based DTI method was used. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were analyzed. Neuropsychological measures of executive functioning (working memory, verbal fluency, cognitive flexibility, inhibitory control) and visuospatial ability were then correlated with regions of interest that showed abnormal diffusivity in the PD group. We found widespread reductions in FA and increases in MD in the PD group relative to controls. These changes were predominantly related to an increase in RD. Increased AD in the PD group was limited to specific frontal tracks of the right hemisphere, possibly signifying more significant tissue changes. Motor symptom severity did not correlate with FA. However, different measures of executive functioning and visuospatial ability correlated with FA in different segments of tracts, which contain fiber pathways to cortical regions that are thought to support specific cognitive processes. The findings suggest that abnormal tissue diffusivity may be sensitive to subtle cognitive changes in PD, some of which may be prognostic of future cognitive decline.

Predictors of discrepancies in Parkinson's disease patient and caregiver ratings of apathy, disinhibition, and executive dysfunction before and after diagnosis.

Parkinson's disease (PD) patient and caregiver reports of patient functioning are often used interchangeably in clinical and research settings; however, the consistency of these reports is largely unknown. This study aimed to investigate the consistency and predictors of discrepancy between self- and caregiver reports of patient apathy, disinhibition, and executive dysfunction. Fifty-one pairs of nondemented PD patients and their caregivers completed the frontal systems behavior scale (FrSBe). Patients were administered a neuropsychological battery, and mood and burden were assessed in a subset of caregivers. Patients and caregivers significantly differed in their ratings of all retrospective prediagnosis behaviors and current levels of disinhibition. Current levodopa equivalent dosages predicted patient-caregiver rating differences in prediagnosis and current apathy and current executive dysfunction, while patient motor function, cognition, and mood failed to predict any disparities in ratings. Caregiver burden and depression were associated with apathy rating discrepancies, while burden was associated with discrepancies in ratings of disinhibition. These results suggest that consistency of patient and caregiver behavioral ratings may vary depending on the behavior assessed; and underscore the importance of considering the reporter when using subjective measures, as discrepancies in behavioral reports may be influenced by specific patient and/or caregiver symptoms or factors.

The need for inducing tolerance in vascularized composite allotransplantation.

Successful hand and face transplantation in the last decade has firmly established the field of vascularized composite allotransplantation (VCA). The experience in VCA has thus far been very similar to solid organ transplantation in terms of the morbidity associated with long-term immunosuppression. The unique immunological features of VCA such as split tolerance and resistance to chronic rejection are being investigated. Simultaneously there has been laboratory work studying tolerogenic protocols in animal VCA models. In order to optimize VCA outcomes, translational studies are needed to develop less toxic immunosuppression and possibly achieve donor-specific tolerance. This article reviews the immunology, animal models, mixed chimerism & tolerance induction in VCA and the direction of future research to enable better understanding and wider application of VCA.

Neurobehavioral mechanisms of temporal processing deficits in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) disrupts temporal processing, but the neuronal sources of deficits and their response to dopamine (DA) therapy are not understood. Though the striatum and DA transmission are thought to be essential for timekeeping, potential working memory (WM) and executive problems could also disrupt timing. METHODOLOGY/FINDINGS: The present study addressed these issues by testing controls and PD volunteers 'on' and 'off' DA therapy as they underwent fMRI while performing a time-perception task. To distinguish systems associated with abnormalities in temporal and non-temporal processes, we separated brain activity during encoding and decision-making phases of a trial. Whereas both phases involved timekeeping, the encoding and decision phases emphasized WM and executive processes, respectively. The methods enabled exploration of both the amplitude and temporal dynamics of neural activity. First, we found that time-perception deficits were associated with striatal, cortical, and cerebellar dysfunction. Unlike studies of timed movement, our results could not be attributed to traditional roles of the striatum and cerebellum in movement. Second, for the first time we identified temporal and non-temporal sources of impaired time perception. Striatal dysfunction was found during both phases consistent with its role in timekeeping. Activation was also abnormal in a WM network (middle-frontal and parietal cortex, lateral cerebellum) during encoding and a network that modulates executive and memory functions (parahippocampus, posterior cingulate) during decision making. Third, hypoactivation typified neuronal dysfunction in PD, but was sometimes characterized by abnormal temporal dynamics (e.g., lagged, prolonged) that were not due to longer response times. Finally, DA therapy did not alleviate timing deficits. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that impaired timing in PD arises from nigrostriatal and mesocortical dysfunction in systems that mediate temporal and non-temporal control-processes. However, time perception impairments were not improved by DA treatment, likely due to inadequate restoration of neuronal activity and perhaps corticostriatal effective-connectivity.

Phase II study of neoadjuvant imatinib in glioblastoma: evaluation of clinical and molecular effects of the treatment.

PURPOSE: Phase I-II studies indicate that imatinib is active in glioblastoma multiforme. To better understand the molecular and clinical effects of imatinib in glioblastoma multiforme, we conducted a neoadjuvant study of imatinib with pretreatment and posttreatment biopsies. EXPERIMENTAL DESIGN: Patients underwent a computerized tomography-guided biopsy of their brain tumors. If diagnosed with glioblastoma multiforme, they were immediately treated with 7 days of imatinib 400 mg orally twice daily followed by either definitive surgery or re-biopsy. Pretreatment and posttreatment tissue specimens were tested by immunohistochemistry for Ki67 and microvessel destiny, and posttreatment specimens were analyzed for the presence of intact imatinib in tissue. Furthermore, pretreatment and posttreatment pairs were analyzed by Western blotting for activation of platelet-derived growth factor receptor, epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/AKT, and mitogen-activated protein kinase signaling pathways. Pharmacokinetic studies were also done. RESULTS: Twenty patients were enrolled. Median survival was 6.2 months. Intact imatinib was detected in the posttreatment tissue specimens using mass spectrometry. There was no evidence of a drug effect on proliferation, as evidenced by a change in Ki67 expression. Biochemical evidence of response, as shown by decreased activation of AKT and mitogen-activated protein kinase or increased p27 level, was detected in 4 of 11 patients with evaluable, matched pre- and post-imatinib biopsies. Two patients showed high-level EGFR activation and homozygous EGFR mutations, whereas one patient had high-level platelet-derived growth factor receptor-B activation. CONCLUSIONS: Intact imatinib was detected in glioblastoma multiforme tissue. However, the histologic and immunoblotting evaluations suggest that glioblastoma multiforme proliferation and survival mechanisms are not substantially reduced by imatinib therapy in most patients.

Predictors of health status in nondepressed and nondemented individuals with Parkinson's disease.

Recent studies have shown that self-perceived health status (HS) in Parkinson's disease (PD) is associated with motor, cognitive, or mood symptoms, with the greatest association typically occurring with mood. The purpose of this study was to determine if these associations are present in nondepressed and nondemented individuals with PD by using sensitive neuropsychological measures and statistically derived factors from mood and motor scales. The best predictors of poor HS in PD participants (N = 32) without dementia or depression were mood symptoms, specific to self-reported cognitive impairment and anxiety. Bivariate correlations between HS and number of correct categories on the Wisconsin Card Sorting Test and the gait-balance factor from the Unified Parkinson's Disease Rating Scale Part III were also significant or approached significance. These findings suggest that specific mood and cognitive symptoms continue to be important factors in HS in those individuals who lack clinical levels of depression or dementia.

Space-based but not object-based inhibition of return is impaired in Parkinson's disease.

Impairments in certain aspects of attention have frequently been reported in Parkinson's disease (PD), including reduced inhibition of return (IOR). Recent evidence suggests that IOR can occur when attention is directed at objects or locations, but previous investigations of IOR in PD have not systematically compared these two frames of reference. The present study compared the performance of 18 nondemented patients with PD and 18 normal controls on an IOR task with two conditions. In the "object-present" condition, objects surrounded the cues and targets so that attention was cued to both a spatial location and to a specific object. In the "object-absent" condition, surrounding objects were not presented so that attention was cued only to a spatial location. When participants had to rely on space-based cues, PD patients demonstrated reduced IOR compared to controls. In contrast, when objects were present in the display and participants could use object-based cues, PD patients exhibited normal IOR. These results suggest that PD patients are impaired in inhibitory aspects of space-based attention, but are able to overcome this impairment when their attention can be directed at object-based frames of reference. This dissociation supports the view that space-based and object-based components of attention involve distinct neurocognitive processes.

Spatial and object working memory deficits in Parkinson's disease are due to impairment in different underlying processes.

Working memory maintenance processes for visual-spatial and visual-object information were evaluated in patients with Parkinson's disease (PD). PD patients and controls performed a working memory task with two conditions that differed only in the aspect of the stimuli that the participant was instructed to remember: their locations or shapes. Maintenance processes were investigated by measuring accuracy over 1-s, 5-s, and 10-s delays. Results indicated that patients were impaired in maintaining object information over the delay. In contrast, the patients showed impairment on the spatial condition only when the to-be-remembered stimulus was highly similar in location to the probe, but this impairment was equivalent across the delays, suggesting that this deficit was not due to maintenance impairment. These results suggest that deficits in working memory for spatial and object information are mediated by distinct cognitive processes in nondemented patients with PD and may differ in their pathophysiological basis.

Implicit category learning performance predicts rate of cognitive decline in nondemented patients with Parkinson's disease.

Nondemented patients with Parkinson's disease (PD) are impaired in learning to categorize simple perceptual stimuli when category membership is defined by a nonlinear relationship between stimulus dimensions but not when the relationship is linear (J. V. Filoteo, W. T. Maddox, D. P. Salmon, & D. D. Song, 2005). In the present study, the authors examined whether performance in either of these 2 category learning conditions was predictive of global cognitive decline following a mean of 1.6 years since the time patients were 1st seen. Results indicated that final block accuracy in the nonlinear condition, but not the linear condition, predicted global cognitive decline. Performance on the Wisconsin Card Sorting Test (WCST) did not significantly predict global cognitive decline, although there was a trend for this to be the case. In addition, the association between nonlinear category learning and global cognitive decline was not impacted by patients' performance on the WCST. Results suggest that nonlinear category learning predicts cognitive decline in nondemented patients with PD and that nonlinear category learning and WCST performances may provide independent measures of integrity of the posterior and anterior caudate, respectively.

Characterizing rule-based category learning deficits in patients with Parkinson's disease.

Parkinson's disease (PD) patients and normal controls were tested in three category learning experiments to determine if previously observed rule-based category learning impairments in PD patients were due to deficits in selective attention or working memory. In Experiment 1, optimal categorization required participants to base their decision on a single stimulus dimension and ignore irrelevant variation on another dimension, thus emphasizing selective attention processes. In Experiment 2, optimal categorization required participants to base their decision on both stimulus dimensions using a conjunction of unidimensional decisions. Thus, this task placed less emphasis on selective attention and more on working memory. In Experiment 3, optimal categorization again required participants to base their decision on both stimulus dimensions using a disjunction of two unidimensional decisions in which an additional verbal operation was needed, thereby placing even greater emphasis on working memory. Results indicated that PD patients were impaired in the unidimensional rule-based condition, but not the other two rule-based conditions. These results are consistent with previous studies that demonstrate that PD patients are impaired in learning rule-based categories when selective attention demands are greatest, whereas these patients are normal in learning rule-based tasks when working memory demands are emphasized. Overall, these findings help to delineate the conditions under which PD patients display rule-based category learning deficits.

The impact of irrelevant dimensional variation on rule-based category learning in patients with Parkinson's disease.

This study examined the impact of irrelevant dimensional variation on rule-based category learning in patients with Parkinson's disease (PD), older controls (OC), and younger controls (YC). Participants were presented with 4-dimensional, binary-valued stimuli and were asked to categorize each into 1 of 2 categories. Category membership was based on the value of a single dimension. Four experimental conditions were administered in which there were zero, 1, 2, or 3 randomly varying irrelevant dimensions. Results indicated that patients with PD were impacted to a greater extent than both the OC and YC participants when the number of randomly varying irrelevant dimensions increased. These results suggest that the degree of working memory and selective attention requirements of a categorization task will impact whether PD patients are impaired in rule-based category learning, and help to clarify recent discrepancies in the literature.

Information-integration category learning in patients with striatal dysfunction.

Information-integration category learning was examined in patients with Parkinson's disease (PD) and in healthy control participants in 2 different conditions. In the linear condition, optimal categorization required a nonverbalizable linear integration of information from the 2 stimulus dimensions, whereas in the nonlinear condition, a nonlinear integration of information was required. Each participant completed 600 trials in each condition and was given corrective feedback following each trial. Results indicated that PD patients were not impaired in the linear condition across all trials, whereas the same patients were impaired in the nonlinear condition, but only later in training. The authors conducted model-based analyses to identify participants who used an information-integration approach, and a comparison of the accuracy rates of those individuals further revealed a specific deficit in information-integration category learning in patients with PD. These findings suggest that the striatum may be particularly involved in information-integration category learning when the rule is highly complex.

Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP.

Recent studies have implicated alpha-synuclein (alpha-S) in the pathogenesis of Parkinson's disease (PD). The mechanisms underlying PD are not completely understood; however, mitochondrial complex I inhibition and oxidative injury may be involved. Because the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent complex I inhibitor that can cause oxidative injury and mimic many aspects of PD in treated animals, we sought to determine whether the overexpression of alpha-S in transgenic (tg) mice (alpha-S-tg) would enhance the substantia nigra (SN) pathology resulting from treatment with MPTP. For this purpose, alpha-S-tg mice were produced expressing high levels of wild-type (wt) human alpha-S under the control of the neuron-specific Thy-1 promoter. Alpha-S-tg mice and non-tg controls were treated with MPTP (15 mg/kg ip, twice a week for 2 weeks) or saline (Sal) and then examined 2 weeks after completion of treatment by transmission electron microscopy (EM). We found that alpha-S-tg mice treated with MPTP had extensive mitochondrial alterations, increases in mitochondrial size, filamentous neuritic aggregations, axonal degeneration, and formation of electron dense perinuclear cytoplasmic inclusions in the SN that did not occur in the hippocampus or neocortex, nor in MPTP-treated non-tg mice or Sal-treated alpha-S-tg mice. These findings support the potential involvement of alpha-S expression in the vulnerability of SN neurons to toxicity from mitochondrial complex I inhibitors and the subsequent development of neurodegenerative pathology.