Neocortical Lewy Body Pathology Parallels Parkinson's Dementia, but Not Always.

OBJECTIVE: The objective of this study was to evaluate the relationship between Parkinson's disease (PD) with dementia and cortical proteinopathies in a large population of pathologically confirmed patients with PD. METHODS: We reviewed clinical data from all patients with autopsy data seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2019. All patients with a diagnosis of PD based on neuropathology were included. We used logistic regression and multivariate analysis of covariance (MANCOVA) to investigate the relationship between neuropathology and dementia. RESULTS: A total of 165 patients with PD met inclusion criteria. Among these, 128 had clinical dementia. Those with dementia had greater mean ages of motor onset and death but equivalent mean disease duration. The delay between motor symptom onset and dementia was 1 year or less in 14 individuals, meeting research diagnostic criteria for possible or probable dementia with Lewy bodies (DLB). Braak Lewy body stage was associated with diagnosis of dementia, whereas severities of Alzheimer's disease neuropathologic change (ADNC) and small vessel pathology did not. Pathology of individuals diagnosed with DLB did not differ significantly from that of other patients with PD with dementia. Six percent of individuals with PD and dementia did not have neocortical Lewy bodies; and 68% of the individuals with PD but without dementia did have neocortical Lewy bodies. INTERPRETATION: Neocortical Lewy bodies almost always accompany dementia in PD; however, they also appear in most PD patients without dementia. In some cases, dementia may occur in patients with PD without neocortical Lewy bodies, ADNC, or small vessel disease. Thus, other factors not directly related to these classic neuropathologic features may contribute to PD dementia. ANN NEUROL 2023;93:184-195.

Pedunculopontine Nucleus Dysconnectivity Correlates With Gait Impairment in Parkinson's Disease: An Exploratory Study.

Background: Gait impairment is a debilitating and progressive feature of Parkinson's disease (PD). Increasing evidence suggests that gait control is partly mediated by cholinergic signaling from the pedunculopontine nucleus (PPN). Objective: We investigated whether PPN structural connectivity correlated with quantitative gait measures in PD. Methods: Twenty PD patients and 15 controls underwent diffusion tensor imaging to quantify structural connectivity of the PPN. Whole brain analysis using tract-based spatial statistics and probabilistic tractography were performed using the PPN as a seed region of interest for cortical and subcortical target structures. Gait metrics were recorded in subjects' medication ON and OFF states, and were used to determine if specific features of gait dysfunction in PD were related to PPN structural connectivity. Results: Tract-based spatial statistics revealed reduced structural connectivity involving the corpus callosum and right superior corona radiata, but did not correlate with gait measures. Abnormalities in PPN structural connectivity in PD were lateralized to the right hemisphere, with pathways involving the right caudate nucleus, amygdala, pre-supplementary motor area, and primary somatosensory cortex. Altered connectivity of the right PPN-caudate nucleus was associated with worsened cadence, stride time, and velocity while in the ON state; altered connectivity of the right PPN-amygdala was associated with reduced stride length in the OFF state. Conclusion: Our exploratory analysis detects a potential correlation between gait dysfunction in PD and a characteristic pattern of connectivity deficits in the PPN network involving the right caudate nucleus and amygdala, which may be investigated in future larger studies.

Subcortical microstructural diffusion changes correlate with gait impairment in Parkinson's disease.

BACKGROUND: Gait impairments are common in Parkinson's Disease (PD) and are likely caused by degeneration in multiple brain circuits, including the basal ganglia, thalamus and mesencephalic locomotion centers (MLC). Diffusion tensor imaging (DTI) assesses fractional anisotropy (FA) and mean diffusivity (MD) that reflect the integrity of neuronal microstructure. We hypothesized that DTI changes in motor circuits correlate with gait changes in PD. OBJECTIVE: We aimed to identify microstructural changes of brain locomotion control centers in PD via DTI and their correlations with clinical and quantitative measures of gait. METHODS: Twenty-one PD patients reporting gait impairment and 15 controls were recruited. Quantitative gait and clinical tests were recorded in PD subjects' medication ON and OFF states. Region of Interest (ROI) analysis of the thalamus, basal ganglia and MLC was performed using ExploreDTI. Correlations between FA/MD with clinical gait parameters were examined. RESULTS: Microstructural changes were seen in the thalamus, caudate and MLC in the PD compared to the control group. Thalamic microstructural changes significantly correlated with gait parameters in the pace domain including the Timed Up and Go in the ON state. Caudate changes correlated with cadence and stride time in the OFF state. CONCLUSIONS: Our pilot study suggests that PD is associated with a characteristic regional pattern of microstructural degradation in the thalamus, caudate and MLC. The DTI changes may represent subcortical locomotion network failure. Overall, DTI ROI analyses might provide a useful tool for assessing PD for functional status and specific motor domains, such as gait, and potentially could serve as an imaging marker.

Is Levodopa Response a Valid Indicator of Parkinson's Disease?

BACKGROUND: The clinical diagnosis of Parkinson's disease (PD) requires the presence of parkinsonism and supportive criteria that include a clear and dramatic beneficial response to dopaminergic therapy. Our aim was to test the diagnostic criterion of dopaminergic response by evaluating its association with pathologically confirmed diagnoses in a large population of parkinsonian patients. METHODS: We reviewed clinical data maintained in an electronic medical record from all patients with autopsy data who had been seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2018. All patients with parkinsonism who underwent postmortem neuropathologic examination were included in this analysis. RESULTS: There were 257 unique parkinsonian patients with autopsy-based diagnoses who had received dopaminergic therapy. Marked or moderate response to dopaminergic therapy occurred in 91.2% (166/182) of those with autopsy-confirmed PD, 52.0% (13/25) of those with autopsy-confirmed multiple systems atrophy, 44.4% (8/18) of those with autopsy-confirmed progressive supranuclear palsy, and 1 (1/8) with autopsy-confirmed corticobasal degeneration. Other diagnoses were responsible for the remaining 24 individuals, 9 of whom had a moderate response to dopaminergic therapy. CONCLUSION: A substantial response to dopaminergic therapy is frequent but not universal in PD. An absent response does not exclude PD. In other neurodegenerative disorders associated with parkinsonism, a prominent response may also be evident, but this occurs less frequently than in PD. © 2020 International Parkinson and Movement Disorder Society.

Pathologic correlates of supranuclear gaze palsy with parkinsonism.

INTRODUCTION: Supranuclear gaze palsy (SGP) is a classic clinical feature of progressive supranuclear palsy (PSP) but is not specific for this diagnosis and has been reported to occur in several other neurodegenerative parkinsonian conditions. Our objective was to evaluate the association between SGP and autopsy-proven diagnoses in a large population of patients with parkinsonism referred to a tertiary movement disorders clinic. METHODS: We reviewed clinical and autopsy data maintained in an electronic medical record from all patients seen in the Movement Disorders Clinic at Washington University, St. Louis between 1996 and 2015. All patients with parkinsonism from this population who had subsequent autopsy confirmation of diagnosis underwent further analysis. RESULTS: 221 unique parkinsonian patients had autopsy-proven diagnoses, 27 of whom had SGP documented at some point during their illness. Major diagnoses associated with SGP were: PSP (9 patients), Parkinson disease (PD) (10 patients), multiple system atrophy (2 patients), corticobasal degeneration (2 patients), Creutzfeld-Jakob disease (1 patient) and Huntington disease (1 patient). In none of the diagnostic groups was the age of onset or disease duration significantly different between cases with SGP and those without SGP. In the PD patients, the UPDRS motor score differed significantly between groups (p = 0.01) with the PD/SGP patients having greater motor deficit than those without SGP. CONCLUSION: Although a common feature of PSP, SGP is not diagnostic for this condition and can be associated with other neurodegenerative causes of parkinsonism including PD.

Regional volumetric change in Parkinson's disease with cognitive decline.

BACKGROUND: Parkinson's disease (PD), characterized by motor dysfunction and cognitive decline, may demonstrate specific patterns of brain atrophy. Although cross-sectional magnetic resonance imaging (MRI) studies show correlation between regional brain volume loss and cognitive impairment, there is only scarce evidence from longitudinal studies validating the link between cognition and brain anatomy in PD. OBJECTIVE: To test the relationship between magnitude and spatial extent of atrophy in PD patients with progressive, significant cognitive decline and dementia (PDD). METHODS: We followed thirty-three initially non-demented patients with prevalent PD for three years while monitoring cognitive function and brain atrophy. Longitudinally acquired T1-weighted magnetic resonance images were analyzed in the voxel-based morphometry framework of SPM. RESULTS: Groups did not differ significantly with respect to age or gender. More males developed PDD (7 males, 3 females) compared to those remaining intact (12 males, 11 females). Clusters of lower grey matter volume were found in PDD compared to PD in left uncus at baseline and an expanded region that included the left hippocampus and parahippocampal gyrus at 36months. The cognitive status by scan interaction showed differential changes between groups in the right insula. At a more liberal statistical threshold we observed changes in the right insula and bilateral hippocampi as well as the right cuneus additional to the lower brain stem. CONCLUSIONS: Region specific atrophy, consistent with the pattern of cortical Lewy body deposition seen in autopsy studies, can be detected with MRI in PD patients with significant cognitive decline. MRI may be useful for tracking cognitive decline in PD.

Parkinson Disease: The Relationship Between Non-motor Symptoms and Motor Phenotype.

BACKGROUND: Parkinson disease (PD) presents with motor and non-motor symptoms (NMS). The NMS often precede the onset of motor symptoms, but may progress throughout the disease course. Tremor dominant, postural instability gait difficulty (PIGD), and indeterminate phenotypes can be distinguished using Unified PD Rating scales (UPDRS-III). We hypothesized that the PIGD phenotype would be more likely to develop NMS, and that the non-dopamine-responsive axial signs would correlate with NMS severity. METHODS: We conducted a retrospective cross-sectional chart review to assess the relationship between NMS and PD motor phenotypes. PD patients were administered the NMS Questionnaire, the UPDRS-III, and the Mini-Mental State Examination score. The relationship between NMS burden and PD subtypes was examined using linear regression models. The prevalence of each NMS among difference PD motor subtypes was analyzed using chi-square test. RESULTS: PD patients with more advanced disease based on their UPDRS-III had higher NMS Questionnaire scores. The axial component of UPDRS-III correlated with higher NMS. There was no correlation between NMS and tremor scores. There was a significant correlation between PIGD score and higher NMS burden. PIGD group had higher prevalence in most NMS domains when compared with tremor dominant and indeterminate groups independent of disease duration and severity. CONCLUSIONS: NMS profile and severity vary according to motor phenotype. We conclude that in the PD population, patients with a PIGD phenotype who have more axial involvement, associated with advanced disease and poor motor response, have a higher risk for a higher NMS burden.

Freezing of gait in early Parkinson's disease: Nigral iron content estimated from magnetic resonance imaging.

PURPOSE: Freezing of gait is a major source of disability associated with the progression of Parkinson's disease (PD). Our objective was to determine whether evolving changes in nigral iron content in association with declining motor function in early PD differentiates subjects who develop freezing from those who do not. METHODS: A cohort of previously untreated individuals with early PD (n=19) was followed for 36 months clinically and with MRI. The cohort was divided into two groups based on the development of freezing during follow-up. A multiple gradient echo MRI sequence provided an index of basal ganglia iron content. RESULTS: There were significant baseline differences between those who developed freezing (n=7) and those who did not (n=12) in Unified Parkinson's Disease Rating Scale motor scores, time to complete a 14 m walk and timed up and go. There was a significant correlation between the measured change in transverse relaxation in the lateral substantia nigra pars compacta and the change in motor score from baseline to 36 months (p=0.002). The freezing group showed a greater change in motor score and iron content than did the non-freezing group. CONCLUSIONS: Individuals destined to develop freezing early in PD have more motor impairment at baseline, more rapid deterioration in motor function, and pars compacta changes suggestive of increased iron content in comparison to those who do not.

Porewater dynamics of silver, lead and copper in coastal sediments and implications for benthic metal fluxes.

To determine the conditions that lead to a diffusive release of dissolved metals from coastal sediments, porewater profiles of Ag, Cu, and Pb have been collected over seven years at two contrasting coastal sites in Massachusetts, USA. The Hingham Bay (HB) site is a contaminated location in Boston Harbor, while the Massachusetts Bay (MB) site is 11 km offshore and less impacted. At both sites, the biogeochemical cycles include scavenging by Fe-oxyhydroxides and release of dissolved metals when Fe-oxyhydroxides are reduced. Important differences in the metal cycles at the two sites, however, result from different redox conditions. Porewater sulfide and seasonal variation in redox zone depth is observed at HB, but not at MB. In summer, as the conditions become more reducing at HB, trace metals are precipitated as sulfides and are no longer associated with Fe-oxyhydroxides. Sulfide precipitation close to the sediment-water interface limits the trace metal flux in summer and autumn at HB, while in winter, oxidation of the sulfide phases drives high benthic fluxes of Cu and Ag, as oxic conditions return. The annual diffusive flux of Cu at HB is found to be significant and contributes to the higher than expected water column Cu concentrations observed in Boston Harbor. At MB, due to the lower sulfide concentrations, the association of trace metals with Fe-oxyhydroxides occurs throughout the year, leading to more stable fluxes. A surface enrichment of solid phase trace metals was found at MB and is attributed to the persistent scavenging by Fe-oxyhydroxides. This process is important, particularly at sites that are less reducing, because it maintains elevated metal concentrations at the surface despite the effects of bioturbation and sediment accumulation, and because it may increase the persistence of metal contamination in surface sediments.

Longitudinal midbrain changes in early Parkinson's disease: iron content estimated from R2*/MRI.

OBJECTIVE: To determine whether, in patients with early Parkinson's disease (PD), longitudinal changes in midbrain iron content are associated with declining motor function over a period of three years. METHODS: Nineteen untreated subjects with early PD and 13 age- and sex-matched controls were followed clinically for 36 months. MRI with a 3 T magnet was performed at baseline, 18 months and 36 months with a multiple gradient echo sequence designed for rapid single-scan mapping of the proton transverse relaxation rate R2*. R2* was calculated for midbrain and forebrain basal ganglia regions. RESULTS: A difference in R2* between patients and controls was observed at baseline (p = 0.035) but not at 18 or 36 months in the lateral substantia nigra pars compacta (SNc). Linear regression indicated significant correlations between the change in R2* in the lateral SNc and the change score in UPDRS III (p = 0.008) and the PDQ-39 -mobility sub-score (p = 0.03) from baseline to 36 months. R2* tended to increase in those with more advanced disease and to decrease in those with milder disease. CONCLUSIONS: High field MRI demonstrates lateral SNc abnormalities that progress over 3 years in early PD consistent with increased iron content in those with more advanced disease, corresponding to the known distribution of neuronal loss occurring in this disorder, and correlating with motor symptomatology. Larger and longer investigations with more precise mapping of iron-containing midbrain structures are needed to fully evaluate the potential of R2* as a biomarker of disease progression in PD.

Dopamine transporter imaging as a diagnostic tool for parkinsonism and related disorders in clinical practice.

BACKGROUND: Accurate diagnosis of Parkinson disease (PD) and other degenerative parkinsonian syndromes is important for management and prognostic purposes. Diagnosis can be challenging in early disease and in atypical cases. METHODS: We reviewed the literature on the application of dopamine transporter single-photon emission computed tomography (DAT-SPECT) in degenerative parkinsonism and related disorders as a diagnostic tool. RESULTS: The use of DAT-SPECT shows some utility in the early diagnosis of PD and differentiation from other non-degenerative parkinsonian disorders (i.e. essential tremor, dystonic tremor, drug-induced and in most cases of psychogenic parkinsonism), since it can accurately detect the presynaptic dopaminergic deficit. The test has been shown to have high sensitivity/specificity by multiple studies. DAT imaging may also have some prognostic value for disease progression. However, it has limited value in differentiating among degenerative causes of parkinsonism. DAT imaging has some limitations. In most studies, true test accuracy is unknown since the gold standard is clinical diagnosis by a movement disorders neurologist. Therefore, the sensitivity of the test cannot exceed that of the clinical diagnosis. In addition, false negative scans occur and highlight the need for clinical follow-up. CONCLUSION: Clinical assessment remains the most important aspect in evaluating these patients. DAT-SPECT is a sensitive modality to detect nigrostriatal degeneration. In spite of increasing data using this technique, however, more long-term clinical studies are required to determine how DAT-SPECT scan can guide decision-making.

Reproduction in grazing dairy cows treated with 14-day controlled internal drug release for presynchronization before timed artificial insemination compared with artificial insemination after observed estrus.

Progesterone-releasing (controlled internal drug release, CIDR) devices inserted for 14 d are used to presynchronize the estrous cycle for timed artificial insemination (TAI) in beef heifers (14-d CIDR-PGF(2α) program). The objective was to test a similar program in dairy cows by measuring first-service conception rates (FSCR), pregnancy rates after 2 AI, and time to pregnancy compared with a control (AI after observed estrus). Postpartum cows (Holstein, Jersey, or crossbred; n=1,363) from 4 grazing dairy farms were assigned to 1 of 2 programs: 14dCIDR_TAI [CIDR in for 14 d, CIDR out, PGF(2α) injection at 19 d after CIDR removal, GnRH injection 56 h later, and then TAI 16 h later; n=737] or control [AI after observed estrus; reproductive program with PGF(2α) (cycling cows) and CIDR (noncycling cows) to synchronize estrus with the start of the breeding season; n=626]. Body condition was scored (1 to 5; thin to fat) at the start of the trial. The interval from the start of the breeding period (final PGF(2α) injection of either program) to first AI was shorter for 14dCIDR_TAI compared with the control (3.0±0.2 vs. 5.3±0.2 d; mean ± SEM) but 14dCIDR_TAI cows had lesser FSCR than controls (48 vs. 61%). Farm affected FSCR (50, 51, 67, and 58% for farms 1 to 4). The BCS affected FSCR (50, 55, and 62% for BCS=2, 2.5, and 3, respectively). Cows that either calved the year before (carryover) or that calved early in the calving season had greater FSCR than cows that calved later in the calving season (55, 61, and 42%, respectively). The percentage of cows pregnant to AI (first and second inseminations within 31-d breeding season) was similar for 14dCIDR_TAI and control (64 vs. 70%) cows, but farm (64, 62, 80, and 69%) and time of calving (70, 76, and 56%: carryover, early, and late, respectively) affected the percentage. Survival analyses showed an initial advantage for 14dCIDR_TAI (more cows inseminated and more pregnancies achieved early in the breeding season) that was not maintained over time. Conclusions were that the 14dCIDR_TAI program achieved acceptable FSCR (48%) and overall AI pregnancy rates (64%), but did not surpass a control program that used AI after observed estrus (61 and 70%, respectively).

Short communication: presynchronization for timed artificial insemination in grazing dairy cows by using progesterone for 14 days with or without prostaglandin F2α at the time of progesterone withdrawal.

Progesterone-containing devices can be inserted intravaginally for 14 d to presynchronize the estrous cycle for timed artificial insemination (TAI) in beef heifers ("14-day CIDR-PG" or "Show-Me-Synch" program). The progesterone treatment is effective for presynchronization because cattle develop a persistent dominant follicle during treatment that ovulates within 3 d after progesterone removal. The subsequent estrous cycle can be effectively used for a TAI program. Some cattle will retain a functional corpus luteum (CL) for the entire 14-d treatment period and will not be synchronized effectively because the interval to ovulation depends on the lifespan of their existing CL. The objective was to test the effect of a luteolytic dose of PGF(2α) at progesterone removal for improving synchrony of estrus after treatment and increasing conception rate to a subsequent TAI in dairy cows. Postpartum cows (n = 1,021) from 2 grazing dairy herds were assigned to 1 of 2 presynchronization programs that used a controlled internal drug releasing (CIDR) device containing progesterone: 14dCIDR (CIDR in, 14 d, CIDR out; n = 523) or 14dCIDR+PGF(2α) (CIDR in, 14 d, CIDR out, and PGF(2α); n = 498). Cows were body condition scored (BCS; 1 to 5, thin to fat) and tail painted at CIDR removal. Paint score (PS) was recorded after CIDR removal [PS = 0 (all paint removed, indication of estrus), PS = 3 (paint partially removed), or PS = 5 (no paint removed; indication of no estrus)]. At 19 d after CIDR removal, all cows were treated with PGF(2α), 56 h later treated with GnRH, and then 16 h later were TAI. Treating cows with PGF(2α) at CIDR removal increased the percentage with PS = 0 within 5 d (58.1% vs. 68.9%; 14dCIDR vs. 14dCIDR+PGF(2α)). We found no effect of treatment, however, on conception rate at TAI (41.1% vs. 43.6%; respectively). The TAI conception rate increased with increasing BCS and was greater for cows that had PS = 0 within 5 d after CIDR removal. In summary, treating cows with PGF(2α) at CIDR removal increased the percentage of cows with all tail paint removed but did not increase percentage of pregnant cows after TAI.

Incidence and mortality of Parkinson's disease in older Canadians.

OBJECTIVE: To estimate the age-specific incidence of Parkinson's disease (PD) in elderly persons in the Canadian province of British Columbia (BC). All-cause and injury mortalities and relative risk of death for those persons with PD were also examined. METHODS: A historical cohort study was conducted using 5 provincial administrative databases from 1991/92 to 2000/2001. A series of algorithms based on the databases were created for case ascertainment of PD for persons 65 years or older. Crude and age-specific incidence and mortality rates were calculated using person-years of follow-up as the denominator. The impact of PD on all-cause and injury mortalities was examined using multivariate Cox regression models to provide adjusted hazard ratios. RESULTS: 10,910 incidence cases over 6,051,682 person-years of follow-up were identified. The crude annual incidence rate was 252 per 100,000 person-years. Over the nine year period, age standardized incidence for males ranged from 207 to 396 per 100,000 person-years and 127 to 259 per 100,000 person-years for females. Persons with PD were at a 43% greater risk of all-cause mortality and specifically, 51% greater risk of injury mortality. CONCLUSIONS: Incidence of PD is substantially higher in advanced age with age adjusted increases for both all-cause and injury mortalities. These findings also highlight falls as a primary factor for injury mortality in PD.