Sharon X. Xie

Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease

Background: Due to the high prevalence of mild cognitive impairment (MCI) and dementia in Parkinson disease (PD), routine cognitive screening is important for the optimal management of patients with PD. The Montreal Cognitive Assessment (MoCA) is more sensitive than the commonly used Mini-Mental State Examination (MMSE) in detecting MCI and dementia in patients without PD, but its validity in PD has not been established. Methods: A representative sample of 132 patients with PD at 2 movement disorders centers was administered the MoCA, MMSE, and a neuropsychological battery with operationalized criteria for deficits. MCI and PD dementia (PDD) criteria were applied by an investigator blinded to the MoCA and MMSE results. The discriminant validity of the MoCA and MMSE as screening and diagnostic instruments was ascertained. Results: Approximately one third of the sample met diagnostic criteria for a cognitive disorder (12.9% PDD and 17.4% MCI). Mean (SD) MoCA and MMSE scores were 25.0 (3.8) and 28.1 (2.0). The overall discriminant validity for detection of any cognitive disorder was similar for the MoCA and the MMSE (receiver operating characteristic area under the curve [95% confidence interval]): MoCA (0.79 [0.72, 0.87]) and MMSE (0.76 [0.67, 0.85]), but as a screening instrument the MoCA (optimal cutoff point = 26/27, 64% correctly diagnosed, lack of ceiling effect) was superior to the MMSE (optimal cutoff point = 29/30, 54% correctly diagnosed, presence of ceiling effect). Conclusions: The Montreal Cognitive Assessment, but not the Mini-Mental State Examination, has adequate psychometric properties as a screening instrument for the detection of mild cognitive impairment or dementia in Parkinson disease. However, a positive screen using either instrument requires additional assessment due to suboptimal specificity at the recommended screening cutoff point.

Neuropathologic substrates of Parkinson disease dementia.

A study was undertaken to examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson disease (PD).

CSF amyloid β 1-42 predicts cognitive decline in Parkinson disease

Objective: Cognitive decline associated with Parkinson disease (PD) is common and highly disabling. Biomarkers that help identify patients at risk for cognitive decline would be useful additions to the clinical management of the disease. Methods: A total of 45 patients with PD were enrolled in this prospective cohort study and had at least 1 yearly longitudinal follow-up evaluation. CSF was collected at baseline and cognition was assessed at baseline and follow-up visits using the Mattis Dementia Rating Scale (DRS-2). CSF was tested for amyloid β 1-42 (Aβ1-42), p-tau181p, and total tau levels using the Luminex xMAP platform. Mixed linear models were used to test for associations between baseline CSF biomarker levels and change in cognition over time. Results: Lower baseline CSF Aβ1-42 was associated with more rapid cognitive decline. Subjects with CSF Aβ1-42 levels ≤192 pg/mL declined an average of 5.85 (95% confidence interval 2.11–9.58, p = 0.002) points per year more rapidly on the DRS-2 than subjects above that cutoff, after adjustment for age, disease duration, and baseline cognitive status. CSF total tau and p-tau181p levels were not significantly associated with cognitive decline. Conclusions: Reduced CSF Aβ1-42 was an independent predictor of cognitive decline in patients with PD. This observation is consistent with previous research showing that Alzheimer disease pathology contributes to cognitive impairment in PD. This biomarker may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD.

Evidence of Multisystem Disorder in Whole-Brain Map of Pathological TDP-43 in Amyotrophic Lateral Sclerosis

BACKGROUND Pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) has been identified recently as the major disease protein in amyotrophic lateral sclerosis (ALS), and in frontotemporal lobar degeneration with ubiquitinated inclusions, with or without motor neuron disease, but the distribution of TDP-43 pathology in ALS may be more widespread than previously described. OBJECTIVE To determine the extent of TDP-43 pathology in the central nervous systems of patients with clinically confirmed and autopsy confirmed diagnoses of ALS. DESIGN Performance of an immunohistochemical whole-central nervous system scan for evidence of pathological TDP-43 in ALS patients. SETTING An academic medical center. PARTICIPANTS We included 31 patients with clinically and pathologically confirmed ALS and 8 control participants. MAIN OUTCOME MEASURES Immunohistochemistry and double-labeling immunofluorescence to assess the frequency and severity of TDP-43 pathology. RESULTS In addition to the stereotypical involvement of upper and lower motor neurons, neuronal and glial TDP-43 pathology was present in multiple areas of the central nervous systems of ALS patients, including in the nigro-striatal system, the neocortical and allocortical areas, and the cerebellum, but not in those of the controls. CONCLUSIONS These findings suggest that ALS does not selectively affect only the pyramidal motor system, but rather is a multisystem neurodegenerative TDP-43 proteinopathy.

The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice

Neurodegenerative tauopathies, such as Alzheimers disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-stabilizing compound will provide benefit in a transgenic model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing.

Clinical and Pathological Continuum of Multisystem TDP-43 Proteinopathies

OBJECTIVE To determine the extent of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system of patients with clinically and autopsy-confirmed diagnoses of frontotemporal lobar degeneration with and without motor neuron disease and amyotrophic lateral sclerosis with and without cognitive impairment. DESIGN Performance of immunohistochemical whole-central nervous system scans for evidence of pathological TDP-43 and retrospective clinical medical record review. SETTING An academic medical center. PARTICIPANTS We included 64 patients with clinically and pathologically confirmed frontotemporal lobar degeneration with ubiquitinated inclusions with or without motor neuron disease and amyotrophic lateral sclerosis with or without cognitive impairment. MAIN OUTCOME MEASURE Neuronal and glial TDP-43 pathology. RESULTS We found evidence of neuronal and glial TDP-43 pathology in all disease groups throughout the neuraxis, albeit with variations in the frequency, morphology, and distribution of TDP-43 lesions. Moreover, the major clinical manifestations (eg, cognitive impairments, motor neuron signs, extrapyramidal symptoms, neuropsychiatric features) were reflected by the predominant distribution and burden of TDP-43 pathology. CONCLUSION These findings strongly suggest that amyotrophic lateral sclerosis, frontotemporal lobar degeneration with amyotrophic lateral sclerosis or motor neuron disease, and frontotemporal lobar degeneration with ubiquitinated inclusions are different manifestations of a multiple-system TDP-43 proteinopathy linked to similar mechanisms of neurodegeneration.

Epothilone D Improves Microtubule Density, Axonal Integrity and Cognition in a Transgenic Mouse Model of Tauopathy

Neurons in the brains of those with Alzheimers disease (AD) and many frontotemporal dementias (FTDs) contain neurofibrillary tangles comprised of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs), and tau misfolding could lead to a loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, a possible therapeutic strategy for AD and related “tauopathies” is treatment with a MT-stabilizing anti-cancer drug such as paclitaxel. However, paclitaxel and related taxanes have poor blood–brain barrier permeability and thus are unsuitable for diseases of the brain. We demonstrate here that the MT-stabilizing agent, epothilone D (EpoD), is brain-penetrant and we subsequently evaluated whether EpoD can compensate for tau loss-of-function in PS19 tau transgenic mice that develop forebrain tau inclusions, axonal degeneration and MT deficits. Treatment of 3-month-old male PS19 mice with low doses of EpoD once weekly for a 3 month period significantly improved CNS MT density and axonal integrity without inducing notable side-effects. Moreover, EpoD treatment reduced cognitive deficits that were observed in the PS19 mice. These results suggest that certain brain-penetrant MT-stabilizing agents might provide a viable therapeutic strategy for the treatment of AD and FTDs.

Pathological TDP-43 in parkinsonism–dementia complex and amyotrophic lateral sclerosis of Guam

Pathological TDP-43 is the major disease protein in frontotemporal lobar degeneration characterized by ubiquitin inclusions (FTLD-U) with/without motor neuron disease (MND) and in amyotrophic lateral sclerosis (ALS). As Guamanian parkinsonism–dementia complex (PDC) or Guamanian ALS (G-PDC or G-ALS) of the Chamorro population may present clinically similar to FTLD-U and ALS, TDP-43 pathology may be present in the G-PDC and G-ALS. Thus, we examined cortical or spinal cord samples from 54 Guamanian subjects for evidence of TDP-43 pathology. In addition to cortical neurofibrillary and glial tau pathology, G-PDC was associated with cortical TDP-43 positive dystrophic neurites and neuronal and glial inclusions in gray and/or white matter. Biochemical analyses showed the presence of FTLD-U-like insoluble TDP-43 in G-PDC, but not in Guam controls (G-C). Spinal cord pathology of G-PDC or G-ALS was characterized by tau positive tangles as well as TDP-43 positive inclusions in lower motor neurons and glial cells. G-C had variable tau and negligible TDP-43 pathology. These results indicate that G-PDC and G-ALS are associated with pathological TDP-43 similar to FTLD-U with/without MND as well as ALS, and that neocortical or hippocampal TDP-43 pathology distinguishes controls from disease subjects better than tau pathology. Finally, we conclude that the spectrum of TDP-43 proteinopathies should be expanded to include neurodegenerative cognitive and motor diseases, affecting the Chamorro population of Guam.

The ability of persons with Alzheimer disease (AD) to make a decision about taking an AD treatment.

Objective: To examine the severity of impairments in the decision-making abilities (understanding, appreciation, reasoning, and choice) and competency to make a decision to use an Alzheimer disease (AD)-slowing medication in patients with AD and the relationships between these impairments, insight, and overall cognition. Methods: Semistructured in-home interviews were conducted with 48 patients with very mild to moderate AD and 102 family caregivers of patients with mild to severe AD recruited from the Memory Disorders Clinic of an AD center. The interview measured performance on the decision-making abilities and three expert psychiatrists’ judgment of competency based on their independent review of the patient interviews. Results: There was considerable variation in patients’ performance on the measures of decision-making abilities. Three expert raters found 19 of 48 (40%) of the subjects competent. Competent patients were more likely to show awareness of their symptoms, prognosis, and diagnosis. A sensitivity analysis suggests that a MMSE score is helpful in discriminating capacity from incapacity only when below 19 or above 23. Conclusions: Persons with mild to moderate Alzheimer disease (AD) have notable impairments in their ability to make an AD treatment decision, especially persons with moderate AD and persons who lack awareness of symptoms, prognosis, or diagnosis.

Symptom Burden Among Cancer Survivors: Impact of Age and Comorbidity

Background: Previous research among specific cancer populations has shown high but variable symptom burden; however, very little is known about its extent and pattern among the entire population of US cancer survivors, which is more clinically relevant to primary care physicians. Methods: To determine the prevalence of ongoing symptom burden among cancer survivors and compare it with the general population without cancer, we analyzed data from the 2002 National Health Interview Survey, which included 1,904 cancer survivors and 29,092 controls. Main outcome measures included self-reported ongoing pain, psychological distress, and insomnia. Multivariate logistic regression models were used to adjust for confounders and test for interactions. Results: The rates of ongoing pain, psychological distress, and insomnia among cancer survivors were 34%, 26%, and 30%, respectively, and were significantly higher (all P < .001) than controls without a history of cancer (18%, 16%, and 17%). Compared with controls in the same age groups, younger survivors (younger than 50) were much more likely to report ongoing symptoms than older survivors (older than 64); adjusted odds ratios were 2.96 and 1.36 for pain in the respective age groups (P < .001). Comorbidities also interact with cancer status and contribute to a marked increase in reports of ongoing symptom burden among cancer survivors, with a greater number of comorbidities leading to greater degree of symptom burden in a dose-dependent manner (P < .001). Conclusions: The symptom burden among cancer survivors on a population level is substantial and can be impacted by other comorbidities. Thus, engaging primary care physicians in the design, testing, and implementation of effective interventions is important to reduce the symptom burden among cancer survivors.