Raymond Y. Lo

Depression and clinical progression in spinocerebellar ataxias

BACKGROUND Depression is a common comorbidity in spinocerebellar ataxias (SCAs) but its association with ataxia progression is not well understood. OBJECTIVES To study the prevalence and influence of depressive symptoms in SCAs. METHODS We studied 300 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and repeatedly measured depressive symptoms by the 9-item Patient Health Questionnaire (PHQ-9) along with other clinical features including ataxia, functional status, and quality of life every 6 months for 2 years. We employed regression models to study the effects of depressive symptoms on clinical progression indexed by Scale for Assessment and Rating of Ataxia (SARA), Unified Huntingtons Disease Rating Scale Part IV (UHDRS-IV) and EQ5D after adjusting for age, sex and pathological CAG repeats. RESULTS Comorbid depression is common in SCAs (26%). Although the baseline prevalence of depression was similar among different SCA types, suicidal ideation was more frequently reported in SCA3 (65%). Depressive symptoms were associated with SARA scores but did not significantly progress over time within 2 years or deteriorate by increased numbers of pathological CAG repeats. The effects of depression on ataxia progression varied across different SCA types. Nevertheless, depression had consistently negative and significant impact on functional status and quality of life in all SCAs, even after accounting for ataxia progression. CONCLUSIONS Depressive symptoms are not simply the consequence of motor disability in SCAs. Comorbid depression per se contributes to different health outcomes and deserves more attention when caring patients with SCAs.

New molecular insights into cellular survival and stress responses: neuroprotective role of cellular prion protein (PrPC).

Knowledge of the physiological function of cellular prion protein has been acquired from prion diseases such as Creutzfeldt–Jakob disease, as well as PRNP knock out and transgenic mice. Recent progress in neurobiology has further delineated the neuroprotective role played by cellular prion protein. In this paper, we review the role of cellular prion protein in cell survival including its antiapoptotic effect on Bax-mediated cell death and its responses to various environmental stresses including oxidative stress, and ischemia. Finally, we discuss the significance of cellular prion protein in different neurodegenerative diseases and the possible development of future therapies.

Coenzyme Q10 and spinocerebellar ataxias

The aim of this study was to investigate the association between drug exposure and disease severity in SCA types 1, 2, 3 and 6. The Clinical Research Consortium for Spinocerebellar Ataxias (CRC‐SCA) enrolled 319 participants with SCA1, 2, 3, and 6 from 12 medical centers in the United States and repeatedly measured clinical severity by the Scale for Assessment and Rating of Ataxia (SARA), the Unified Huntingtons Disease Rating Scale part IV (UHDRS‐IV), and the 9‐item Patient Health Questionnaire during July 2009 to May 2012. We employed generalized estimating equations in regression models to study the longitudinal effects of coenzyme Q10 (CoQ10), statin, and vitamin E on clinical severity of ataxia after adjusting for age, sex, and pathological CAG repeat number. Cross‐sectionally, exposure to CoQ10 was associated with lower SARA and higher UHDRS‐IV scores in SCA1 and 3. No association was found between statins, vitamin E, and clinical outcome. Longitudinally, CoQ10, statins, and vitamin E did not change the rates of clinical deterioration indexed by SARA and UHDRS‐IV scores within 2 years. CoQ10 is associated with better clinical outcome in SCA1 and 3. These drug exposures did not appear to influence clinical progression within 2 years. Further studies are warranted to confirm the association.

Longitudinal Alteration of Intrinsic Brain Activity in the Striatum in Mild Cognitive Impairment

The striatum is a critical functional hub in understanding neurological disorders. However, the Alzheimers disease (AD)-associated striatal change is unclear, as is the relationship between striatal change and AD pathology. Three-year resting-state fMRI data from 15 healthy control (HC) and 20 mild cognitive impairment (MCI) participants were obtained. We analyzed the amplitude of low-frequency fluctuations (ALFF) (0.01-0.08 Hz) and two subdivided bands (slow-4:0.027-0.073 Hz; slow-5:0.01-0.027 Hz). We calculated Aβ/pTau ratio using baseline cerebrospinal fluid pTau and Aβ1-42 to represent AD pathology. Compared to HC, MCI participants showed greater decline in right putaminal ALFF, including the slow-4 band. Greater decline of ALFF in the right putamen was significantly related to the memory decline over time and lower baseline Aβ/pTau ratio regardless of age or group. The slow-4 band, relative to slow-5 band, showed a stronger correlation between Aβ/pTau ratio and decline of ALFF in the right putamen. The results suggest that the putaminal function declines early in the AD-associated neurodegeneration. The continuous decline in putaminal ALFF, especially slow-4 band, may be a sensitive marker of AD pathology such as Aβ/pTau ratio regardless of clinical diagnosis.

Insula and Inferior Frontal Gyrus' Activities Protect Memory Performance Against Alzheimer's Disease Pathology in Old Age.

Apolipoprotein E (APOE) ɛ4 carriers and patients with amnestic mild cognitive impairment (MCI) have high risk of developing Alzheimers disease (AD). The Scaffolding Theory of Aging and Cognition proposes that recruitment of additional frontal brain regions can protect cognition against aging. This thesis has yet to be fully tested in older adults at high risk for AD. In the present study, 75 older participants (mean age: 74 years) were included. Applying a voxel-wise approach, fractional amplitude of low-frequency fluctuations (fALFF) in resting-state functional neuroimaging data were analyzed as a function of APOEɛ4 status (carrier versus noncarrier) and clinical status (healthy control [HC] versus MCI) using a 2×2 analysis of covariance (ANCOVA). Measures of cognition and cerebrospinal fluid levels of amyloid- β were also obtained. Three frontal regions were identified with significant interaction effects using ANCOVA (corrected p < 0.01): left-insula, left-inferior frontal gyrus (IFG), and right-precentral gyrus. The HC/APOEɛ4 carrier group had significantly higher fALFF in all three regions than other groups. In the entire sample, for two regions (left insula and left IFG), a significant positive relationship between amyloid-β and memory was only observed among individuals with low fALFF. Our results suggest higher activity in frontal regions may explain being cognitively normal among a subgroup of APOEɛ4 carriers and protect against the negative impact of AD-associated pathology on memory. This is an observation with potential implications for AD therapeutics.

Dystonia and ataxia progression in spinocerebellar ataxias

BACKGROUND Dystonia is a common feature in spinocerebellar ataxias (SCAs). Whether the presence of dystonia is associated with different rate of ataxia progression is not known. OBJECTIVES To study clinical characteristics and ataxia progression in SCAs with and without dystonia. METHODS We studied 334 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and compared the clinical characteristics of SCAs with and without dystonia. We repeatedly measured ataxia progression by the Scale for Assessment and Rating of Ataxia every 6 months for 2 years. Regression models were employed to study the association between dystonia and ataxia progression after adjusting for age, sex and pathological CAG repeats. We used logistic regression to analyze the impact of different repeat expansion genes on dystonia in SCAs. RESULTS Dystonia was most commonly observed in SCA3, followed by SCA2, SCA1, and SCA6. Dystonia was associated with longer CAG repeats in SCA3. The CAG repeat number in TBP normal alleles appeared to modify the presence of dystonia in SCA1. The presence of dystonia was associated with higher SARA scores in SCA1, 2, and 3. Although relatively rare in SCA6, the presence of dystonia was associated with slower progression of ataxia. CONCLUSIONS The presence of dystonia is associated with greater severity of ataxia in SCA1, 2, and 3, but predictive of a slower progression in SCA6. Complex genetic interactions among repeat expansion genes can lead to diverse clinical symptoms and progression in SCAs.

The borderland between normal aging and dementia

Alzheimers disease (AD) has become a global health issue as the population ages. There is no effective treatment to protect against its occurrence or progression. Some argue that the lack of treatment response is due to delays in diagnosis. By the time a diagnosis of AD is made, neurodegenerative changes are at the stage where very few neurons can be salvaged by medication. The AD research community has developed the idea of mild cognitive impairment (MCI) in an attempt to find predementia patients who might benefit from potentially therapeutic drugs that have proven ineffective in the past. However, MCI is heterogeneous in terms of its underlying pathology and practicality for predicting dementia. This article first reviews the conceptual evolution of MCI as the borderland between normal aging and dementia, and then proposes that built environment and sociocultural context are two key elements in formulating a diagnosis of dementia. Dementia is more than a biomedical term. Cognitive impairment is considered a dynamic outcome of how an individual interacts with cognitive challenges. To focus on amyloid deposition as a single etiology for AD does not adequately capture the social implications and geriatric aspects of dementia. Moreover, MCI is nosologically questionable. Unlike a diagnosis of AD, for which a prototype has been well established, MCI is defined by operational criteria and there are no cases seen as typical MCI. Biofluid and imaging markers are under active development for early detection of amyloid deposition and neurofibrillary tangles in the brain, whereas vascular risks, chronic medical diseases, and polypharmacy continue to add to the complexity of dementia in old age. The paradigm of dementia care policy may shift to early diagnosis of AD pathology and comprehensive care for chronic diseases in the elderly population.

Vascular Risk Factors and Clinical Progression in Spinocerebellar Ataxias

Background The contributions of vascular risk factors to spinocerebellar ataxia (SCA) are not known. Methods We studied 319 participants with SCA 1, 2, 3, and 6 and repeatedly measured clinical severity using the Scale for Assessment and Rating of Ataxia (SARA) for 2 years. Vascular risk factors were summarized by CHA2DS2-VASc scores as the vascular risk factor index. We employed regression models to study the effects of vascular risk factors on ataxia onset and progression after adjusting for age, sex, and pathological CAG repeats. Our secondary analyses took hyperlipidemia into account. Results Nearly 60% of SCA participants were at low vascular risks with CHA2DS2-VASc = 0, and 31% scored 2 or greater. Higher CHA2DS2-VASc scores were not associated with either earlier onset or faster progression of ataxia. These findings were not altered after accounting for hyperlipidemia. Discussion Vascular risks are not common in SCAs and are not associated with earlier onset or faster ataxia progression.

Long-duration sCJD with PRNP codon 129 methionine homozygosity and cerebral cortical plaques

The authors investigated a 40-year-old woman who presented with ataxia and dementia with little progression for over 40 months. The results of a CSF 14-3-3 protein and EEG study did not reveal major abnormalities. Brain MRI showed increased signal intensity over the occipital cortex in diffusion-weighted imaging. To our knowledge, this is the longest MM-type sporadic Creutzfeldt–Jakob disease case with cortical kuru-type plaques.

COMORBIDITY IN ALZHEIMER'S DISEASE: A NESTED CASE-CONTROL STUDY

Background:We aimed to describe the multiplicity of chronic diseases in Alzheimer disease (AD) in a nested case-control study. Methods: We used a random sample of 1 million individuals from the year 2000 registration data in Taiwan National Health Insurance program to describe the comorbid pattern among patients with dementia during 2001-2011. Incident dementia was identified by International Classification of Diseases, Ninth Revision, first ever coded after 2001. Incident AD was further restricted to those treated with cholinesterase inhibitors or memantine of approved reimbursement. We selected 14 comorbid medical diseases with reference to the list of multiple chronic conditions developed by the US Department of Health and Human Services. Incident dementia and AD cases were ageand sex-matched to a set of control subjects (1: 2 ratio). We described the frequency and pattern of comorbidity in AD and validated in a smaller sample from a regional hospital by in-person interview and medical records review. We employed conditional logistic regression to estimate the associations between chronic diseases and AD. Results:A total of 16,381 incident dementia cases were identified during 2001-2011 with mean age at 76.1 years (SD1⁄410.5) and female preponderance (52%). About 8% of these dementia cases were deemed AD with approved AD drug reimbursement. The most common 5 comorbidities in AD were hypertension (54%), osteoarthritis (38%), depression (32%), diabetes mellitus (27%) and cerebrovascular diseases (24%); and they were also more often associated with AD cases than their matched controls after adjusting for age and sex (respective odds ratios: 1.36, 1.44, 3.23, 1.51, 2.26, p < 0.001). The number of comorbidity was 3-fold greater (p < 0.001) in the AD group (median: 3; range: 0-8) than the control group (median: 1; range: 0-10). Conclusions:Multimorbidity in AD is very common. Cerebrovascular risks are associated with AD even among those relatively “pure” cases deemed eligible for AD drug reimbursement, supporting that the co-existence is a typical feature of AD at old age and integrated medical care is much needed.