Therapeutic role of memantine for the prevention of cognitive decline in cancer patients with brain metastasis receiving whole-brain radiotherapy: a narrative review / Papel terapêutico da memantina na prevenção do declínio cognitivo em pacientes com câncer com metástase cerebral recebendo radioterapia cerebral total: uma revisão narrativa

ABSTRACT. Brain metastases are the most common central nervous system tumors. The mainstay treatment for this tumor in low to middle income countries is whole brain radiation therapy. Irreversible cognitive decline is associated with the use of whole brain radiotherapy. Several pharmacologic and nonpharmacologic options have been employed in studies focusing on the prevention of cognitive decline following whole-brain radiation therapy. Memantine use has been shown to provide some benefit in reducing the rate of decline in cognitive function and time to cognitive failure. The objective of this review article is to provide a summary on available primary literature on the therapeutic role of memantine for the prevention of cognitive decline in cancer patients with brain metastasis receiving whole brain radiotherapy.

RESUMO. As metástases cerebrais são os tumores mais comuns do sistema nervoso central. O tratamento principal para este tumor em países de baixa e média renda é a radioterapia de cérebro inteiro. O declínio cognitivo irreversível está associado ao uso de radioterapia cerebral total. Várias opções farmacológicas e não farmacológicas têm sido empregadas em estudos com foco na prevenção do declínio cognitivo após radioterapia de cérebro inteiro. O uso de memantina demonstrou fornecer algum benefício na redução da taxa de declínio na função cognitiva e no tempo até a falha cognitiva. O objetivo deste artigo de revisão foi fornecer um resumo da literatura primária disponível sobre o papel terapêutico da memantina para a prevenção do declínio cognitivo em pacientes com câncer com metástase cerebral recebendo radioterapia cerebral total.

Therapeutic role of memantine for the prevention of cognitive decline in cancer patients with brain metastasis receiving whole-brain radiotherapy: a narrative review.

Brain metastases are the most common central nervous system tumors. The mainstay treatment for this tumor in low to middle income countries is whole brain radiation therapy. Irreversible cognitive decline is associated with the use of whole brain radiotherapy. Several pharmacologic and nonpharmacologic options have been employed in studies focusing on the prevention of cognitive decline following whole-brain radiation therapy. Memantine use has been shown to provide some benefit in reducing the rate of decline in cognitive function and time to cognitive failure. The objective of this review article is to provide a summary on available primary literature on the therapeutic role of memantine for the prevention of cognitive decline in cancer patients with brain metastasis receiving whole brain radiotherapy.

As metástases cerebrais são os tumores mais comuns do sistema nervoso central. O tratamento principal para este tumor em países de baixa e média renda é a radioterapia de cérebro inteiro. O declínio cognitivo irreversível está associado ao uso de radioterapia cerebral total. Várias opções farmacológicas e não farmacológicas têm sido empregadas em estudos com foco na prevenção do declínio cognitivo após radioterapia de cérebro inteiro. O uso de memantina demonstrou fornecer algum benefício na redução da taxa de declínio na função cognitiva e no tempo até a falha cognitiva. O objetivo deste artigo de revisão foi fornecer um resumo da literatura primária disponível sobre o papel terapêutico da memantina para a prevenção do declínio cognitivo em pacientes com câncer com metástase cerebral recebendo radioterapia cerebral total.

Autosomal Dominant Frontotemporal Lobar Degeneration in a Filipino Family with Progranulin Mutation.

BACKGROUND: Compared to Western populations, familial frontotemporal lobar degeneration (FTLD) is rare among Asians. Progranulin (GRN) gene mutation, which is a major cause of FTLD, is likewise rare. We present a family with FTLD from the Philippines with an autosomal dominant pattern of inheritance and GRN mutation and briefly review reports of GRN mutations in Asia. CASE PRESENTATION: The proband is 66 years old with progressive nonfluent aphasia (PNFA)-corticobasal syndrome . We assessed 3 generations of her pedigree and found 11 affected relatives with heterogenous phenotypes, usually behavioral variant frontotemporal dementia (FTD) and PNFA. Neuroimaging showed atrophy and hypometabolism consistent with FTD syndromes. White matter hyperintensities were seen in affected members even in the absence of vascular risk factors. A GRN mutation R110X was found in 6 members, 3 with symptoms and 3 were asymptomatic. Plasma GRN was low (<112 ng/mL) in all mutation carriers. No mutations were found in microtubule-associated protein tau, APP, PSEN1, and PSEN2 genes, and all were APOE3. CONCLUSION: This is the first Filipino family with autosomal dominant FTD documented with GRN mutation. Identifying families and cohorts would contribute to therapeutic developments in an area with FTD-GRN.

When a Little Knowledge Can Be Dangerous: False-Positive Diagnosis of Behavioral Variant Frontotemporal Dementia among Community Clinicians.

BACKGROUND: Accurate diagnosis of behavioral variant frontotemporal dementia (bvFTD) is important as patients' behavioral symptoms have profound implications for their families and communities. Since the diagnosis of bvFTD derives from behavioral features, accurate identification of patients can be difficult for non-specialists. Concrete rates of diagnostic accuracy among non-specialists are unavailable. METHODS: To examine the accuracy of community clinicians' diagnoses of bvFTD and to identify patient characteristics leading to misdiagnosis, we reviewed the charts and referral letters of 3,578 patients who were seen at our specialized center. Referral diagnosis and reasons, manifesting symptoms, demographic data, Mini-Mental State Examination score, Clinical Dementia Rating score and Neuropsychiatric Inventory score were extracted. RESULTS: 60% of patients assigned a single diagnosis of bvFTD by community clinicians did not have bvFTD according to specialists. Compared to specialist-confirmed bvFTD patients, false bvFTD patients were more likely to be depressed and to be non-Caucasian, showed less euphoria, apathy, disinhibition and abnormal eating behaviors, had milder disease severity and better overall cognition. bvFTD was mentioned by referring clinicians in 86% of specialist-confirmed bvFTD cases, but missed cases were called Alzheimer's, Parkinson's or Huntington's disease, or progressive aphasia. CONCLUSION: These results revealed a widespread lack of familiarity with core diagnostic symptoms among non-specialists and suggest that community clinicians require specialized diagnostic support before providing a definitive diagnosis of bvFTD.

Ankle-brachial index, cognitive impairment and cerebrovascular disease in a Chinese population.

BACKGROUND: Previous studies have assessed the association between ankle-brachial index (ABI) and cognition, mainly using brief cognitive tests. We investigated whether ABI was associated with cognition independent of neuroimaging markers of cerebrovascular disease. METHODS: Chinese subjects (n = 278, aged ≥60 years) were recruited from the ongoing Epidemiology of Dementia in Singapore (EDIS) Study. Ankle and brachial blood pressures were measured, and low ABI was defined as ≤0.9. A neuropsychological battery was utilized to determine cognition. Cognitive impairment no dementia (CIND) and dementia were diagnosed according to standard diagnostic criteria. Magnetic resonance imaging (MRI) was used to obtain semiquantitative and quantitative markers of cerebrovascular disease and atrophy. RESULTS: A low ABI was related to the presence of intracranial stenosis (odds ratio, OR = 1.71; 95% confidence interval, CI: 1.13-2.59), but not with the presence of infarcts, microbleeds or grey matter, white matter and white matter lesion volumes. Furthermore, a low ABI was associated with poorer overall cognitive function and CIND-moderate/dementia (OR = 2.26; 95% CI: 1.11-4.59), independent of cardiovascular risk factors, and the MRI markers related to cerebrovascular disease and atrophy. CONCLUSION: We found an association between a low ABI and cognitive impairment, independent of any MRI marker of cerebral small vessel disease or large artery atherosclerotic disease.

Microvascular network alterations in the retina of patients with Alzheimer's disease.

BACKGROUND: Although cerebral small-vessel disease has been implicated in the development of Alzheimer's disease (AD), the cerebral microcirculation is difficult to visualize directly in vivo. Because the retina provides a noninvasive window to assess the microcirculation, we determined whether quantitatively measured retinal microvascular parameters are associated with AD. METHODS: We conducted a case-control study (case:control matching ≈ 1:2). Retinal photographs were analyzed using a computer program, and a spectrum of quantitative retinal microvascular parameters (caliber, fractal dimension, tortuosity, and bifurcation) were measured. Logistic regression models were used to compute the odds ratio (OR) and 95% confidence interval for AD adjusting for age, gender, ethnicity, smoking, hypertension, diabetes, hypercholesterolemia, and history of myocardial infarction. RESULTS: We included 136 demented patients with AD and 290 age-gender-race-matched controls. Persons with narrower venular caliber (OR per standard deviation [SD] decrease, 2.01 [1.27-3.19]), decreased arteriolar and venular fractal dimension (OR per SD decrease 1.35 [1.08-1.68], 1.47 [1.17-1.84], respectively) and increased arteriolar and venular tortuosity (OR per SD increase, 1.84 [1.40-2.31], 1.94 [1.48-2.53], respectively) were more likely to have AD. These associations still persisted when only AD cases without a history of cerebrovascular disease were included. CONCLUSIONS: Patients with AD have altered microvascular network in the retina (narrower retinal venules and a sparser and more tortuous retinal vessels) compared with matched nondemented controls. These changes in retinal microvasculature may reflect similar pathophysiological processes in cerebral microvasculature in the brains of patients with AD.

Prevalence of cognitive impairment in Chinese: epidemiology of dementia in Singapore study.

OBJECTIVE: To study the prevalence of and associated factors for cognitive impairment and dementia in community dwelling Chinese from Singapore. METHODS: This study includes Chinese subjects from the Epidemiology of Dementia in Singapore (EDIS) study, aged ≥60 years, who underwent comprehensive examinations, including cognitive screening with the locally validated Abbreviated Mental Test and Progressive Forgetfulness Questionnaire. Screen positive participants subsequently underwent extensive neuropsychological testing and cerebral MRI. Cognitive impairment no dementia (CIND) and dementia were diagnosed according to internationally accepted criteria. The prevalence of cognitive impairment and dementia were computed per 5 year age categories and gender. To examine the relationship between baseline associated factors and cognitive impairment, we used logistic regression models to compute odd ratios with 95% CI. RESULTS: 1538 Chinese subjects, aged ≥60 years, underwent cognitive screening: 171 (15.2%) were diagnosed with any cognitive impairment, of whom 84 were CIND mild, 80 CIND moderate and seven had dementia. The overall age adjusted prevalence of CIND mild was 7.2%; CIND moderate/dementia was 7.9%. The prevalence increased with age, from 5.9% in those aged 60-64 years to 31.3% in those aged 75-79 years and 44.1% in those aged ≥80 years. Multivariate analysis revealed age, diabetes and hyperlipidaemia to be independently associated with cognitive impairment. CONCLUSIONS: In present study, the overall prevalence of cognitive impairment and dementia in Chinese was 15.2%, which is in the same range as the prevalence reported in Caucasian and other Asian populations.

Epidemiology of dementia in Asia: insights on prevalence, trends and novel risk factors.

Asia is the most populous region in the world and its rapidly growing societies are the sources of global development. However, accompanying this rapid growth is aging of the population with increasing occurrence of diseases, of which dementia is the most prominent, which provide major challenges to healthcare systems. Dementia prevalence in Asia has previously been found to be lower than Western populations, but recent studies show that age-specific prevalence rates are similar globally. Overall dementia prevalence is expected to rise dramatically across Asia due to maturing populations. Earlier Asian studies reported a lower prevalence of Alzheimer's disease (AD) and a higher prevalence of vascular dementia (VaD). Recent studies, however, show a reversal of this ratio that now parallels that of Western countries. This change may be attributed to an altered demographic profile, urbanization, environmental reactions, ethnicity and advances in the use of neuroimaging modalities. Several factors may influence the results of epidemiological studies including changes in societal perception of aging, family attitudes, validity of assessment tools due to language and literacy, and medical practitioners' expertise in recognizing dementia. Nevertheless, epidemiological studies in Asia may reveal factors contributory to inter-ethnic differences in dementia. Potentially modifiable risk factors apparent only in low and middle-income countries and gene-environment interactions may underlie these disparities and identification of such factors may lead to effective treatments.

Multi-stage segmentation of white matter hyperintensity, cortical and lacunar infarcts.

Cerebral abnormalities such as white matter hyperintensity (WMH), cortical infarct (CI), and lacunar infarct (LI) are of clinical importance and frequently present in patients with stroke and dementia. Up to date, there are limited algorithms available to automatically delineate these cerebral abnormalities partially due to their complex appearance in MR images. In this paper, we describe an automated multi-stage segmentation approach for labeling the WMH, CI, and LI using multi-modal MR images. We first automatically segment brain tissues (white matter, gray matter, and CSF) based on the T1-weighted image and then identify hyperintense voxels based on the fluid attenuated inversion recovery (FLAIR) image. We finally label the WMH, CI, and LI based on the T1-weighted, T2-weighted, and FLAIR images. The segmentation accuracy is evaluated using a community-based sample of 272 old adults. Our results show that the automated segmentation of the WMH, CI, and LI is comparable with manual labeling in terms of spatial location, volume, and the number of lacunes. Additionally, the WMH volume is highly correlated with the visual grading score based on the Age-Related White Matter Changes (ARWMC) protocol. The evaluations against the manual labeling and ARWMC visual grading suggest that our algorithm provides reasonable segmentation accuracy for the WMH, CI, and LI.