Clinical Significance of Physical Frailty in Subjects With Subjective Cognitive Decline: A Prospective Study With Amyloid PET Data.

BACKGROUND AND PURPOSE: Physical frailty is known to be closely associated with cognitive impairment and to be an early sign of Alzheimer's disease. We aimed to understand the characteristics of physical frailty and define factors associated with physical frailty in subjects with subjective cognitive decline (SCD) by analyzing amyloid data. METHODS: We prospectively enrolled subjects with SCD from a cohort study to identify predictors for the clinical progression to mild cognitive impairment or dementia from SCD (CoSCo). All of the subjects underwent brain magnetic resonance imaging, and brain amyloid positron-emission tomography (PET) to detect amyloid beta plaques. Self-reported exhaustion, handgrip strength, and gait speed were used to measure physical frailty. RESULTS: Of 120 subjects with SCD, 26 (21.7%) were amyloid-positive in PET. Female (odds ratio [OR]=3.79, p=0.002) and amyloid-PET-positive (OR=3.80, p=0.008) subjects with SCD were at high risks of self-reported exhaustion. Amyloid PET positivity (OR=3.22, p=0.047) and high burden from periventricular white-matter hyperintensity (OR=3.34, 95% confidence interval=1.18-9.46, p=0.023) were significantly associated with a weaker handgrip. The subjects with SCD with self-reported exhaustion and weaker handgrip presented with lower cognitive performance in neuropsychological tests, especially for information processing speed and executive function. Subjects with a slower gait performed worse in visual memory function tests. CONCLUSIONS: Amyloid PET positivity was associated with a higher risk of self-reported exhaustion and weaker handgrip in subjects with SCD. The subjects with SCD and physical frailty also performed worse in neuropsychological tests.

Dynamic Changes of Carotid Atherosclerosis and Their Relation with Stroke Recurrence in Patients with Stroke or Transient Ischemic Attack.

BACKGROUND AND PURPOSE: The purpose of this study was to show dynamic changes in carotid and vertebral artery using carotid Doppler ultrasonography (DUS) through a long-term follow- up exam, and determine their associations with stroke recurrence. METHODS: We consecutively enrolled stroke or transient ischemic attack (TIA) patients who had undergone DUS more than twice with intervals of three months or more. Stroke recurrence during follow-up was also investigated by reviewing medical records. Progress or regress of plaque was defined as more than 0.1 mm change from the initial scan with a semi-quantitative measurement. The development of new plaque was also regarded as plaque progress. Increased intima-media thickness and plaque presence were interpreted at the initial and follow-up scans. Factors related to progression or regression were analyzed. The relationship between plaque change and stroke recurrence was investigated. RESULTS: A total of 201 patients were enrolled (186 ischemic stroke patients and 15 TIA patients). There were 61 (30.3%) females. Their mean age was 64.2 ± 9.9 years. During a follow-up of 35.0 ± 22.6 (mean ± SD) months, plaque progress was observed in 92 (45.8%) and plaque regress in 13 (6.5%). Stroke recurred in 18 patients. Plaque progression showed no significant association with age, risk factors, statin use, or subtype. After adjustment of age, sex, diabetes, and stroke subtype, multiple logistic regression showed a significant association of plaque progression with stroke recurrence (odds ratio: 3.8, 95% confidence interval: 1.1 to 13.1, p = 0.034). Patients with plaque regress were significantly younger than those without plaque regress (57.8 years vs. 64.6 years, p = 0.041). CONCLUSION: Plaque progression occurred in 46% of stroke or TIA patients. Plaque progression was significantly associated with clinical stroke recurrence. Plaque regressed in 6.5% of patients. Patients with regression were younger than those without.

A systematic review and meta-analysis of the clinical effects of Souvenaid in patients with Alzheimer's disease.

BACKGROUND AND OBJECTIVES: We conducted this meta-analysis about the effects of Souvenaid on cognition and functional abilities, with the hypothesis that Souvenaid may have beneficial effects in certain groups and the goal of finding the outcome measures, disease states, and so on, applicable for further clinical trials. METHODS AND STUDY DESIGN: We searched Medline, Embase, Web of Science, CINAHL, and the Cochrane Library. Only double- blind randomized controlled trials were included. Outcome measurements were cognition, clinical global change, functional ability, and adverse events. The duration of treatment was not restricted, but trials performed in patients who did not have Alzheimer's disease (AD) were excluded. RESULTS: This review using meta-analyses of 4 clinical trials showed that Souvenaid had no significant effects on cognition as measured by ADAS-Cog (MD=0.08, 95% CI=-0.71-0.88) and the neuropsychological test battery total scores (MD=0.05, 95% CI=-0,02- 0.12), on global clinical function as measured by CDR-SB (MD=-0.21, 95% CI=-0.47-0.06), or on functional ability as measured by ADCS-ADL (MD=0.36, 95% CI=-0.54-1.25). There were no differences in any adverse events (OR=0.84, 95% CI=0.63-1.12) or in serious adverse events (OR=0.95, 95% CI=0.66-1.36). However, Souvenaid may benefit the domains of cognition that are affected by AD (attention, memory, and executive function), and it may have greater potential for benefits earlier rather than later in the disease. CONCLUSIONS: The results of current clinical trials do not suggest that Souvenaid has any beneficial effects on cognition, functional ability, or global clinical change. Further studies with outcome measures suitable in patients with early stages of AD will be needed.

Coexistence of Cerebral Microbleeds and Amyloid Pathology in Patients with Cognitive Complaints.

BACKGROUND AND PURPOSE: We investigated the prevalence of amyloid positivity and cerebral microbleeds (CMBs) in subjects with cognitive complaints with the aim of identifying differences in clinical parameters and cognitive function according to the pattern of coexistence. METHODS: We retrospectively enrolled 200 subjects with memory impairment and applied both standardized ¹8F-florbetaben PET and brain MRI, including susceptibility-weighted imaging. The amyloid burden was visually classified as positive or negative, and the number and location of CMBs were also analyzed visually. Descriptive analysis was performed for the prevalence of amyloid positivity and CMBs. The relationship between the coexisting pattern of those two findings and clinical parameters including the results of neuropsychiatric tests was analyzed. RESULTS: Positive amyloid PET scans were exhibited by 102 (51.5%) of the 200 patients, and 51 (25.5%) of them had CMBs, which were mostly located in lobar areas in the patients with positive amyloid scans. The patients with CMBs were older and had a higher burden of white-matter hyperintensities than the patients without CMBs. The patients with CMBs also performed worse in confrontation naming and frontal/executive function. When classified by topographical region, parietal CMBs (odds ratio=3.739, p=0.024) were significantly associated with amyloid positivity. CONCLUSIONS: The prevalence of CMBs was higher in patients with cognitive decline than in the general population. CMBs play distinctive roles in affecting clinical parameters and neuropsychological profiles according to the coexistence of amyloid pathology.

Different Cortical Thinning Patterns Depending on Their Prognosis in Individuals with Subjective Cognitive Decline.

BACKGROUND AND PURPOSE: Subjective cognitive decline (SCD) may be the first stage corresponding to subtle cognitive changes in patients with Alzheimer's disease (AD) spectrum disorders. We evaluated the differences in cortical thinning patterns among patients with SCD who progressed to mild cognitive impairment or dementia (pSCD), those who remained stable (sSCD), and healthy normal controls (NCs). METHODS: We retrospectively recruited SCD subjects (14 pSCD and 21 sSCD cases) and 29 NCs. Structural 3-dimensional-T1-weighted magnetic resonance imaging was performed using a single 1.5 Tesla scanner. Freesurfer software was used to map cortical thickness for group comparisons. RESULTS: Compared with NC group, the sSCD group showed diffuse cortical atrophy associated with bilateral fronto-parieto-temporal area. The pSCD group showed further characteristic cortical atrophy in AD-vulnerable regions including the inferior parieto-temporal and middle temporal areas. Cortical thinning in the bilateral medial frontal areas was observed in patients with sSCD and involved the right inferior temporal and left precentral areas in those with pSCD. CONCLUSIONS: Our study showed that SCD subjects exhibit different cortical thinning patterns depending on their prognosis.

Cerebrovascular Hemodynamics on Transcranial Doppler Ultrasonography and Cognitive Decline in Mild Cognitive Impairment.

BACKGROUND/OBJECTIVE: Vascular risk factors and neurovascular dysfunction may be closely related to cognitive impairment and dementia. In this study, we evaluated the association between hemodynamic markers and longitudinal cognitive changes in patients with mild cognitive impairment (MCI). Furthermore, we investigated whether hemodynamic markers could predict the risk of progression to Alzheimer's disease (AD) in patients with MCI. METHODS: A total of 68 subjects with amnestic MCI were recruited. Using transcranial Doppler (TCD) ultrasonography, cerebrovascular reactivity was evaluated with a breath-holding test (breath holding index; BHI) in addition to the mean flow velocity (MFV) and pulsatility index (PI) of the middle cerebral artery. We followed subjects for 24 months and each subject underwent neuropsychological testing and TCD ultrasonography, annually. According to the follow-up neuropsychological studies and clinical interviews at 12 months, we divided the patients with MCI into two groups: patients with stable cognitive performance and patients who progressed to AD. RESULTS: Lower BHI and higher PI were observed in patients who progressed to AD. The changes of MMSE score over the first 12 months correlated with lower baseline MMSE score and changes of MFV and BHI. The changes of MMSE score over 24 months were closely related to higher baseline resistance index and PI values. Multivariate logistic regression showed that abnormal baseline BHI value could predict a conversion from MCI to AD. CONCLUSIONS: We confirmed there is a close association between hemodynamic changes represented by TCD markers and cognitive decline, supporting the clinical value of hemodynamic markers in predicting MCI patients who will progress to AD.

Safety and Efficacy of Anti-dementia Agents in the Extremely Elderly Patients with Dementia.

BACKGROUND: There are debates on representation and generalizability of previous randomized controlled trials about anti-dementia agents in the oldest old population. In this context, we aimed to investigate the efficacy and safety of anti-dementia agents in the very elderly patients with dementia. METHODS: We conducted a retrospective study of patients with dementia 1) who were 85 years or older, 2) got started anti-dementia agents, and 3) went through follow-up evaluation about one year thereafter. As a control, patients with dementia who were less than 85 years old with similar inclusion criteria were randomly selected during the same period. The adverse drug effects and discontinuation rates were investigated with self-reported complaint after starting or increasing anti-dementia drugs. For efficacy outcome, we also analyzed the change in neuropsychological results during follow-up period. RESULTS: A total of 77 dementia patients who were at least 85 years were enrolled. As a control group, 78 patients with dementia who were younger than 85 was analyzed. The adverse drug effects were observed in 26 (33.3%) patients in the younger old and in 26 (33.8%) in the oldest old (P = 0.095). Twenty-one patients (26.9%) in the younger old group and 13 patients (16.9%) in the oldest old group discontinued their medication (P = 0.131). There were no differences between the two groups about changes of Mini-Mental State Examination and Instrumental Activity of Daily Living scores over time. CONCLUSION: The use of anti-dementia agents in the oldest old dementia patients may be safe and effective as the younger old dementia patients.

The Fate of Acute Lacunar Lesions in Terms of Shape and Size.

BACKGROUND: The description of lacunar infarcts on imaging is widely variable. In particular, there are fewer agreements on lacunar lesion size and the presence of cavitation. In this regard, we investigated the changes in size and shape of acute ischemic lesion that is possibly considered as small vessel occlusion on long-term follow-up. METHODS: Patients with acute single subcortical ischemic lesion on penetrating arterial territories and without definite cause of cardioembolism and large vessel disease were included. Magnetic resonance imaging (MRI) was performed during an acute stroke period and approximately 1 year after the stroke. Maximal diameters on diffusion-weighted image and on follow-up (T2 or fluid attenuation inversion recovery) were measured. The change in lesion diameter over time was analyzed. Regarding the change in shape, lacunar lesions on follow-up were classified as either "disappeared," "cavitated," or "white matter lesion." RESULTS: A total of 64 patients were included. The mean age was 64.94 ± 11.29 years and 32 patients were male. The mean time interval between initial and follow-up MR scan was 23.39 ± 14.88 months. The mean diameter of acute lacunar lesion was 14.11 ± 5.77 mm. On follow-up, the mean diameter reduced to 7.76 ± 5.19 mm. The mean percentage of final diameter over initial diameter was 53.57 ± 26.45%. All of the lesions were less than 15 mm on follow-up. Regarding the shape of the lesion on follow-up, the lesions of 33 (51.6%) patients remained cavitated, the lesions of 14 (21.9%) patients remained as white matter lesions, and the lesions of 17 (26.6%) patients disappeared. There were no differences on clinical characteristics between patients with cavitation and those without. CONCLUSIONS: The diameter of acute lacunar lesions on initial diffusion-weighted MRI was markedly reduced on follow-up. In 52% of the patients, acute lacunar lesions were cavitated.

Hippocampal and entorhinal structures in subjective memory impairment: a combined MRI volumetric and DTI study.

BACKGROUND: Subjective memory impairment (SMI) is common among older adults. Increasing evidence suggests that SMI is a risk factor for future cognitive decline, as well as for mild cognitive impairment and dementia. Medial temporal lobe structures, including the hippocampus and entorhinal cortex, are affected in the early stages of Alzheimer's disease. The current study examined the gray matter (GM) volume and microstructural changes of hippocampal and entorhinal regions in individuals with SMI, compared with elderly control participants without memory complaints. METHODS: A total of 45 participants (mean age: 70.31 ± 6.07 years) took part in the study, including 18 participants with SMI and 27 elderly controls without memory complaints. We compared the GM volume and diffusion tensor imaging (DTI) measures in the hippocampal and entorhinal regions between SMI and control groups. RESULTS: Individuals with SMI had lower entorhinal cortical volumes than control participants, but no differences in hippocampal volume were found between groups. In addition, SMI patients exhibited DTI changes (lower fractional anisotropy (FA) and higher mean diffusivity in SMI) in the hippocampal body and entorhinal white matter compared with controls. Combining entorhinal cortical volume and FA in the hippocampal body improved the accuracy of classification between SMI and control groups. CONCLUSIONS: These findings suggest that the entorhinal region exhibits macrostructural as well as microstructural changes in individuals with SMI, whereas the hippocampus exhibits only microstructural alterations.