A complex multimodal activity intervention to reduce the risk of dementia in mild cognitive impairment--ThinkingFit: pilot and feasibility study for a randomized controlled trial.

BACKGROUND: Dementia affects 35 million people worldwide and is currently incurable. Many cases may be preventable because regular participation in physical, mental and social leisure activities during middle age is associated with up to 47% dementia risk reduction. However, the majority of middle-aged adults are not active enough. MCI is therefore a clear target for activity interventions aimed at reducing dementia risk. An active lifestyle during middle age reduces dementia risk but it remains to be determined if increased activity reduces dementia risk when MCI is already evident. Before this can be investigated conclusively, complex multimodal activity programmes are required that (1) combine multiple health promoting activities, (2) engage people with MCI, and (3) result in sufficient adherence rates. METHODS: We designed the ThinkingFit programme to engage people with MCI in a complex intervention comprised of three activity components: physical activity, group-based cognitive stimulation (GCST) and individual cognitive stimulation (ICST). Engagement and adherence was promoted by applying specific psychological techniques to enhance behavioural flexibility in an early pre-phase and during the course of the intervention. To pilot the intervention, participants served as their own controls during a 6- to 12-week run-in period, which was followed by 12 weeks of activity intervention. RESULTS: Out of 212 MCI patients screened, 163 were eligible, 70 consented and 67 completed the intervention (mean age 74 years). Activity adherence rates were high: physical activity = 71%; GCST = 83%; ICST = 67%. Significant treatment effects (p < .05) were evident on physical health outcomes (decreased BMI and systolic blood pressure, [pre/post values of 26.3/25.9 kg/m2 and 145/136 mmHg respectively]), fitness (decreased resting and recovery heart rate [68/65 bpm and 75/69 bpm]), and cognition (improved working memory [5.3/6.3 items]). CONCLUSIONS: We found satisfactory recruitment, retention and engagement rates, coupled with significant treatment effects in elderly MCI patients. It appears feasible to conduct randomized controlled trials of the dementia prevention potential of complex multimodal activity programmes like ThinkingFit. TRIAL REGISTRATION: ClinicalTrials.gov registration nr: NCT01603862; date: 17/5/2012.

Memory complaints with and without memory impairment: the impact of leukoaraiosis on cognition.

White matter alterations, leukoaraiosis (LA) on structural MRI, are associated with cognitive deficits and increased risk of dementia. LA may also impact on subjective memory complaints in otherwise healthy older adults. Little is known about the interplay between LA memory complaints and cognition. We investigated cognitive phenotypes associated with LA in 42 non-demented older adults categorized as having subjective cognitive complaints with no objective cognitive impairment-the subjective cognitive impairment group (SCI; n = 12), amnesic mild cognitive impairment (aMCI; n = 20), or healthy controls (HC; n = 11). We measured LA severity on MRI with a 40-point visual rating scale. Controlling for age and Mini-Mental State Examination (MMSE) score, analyses revealed multiple between-group differences. Follow-up linear regression models investigating the underlying contributors to each clinic group's cognitive profile indicated that LA contributed to learning slope variance (after accounting for age and MMSE) but only for the SCI group. Although the SCI group showed a significantly steeper learning slope when compared to HC and aMCI, increasing LA severity negatively impacted this group's rate of learning. This, in conjunction with the significant contribution of age on SCI learning slope performance variance suggests that greater LA burden at a younger age may contribute to subtle changes in learning for individuals with subjective cognitive complaints.

Subjective cognitive impairment: increased prefrontal cortex activation compared to controls during an encoding task.

OBJECTIVE: Subjective cognitive impairment (SCI) has been proposed as a clinical stage which may precede mild cognitive impairment in the clinical continuum of AD, and is characterised by the presence of subjective memory complaints in the absence of objective cognitive deficits. Specific memory-related brain activation differences have been reported in mild cognitive impairment and in cognitively normal individuals at known genetic risk of AD; our objective was to determine whether similar differences are present in people with SCI. METHODS: We compared brain activation in a memory clinic sample of 10 SCI subjects and 10 controls during a verbal episodic memory encoding task using functional magnetic resonance imaging (fMRI). RESULTS: There were no differences between groups on measures of encoding success (recognition accuracy) nor was there evidence of altered semantic processing. Both groups activated left prefrontal cortex (PFC) and cerebellum during encoding. The SCI group also demonstrated activation in left medial temporal, occipitoparietal and medial frontal cortex. Group comparisons revealed increased activation in SCI in left PFC, where activation strength correlated with memory task performance. CONCLUSIONS: The activation differences reported in this study may reflect the employment of compensatory strategies in the face of early AD pathology, although a number of alternative explanations need to be considered. Further studies with larger samples may help to determine whether the observed activation changes are likely to be associated with early neuropathological processes or with other unrelated factors.

An fMRI study of verbal episodic memory encoding in amnestic mild cognitive impairment.

Amnestic mild cognitive impairment (aMCI) is a high-risk and often prodromal state for the development of Alzheimer's disease (AD) and is characterised by isolated episodic memory impairment. Functional neuroimaging studies in healthy subjects consistently report left prefrontal cortex (PFC) activation during verbal episodic memory encoding. The PFC activation at encoding is related to semantic processing which enhances memory. The purpose of this study was to ascertain whether impaired verbal episodic memory in aMCI is related to PFC dysfunction. Using functional magnetic resonance imaging (fMRI) we compared 10 aMCI patients with 10 elderly controls during verbal encoding. The encoding task was sensitive to the effects of semantic processing. Subsequent recognition was tested to measure encoding success. Behavioural results revealed impaired recognition and a lower false recognition rate for semantically related distracters (lures) in aMCI, which suggest impaired semantic processing at encoding. Both groups activated left hemispheric PFC, insula, premotor cortex and cerebellum, but group comparisons revealed decreased activation in left ventrolateral PFC in the aMCI group. The magnitude of activation in left ventrolateral PFC during encoding was positively correlated with recognition accuracy in the control group but not in the aMCI group. We propose that verbal episodic memory impairment in aMCI is related to PFC dysfunction which affects semantic processing at encoding.

The functional anatomy of divided attention in amnestic mild cognitive impairment.

Recent neuroimaging studies have demonstrated changes in brain function in cognitively normal subjects at increased risk of developing Alzheimer's disease. Amnestic mild cognitive impairment (AMCI) carries a high risk of developing into Alzheimer's disease. In AMCI altered cortical activation has been demonstrated during memory tasks, using functional MRI (fMRI). Memory and attention are closely related cognitive functions. It is unclear whether the memory impairment of AMCI is associated with attentional deficits of the sort likely to be revealed by tasks requiring divided attention. Ten older adults (mean age 72 years, range 57-81 years) with AMCI were compared with healthy matched controls on divided attention and passive sensory processing tasks using fMRI. During the divided attention task both groups activated similar regions of left hemispheric prefrontal and extrastriate visual cortex. However, the AMCI group had attenuated prefrontal activation compared with age matched controls. On the passive sensory processing task there was no difference between the AMCI and control groups. We conclude that there are changes in the functional network subserving divided attention in patients with AMCI as reflected in the attenuation of prefrontal cortical activation. These findings have implications for evaluating cognition in AMCI and also for monitoring the effects of future treatments in AMCI.