Perspective: Clinical relevance of the dichotomous classification of Alzheimer's disease biomarkers: Should there be a "gray zone"?

The 2018 National Institute on Aging and the Alzheimer's Association (NIA-AA) research framework recently redefined Alzheimer's disease (AD) as a biological construct, based on in vivo biomarkers reflecting key neuropathologic features. Combinations of normal/abnormal levels of three biomarker categories, based on single thresholds, form the AD signature profile that defines the biological disease state as a continuum, independent of clinical symptomatology. While single thresholds may be useful in defining the biological signature profile, we provide evidence that their use in studies with cognitive outcomes merits further consideration. Using data from the Alzheimer's Disease Neuroimaging Initiative with a focus on cortical amyloid binding, we discuss the limitations of applying the biological definition of disease status as a tool to define the increased likelihood of the onset of the Alzheimer's clinical syndrome and the effects that this may have on trial study design. We also suggest potential research objectives going forward and what the related data requirements would be.

Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment.

Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer's disease (AD)? One approach is to modify nongenetic risk factors, for instance by lowering elevated plasma homocysteine using B vitamins. In an initial, randomized controlled study on elderly subjects with increased dementia risk (mild cognitive impairment according to 2004 Petersen criteria), we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 y. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine (above the median, 11 µmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline. Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline. Further B-vitamin supplementation trials focusing on elderly subjets with high homocysteine levels are warranted to see if progression to dementia can be prevented.

Connected speech as a marker of disease progression in autopsy-proven Alzheimer's disease.

Although an insidious history of episodic memory difficulty is a typical presenting symptom of Alzheimer's disease, detailed neuropsychological profiling frequently demonstrates deficits in other cognitive domains, including language. Previous studies from our group have shown that language changes may be reflected in connected speech production in the earliest stages of typical Alzheimer's disease. The aim of the present study was to identify features of connected speech that could be used to examine longitudinal profiles of impairment in Alzheimer's disease. Samples of connected speech were obtained from 15 former participants in a longitudinal cohort study of ageing and dementia, in whom Alzheimer's disease was diagnosed during life and confirmed at post-mortem. All patients met clinical and neuropsychological criteria for mild cognitive impairment between 6 and 18 months before converting to a status of probable Alzheimer's disease. In a subset of these patients neuropsychological data were available, both at the point of conversion to Alzheimer's disease, and after disease severity had progressed from the mild to moderate stage. Connected speech samples from these patients were examined at later disease stages. Spoken language samples were obtained using the Cookie Theft picture description task. Samples were analysed using measures of syntactic complexity, lexical content, speech production, fluency and semantic content. Individual case analysis revealed that subtle changes in language were evident during the prodromal stages of Alzheimer's disease, with two-thirds of patients with mild cognitive impairment showing significant but heterogeneous changes in connected speech. However, impairments at the mild cognitive impairment stage did not necessarily entail deficits at mild or moderate stages of disease, suggesting non-language influences on some aspects of performance. Subsequent examination of these measures revealed significant linear trends over the three stages of disease in syntactic complexity, semantic and lexical content. The findings suggest, first, that there is a progressive disruption in language integrity, detectable from the prodromal stage in a subset of patients with Alzheimer's disease, and secondly that measures of semantic and lexical content and syntactic complexity best capture the global progression of linguistic impairment through the successive clinical stages of disease. The identification of disease-specific language impairment in prodromal Alzheimer's disease could enhance clinicians' ability to distinguish probable Alzheimer's disease from changes attributable to ageing, while longitudinal assessment could provide a simple approach to disease monitoring in therapeutic trials.

Piloting and validation of a novel self-administered online cognitive screening tool in normal older persons: the Cognitive Function Test.

BACKGROUND: Subtle cognitive changes have been described that may predate the onset of clinically recognizable Alzheimer's disease (AD) and may reflect pathological changes in the brain that are detectable up to 10 years before the onset of AD. Early screening for cognitive status can have benefits in terms of early management and prevention strategies for cognitive decline. METHOD: A novel computerized cognitive screening tool, the Cognitive Function Test (CFT), was compared with established paper tests of episodic memory, executive function and processing speed, domains previously shown to be predictive of AD, with 50 normal participants, Mini Mental State Examination ≥24, mean age 58.1, SD 5.6 years (range 50-65). An online version, self-administered by 195 eligible respondents without significant memory complaints or dementia, was assessed. RESULTS: Significant correlations (r = 0.75, p < 0.0001) were found between the CFT and paper tests in a pilot study, showing concurrent validity. The pilot computerized tests were compared with the online version, and no differences were found in mean scores on the total test and domain-specific scores using an algorithm derived from the pilot CFT scores, thus showing internal consistency and reliability of the online format. Norms and 1.5 SD cut-offs for the CFT are presented. CONCLUSION: The online CFT was shown to be suitable for self-administration in online format (with a mouse response mode) for this midlife age group. Individuals may wish to monitor their cognitive performance before memory concerns are sufficient to warrant visiting a GP or memory clinic.

An assessment of neurocognitive speed in relation to frailty.

OBJECTIVES: to evaluate the relationship between neurocognitive speed (NCS) and frailty; to consider how this relationship is affected by how frailty is operationalised. DESIGN: secondary analysis of the baseline cohort of the Oxford Project To Investigate Memory and Aging (OPTIMA), a longitudinal observational cohort. SUBJECTS: of 388 participants who underwent a comprehensive intake assessment followed by an annual follow-up for at least 3 years, data on all measures were available on 164 people. MEASUREMENTS: NCS was defined as a combined score of <18 on the pattern comparison test (<11 is abnormal) and letter comparison test (<7 is abnormal). Frailty was defined from a modified Phenotype model, the Edmonton Frailty Scales (EFS) and a frailty index (FI); the latter two were adapted here to exclude cognitive measures. RESULTS: in multivariate logistic (NCS as < or ≥18) and linear regression (NCS as continuous variable), only the FI (OR = 0.87) was significant (P < 0.05). When all frailty measures were included in the multivariate analysis only, FI (OR = 0.88) was significant (P < 0.05). Mini-mental Status Examination remained significantly related to NCS throughout all analysis. CONCLUSION: NCS slows with increasing frailty as shown with the FI.

Logopenic aphasia in Alzheimer's disease: clinical variant or clinical feature?

BACKGROUND: Primary progressive aphasia (PPA) is a clinical syndrome characterised by progressive decline in components of the language system. Recent evidence suggests that the logopenic/phonological (LPA) variant is a reliable in vivo marker of Alzheimer related pathology. The aim of this study was to determine if patients with clinically typical early stage Alzheimer's disease (AD) display a characteristic language disorder that resembles LPA, or if LPA is a clinical manifestation of an atypical form of AD. METHODS: Spoken language samples were obtained using the Cookie Theft picture description task from 18 post mortem confirmed cases of AD, where speech samples were taken at the first point of clinical diagnosis, and 18 post mortem confirmed healthy controls. Spoken samples were transcribed from tape recordings and analysed using the scoring system described by Wilson et al. RESULTS: Group comparisons between normal controls and AD patients showed no significant overall differences. Individual review of the linguistic variables compared with the PPA variants showed that a third of patients had normal language (n=6). The remainder showed varied patterns of linguistic impairment. In the majority of the affected group, the most salient feature was a reduction in one or more measures of syntactic complexity. One patient's deficit was comparable to that found in LPA. CONCLUSIONS: The impairment found in clinically typical early stage AD did not correspond consistently to the linguistic profiles described in any of the sub-syndromes of PPA. The only reliably distinguishing feature was a reduction across a range of syntactic complexity measures. The findings suggest that LPA represents an atypical clinical presentation of AD rather than a common clinical feature of typical AD.

Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial.

BACKGROUND: Homocysteine is a risk factor for Alzheimer's disease. In the first report on the VITACOG trial, we showed that homocysteine-lowering treatment with B vitamins slows the rate of brain atrophy in mild cognitive impairment (MCI). Here we report the effect of B vitamins on cognitive and clinical decline (secondary outcomes) in the same study. METHODS: This was a double-blind, single-centre study, which included participants with MCI, aged ≥ 70 y, randomly assigned to receive a daily dose of 0.8 mg folic acid, 0.5 mg vitamin B(12) and 20 mg vitamin B(6) (133 participants) or placebo (133 participants) for 2 y. Changes in cognitive or clinical function were analysed by generalized linear models or mixed-effects models. RESULTS: The mean plasma total homocysteine was 30% lower in those treated with B vitamins relative to placebo. B vitamins stabilized executive function (CLOX) relative to placebo (P = 0.015). There was significant benefit of B-vitamin treatment among participants with baseline homocysteine above the median (11.3 µmol/L) in global cognition (Mini Mental State Examination, P < 0.001), episodic memory (Hopkins Verbal Learning Test-delayed recall, P = 0.001) and semantic memory (category fluency, P = 0.037). Clinical benefit occurred in the B-vitamin group for those in the upper quartile of homocysteine at baseline in global clinical dementia rating score (P = 0.02) and IQCODE score (P = 0.01). CONCLUSION: In this small intervention trial, B vitamins appear to slow cognitive and clinical decline in people with MCI, in particular in those with elevated homocysteine. Further trials are needed to see if this treatment will slow or prevent conversion from MCI to dementia.

Paraoxonase 1, B Vitamins Supplementation, and Mild Cognitive Impairment.

BACKGROUND: Identification of modifiable risk factors that affect cognitive decline is important for the development of preventive and treatment strategies. Status of paraoxonase 1 (PON1), a high-density lipoprotein-associated enzyme, may play a role in the development of neurological diseases, including Alzheimer's disease. OBJECTIVE: We tested a hypothesis that PON1 status predicts cognition in individuals with mild cognitive impairment (MCI). METHODS: Individuals with MCI (n = 196, 76.8-years-old, 60% women) participating in a randomized, double-blind placebo-controlled trial (VITACOG) were assigned to receive a daily dose of folic acid (0.8 mg), vitamin B12 (0.5 mg) and B6 (20 mg) (n = 95) or placebo (n = 101) for 2 years. Cognition was analyzed by neuropsychological tests. Brain atrophy was quantified in a subset of participants (n = 168) by MRI. PON1 status, including PON1 Q192R genotype, was determined by quantifying enzymatic activity of PON1 using paraoxon and phenyl acetate as substrates. RESULTS: In the placebo group, baseline phenylacetate hydrolase (PhAcase) activity of PON1 (but not paraoxonase activity or PON1 Q192R genotype) was significantly associated with global cognition (Mini-Mental State Examination, MMSE; Telephone Inventory for Cognitive Status-modified, TICS-m), verbal episodic memory (Hopkins Verbal Learning Test-revised: Total Recall, HVLT-TR; Delayed Recall, HVLT-DR), and attention/processing speed (Trail Making A and Symbol Digits Modalities Test, SDMT) at the end of study. In addition to PhAcase, baseline iron and triglycerides predicted MMSE, baseline fatty acids predicted SDMT, baseline anti-N-Hcy-protein autoantibodies predicted TICS-m, SDMT, Trail Making A, while BDNF V66M genotype predicted HVLT-TR and HVLT-DR scores at the end of study. B-vitamins abrogated associations of PON1 and other variables with cognition. CONCLUSION: PON1 is a new factor associated with impaired cognition that can be ameliorated by B-vitamins in individuals with MCI.

Retrospective evaluation of revised criteria for the diagnosis of Alzheimer's disease using a cohort with post-mortem diagnosis.

OBJECTIVE: The criteria currently used to diagnose Alzheimer's disease (AD) require the presence of dementia, i.e. cognitive impairment sufficient to affect normal social and/or occupational function. Dubois et al. (Dubois et al., 2007) have recently proposed a set of revised criteria that may aid the diagnosis of the earlier stages of AD, and do not require the presence of dementia. We aimed to evaluate the new predementia-AD criteria through their retrospective application to the OPTIMA cohort with post-mortem (PM) confirmed diagnoses. METHODS: The criteria were evaluated for sensitivity and specificity using cognitive, neuroimaging and cerebrospinal fluid data and clinical information for exclusion criteria. Limitations in choice of cognitive test, use of CT scans rather than MRI and missing CSFs affected the outcomes. Analyses were carried out for the whole cohort (n = 243) and on a mild-stage subgroup (n = 99) defined by MMSE ≥ 21. RESULTS: Of the four options for fulfilling the revised-criteria, the best results for the whole cohort were achieved using memory and CSF data with exclusion criteria applied (.68 sensitivity and .93 specificity). The pattern was similar for the mild cohort, but with lower sensitivity. Specificities of 1.0 were reached with supportive criteria, CSF and CSF plus MTL. CONCLUSIONS: The revised-criteria, when applied to our cohort, offer good specificity and reasonable sensitivity when compared with the gold standard of PM diagnosis. The criteria were not more effective for early stage dementia.

Strategy or symptom: Semantic clustering and risk of Alzheimer's disease-related impairment.

Alzheimer's disease (AD) is the most common form of dementia, impacting global cognitive performance, including episodic memory. Semantic clustering is a learning strategy involving grouping words of similar meaning and can improve episodic memory performance, e.g., list learning. As the APOE ε4 allele is the most validated genetic risk factor for AD, we predicted that its presence would be associated with poorer list learning performance, and we hypothesized that semantic clustering moderates or mediates this association. The sample comprised 699 healthy older adults participating in the CHARIOT PRO Main Study, 169 of whom were APOE ε4 carriers. Participants' ability to form groups of related stimuli (assessed via a categorization task, CAT), and their use of semantic clustering during list learning, were investigated using the Neuropsychological Assessment Battery (NAB). CAT scores predicted the use of semantic clustering in, and performance on, the list learning task. CAT scores were not significantly lower in APOE ε4 carriers, suggesting that the ability to categorize was preserved. However, APOE ε4 carriers made less use of semantic clustering in list learning. Semantic clustering use partially mediated the relationship between CAT scores and list learning performance, and, in women only, moderated the impact of APOE ε4 on list learning performance. The results suggest that better categorization ability is associated with greater use of mnemonic strategies and better performance on memory tasks regardless of genetic risk, but that APOE ε4 carriers make less use of such strategies. Furthermore, female APOE ε4 carriers may benefit more than their non-carriers from using semantic clustering to aid list learning. Thus, semantic clustering may be a contributing factor of their "cognitive reserve", compensating for potential deficits in episodic memory.

Associations of Social Isolation with Anxiety and Depression During the Early COVID-19 Pandemic: A Survey of Older Adults in London, UK.

The COVID-19 pandemic is imposing a profound negative impact on the health and wellbeing of societies and individuals, worldwide. One concern is the effect of social isolation as a result of social distancing on the mental health of vulnerable populations, including older people. Within six weeks of lockdown, we initiated the CHARIOT COVID-19 Rapid Response Study, a bespoke survey of cognitively healthy older people living in London, to investigate the impact of COVID-19 and associated social isolation on mental and physical wellbeing. The sample was drawn from CHARIOT, a register of people over 50 who have consented to be contacted for aging related research. A total of 7,127 men and women (mean age=70.7 [SD=7.4]) participated in the baseline survey, May-July 2020. Participants were asked about changes to the 14 components of the Hospital Anxiety Depression scale (HADS) after lockdown was introduced in the UK, on 23rd March. A total of 12.8% of participants reported feeling worse on the depression components of HADS (7.8% men and 17.3% women) and 12.3% reported feeling worse on the anxiety components (7.8% men and 16.5% women). Fewer participants reported feeling improved (1.5% for depression and 4.9% for anxiety). Women, younger participants, those single/widowed/divorced, reporting poor sleep, feelings of loneliness and who reported living alone were more likely to indicate feeling worse on both the depression and/or anxiety components of the HADS. There was a significant negative association between subjective loneliness and worsened components of both depression (OR 17.24, 95% CI 13.20, 22.50) and anxiety (OR 10.85, 95% CI 8.39, 14.03). Results may inform targeted interventions and help guide policy recommendations in reducing the effects of social isolation related to the pandemic, and beyond, on the mental health of older people.

The effect of recent consumption of caffeine-containing foodstuffs on neuropsychological tests in the elderly.

We investigated the effect of recent intake of caffeine-containing foodstuffs (CCFS) on a group of elderly participants (age range 67-95 years) on a series of neuropsychological tests. There was no significant effect of CCFS intake on performance in any of the tests in the battery used. However, a significant interaction effect was found between age and CCFS consumption on scores of some neuropsychological tests. In these tests, participants with recent consumption of CCFS show a linear decrease in performance with increasing age, a pattern not seen for those that have no CCFS in their system. Accuracy in the neuropsychological assessment is of great importance when determining whether someone has a cognitive impairment or early Alzheimer's disease. We therefore propose that recent consumption of CCFS should be taken into account when scoring the neuropsychological assessment.

Detection of MCI in the clinic: evaluation of the sensitivity and specificity of a computerised test battery, the Hopkins Verbal Learning Test and the MMSE.

INTRODUCTION: the sensitive detection of mild cognitive impairment (MCI) in older adults is an important problem that requires objective assessment. We evaluated whether the computerised cognitive test battery, CogState, was as sensitive to MCI as two well-validated 'paper-and-pencil' tests, the Hopkins Verbal Learning Test (HVLT) and the Mini-Mental Status Examination (MMSE). METHODS: these tests were administered with a subjective memory questionnaire and an 'Activities of Daily Living' scale to 21 individuals with MCI and 98 cognitively healthy controls matched for sex, education and IQ levels. The sensitivity and specificity of the tests and their discrimination between groups were determined. RESULTS: the HVLT had a maximum discrimination between controls and MCI cases of 90%, compared with 86% for CogState and 65% for the MMSE. Only CogState showed correlations with subjective memory complaints (SMC) and activities of daily living for the whole cohort when controlled for age, sex and years of education. Logistic regression analyses showed that diagnosis (control:MCI) was predicted by HVLT and a CogState ratio score. Age was a significant predictor of HVLT performance, while age and SMC predicted CogState performance. The computerised test battery was well tolerated by older adults, but presentation speed was a limiting factor for some participants. CONCLUSIONS: overall, we conclude that the HVLT has better sensitivity for the detection of MCI in older adults than the CogState, but that CogState may enable the identification of cognitive deficits above and beyond impairments in memory.

Prevalence of HIV-1 Infection in an elderly rural population and associations with neurocognitive impairment.

OBJECTIVE: We explored the prevalence of HIV infection in older rural South Africans and its associations, as well as the point prevalence of dementia and its associations with HIV and aging. DESIGN: We utilized a cross-sectional analytic design. METHODS: Using the brief Community Screening Instrument for Dementia together with a rapid HIV test, we conducted a home-based screening survey among 1150 older South Africans. We explored the prevalence of HIV and dementia, and their associations using descriptive statistics and logistic regression analysis. RESULTS: The HIV prevalence was 4.78%. Overall, participants were on average 71.3 years old, with nearly 70% having no primary school education. HIV+ participants were significantly younger, more likely to be single and had lower BMI. The overall dementia prevalence was 11.04%. HIV+ participants had higher rates of dementia compared with HIV- participants (18.18 vs. 10.68%) but the difference was NS. In adjusted analysis, screened dementia was associated with older age, the presence of self-reported depression and HIV+ status. Participants were also more likely to self-report cognitive impairment if they were older, depressed and had objective evidence of dementia. CONCLUSION: Infection with HIV in rural older South Africans is a prevalent problem, and together with older age, is a significant contributor to cognitive impairment. It is possible that HIV infection contributes to dementia on the basis of an acceleration of degeneration - because our HIV-infected participants were younger - AND an accentuation of aging - because of the higher rates of impairment for similar age groups.

Vitamin B12 status of pregnant Indian women and cognitive function in their 9-year-old children.

BACKGROUND: Recent research has highlighted the influence of maternal factors on the health of the offspring. Intrauterine experiences may program metabolic, cardiovascular, and psychiatric disorders. We have shown that maternal vitamin B12 status affects adiposity and insulin resistance in the child. Vitamin B12 is important for brain development and function. OBJECTIVE: We investigated the relationship between maternal plasma vitamin B12 status during pregnancy and the child's cognitive function at 9 years of age. METHODS: We studied children born in the Pune Maternal Nutrition Study. Two groups of children were selected on the basis of maternal plasma vitamin B12 concentration at 28 weeks of gestation: group 1 (n = 49) included children of mothers with low plasma vitamin B12 (lowest decile, < 77 pM) and group 2 (n = 59) children of mothers with high plasma vitamin B12 (highest decile, > 224 pM). RESULTS: Children from group 1 performed more slowly than those from group 2 on the Color Trail A test (sustained attention, 182 vs. 159 seconds; p < .05) and the Digit Span Backward test (short-term memory, p < .05), after appropriate adjustment for confounders. There were no differences between group 1 and group 2 on other tests of cognitive function (intelligence, visual agnosia). CONCLUSIONS: Maternal vitamin B12 status in pregnancy influences cognitive function in offspring.

Utility of the Malayalam translation of the 7- minute screen for Alzheimer's disease risk in an Indian community.

BACKGROUND: Alzheimer's disease (AD) is suspected to be currently under-diagnosed in India, thus the need for a brief, effective screening test for the condition. AIMS: We aimed to test the Malayalam translation of the 7-Minute Screen (7MS) for detecting those at high risk for AD and to report on the subscores used to derive the Alzheimer's risk score. SETTING AND DESIGN: This study was performed in Kerala State amongst young university students and elders in residential care homes. MATERIALS AND METHODS: Two hundred and eighty-two volunteers were tested, 178 young controls (aged 20-29) and 104 literate elders, (55-92 years). None were clinically diagnosed with AD. STATISTICAL ANALYSES: Elders and controls were assessed as High or Low AD Risk with the published 7MS algorithm. Performance was compared between groups with ANOVA. RESULTS: The algorithm estimated high (n=61/104) or low (n=40/104) AD risk in the elderly. Significant differences were found between controls, low- and high-risk groups on all four components of the screen (Orientation: F=131.1, Enhanced Cued Recall: F=23.4, Clock Drawing: F=65.1, Verbal Fluency: F=15.7, P<0.0001 for all) and in the risk scores (F=144.7, P<0.0001). Age and gender affected verbal fluency, orientation and clock drawing performance. The high-risk group had worse scores for orientation and better scores for memory than previously reported for AD cases in other populations. CONCLUSIONS: The 7MS may be a useful screening test for cognitive impairment in India. Suggestions are given for revising the 'risk algorithm' for more appropriate AD risk assessment in this population.

Dementia Prevalence in a Rural Region of South Africa: A Cross-Sectional Community Study.

BACKGROUND: Dementia is a growing concern for low- and middle-income countries where longevity is increasing and service provision is poor. Global prevalence estimates vary from 2% to 8.5% for those aged 60 years and older. There have been few dementia studies in sub-Saharan Africa, and prevalence data are lacking for South Africa. OBJECTIVE: To conduct a large dementia prevalence study in a low income rural population in South Africa. METHODS: 1,394 Xhosa-speaking community dwellers, aged ≥60 y (mean age±sd 71.3±8.3 y), in three clinic catchment areas, were screened at home. Trained community health workers administered the brief Community Screening Instrument for Dementia (CSID) to participants and informants to assess cognitive and functional capacity. Depressive symptoms were assessed with three questions from the EURO-D. RESULTS: The prevalence estimate using published CSID sensitivity/specificity values was 0.8 (95% CI: 0.06-0.09). Using CSID cut-off scores the estimated prevalence was 0.12 (95% CI: 0.10-0.13), with 161 screen-positives. Both methods gave a rate of 0.11 (95% CI: 0.09-0.13) for those over 65 years (n = 1051). 68.6% of participants were female and 69.8% had less than 7 years of education. Dementia risk was associated with older age and symptoms of depression, but not with sex. The association with education was not significant when controlled for by age. CONCLUSIONS: Dementia prevalence estimates were higher than expected for this low-income rural community. There is a need for increased dementia awareness and feasible support interventions. We also need further studies of regional prevalences, dementia subtypes, and modifiable risk factors in South Africa.

Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment.

A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD.

Changes over time in memory, processing speed and clock drawing tests help to discriminate between vascular cognitive impairment, mild cognitive impairment and Alzheimer's disease.

Measures of cognitive change over time may help to better discriminate between mild cognitive impairment, Alzheimer's disease and vascular cognitive impairment than single assessments. Our hypothesis was that performance in processing speed and executive function would decline with mild cognitive impairment and Alzheimer's disease. Subjects included 36 controls, 18 cases with mild cognitive impairment, eight with vascular cognitive impairment and 24 with Alzheimer's disease who were tested on a cognitive battery at two episodes with a 12-month interval. Changes in performance were determined for each group with paired means tests. Controls improved in pattern comparison speed and the CLOX, a clock-drawing task to detect dysexecutive function. Those with vascular cognitive impairment declined in letter comparison speed, but improved in paragraph recall. Alzheimer's disease patients declined in CLOX and the Hopkins Verbal Learning Test. The mild cognitive impairment group showed no significant changes. Alzheimer's disease patients on treatment declined in Hopkins Verbal Learning Test, while those without treatment declined in The Placing Test and CLOX. Processing speed decline may be a marker of cerebrovascular disease, while decline in memory and executive function was more evident with Alzheimer's disease.