Sindre Rolstad

The Goteborg MCI study: mild cognitive impairment is a heterogeneous condition

Background: Mild cognitive impairment (MCI) has been considered a transitional state between normal aging and dementia, characterised by memory impairment but normal general cognitive functioning. Recently other cognitive deficits have been reported. This has led to a modification of MCI criteria. Objective: To examine which neuropsychological tests most clearly distinguish MCI subjects from normal controls. Methods: 112 consecutive MCI subjects and 35 controls were included in the study. The diagnosis of MCI was based on an objective history of cognitive decline and a neuropsychiatric examination, comprising instruments STEP, I-Flex, MMSE, and CDR. Participants were examined with 21 neuropsychological tests in the cognitive domains speed/attention, memory and learning, visuospatial function, language, and executive function. Results: Controls were significantly older. No differences were found in education or general intellectual capacity. Controls performed significantly better than MCI on tests within all five cognitive domains. The clearest differences were seen on language tests, followed by executive function, and learning and memory. Only two subjects (1.8%) were purely amnestic; 17% showed no impairment compared with controls, with a cut off of 1.5 SD below age mean. These subjects were better educated and performed significantly better on measures of general cognitive capacity. Conclusions: The results illustrate the heterogeneity of MCI, with a significant degree of impairment in all five cognitive domains. When examined with a comprehensive neuropsychological battery, very few subjects had an isolated memory impairment.

Prediction and longitudinal study of CSF biomarkers in mild cognitive impairment

OBJECTIVES To longitudinally evaluate five cerebrospinal fluid (CSF) biomarkers in the transition from mild cognitive impairment (MCI) to Alzheimers disease (AD). METHODS A baseline and 2-year follow-up clinical and CSF study of 86 subjects, including 22 MCI patients that declined to AD (MCI-AD), 43 MCI that did not deteriorate (MCI-MCI) and 21 controls (NL-NL). All subjects were studied for total and phosphorylated tau (T-tau, P-tau(231)), amyloid beta (Abeta) Abeta(42)/Abeta(40) ratio, isoprostane (IP) as well as P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios. RESULTS At baseline and at follow-up MCI-AD showed higher levels P-tau(231), T-tau, IP, P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios and lower Abeta(42)/Abeta(40) than MCI-MCI or NL-NL. Baseline P-tau(231) best predicted MCI-AD (80%, p<0.001) followed in accuracy by P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios (both 75%, ps<0.001), T-tau (74%, p<0.001), Abeta(42)/Abeta(40) (69%, p<0.01), and IP (68%, p<0.01). Only IP showed longitudinal effects (p<0.05). CONCLUSIONS P-tau(231) is the strongest predictor of the decline from MCI to AD. IP levels uniquely show longitudinal progression effects. These results suggest the use of CSF biomarkers in secondary prevention trials.

Intra-individual stability of CSF biomarkers for Alzheimer's disease over two years.

This study examines the intra-individual stability of cerebrospinal fluid (CSF) biomarkers for Alzheimers disease (AD) over 2 years in 83 patients with mild cognitive impairment (MCI) and 17 cognitively healthy control individuals. All participants underwent clinical and neuropsychological evaluation and lumbar puncture at baseline and after 2 years at a university hospital memory clinic. CSF was analyzed for total tau (T-tau), phospho-tau(181) (P-tau(181)) and amyloid-beta(1-42) (Abeta(1-42)). During the 2-year observational time, 12 MCI patients progressed to AD and 3 progressed to vascular dementia, while 68 remained stable. Baseline T-tau and P-tau(181) levels were elevated in the MCI-AD group as compared to the stable MCI patients and the control group (p<0.01), while baseline Abeta(1-42) levels were lower (p<0.001). Stable MCI patients were biochemically indistinguishable from controls. The biomarker levels at baseline and after 2 years showed Pearson R values between 0.81 and 0.91 (p<0.001) and coefficients of variation of 7.2 to 8.7%. In conclusion, intra-individual biomarker levels are remarkably stable over 2 years. Thus, even minor biochemical changes induced by treatment against AD should be detectable using these biomarkers, which bodes well for their usefulness as surrogate markers for drug efficacy in clinical trials.

Two-year outcome of MCI subtypes and aetiologies in the Göteborg MCI study

Objective The objective was to study the 2-year outcome of subjects diagnosed as having mild cognitive impairment (MCI). Methods Two hundred and nine subjects diagnosed as having MCI were examined with a comprehensive neuropsychological test battery and followed up after 2 years. Results After 2 years, 34 subjects (16%) were lost for follow-up. Those subjects did not differ significantly in terms of MCI subclassification, MMSE score or age and education. Of the 175 subjects followed up, eight (4.5%) had improved to normal, two with amnestic MCI, one from multiple domains MCI, three with single domain MCI and two without any significant impairment at baseline. Forty-four subjects (25%) had progressed to dementia. Of these, 35 were from the multidomain amnestic group and nine from the multidomain non-amnestic group. The combination of Alzheimer-typical biomarkers (total-τ and amyloid beta) and multidomain amnestic MCI was the strongest predictor of progression to Alzheimers disease, while vascular disease and multidomain amnestic MCI preceded mixed and vascular dementia. Conclusion The results suggest that memory impairment alone, or impairment in any one cognitive domain alone, is a rather benign condition. Impairment in several cognitive domains is associated with a more severe outcome over 2 years. Also, 20% of the subjects who progressed to dementia, including Alzheimers disease, did not show memory impairment at baseline, which suggests that memory impairment is not always the first symptom of even the most common dementia disorders.

Small baseline volume of left hippocampus is associated with subsequent conversion of MCI into dementia: The Göteborg MCI study

BACKGROUND Earlier studies have reported that hippocampal atrophy can to some extent predict which patients with mild cognitive impairment (MCI) will subsequently convert to dementia, and that converters have an enhanced rate of hippocampal volume loss. OBJECTIVE To further validate the hypothesis that hippocampal atrophy predicts conversion from MCI to dementia, to relate baseline hippocampal volume to different forms of dementia, and to investigate the role of hippocampal side differences and rate of volume loss over time. PATIENTS The subjects (N=68) include patients with MCI at baseline and progression to dementia at the two-year follow-up (N=21), stable MCI patients (N=21), and controls (N=26). Among the progressing patients, 13 were diagnosed as having AD. METHODS The Göteborg MCI study is a clinically based longitudinal study with biannual clinical assessments. Hippocampal volumetry was performed manually on the MRI investigations at baseline and at the two-year follow-up. RESULTS Hippocampal volumetry could predict conversion to dementia in both the AD and the non-AD subgroup of converters. Left hippocampal volume in particular discriminated between converting and stable MCI. Cut off points for individual discrimination were shown to be potentially useful. The converting MCI group had a significantly higher rate of hippocampal volume loss as compared to the stable MCI group. CONCLUSIONS In MCI patients, hippocampal volumetry at baseline gives prognostic information about possible development of AD and non-AD dementia. Contrary to earlier studies, we found that left hippocampal volume has the best predictive power. Reliable predictions appear to be possible in many individual cases.

Cognitive profiles of mild cognitive impairment with and without vascular disease

This study examined whether the cognitive profile of subjects with mild cognitive impairment (MCI) with vascular disease differs from that of MCI subjects with no vascular disease. Consecutive MCI subjects with vascular disease (n=60) and matched MCI subjects with no vascular disease (n=60) were included in the study and were compared with healthy control subjects (n=60). The neuropsychological assessment comprised tests of speed and attention, episodic memory, visuospatial function, language, and executive function. Control subjects performed significantly better than did both MCI groups on the neuropsychological battery. MCI subjects with no vascular disease performed better overall than did MCI subjects with vascular disease, most clearly on tests of speed and attention, visuospatial function, and executive function. MCI subjects with and without vascular disease exhibited differences, both in terms of overall performance and of cognitive profiles. These differences can be largely explained by deficits in speed and attention and in executive function of the MCI subjects with vascular disease.

Longitudinal cerebrospinal fluid biomarkers over four years in mild cognitive impairment.

Cerebrospinal fluid (CSF) measurements of amyloid-β42 (Aβ42), total-tau (T-tau), and phosphorylated tau (P-tau) may be used to predict future Alzheimers disease (AD) dementia in patients with mild cognitive impairment (MCI). The precise temporal development of these biomarkers in relation to clinical progression is unclear. Earlier studies have been hampered by short follow-up. In an MCI cohort, we selected 15 patients who developed AD (MCI-AD) and 15 who remained cognitively stable during 4 years of follow-up. CSF was sampled at three serial occasions from each patient and analyzed for Aβ peptides, the soluble amyloid-β protein precursor protein fragments sAβPPα and sAβPPβ, T-tau, P-tau, and chromogranin B, which is a protein linked to regulated neuronal secretion. We also measured, for the first time in MCI patients, an extended panel of Aβ peptides by matrix-assisted-laser-desorption/ionization time-of-flight mass spectrometry (MS). Most biomarkers were surprisingly stable over the four years with coefficients of variation below or close to 10%. However, MCI-AD patients decreased in CSF AβX₋₄₀ and chromogranin B concentrations, which may indicate a reduced number of functional neurons or synapses with disease progression. The MS Aβ peptide panel was more useful than any single Aβ peptide to identify MCI-AD patients already at baseline. Knowledge on these biomarkers and their trajectories may facilitate early diagnosis of AD and be useful in future clinical trials to track effects of disease modifying drugs.

Cognitive profiles of incipient dementia in the Goteborg MCI study.

Objective: To study which cognitive profiles of incipient dementia strongest predict the conversion to Alzheimer’s disease (AD) and mixed dementia (MD)/vascular dementia (VaD). Methods: 260 subjects with mild cognitive impairment (MCI) were included in the study and 209 (79%) were followed up after 2 years. At baseline, the subjects were assessed with a neuropsychological battery covering the cognitive domains speed/attention, memory, visuospatial, language and executive functions. Results: After 2 years, 9 subjects were considered normal, 148 had stationary MCI and 47 (23%) had converted to dementia. Twenty subjects were diagnosed with AD, 15 with MD and 9 with VaD. The others were 2 with unspecified dementias and 1 with primary progressive aphasia. Dementia converters had a high proportion of impairment in all cognitive domains. The profiles of incipient AD and MD/VaD differed, with memory, visuospatial and language symptoms preceding AD, and executive and speed/attention symptoms preceding MD/VaD. Conclusions: The risk of converting to dementia is increased when domains in addition to memory are impaired. The incipient AD and MD/VaD profiles differed quite clearly. Considering that the vascular group consisted of a majority of patients with MD, the differences are convincing – vascular disease seems to have an essential impact on cognition.

Apathy is a prominent neuropsychiatric feature of radiological white‐matter changes in patients with dementia

Cerebral white‐matter changes (WMCs) are frequently found in dementia and have been proposed to be related to vascular factors and a certain symptomatological profile. However, few studies have included both vascular factors and a broad spectrum of cognitive, neurological and psychiatric symptoms, easily detectable by the physician in the everyday clinical work. The objective was to study the relationships between WMCs on MRI/CT and neuropsychiatric symptoms and vascular factors in patients with cognitive impairment.

Episodic memory and speed/attention deficits are associated with Alzheimer-typical CSF abnormalities in MCI

UNLABELLED Mild cognitive impairment (MCI) is regarded as the prodromal stage of dementia disorders, such as Alzheimers disease (AD). OBJECTIVE To compare the neuropsychological profiles of MCI subjects with normal concentrations of total tau (T-tau) and Abeta42 in CSF (MCI-norm) to MCI subjects with deviating concentrations of the biomarkers (MCI-dev). MCI-norm (N = 73) and MCI-dev (N = 73) subjects were compared to normal controls (N = 50) on tests of speed/attention, memory, visuospatial function, language and executive function. RESULTS MCI-norm performed overall better than MCI-dev, specifically on tests of speed and attention and episodic memory. When MCI-dev subjects were subclassified into those with only high T-tau (MCI-tau), only low Abeta42 (MCI-Abeta) and both high T-tau and low Abeta42 (MCI-tauAbeta), MCI-tauAbeta tended to perform slightly worse. MCI-tau and MCI-Abeta performed quite similarly. CONCLUSIONS Considering the neuropsychological differences, many MCI-norm probably had more benign forms of MCI, or early non-AD forms of neurodegenerative disorders. Although most MCI-dev performed clearly worse than MCI-norm on the neuropsychological battery, some did not show any deficits when compared to age norms. A combination of CSF analyses and neuropsychology could be a step toward a more exact diagnosis of MCI as prodromal AD.