Huub A. M. Middelkoop

Strongly reduced volumes of putamen and thalamus in Alzheimer's disease: an MRI study

Atrophy is regarded a sensitive marker of neurodegenerative pathology. In addition to confirming the well-known presence of decreased global grey matter and hippocampal volumes in Alzheimers disease, this study investigated whether deep grey matter structure also suffer degeneration in Alzheimers disease, and whether such degeneration is associated with cognitive deterioration. In this cross-sectional correlation study, two groups were compared on volumes of seven subcortical regions: 70 memory complainers (MCs) and 69 subjects diagnosed with probable Alzheimers disease. Using 3T 3D T1 MR images, volumes of nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen and thalamus were automatically calculated by the FMRIBs Integrated Registration and Segmentation Tool (FIRST)—algorithm FMRIBs Software Library (FSL). Subsequently, the volumes of the different regions were correlated with cognitive test results. In addition to finding the expected association between hippocampal atrophy and cognitive decline in Alzheimers disease, volumes of putamen and thalamus were significantly reduced in patients diagnosed with probable Alzheimers disease. We also found that the decrease in volume correlated linearly with impaired global cognitive performance. These findings strongly suggest that, beside neo-cortical atrophy, deep grey matter structures in Alzheimers disease suffer atrophy as well and that degenerative processes in the putamen and thalamus, like the hippocampus, may contribute to cognitive decline in Alzheimers disease.

Assessment of cognition in Parkinson’s disease

Objective: To develop a short, practical instrument that is sensitive to the specific cognitive deficits in Parkinson’s disease (PD) for comparing groups in research situations and for assessing change in cognitive functioning over time. Methods: A literature search was conducted to identify the most frequently affected cognitive domains in PD and to select candidate items for the initial scale. This scale was tested in 85 patients and 75 age-, education-, and sex-matched control subjects. Items that met predefined criteria for data quality, reproducibility, and discriminative properties were included in the final scale. Results: The final scale, the SCOPA-COG (SCales for Outcomes of PArkinson’s disease–cognition), consists of 10 items with a maximum score of 43, with higher scores reflecting better performance. The test–retest reliability of the total score was 0.78 (intraclass correlation coefficient) and ranged from 0.40 to 0.75 for individual items (weighted κ). Cronbach’s α was 0.83. Construct validity of the scale was supported by the expected correlations with the CAMCOG (Cambridge Cognitive Examination) and the Mini-Mental State Examination (MMSE) and by differences found between groups of participants classified by dementia status and between patients grouped by disease severity. The scale showed a clear trend toward lower cognition scores for patients with more advanced PD. The coefficient of variation of the SCOPA-COG was higher than that of the CAMCOG or the MMSE, indicating a better ability to detect differences between individuals. Conclusion: The SCOPA-COG is a short, reliable, and valid instrument that is sensitive to the specific cognitive deficits in PD.

Cognitive impairment in Parkinson's disease

Background: Cognitive impairment plays a role in Parkinson’s disease (PD) and has important consequences for patient management. However, many aspects of cognitive impairment in PD remain unclear because of the use of different and often invalid measurement instruments. In this study, a reliable and valid instrument, the SCales for Outcomes in PArkinson’s disease-COGnition (SCOPA-COG), was used. Aim: To evaluate cognitive functioning in a large cohort of patients with Parkinson’s disease and to assess the relations with demographic, disease related and clinical variables. Methods: A cohort of 400 patients with PD was evaluated for cognition, motor and non-motor domains, as well as for demographic and disease related characteristics. Results were compared with 150 controls matched for overall age, sex and education distribution. Results: Patients with PD scored significantly lower on all cognitive subdomains compared with controls, with the largest differences for executive functioning and memory. After correction for age and years of education, 22% of patients had impaired cognition, as measured by the total SCOPA-COG score, compared with controls. Across all patients, more severe cognitive impairment was associated with significantly more impairment in motor, autonomic, depressive and psychotic domains. Patients with the postural instability gait difficulty (PIGD) dominant phenotype showed more cognitive impairment compared with patients with the tremor dominant phenotype. Contrary to tremor scores, PIGD scores significantly worsened with increasing disease severity. Conclusions: Cognition is an important domain of the clinical spectrum of PD and poorer cognitive performance is associated with greater impairment in motor and non-motor domains in PD. The difference in cognitive scores between PIGD dominant patients and tremor dominant patients likely reflects more advanced disease.

Magnetization transfer imaging in normal aging, mild cognitive impairment, and Alzheimer's disease.

The purpose of this study was to assess whether structural brain damage as detected by volumetric magnetization transfer imaging (MTI) is present in mild cognitive impairment (MCI) and Alzheimers disease (AD) and, if so, whether these abnormalities are global in character or restricted to the temporal lobe. Volumetric MTI analysis of the whole brain and temporal and frontal lobes was performed in 25 patients with probable AD, in 13 patients with MCI, and in 28 controls. Magnetization transfer ratio (MTR) histograms were produced, from which we derived measures for structural brain damage and atrophy. The peak heights of the MTR histograms of MCI and AD patients were lower than those of controls for the whole brain and temporal and frontal lobes, reflecting structural brain damage. AD patients had more atrophy than controls in all regions that were studied. MCI patients differed from controls for temporal lobe atrophy only. Volumetric MTI demonstrates structural changes that are related to cognitive decline in large parts of the brain of AD patients. Moreover, structural changes also were observed in MCI patients, indicating that widespread brain damage can be demonstrated before patients are clinically demented.

Memory complaints in patients with normal cognition are associated with smaller hippocampal volumes.

Abstract.We aimed to investigate volumetry of the medial temporal lobe in patients with subjective memory complaints without any cognitive impairment. This study included 20 patients with subjective memory complaints and normal cognitive function and 28 controls without memory complaints. Volumes of the hippocampus and parahippocampal gyrus (PHG) were measured using coronal T1-weighted MR images. Cognitive functions were assessed using the Cambridge Cognitive Examination. Depressive symptoms were assessed using the Geriatric Depression Scale. Differences between groups were analysed using t-tests. Patients with subjective memory complaints had a higher education and more depressive symptoms than controls (p < 0.01). Moreover, they had smaller left hippocampal volumes than controls (p < 0.01). There were no differences between groups in the volume of the right hippocampus or PHG. There was a moderate association between the volume of left hippocampus and left PHG and memory-score (r = 0.32, p = 0.03; r = 0.34, p = 0.02). We concluded that memory complaints in patients without any cognitive impairment were associated with smaller left hippocampal volumes and more depressive symptoms. These preliminary results suggest that memory complaints may reflect minimal brain deficits associated with impending dementia, depression or a combination of both disorders.

Progression of brain atrophy and cognitive decline in diabetes mellitus A 3-year follow-up

Objective: To investigate progression of MRI-assessed manifestations of cerebral degeneration related to cognitive changes in a population of elderly patients with diabetes mellitus (DM) compared to age-matched control subjects. Methods: From a randomized controlled trial (PROSPER study), a study sample of 89 patients with DM and 438 control subjects without DM aged 70–82 years were included for brain MRI scanning and cognitive function testing at baseline and reexamination after 3 years. Changes in brain atrophy, white matter hyperintensities (WMHs), number of infarctions, and cognitive function test results were determined in patients with DM and subjects without DM. Linear regression analysis was performed with correction for age, gender, hypertension, pravastatin treatment, educational level, and baseline test results. In patients with DM, baseline MRI parameters were correlated with change in cognitive function test result using linear regression analysis with covariates age and gender. Results: Patients with DM showed increased progression of brain atrophy (p < 0.01) after follow-up compared to control subjects. No difference in progression of WMH volume or infarctions was found. Patients with DM showed increased decline in cognitive performance on Stroop Test (p = 0.04) and Picture Learning Test (p = 0.03). Furthermore, in patients with DM, change in Picture Learning Test was associated with baseline brain atrophy (p < 0.02). Conclusion: Our data show that elderly patients with DM without dementia have accelerated progression of brain atrophy with significant consequences in cognition compared to subjects without DM. Our findings add further evidence to the hypothesis that diabetes exerts deleterious effects on neuronal integrity.

EEG correlates in the spectrum of cognitive decline

OBJECTIVE To investigate relations between EEG measures and performance on tests of global cognition, memory, language and executive functioning. METHODS Twenty-two controls, 18 patients with mild cognitive impairment (MCI) and 16 with probable Alzheimers disease (AD) underwent neuropsychological and EEG investigations. We used the following EEG measures: theta relative power during eyes closed, alpha reactivity during memory activation (i.e. the percentual decrease in alpha power as compared to eyes closed) and alpha coherence during eyes closed and memory activation. RESULTS Theta relative power was increased in AD patients as compared with controls (p<0.001) and MCI patients (p<0.01) and related to decreased performance in all cognitive domains. Alpha reactivity was decreased in AD patients as compared with controls (p<0.005) and related to decreased performance on tests of global cognition, memory and executive functioning. Alpha coherence did not differ between groups and was unrelated to cognition. CONCLUSIONS EEG power measures were associated with decreased performance on tests of global cognition, memory, language and executive functioning, while coherence measures were not. SIGNIFICANCE The EEG yielded several power measures related to cognitive functions. These EEG power measures might prove useful in prospective studies aimed at predicting longitudinal cognitive decline and dementia.

Structural Brain Changes in Migraine

CONTEXT A previous cross-sectional study showed an association of migraine with a higher prevalence of magnetic resonance imaging (MRI)-measured ischemic lesions in the brain. OBJECTIVE To determine whether women or men with migraine (with and without aura) have a higher incidence of brain lesions 9 years after initial MRI, whether migraine frequency was associated with progression of brain lesions, and whether progression of brain lesions was associated with cognitive decline. DESIGN, SETTING, AND PARTICIPANTS In a follow-up of the 2000 Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis cohort, a prospective population-based observational study of Dutch participants with migraine and an age- and sex-matched control group, 203 of the 295 baseline participants in the migraine group and 83 of 140 in the control group underwent MRI scan in 2009 to identify progression of MRI-measured brain lesions. Comparisons were adjusted for age, sex, hypertension, diabetes, and educational level. The participants in the migraine group were a mean 57 years (range, 43-72 years), and 71% were women. Those in the control group were a mean 55 years (range, 44-71 years), and 69% were women. MAIN OUTCOME MEASURES Progression of MRI-measured cerebral deep white matter hyperintensities, infratentorial hyperintensities, and posterior circulation territory infarctlike lesions. Change in cognition was also measured. RESULTS Of the 145 women in the migraine group, 112 (77%) vs 33 of 55 women (60%) in the control group had progression of deep white matter hyperintensities (adjusted odds ratio [OR], 2.1; 95%CI, 1.0-4.1; P = .04). There were no significant associations of migraine with progression of infratentorial hyperintensities: 21 participants (15%) in the migraine group and 1 of 57 participants (2%) in the control group showed progression (adjusted OR, 7.7; 95% CI, 1.0-59.5; P = .05) or new posterior circulation territory infarctlike lesions: 10 of 203 participants (5%) in the migraine group but none of 83 in the control group (P = .07). There was no association of number or frequency of migraine headaches with progression of lesions. There was no significant association of high vs nonhigh deep white matter hyperintensity load with change in cognitive scores (-3.7 in the migraine group vs 1.4 in the control group; 95% CI, -4.4 to 0.2; adjusted P = .07). CONCLUSIONS In a community-based cohort followed up after 9 years, women with migraine had a higher incidence of deep white matter hyperintensities but did not have significantly higher progression of other MRI-measured brain changes. There was no association of migraine with progression of any MRI-measured brain lesions in men.

Increased Prevalence of Psychopathology and Maladaptive Personality Traits after Long-Term Cure of Cushing’s Disease

CONTEXT AND OBJECTIVE Psychopathology and maladaptive personality traits are often observed during the active phase of Cushings disease (CD). We hypothesized that patients with long-term cure of CD show persistent psychopathology and maladaptive personality traits. DESIGN Four questionnaires on frequently occurring psychopathology in somatic illnesses were used, including the Apathy Scale, Irritability Scale, Hospital Anxiety and Depression Scale, and Mood and Anxiety Symptoms Questionnaire short-form. Personality was assessed using the Dimensional Assessment of Personality Pathology short-form (DAPPs). PATIENTS AND CONTROL SUBJECTS We included 51 patients cured of CD (16% men, 53 ± 13 yr) and 51 matched controls. In addition, we included 55 patients treated for nonfunctioning pituitary macroadenomas (55% men, 62 ± 10 yr), and 55 matched controls. RESULTS Mean duration of remission was 11 yr (range 1-32 yr). Compared with matched controls, patients cured from CD scored significantly worse on virtually all questionnaires. Compared with nonfunctioning pituitary macroadenoma patients, patients treated for CD scored worse on apathy (P < 0.001), irritability (P < 0.001), anxiety (P < 0.001), negative affect and lack of positive affect (P < 0.001 on both scales), somatic arousal (P < 0.001), and 11 of 18 subscales of the Dimensional Assessment of Personality Pathology short-form (P < 0.05). CONCLUSIONS Patients with long-term cured CD show an increased prevalence of psychopathology and maladaptive personality traits. These observations suggest irreversible effects of previous glucocorticoid excess on the central nervous system rather than an effect of pituitary tumors and/or their treatment in general. This may also be of relevance for patients treated with high doses of exogenous glucocorticoids.

Subtle Cognitive Impairments in Patients with Long-Term Cure of Cushing’s Disease

CONTEXT AND OBJECTIVE Active Cushings disease is associated with cognitive impairments. We hypothesized that previous hypercortisolism in patients with Cushings disease results in irreversible impairments in cognitive functioning. Therefore, our aim was to assess cognitive functioning after long-term cure of Cushings disease. DESIGN Cognitive assessment consisted of 11 tests, which evaluated global cognitive functioning, memory, and executive functioning. PATIENTS AND CONTROL SUBJECTS We included 74 patients cured of Cushings disease and 74 controls matched for age, gender, and education. Furthermore, we included 54 patients previously treated for nonfunctioning pituitary macroadenomas (NFMA) and 54 controls matched for age, gender, and education. RESULTS Compared with NFMA patients, patients cured from Cushings disease had lower scores on the Mini Mental State Examination (P = 0.001), and on the memory quotient of the Wechsler Memory Scale (P = 0.050). Furthermore, patients cured from Cushings disease tended to recall fewer words on the imprinting (P = 0.013), immediate recall (P = 0.012), and delayed recall (P = 0.003) trials of the Verbal Learning Test of Rey. On the Rey Complex Figure Test, patients cured from Cushings disease had lower scores on both trials (P = 0.002 and P = 0.007) compared with NFMA patients. Patients cured from Cushings disease also made fewer correct substitutions on the Letter-Digit Substitution Test (P = 0.039) and came up with fewer correct patterns on the Figure Fluency Test (P = 0.003) compared with treated NFMA patients. CONCLUSIONS Cognitive function, reflecting memory and executive functions, is impaired in patients despite long-term cure of Cushings disease. These observations indicate irreversible effects of previous hypercortisolism on cognitive function and, thus, on the central nervous system. These observations may also be of relevance for patients treated with high-dose exogenous glucocorticoids.