Anne Börjesson-Hanson

The prevalence of dementia in 95 year olds

The authors determined the prevalence of dementia in 338 (response rate 65%) 95-year-old persons, living in Göteborg, Sweden, and compared the result with a previously examined population sample of 85 year olds. The prevalence of dementia according to the Diagnostic and Statistical Manual of Mental Disorders (3rd rev. ed) was higher in women (55%) than in men (37%) at age 95, and the proportion of mild dementia and vascular dementia was lower in 95 than in 85 year olds.

MRI characteristics and scoring in HDLS due to CSF1R gene mutations

Objective: To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5. Methods: We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0−57) for each MRI scan. Results: Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10−33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology. Conclusion: Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion.

Five-year mortality in relation to dementia and cognitive function in 95-year-olds

Background: Dementia is a known predictor of mortality, but most studies include small numbers of participants above age 90. The influence of dementia or cognition on mortality in this age group is therefore uncertain. Objective: To examine 5-year mortality in relation to dementia and cognitive performance at age 95. Methods: A population sample of 338 individuals examined at age 95 was followed to age 100. Dementia was diagnosed according to DSM–III-R criteria. Cognitive function was measured using the Mini-Mental State Examination (MMSE). Information on severe physical disorders was obtained from the Swedish Hospital Discharge Register, and date of death from the Swedish Population Register. Results: Five-year mortality was higher in 95-year-olds with dementia than in 95-year-olds without dementia (96% vs 73%; p < 0.0001), even when adjusting for severe physical disorders. A Cox regression analysis with calculation of population attributable risk (PAR), calculated from adjusted relative risks, showed that mortality was predicted by dementia (PAR 42%), cardiac disease (PAR 17%), cancer (PAR 6%), and male sex (PAR 7%), but not by stroke. Among the subjects without dementia, cognitive performance measured using the MMSE (n = 133 with complete tests; 81% of the subjects without dementia) predicted mortality. For each point increase in the MMSE, mortality decreased by 13%. Conclusions: In 95-year-olds, dementia, as well as cognitive performance in the subjects without dementia, influences mortality. When controlling for other severe medical conditions we found dementia to be the leading cause of deaths among the oldest old. The reason why dementia and cognitive function predict life expectancy requires further elucidation.

Higher CSF interleukin-6 and CSF interleukin-8 in current depression in older women. Results from a population-based sample

OBJECTIVE The literature regarding cerebrospinal fluid (CSF) cytokines in geriatric depression is sparse. The aim of this study was to examine associations between CSF interleukin-6 (IL-6), interleukin-8 (IL-8) and depression in a population-based sample of older women who were followed for 17 years. METHODS 86 dementia-free women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992-3. CSF IL-6 and CSF IL-8 were measured. Psychiatric symptoms were rated with the Comprehensive Psychopathological Rating Scale at baseline and at three subsequent face-to-face examinations. Depression (major or minor) was diagnosed in accordance with DSM-IV/DSM-IV research criteria. RESULTS At baseline, women with ongoing major (n=10) or minor depression (n=9) had higher levels of CSF IL-6 (p=0.008) and CSF IL-8 (p=0.007) compared with those without depression (n=67). Higher CSF IL-8 was related to higher MADRS score (p=0.003). New cases of depression were observed in 9 women during follow-ups. No associations between CSF cytokine levels and future depression could be shown in women without depression at baseline. CONCLUSION Higher levels of CSF IL-6 and IL-8 were associated with current depression in this population-based sample. CSF IL-6 and CSF IL-8 may play a role in depression in late life.

A 9-Year Prospective Population-Based Study on the Association Between the APOE*E4 Allele and Late-Life Depression in Sweden

BACKGROUND It is well established that there is an association between the apolipoprotein E (APOE) ε4 allele (APOE*E4) and Alzheimers disease. It is less clear whether there is also an association with geriatric depression. We examined the relationship between APOE*E4 and 5-year incidence of depression in a Swedish population-based sample of older adults without dementia and excluding older adults who developed dementia within 4 years after the diagnosis of depression. METHODS In 2000-2001, 839 women and men (age range, 70-92 years; mean age, 73.8 years) free from dementia and depression underwent neuropsychiatric and neuropsychological examinations and genotyping of the APOE*E4 allele. Follow-up evaluations were conducted in 2005 and 2009.The association between APOE*E4 allele and 5-year incidence of depression was examined, while avoiding possible confounding effects of clinical or preclinical dementia by excluding participants who had dementia at study entry, subsequently developed dementia during the 9-year follow-up period, or had a decline in Mini-Mental State Examination score of ≥5 points. RESULTS Among subjects without depression at study entry and without dementia or significant cognitive decline during the subsequent 9 years, APOE*E4 was prospectively associated with more severe depressive symptoms (b = 1.56, p = .007), incident minor depression (odds ratio = 1.99 [confidence interval = 1.11-3.55], p = .020), and any depression (odds ratio = 1.75 [confidence interval = 1.01-3.03], p = .048). CONCLUSIONS The presence of the APOE*E4 allele predicted future depression in this Swedish population study, even after excluding depressed individuals who later developed dementia, suggesting that the APOE*E4 allele could potentially identify people at high risk for clinically significant depression.

Onset and rate of cognitive change before dementia diagnosis: findings from two Swedish population-based longitudinal studies.

We used data from two population-based longitudinal studies to estimate time of onset and rate of accelerated decline across cognitive domains before dementia diagnosis. The H70 includes an age-homogeneous sample (127 cases and 255 non-cases) initially assessed at age 70 with 12 follow-ups over 30 years. The Kungsholmen Project (KP) includes an age-heterogeneous sample (279 cases and 562 non-cases), with an average age of 82 years at initial assessment, and 4 follow-ups spanning 13 years. We fit mixed linear models to the data and determined placement of change points by a profile likelihood method. Results demonstrated onset of accelerated decline for fluid (speed, memory) versus crystallized (verbal, clock reading) abilities occurring approximately 10 and 5 years before diagnosis, respectively. Although decline before change points was greater for fluid abilities, acceleration was more pronounced for crystallized abilities after the change points. This suggests that onset and rate of acceleration vary systematically along the fluid-crystallized ability continuum. There is early onset in fluid abilities, but these changes are difficult to detect due to substantial age-related decline. Onset occurred later and acceleration was greater in crystallized abilities, suggesting that those markers may provide more valid identification of cases in later stages of the prodromal phase.

Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations

Atypical Parkinsonism associated with white matter pathology has been described in cerebrovascular diseases, mitochondrial cytopathies, osmotic demyelinating disorders, leukoencephalopathies leukodystrophies, and others. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder with symptomatic onset in midlife and death within a few years after symptom onset. Neuroimaging reveals cerebral white matter lesions that are pathologically characterized by non-inflammatory myelin loss, reactive astrocytosis, and axonal spheroids. Most cases are caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. We studied neuropathologically verified HDLS patients with CSF1R mutations to assess parkinsonian features. Ten families were evaluated with 16 affected individuals. During the course of the illness, all patients had at least some degree of bradykinesia. Fifteen patients had postural instability, and seven had rigidity. Two patients initially presented with parkinsonian gait and asymmetrical bradykinesia. These two patients and two others exhibited bradykinesia, rigidity, postural instability, and tremor (two with resting) early in the course of the illness. Levodopa/carbidopa therapy in these four patients provided no benefit, and the remaining 12 patients were not treated. The mean age of onset for all patients was about 45 years (range, 18-71) and the mean disease duration was approximately six years (range, 3-11). We also reviewed HDLS patients published prior to the CSF1R discovery for the presence of parkinsonian features. Out of 50 patients, 37 had gait impairments, 8 rigidity, 7 bradykinesia, and 5 resting tremor. Our report emphasizes the presence of atypical Parkinsonism in HDLS due to CSF1R mutations.

The Gothenburg MCI study: Design and distribution of Alzheimer’s disease and subcortical vascular disease diagnoses from baseline to 6-year follow-up

There is a need for increased nosological knowledge to enable rational trials in Alzheimer’s disease (AD) and related disorders. The ongoing Gothenburg mild cognitive impairment (MCI) study is an attempt to conduct longitudinal in-depth phenotyping of patients with different forms and degrees of cognitive impairment using neuropsychological, neuroimaging, and neurochemical tools. Particular attention is paid to the interplay between AD and subcortical vascular disease, the latter representing a disease entity that may cause or contribute to cognitive impairment with an effect size that may be comparable to AD. Of 664 patients enrolled between 1999 and 2013, 195 were diagnosed with subjective cognitive impairment (SCI), 274 with mild cognitive impairment (MCI), and 195 with dementia, at baseline. Of the 195 (29%) patients with dementia at baseline, 81 (42%) had AD, 27 (14%) SVD, 41 (21%) mixed type dementia (=AD + SVD = MixD), and 46 (23%) other etiologies. After 6 years, 292 SCI/MCI patients were eligible for follow-up. Of these 292, 69 (24%) had converted to dementia (29 (42%) AD, 16 (23%) SVD, 15 (22%) MixD, 9 (13%) other etiologies). The study has shown that it is possible to identify not only AD but also incipient and manifest MixD/SVD in a memory clinic setting. These conditions should be taken into account in clinical trials.

Quantitative vascular pathology and phenotyping familial and sporadic cerebral small vessel diseases

We quantified vascular changes in the frontal lobe and basal ganglia of four inherited small vessel diseases (SVDs) including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), hereditary multi‐infarct dementia of Swedish type (Swedish hMID), and hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Vascular pathology was most severe in CADASIL, and varied with marginally greater severity in the basal ganglia compared to the frontal lobe. The overall sclerotic index values in frontal lobe were in the order CADASIL ≥ HERNS > PADMAL > Swedish hMID > sporadic SVD, and in basal ganglia CADASIL > HERNS > Swedish hMID > PADMAL> sporadic SVD. The subcortical white matter was almost always more affected than any gray matter. We observed glucose transporter‐1 (GLUT‐1) protein immunoreactivities were most affected in the white matter indicating capillary degeneration whereas collagen IV (COL4) immunostaining was increased in PADMAL cases in all regions and tissue types. Overall, GLUT‐1 : COL4 ratios were higher in the basal ganglia indicating modifications in capillary density compared to the frontal lobe. Our study shows that the extent of microvascular degeneration varies in these genetic disorders exhibiting common end‐stage pathologies but is the most aggressive in CADASIL.

Suicidal feelings in the twilight of life: a cross-sectional population-based study of 97-year-olds.

Objective To examine the occurrence of past month suicidal feelings in extreme old age. Further, to identify factors associated with such feelings. Design Cross-sectional population-based study. Setting Gothenburg, Sweden. Participants 269 adults (197 women, 72 men) without dementia born in 1901–1909 who participated in a psychiatric examination. Main outcome measures Death thoughts and suicidal feelings. The latter were rated in accordance with the Paykel questions (life not worth living, death wishes, thoughts of taking own life, seriously considered taking own life, attempted suicide) during the past month. Results One quarter of the sample (26.7%) reported that they thought about their own death at least once a month. Past month thoughts that life was not worth living were acknowledged by 7.9% of the total sample, death wishes by 10.5% and thoughts of taking life by 3.8%. Few had serious thoughts of taking own life (0.8%) and none had attempted suicide. In all, 11.5% acknowledged some level of suicidal feelings. Most (77.4%) of those who reported such feelings fulfilled criteria for neither major nor minor depression. Neither poor perceived health nor disability (hearing, vision and motor function) was associated with suicidal feelings. Problematic sleep and deficient social contacts were also related to suicidal feelings after adjustment for depression. Conclusions Suicidal feelings may occur outside the context of depression and disability in this age group. Results can inform clinicians who care for persons who reach extreme old age.