Alzheimer Disease: Johannsen P

Johannsen P. · H:S Hukommelsesklinikken, Neurologisk Klinik, H:S Rigshospitalet, København Ø. · Ugeskr Laeger. · Pubmed #17032609 No free full text.

Abstract: In Denmark, Alzheimer drugs have been registered since 1997. Three cholinesterase inhibitors (donepezil, rivastigmin og galantamin) are approved mild to moderate Alzheimer's disease and one partial NMDA receptor antagonist (memantin) with the indication moderate to severe Alzheimer's disease. The treatment is symptomatic with a parallel shift of the course. The life expectancy does not seem to be altered. There is documented effect on the cholinesterase inhibitors of up to two years and for memantine for 6 months. New disease modifying agents are under clinical development.

Johannsen P. · Memory Disorder Unit, Copenhagen University Hospital, Copenhagen, DK-2100 Denmark. · CNS Drugs. · Pubmed #15377166 No free full text.

Abstract: The most prevalent cause of dementia--Alzheimer's disease--is characterised by an early cholinergic deficit that is in part responsible for the cognitive deficits, especially memory and attention defects, seen with this condition. Three cholinesterase inhibitors (ChEIs), namely donepezil, rivastigmine and galantamine, are widely used for the symptomatic treatment of patients with Alzheimer's disease. Placebo-controlled, randomised clinical trials have shown significant effects of these drugs on global function, cognition, activities of daily living (ADL) and behavioural symptoms in patients with this disorder. These trials have been conducted for up to 12 months and were followed by open-label extension studies. One placebo-controlled, randomised clinical trial followed patients for up to 4 years. Both retrospective and prospective follow-up studies suggest a treatment effect for ChEIs that lasts for up to 5 years. Studies have shown comparable effects for ChEIs in patients with moderate-to-severe Alzheimer's disease or mild Alzheimer's disease. Clinically relevant responses consist not only of improvement over 3-6 months but also stabilisation and possibly slower than expected decline. Lack of overt clinical improvement in one domain (e.g. global function, cognition, ADL or behaviour) does not preclude clinically relevant benefit(s) in other domains. If it is judged that the patient has experienced a treatment effect from ChEI therapy during the first 6 months, it is recommended that treatment be continued for at least 1 year before discontinuation is considered again. On average, patients will return to their pre-treatment status between 9 and 12 months of initiation of treatment. However, this return to pre-treatment level does not mean that the treatment effect has disappeared. At this point in time, the patient may still function better than he or she would have without treatment. Setting a fixed measurement, e.g. a Mini-Mental State Examination score, as a 'when to stop treatment limit' is not clinically rational. The length of treatment should depend on several individual patient factors. The earlier the diagnosis is made and the slower the rate of disease progression, the longer the treatment period will tend to be. Treatment duration must therefore be evaluated on an individual basis, and the patient's status compared with what would have been expected without treatment. If a clinical evaluation is conducted with a view to stopping or switching treatment, it is crucial that all domains are evaluated and that the patient is evaluated at more than one point in time before the decision is made.

Johannsen P, Salmon E, Hampel H, Xu Y, Richardson S, Qvitzau S, Schindler R, Anonymous00376. · Memory Disorder Unit, Department of Neurology, Rigshospitalet, Copenhagen, Denmark. · CNS Drugs. · Pubmed #16599649 No free full text.

Abstract: OBJECTIVE: To determine the value of continued donepezil treatment in patients with Alzheimer's disease for whom clinical benefit was initially judged to be uncertain. METHODS: The study consisted of three phases: (i) a 12- to 24-week, pre-randomisation, open-label donepezil-treatment phase; (ii) a 12-week, randomised, double-blind, placebo-controlled phase; and (iii) a 12-week, single-blind (i.e. patient-blind) donepezil-treatment phase. Patients with mild to moderate Alzheimer's disease received open-label treatment with donepezil (5 mg/day for 4 weeks, then 10 mg/day for the remainder of the phase) for 12-24 weeks. Patients who exhibited a decline or no change from baseline on the Mini-Mental State Examination (MMSE) and whose physician was not sufficiently certain of clinical benefit to warrant continued treatment were randomised into the double-blind phase in which patients received 12 weeks of treatment with donepezil (10 mg/day) or placebo. At the end of the double-blind phase, donepezil-treated patients continued to receive donepezil, while placebo-treated patients were rechallenged with donepezil, in a 12-week single-blind phase. Patients were assessed at the start of the double-blind phase and at weeks 6 and 12 of this phase, and at the end of the single-blind phase. RESULTS: Six hundred and nineteen patients completed the open-label phase; 69% showed clear clinical benefit and 31% showed uncertain benefit. 202 patients were randomised to continued donepezil treatment (n = 99) or placebo (n = 103). Differences in favour of continued donepezil versus placebo were observed in cognition and behaviour. In addition, there was a non-significant trend favouring donepezil in activities of daily living (ADL) [week 12 observed case mean treatment differences: MMSE, 1.13 (p = 0.02); Alzheimer's Disease Assessment Scale - cognitive subscale, 0.57 (p = 0.5); the Neuropsychiatric Inventory, -3.16 (p = 0.02); Disability Assessment for Dementia scale, 3.67 (p = 0.1)]. CONCLUSION: Most patients showed clear clinical benefit during initial donepezil treatment. Among patients for whom clinical benefit was uncertain, improvement in cognition and behaviour were observed for those who continued donepezil treatment compared with the group switched to placebo. Initial decline or stabilisation does not necessarily indicate a lack of efficacy in Alzheimer's disease, and the decision to discontinue treatment should be based on an evaluation of all domains (cognition, behaviour and ADL) and performed at several timepoints.

Stokholm J, Vogel A, Johannsen P, Waldemar G. · Memory Disorders Research Group, The Neuroscience Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Dement Geriatr Cogn Disord. · Pubmed #19299896 No free full text.

Abstract: BACKGROUND: Addenbrooke's Cognitive Examination (ACE) is a cognitive screening test developed to detect dementia. It has been validated in several countries. Validation studies have predominantly included patients with various degrees of dementia and healthy controls. OBJECTIVE: The aim of this study was to evaluate the Danish version of ACE as a screening test for early dementia in an outpatient memory clinic. Further, we wanted to investigate the ability of the ACE to discriminate patients with early Alzheimer's disease (AD) from patients with depression. METHOD: 78 patients with mild AD (MMSE >or=20), 30 non-demented patients diagnosed with depression (originally referred for evaluation of cognitive symptoms), and 63 healthy volunteers, all between 60 and 85 years of age, were included. All patients were given the ACE as a supplement to the standard diagnostic work-up. RESULTS: The cut-off points for optimal trade-off between sensitivity and specificity for ACE were 85/86 (sensitivity 0.99, specificity 0.94). When these cut-off points were applied to the group of depressive patients, the specificity dropped to 0.64, indicating a great overlap in individual test scores for demented and depressed patients. CONCLUSION: The optimal cut-off points for ACE found in this Danish study were close to what is reported in most other European studies. The great overlap in ACE scores for demented and depressed patients emphasize that test scores must be interpreted with great caution when used in diagnostic work-up.

Winblad B, Frisoni GB, Frolich L, Johannsen P, Johansson G, Kehoe P, Lovestone S, Olde-Rikkert M, Reynish E, Visser PJ, Vellas B. · B. Winblad, Karolinska Institute - Alzheimer Disease Research Center, Stockholm, Sweden. · J Nutr Health Aging. · Pubmed #19043641 No free full text.

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Frisoni GB, Henneman WJ, Weiner MW, Scheltens P, Vellas B, Reynish E, Hudecova J, Hampel H, Burger K, Blennow K, Waldemar G, Johannsen P, Wahlund LO, Zito G, Rossini PM, Winblad B, Barkhof F, Anonymous00039. · IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. · Alzheimers Dement. · Pubmed #18631976 links to  free full text

Abstract: BACKGROUND: In North America, the Alzheimer's Disease Neuroimaging Initiative (ADNI) has established a platform to track the brain changes of Alzheimer's disease. A pilot study has been carried out in Europe to test the feasibility of the adoption of the ADNI platform (pilot E-ADNI). METHODS: Seven academic sites of the European Alzheimer's Disease Consortium (EADC) enrolled 19 patients with mild cognitive impairment (MCI), 22 with AD, and 18 older healthy persons by using the ADNI clinical and neuropsychological battery. ADNI compliant magnetic resonance imaging (MRI) scans, cerebrospinal fluid, and blood samples were shipped to central repositories. Medial temporal atrophy (MTA) and white matter hyperintensities (WMH) were assessed by a single rater by using visual rating scales. RESULTS: Recruitment rate was 3.5 subjects per month per site. The cognitive, behavioral, and neuropsychological features of the European subjects were very similar to their U.S. counterparts. Three-dimensional T1-weighted MRI sequences were successfully performed on all subjects, and cerebrospinal fluid samples were obtained from 77%, 68%, and 83% of AD patients, MCI patients, and controls, respectively. Mean MTA score showed a significant increase from controls (left, right: 0.4, 0.3) to MCI patients (0.9, 0.8) to AD patients (2.3, 2.0), whereas mean WMH score did not differ among the three diagnostic groups (between 0.7 and 0.9). The distribution of both MRI markers was comparable to matched US-ADNI subjects. CONCLUSIONS: Academic EADC centers can adopt the ADNI platform to enroll MCI and AD patients and older controls with global cognitive and structural imaging features remarkably similar to those of the US-ADNI.

Brandt C, Bahl JC, Heegaard NH, Waldemar G, Johannsen P. · Memory Clinic, Section 6702, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. · Dement Geriatr Cogn Disord. · Pubmed #18536519 No free full text.

Abstract: AIM: Assays for cerebrospinal fluid (CSF) levels of total tau, phospho-tau protein and beta-amyloid 1-42 have been available for some years. The aim of the study was to assess the usability of these biomarkers in a mixed population of tertiary dementia referral patients in a university-based memory clinic. METHODS: 147 consecutive patients with a lumbar puncture as a part of their clinical workup were studied. A retrospective diagnosis was established based on consensus criteria without the knowledge of the CSF results. RESULTS: When diagnosing Alzheimer's disease (AD) compared to other diagnoses, the sensitivity of a single abnormal value was between 33 and 66%. The specificity was high except when discriminating AD from amnestic mild cognitive impairment. Two or more abnormal markers further increased the specificity and decreased the sensitivity. CONCLUSION: In a tertiary setting, abnormal CSF biomarker results may be of a diagnostic value - whereas normal results do not exclude neurodegenerative disease.

Johannsen P, Jakobsen J, Gjedde A. · PET Center and Department of Neurology, Aarhus University Hospital, Denmark. · Eur J Neurol. · Pubmed #10971597 No free full text.

Abstract: Images of cerebral blood flow or metabolism are useful as adjunct to the differential diagnosis of cortical dementia. The aim of this study was to create statistical objective voxel maps of significant differences in regional cerebral blood flow between patients with Alzheimer's disease and age-matched healthy volunteers. Maps of significantly reduced cerebral blood flow were created based on a spatially normalized distribution of cerebral blood flow, measured with O-15-water and positron emission tomography in 16 Alzheimer's patients, compared to 16 healthy age-matched volunteers. After spatial normalization of voxel counts, the t-statistic of the cerebral blood flow deficit was determined from the local voxel-SDs. In the patients, significant reduction (P < 0.05) of the flow distribution was present in regions near the hippocampus, extending rostrally to the temporo-parietal region in both hemispheres, including the medial parietal cortex plus smaller frontal areas. The maximum reduction occurred in the left tapetum/hippocampus (53%, P = 0.061). In conclusion, statistical maps of cerebral blood flow deficits objectively reveal the location of deficits, identifying areas that are difficult to identify by subjective visual inspection of conventional sections of cerebral blood flow maps. This is particularly well illustrated by the pronounced flow reduction of the medial parietal cortices.

Johannsen P, Jakobsen J, Bruhn P, Gjedde A. · Department of Neurology, Aarhus University Hospitals, Aarhus C, DK-8000, Denmark. · Neuroimage. · Pubmed #10458942 No free full text.

Abstract: Neuropsychological data suggests that divided attention is more impaired than sustained attention during the early phases of Alzheimer's disease. The purpose of the present study was to compare cerebral activation patterns during sustained and divided attention between Alzheimer patients and healthy elderly. The O-15-water PET activation method was used to map sustained and divided attention in 16 patients with Alzheimer's disease (mean age +/- SD: 68 +/- 5 years; MMSE: 11-25, mean +/- SD = 19.5 +/- 4.9) and in 16 healthy age-matched control subjects. After stereotactical normalization, voxel-by-voxel t statistics was used to assess the significance of activated brain areas and to compare activations between patients and control subjects. In the healthy elderly, sustained and divided attention both elicited activation of the right inferior parietal lobule, and the right middle frontal gyrus, whereas the anterior cingulate gyrus was activated during sustained attention only. Only medial frontal structures (Brodmann Area (BA) 32/34) were activated in Alzheimer patients, and both frontal (BA-10), posterior cingulate (BA-23/31), and subcortical sites were deactivated. Compared to the healthy elderly, the activations in the patients of the right medial (BA-11) superior (BA-10) and inferior (BA-47) frontal gyri, the right middle temporal (BA-20), and the left lingual (BA-17) gyri were significantly reduced. More cortical sites differed statistically between Alzheimer patients and control subjects during divided than during sustained attention. The activation pattern elicited by attention supports the neuropsychological data that divided attention is more impaired than sustained attention in early Alzheimer's disease.

Johannsen P, Abelskov KE, Almar K, Christensen PH, Hasselbalch SG, Laugesen LP, Hansen FR, Skausig OB. · No affiliation provided · Ugeskr Laeger. · Pubmed #15449538 No free full text.

This publication has no abstract.