Bupropion for the Treatment of Apathy in Alzheimer Disease: A Randomized Clinical Trial.

Importance: Apathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients' and caregivers' quality of life. Effective treatment options are needed. Objective: To examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type. Design, Setting, and Participants: This 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted in a psychiatric and neurological outpatient setting between July 2010 and July 2014 in Germany. Patients with mild-to-moderate dementia of Alzheimer type and clinically relevant apathy were included. Patients with additional clinically relevant depressed mood were excluded. Data analyses were performed between August 2018 and August 2019. Interventions: Patients received either bupropion or placebo (150 mg for 4 weeks plus 300 mg for 8 weeks). In case of intolerability of 300 mg, patients continued to receive 150 mg throughout the study. Main Outcomes and Measures: Change on the Apathy Evaluation Scale-Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12 was the primary outcome parameter. Secondary outcome parameters included measures of neuropsychiatric symptoms, cognition, activities of daily living, and quality of life. Outcome measures were assessed at baseline and at 4, 8, and 12 weeks. Results: A total of 108 patients (mean [SD] age, 74.8 [5.9] years; 67 men [62%]) were included in the intention-to-treat analysis, with 54 randomized to receive bupropion and 54 randomized to receive placebo. The baseline AES-C score was comparable between the bupropion group and the placebo group (mean [SD], 52.2 [8.7] vs 50.4 [8.2]). After controlling for the baseline AES-C score, site, and comedication with donepezil or galantamine, the mean change in the AES-C score between the bupropion and placebo groups was not statistically significant (mean change, 2.22; 95% CI, -0.47 to 4.91; P = .11). Results on secondary outcomes showed statistically significant differences between bupropion and placebo in terms of total neuropsychiatric symptoms (mean change, 5.52; 95% CI, 2.00 to 9.04; P = .003) and health-related quality of life (uncorrected for multiple comparisons; mean change, -1.66; 95% CI, -3.01 to -0.31; P = .02) with greater improvement in the placebo group. No statistically significant changes between groups were found for activities of daily living (mean change, -2.92; 95% CI, -5.89 to 0.06; P = .05) and cognition (mean change, -0.27; 95% CI, -3.26 to 2.73; P = .86). The numbers of adverse events (bupropion group, 39 patients [72.2%]; placebo group, 33 patients [61.1%]) and serious adverse events (bupropion group, 5 patients [9.3%]; placebo group, 2 patients [3.7%]) were comparable between groups. Conclusions and Relevance: Although it is safe, bupropion was not superior to placebo for the treatment of apathy in patients with dementia of Alzheimer type in the absence of clinically relevant depressed mood. Trial Registration: EU Clinical Trials Register Identifier: 2007-005352-17.

Case report: a giant arachnoid cyst masking Alzheimer's disease.

BACKGROUND: Intracranial arachnoid cysts are usually benign congenital findings of neuroimaging modalities, sometimes however, leading to focal neurological and psychiatric comorbidities. Whether primarily clinically silent cysts may become causally involved in cognitive decline in old age is neither well examined nor understood. CASE PRESENTATION: A 66-year old caucasian man presenting with a giant left-hemispheric frontotemporal cyst without progression of size, presented with slowly progressive cognitive decline. Neuropsychological assessment revealed an amnestic mild cognitive impairment (MCI) without further neurological or psychiatric symptoms. The patient showed mild medio-temporal lobe atrophy on structural MRI. Diffusion tensor and functional magnetic resonance imaging depicted a rather sustained function of the strongly suppressed left hemisphere. Amyloid-PET imaging was positive for increased amyloid burden and he was homozygous for the APOEε3-gene. A diagnosis of MCI due to Alzheimer's disease was given and a co-morbidity with a silent arachnoid cyst was assumed. To investigate, if a potentially reduced CSF flow due to the giant arachnoid cyst contributed to the early manifestation of AD, we reviewed 15 case series of subjects with frontotemporal arachnoid cysts and cognitive decline. However, no increased manifestation of neurodegenerative disorders was reported. CONCLUSIONS: With this case report, we illustrate the necessity of a systematic work-up for neurodegenerative disorders in patients with arachnoid cysts and emerging cognitive decline. We finally propose a modus operandi for the stratification and management of patients with arachnoid cysts potentially susceptive for cognitive dysfunction.

Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort.

INTRODUCTION: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers. METHODS: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis. RESULTS: Eight metabolites were associated with amyloid ß and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory. DISCUSSION: PFAMs have been found increased and associated with amyloid ß burden in CSF and clinical measures.

Association Between Later Life Lifestyle Factors and Alzheimer's Disease Biomarkers in Non-Demented Individuals: A Longitudinal Descriptive Cohort Study.

BACKGROUND: Lifestyle factors have been associated with the risk of dementia, but the association with Alzheimer's disease (AD) remains unclear. OBJECTIVE: To examine the association between later life lifestyle factors and AD biomarkers (i.e., amyloid-ß 1-42 (Aß42) and tau in cerebrospinal fluid (CSF), and hippocampal volume) in individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). In addition, to examine the effect of later life lifestyle factors on developing AD-type dementia in individuals with MCI. METHODS: We selected individuals with SCD (n = 111) and MCI (n = 353) from the DESCRIPA and Kuopio Longitudinal MCI studies. CSF Aß42 and tau concentrations were assessed with ELISA assay and hippocampal volume with multi-atlas segmentation. Lifestyle was assessed by clinical interview at baseline for: social activity, physical activity, cognitive activity, smoking, alcohol consumption, and sleep. We performed logistic and Cox regression analyses adjusted for study site, age, gender, education, and diagnosis. Prediction for AD-type dementia was performed in individuals with MCI only. RESULTS: Later life lifestyle factors were not associated with AD biomarkers or with conversion to AD-type dementia. AD biomarkers were strongly associated with conversion to AD-type dementia, but these relations were not modulated by lifestyle factors. Apolipoprotein E (APOE) genotype did not influence the results. CONCLUSIONS: Later life lifestyle factors had no impact on key AD biomarkers in individuals with SCD and MCI or on conversion to AD-type dementia in MCI.

The use of biomarkers for the etiologic diagnosis of MCI in Europe: an EADC survey.

We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aß42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.

Efficacy and cognitive side effects of electroconvulsive therapy (ECT) in depressed elderly inpatients with coexisting mild cognitive impairment or dementia.

OBJECTIVE: To study cognitive performance in depressed geriatric inpatients with or without preexisting cognitive impairment who received a first course of electroconvulsive therapy (ECT). METHOD: Forty-four elderly inpatients with major depressive disorder (ICD-10 criteria) were included in a prospective consecutive case series of a university hospital. The patients were divided into 3 groups (no cognitive impairment [NCI], mild cognitive impairment [MCI], dementia) and rated for cognitive performance with the MMSE before first ECT, after sixth ECT, and 6 weeks and 6 months after ECT termination. Affective symptoms were rated by 21-item Hamilton Depression Rating Scale (HDRS-21) before and 6 weeks after ECT. Analysis of variance or Kruskal-Wallis tests on ECT-induced MMSE and HDRS-21 score changes were compared to baseline. Binary logistic regression was used for predictor analysis. The study was conducted from April 2004 to April 2008. RESULTS: After initial nonsignificant cognitive deterioration in all 3 groups, the NCI group improved cognitively 6 weeks (P = .018) and 6 months (P = .027) after ECT. The MCI group improved in cognition 6 months (P = .036) after ECT. In the dementia group, mean MMSE scores also improved numerically over the course of ECT without significance. Dementia patients with antidementia treatment improved in cognition to a clinically relevant extent after the sixth ECT. Dementia subjects without antidementia treatment deteriorated. After the sixth ECT, 70.0% of dementia patients (P = .004) presented a cognitive decline, and 68.8% of MCI patients (P < .001) presented a decline 6 weeks after ECT. Six months after ECT, one-third of the dementia patients (P < .036) still had a cognitive decline. Affective symptoms remitted after ECT in all 3 groups (P < .001). Pre-ECT cognitive deficits were the best predictor of MMSE decline (6 weeks after ECT, P = .007; 6 months after ECT, P = .055). CONCLUSIONS: ECT is effective and well tolerated in geriatric depressed inpatients regardless of preexisting cognitive impairment. Cognitive deficits were transient.

Occupational exposure to low frequency magnetic fields and dementia: a case-control study.

BACKGROUND: Several studies point to a potential aetiological relevance to dementia of exposure to low-frequency magnetic fields, but the evidence is inconclusive. OBJECTIVE: To further examine the relationship between low frequency magnetic fields and dementia. METHODS: From 23 general practices, 195 patients with dementia were recruited. Of these, 108 had possible Alzheimer's disease, 59 had possible vascular dementia and 28 had secondary or unclassified dementia. A total of 229 controls were recruited: 122 population controls and 107 ambulatory patients free from dementia. Data were gathered in a structured personal interview; in cases, the interview was administered to the next of kin. Exposure to low-frequency electromagnetic fields was assessed by expert rating. To identify occupations suspected to be associated with dementia, major occupations were a priori formed. Odds ratios were calculated using logistic regression, to control for age, region, sex, dementia in parents and smoking. RESULTS: Exposure to magnetic fields was not significantly associated with dementia; restriction of the analysis to cases with possible Alzheimer's disease or possible vascular dementia did not lead to statistically significant results. We found an increased risk of dementia in blue-collar occupations (electrical and electronics workers, metal workers, construction workers, food and beverage processors and labourers). CONCLUSIONS: Our study does not support a strong association between occupational exposure to low-frequency magnetic fields and dementia. Further studies should consider the relationship between blue-collar work and the late development of dementia.

Nicotine use in suicides: a case-control study.

PURPOSE: Despite of higher rates of substance-related disorders in psychiatric patients and suicides than in the general population, there is no clear specificity to the relationship between nicotine use and other psychiatric disorders for suicide risk. METHODS: One hundred and sixty-three suicides (mean age 49.8 +/- 19.3 years; 64.4% males; using psychological autopsy method) and 396 control persons (mean age 51.6 +/- 17.0 years; 55.8% males) were assessed with a standardised semi-structured interview including SCID-I and SCID-II (for DSM-IV). Suicides and controls were compared in terms of nicotine consumption and psychiatric disorders. Logistic regression was used to evaluate the interactions of tobacco consumption with psychiatric disorders. RESULTS: Suicides were significantly more often current smokers and heavy users of cigarettes (> 20 cigarettes per day; P < 0.001, each). Alcohol dependence, other axis I disorders than substance-related disorders, and cluster B personality disorder(s) remained independent predictors for suicide in both genders, current nicotine consumption only in men (OR = 2.6, 95% CI 1.3-5.2). DISCUSSION AND CONCLUSIONS: In males, but not in females, nicotine consumption contributed to risk of completed suicide after control for psychiatric disorders and has to be considered as independent risk factor for suicide.

Combination therapy in Alzheimer's disease: a review of current evidence.

Treating dementia has become a major challenge in clinical practice. Presently, acetylcholinesterase inhibitors are the first-line drugs in the treatment of Alzheimer's disease (AD). These options are now complemented by memantine, which is approved for the treatment of moderate-to-severe AD. Altogether, a minimum of six agent classes already exist, all of which are approved for clinical use and are either already being tested or ready for phase III clinical trials for the treatment of AD. These include cholinesterase inhibitors, blockers of the NMDA receptor, antioxidants or blockers of oxidative deamination (including Gingko biloba), anti-inflammatory agents, neurotrophic factors (including hormone replacement therapy and drugs acting on insulin signal transduction) and antiamyloid agents (including cholesterol-lowering therapy). These approaches hold promise for disease modification and have a potential to be used as combination therapy for cognitive enhancement. Presently, only nine clinical studies have been published that have investigated the effects of a combination regimen on cognitive performance or AD. Among those, one study was conducted in elderly cognitively intact persons; the others involved patients with AD. Only five of the treatment studies followed a randomised, controlled design. Not all studies favoured the superior efficacy of combination therapy over monotherapy. Some studies, however, showed some evidence for synergistic combination effects of symptomatic therapy, including delay or prevention of disease progression in AD patients. In addition, six studies investigated the effects of AChE inhibitor in combination with antipsychotic or antidepressant therapy on behavioural aspects of AD symptomatology. In four of those studies there were indications that combination therapy had greater efficacy over monotherapy. The treatment of AD patients requires optimised options for all stages of illness based on the available drugs. There is a great need for further well designed studies on combination therapy in AD.

Association between the psychosocial network and dementia--a case-control study.

In a case-control study, we investigated the possible etiological relevance to dementia of psychosocial network factors, such as marital status, confidants and close relatives, sports activities, cultural activities, club membership; and education. In 23 general practices we recruited 195 patients with dementia. Of these, 108 were suffering from possible Alzheimer's disease, 59 from possible vascular dementia and 28 from secondary or unclassified dementia. A total of 229 control subjects was recruited: 122 population controls and 107 dementia-free ambulatory patients. Data were gathered in a structured personal interview and analyzed using logistic regression, to control for age, region, sex, dementia in parents, education and smoking. There were significantly decreased odds ratios for the number of confidants, sports activities, and cultural activities at age 30, at age 50 and at 10 years before data collection. When all psychosocial network factors were included simultaneously in the logistic regression model, these factors remained statistically significant, indicating independent effects. Restriction of the analysis to cases with possible Alzheimer's disease or to cases with possible vascular dementia led to similar results. Adjustment for the psychosocial network neutralized the otherwise protective effect of education for dementia of any type and for possible vascular dementia. In keeping with the results from recently published studies, these results support a protective role for the psychosocial network-especially for the number of confidants and for sports and cultural activities-in the etiology of dementia.

Psychometric properties of Clock Drawing Test and MMSE or Short Performance Test (SKT) in dementia screening in a memory clinic population.

OBJECTIVE: To evaluate five different scoring methods of the Clock Drawing Test (CDT) and to examine whether a combination of Mini Mental State Examination (MMSE) or Short Performance Test (Syndrom Kurz Test, SKT), respectively, with CDT can be used for cognitive screening. METHODS: Retrospective blinded analysis of clock drawing performance using five scoring methods (Shulman et al. (1986), Sunderland et al. (1989), Wolf-Klein et al. (1989), Watson et al. (1997), Manos (1997)). A Memory Clinic at an academic psychiatric hospital (University of Frankfurt am Main, Germany). 123 consecutive patients (79 dementia patients, 44 controls). Inter-rater reliability and correlation of five different scoring methods of the CDT with established psychometric tests. Sensitivity and specificity of all five CDT's using the original and modified cut-off scores. Sensitivity, specificity and positive and negative predictive value of a combination of the CDT with MMSE and SKT, respectively. RESULTS: All scoring methods of the CDT showed a highly significant interrater reliability (0.82 to 0.94). Correlation with the MMSE and the SKT was also significant (p < 0.01) for all five CDTs. Highest sensitivity was achieved by the Shulman scoring method (81% sensitivity, specificity 79%). Sensitivity of all scoring methods could be improved up to 89% by modifying the originally proposed cut-off scores at the cost of lower specificity. By combining the CDT with the MMSE or the SKT, respectively, the sensitivity of each of the tests could be improved to 92% (SKT and Shulman scale). In patients with mild dementia (GDS 3), a combination of the Shulman Scale with the SKT (92%) and the MMSE (75%) achieved the highest sensitivity. CONCLUSIONS: The CDT in combination with the MMSE or SKT is an easily administered, non threatening and highly sensitive screening test for dementia in the setting of a memory clinic.