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Analyzing the progression of Alzheimer's disease (AD) is challenging due to lacking sensitivity in currently available measures. AD stages are typically defined based on cognitive cut-offs, but this results in heterogeneous patient groups. More accurate modeling of the continuous progression of the disease would enable more accurate patient prognosis. To address these issues, we propose a new multivariate continuous-time disease progression (MCDP) model. The model is formulated as a nonlinear mixed-effects model that aligns patients based on their predicted disease progression along a continuous latent disease timeline. The model is evaluated using long-term follow-up data from 2152 participants in the Alzheimer's Disease Neuroimaging Initiative. The MCDP model was used to simultaneously model three cognitive scales; the Alzheimer's Disease Assessment Scale-cognitive subscale, the Mini-Mental State Examination, and the Clinical Dementia Rating scale-sum of boxes. Compared with univariate modeling and previously proposed multivariate disease progression models, the MCDP model showed superior ability to predict future patient trajectories. Finally, based on the multivariate disease timeline estimated using the MCDP model, the sensitivity of the individual items of the cognitive scales along the different stages of disease was analyzed. The analysis showed that delayed memory recall items had the highest sensitivity in the early stages of disease, whereas language and attention items were sensitive later in disease.

Background and aims Although several studies have been conducted, knowledge about chronic pain and dyspareunia after childbirth is still limited. The aim of this study was to explore the prevalence of chronic pain 8 months after childbirth in a cohort of Swedish women. The characteristics of chronic pain, such as, pain intensity, localization and frequency as well as pain interference with daily activities were examined. An additional aim was to describe the prevalence and intensity of dyspareunia. Methods Data were obtained through two self-administered questionnaires and the patient record system, Obstetrix. The first questionnaire was distributed on the maternity ward, 24–36 h after labour, to Swedish-speaking women who had given birth to a living child (n = 1,507). The second questionnaire was sent by post 8 months after childbirth. We collected data about demographic and social characteristics, pain presence and its onset, as well as pain intensity, frequency, bodily localization and pain interference with activities of women’s daily life. Results In total, 1,171 (77.7%) responded to both questionnaires and were included in the analysis. Eight months after giving birth, totally 16.7% (195/1,171) of the women reported chronic pain related to childbirth. Of these, 9.1% (106/1,171) of women reported chronic pain with onset during pregnancy, 4.5% (53/1,171) experienced chronic pain with onset following labour and 3.1% (36/1,171) of women had both chronic pain with onset during pregnancy and chronic pain with onset following labour (each participant could only appear in one of the groups). Women reported a lower prevalence of chronic pain after vaginal delivery than caesarean section (61/916, 6.7% vs. 28/255, 11%, p = 0.021, OR 1.73, 95% CI 1.1–2.8). Moreover, 19.2% (211/1,098) of women experienced dyspareunia. There was no difference regarding prevalence of dyspareunia and the mode of delivery. Of those women who had a vaginal delivery, 19.5% (167/858) experienced pain during intercourse and the corresponding number for women after caesarean section was 18.3% (44/240) (p = 0.694, OR 0.929, CI 0.6–1.3). Approximately 80% of women with chronic pain, and 60% of women that experienced dyspareunia, rated their worst pain as moderate or severe (NRS 4–10). The corresponding number regarding average chronic pain was between 50 and 70%. More than 35% of the women with chronic pain scored pain interference with daily activities as ≥4 on a 0–10 NRS. Conclusions In our study, chronic pain 8 months after childbirth was reported by one in six women and one in five of the women experienced dyspareunia. The intensity of both chronic pain and dyspareunia was reported as moderate to severe in a significant proportion of women and chronic pain interfered considerably with daily activities. Implications There is a need to raise awareness among healthcare providers of this clinical problem as well as to revise and upgrade education regarding pain after childbirth to prevent potential long-term health problems, women’s suffering and increased need for health care. The development of strategies for prevention, follow-up and treatment of pain is warranted. More research, including women’s experiences of pain as well as intervention studies, are also needed.

The Unified Multiple System Atrophy Rating Scale (UMSARS) is a commonly used semiquantitative rating scale to assess symptoms and measure disease progression in multiple system atrophy (MSA). However, it is currently incompletely understood which UMSARS items are the most sensitive to change and most relevant to the patient.The objective of this study was to assess sensitivity to change and patient-centricity of single UMSARS items.Data were taken from the European Multiple System Atrophy Study Group Natural History Study and the Rasagiline for Multiple System Atrophy trial. Sensitivity of change of an item of the UMSARS was assessed by calculation of a sensitivity-to-change ratio using its mean slope of progression divided by the standard deviation of the slope when modeling its progression over time. Patient-centricity was assessed through correlation of UMSARS items with quality-of-life measures.Progression rates above the mean in at least one of the two studies examined here were seen for seven items of UMSARS I and 11 items of UMSARS II. These items related to key motor functions such as swallowing, speech, handwriting, cutting food, hygiene, and dressing or walking, whereas items related to autonomic dysfunction were generally less sensitive to change in either data set. More UMSARS I items were identified as patient-centric compared with UMSARS II items, and items most strongly impacting patients' quality of life were those affecting verbal communication skills, personal hygiene, and walking.The present results illustrate the potential to optimize the UMSARS to enhance sensitivity to change and patient centricity. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Unified Multiple System Atrophy (MSA) Rating Scale was developed to provide a surrogate marker of disease severity and clinical progression in patients with MSA. It is comprised of four subscales: UMSARS-I (12 items) rates patient-reported functional disability; UMSARS-II (14 items) assesses motor impairment based on a clinical examination; UMSARS-III records blood pressure and heart rate in the supine and standing positions; and UMSARS-IV (1 item) rates chore-based disability. Strengths of the UMSARS include its wide acceptance in the field, the comprehensive coverage of motor symptoms and its clinimetric properties (including reliability and validity). However, with its increasing use, potential areas of improvement in the UMSARS have become apparent. To address these limitations, a task force, involving clinicians, researchers, patient groups, and industry representatives, has recently been endorsed by the International Parkinson’s Disease and Movement Disorders Society. The present viewpoint summarizes strengths and weaknesses of the UMSARS and suggests a roadmap to develop an improved MSA clinical outcome assessment.

Demonstrating that treatments are clinically meaningful across the Alzheimer's disease (AD) continuum is critical for meeting our goals of accelerating a cure by 2025. While this topic has been a focus of several Alzheimer's Association Research Roundtable (AARR) meetings, there remains no consensus as to what constitutes a “clinically meaningful outcome” in the eyes of patients, clinicians, care partners, policymakers, payers, and regulatory bodies. Furthermore, the field has not come to agreement as to what constitutes a clinically meaningful treatment effect at each stage of disease severity. The AARR meeting on November 19–20, 2019, reviewed current approaches to defining clinical meaningfulness from various perspectives including those of patients and care partners, clinicians, regulators, health economists, and public policymakers. Participants discussed approaches that may confer clinical relevance at each stage of the disease continuum and fostered discussion about what should guide us in the future.

OBJECTIVE: To describe women's experiences of chronic pain related to childbirth approximately one year after labour. DESIGN: A qualitative design with face-to-face interviews analysed using inductive qualitative content analysis. PARTICIPANTS: Twenty women who reported chronic pain, with onset during pregnancy and/or following labour, approximately one year after childbirth. FINDINGS: The analysis revealed an essential theme, "Grieving over the past and struggling forward", and three categories "Mourning the losses", "Struggling with the present" and "Managing the future". CONCLUSIONS: This study provides new knowledge about women's experiences of chronic pain one year after childbirth. The pain severely reduced women´s previous ability to perform physical and social activities, negatively impacted psychological well-being and altered their self-image. Most of the women adopted a positive attitude and hoped for improved health in the future, although constantly struggling with the pain and its consequences. IMPLICATIONS FOR PRACTICE: This knowledge is particularly important as chronic pain may not diminish with time in predisposed individuals who may need help and support from health professionals in their endeavour to manage their pain. Healthcare providers, i.e. midwives, gynaecologists and general practitioners need to understand women´s experiences of chronic pain from their own perspective to improve identification and treatment of pain following childbirth, thus preventing women's suffering and potential long-term health problems. Future studies are warranted to further explore and discuss women's coping strategies, health seeking behaviour and experiences of health care. This study was supported by a grant from the Capio Research Foundation [grant no. 2016-2900, 2017- 2996] and funding from Sophiahemmet University, Stockholm.

The effects of depressive symptoms on prospective and retrospective memory were examined in a population-based sample of elderly persons (n = 404). Depression was assessed using the Comprehensive Psychopathological Rating Scale and treated as a continuous variable. The variation in depressive symptoms ranged from no symptoms to presence of a clinical depression. Depressive symptoms had a negative effect on consolidation and retrieval in retrospective memory. However, the retrospective, but not the prospective, component of prospective memory was affected by depression. The findings are discussed in light of medial-temporal lobe alterations in depression.

The literature on cognitive markers in preclinical AD is reviewed. The findings demonstrate that impairment in multiple cognitive domains is typically observed several years before clinical diagnosis. Measures of executive functioning, episodic memory and perceptual speed appear to be most effective at identifying at-risk individuals. The fact that these cognitive domains are most implicated in normal cognitive aging suggests that the cognitive deficit observed preclinically is not qualitatively different from that observed in normal aging. The degree of cognitive impairment prior to the diagnosis of Alzheimer's disease (AD) appears to generalize relatively well across major study characteristics, including sample ascertainment procedures, age and cognitive status of participants, as well as time to diagnosis of dementia. In episodic memory, there is evidence that the size of the preclinical deficit increases with increasing cognitive demands. The global cognitive impairment observed is highly consistent with observations that multiple brain structures and functions are affected long before the diagnosis of AD. However, there is substantial overlap in the distribution of cognitive scores between those who will and those who will not be diagnosed with AD, hence limiting the clinical utility of cognitive markers for early identification of cases. Future research should consider combining cognitive indicators with other types of markers (i.e. social, somatic, genetic, brain-based) in order to increase prediction accuracy.

Objective: To determine the occurrence of neuropsychiatric symptomatology and the relation to future development of Alzheimer disease (AD) in persons with and without mild cognitive impairment (MCI). Method: We followed 185 persons with no cognitive impairment and 47 with MCI (amnestic and multidomain), ages 75 to 95, from the population-based Kungsholmen Project, Stockholm, Sweden, for 3 years. Three types of neuropsychiatric symptoms were assessed at baseline: mood-related depressive symptoms, motivation-related depressive symptoms, and anxiety-related symptomatology. AD at 3-year follow-up was diagnosed according to Diagnostic and Statistical Manual for Mental Disorders-III-R criteria. Results: Psychiatric symptoms occurred more frequently in persons with MCI (36.2% mood, 36.2% motivation, and 46.8% anxiety symptoms) than in cognitively intact elderly individuals (18.4% mood, 13.0% motivation, and 24.9% anxiety). Of persons with both MCI and anxiety symptoms, 83.3% developed AD over follow-up vs 6.1% of cognitively intact persons and 40.9% persons who had MCI without anxiety. Among persons with MCI, the 3-year risk of progressing to AD almost doubled with each anxiety symptom (relative risk [RR] = 1.8 [1.2 to 2.7] per symptom). Conversely, among cognitively intact subjects, only symptoms of depressive mood were related to AD development (RR = 1.9 [1.0 to 3.6] per symptom). Conclusions: The predictive validity of mild cognitive impairment (MCI) for identifying future Alzheimer disease (AD) cases is improved in the presence of anxiety symptoms. Mood-related depressive symptoms (dysphoria, suicidal ideation, etc.) in preclinical AD might be related to the neuropathologic mechanism, as they appear preclinically in persons both with and without MCI.

To determine the size of the impairment across different cognitive domains in preclinical Alzheimer's disease (AD), a meta-analysis based on 47 studies involving 9,097 controls and 1,207 preclinical AD cases was conducted. There were marked preclinical deficits in global cognitive ability, episodic memory, perceptual speed, and executive functioning; somewhat smaller deficits in verbal ability, visuospatial skill, and attention; and no preclinical impairment in primary memory. Younger age (< 75 years) and shorter follow-up intervals (< 3 years) were associated with larger effect sizes for both global cognitive ability and episodic memory. For global cognitive ability, studies that used population-based sampling yielded larger effect sizes; for episodic memory, larger differences were seen in studies that preidentified groups in terms of baseline cognitive impairment. Within episodic memory, delayed testing and recall-based assessment resulted in the largest effect sizes. The authors conclude that deficits in multiple cognitive domains are characteristic of AD several years before clinical diagnosis. The generalized nature of the deficit is consistent with recent observations that multiple brain structures and functions are affected long before the AD diagnosis.

Both Alzheimer's disease (AD) and depression (D) are prevalent disorders in old age and may co-occur in the same individual. The present study examined whether a diagnosis of D in AD has negative effects on cognitive functioning in the preclinical stage of the diseases, as well as at the time when the diagnoses were rendered. Population-based samples of 13 individuals with incident AD and D, 109 incident AD cases without D, and 179 normal older adults were followed over a three-year period. The groups were compared preclinically and at the time of diagnosis on global cognitive functioning using the MMSE total and the specific item scores, as well as the occurrence of depressive symptoms. As expected, there were clear AD-related deficits preclinically, which were exacerbated at follow-up. In addition, there were D-related deficits on three MMSE items (i.e., following commands, reading, and writing). The poorer performance on the three MMSE items was linked to an elevation of depressive symptoms. However, D was not associated with greater decline in cognitive functioning over the three-year follow-up period. Thus, although depressive symptoms may result in slight cognitive deficits in preclinical AD, at the time of the dementia diagnosis these effects may be absorbed by the neurodegenerative process.

We examined whether a diagnosis of depression affects verbal and visuospatial performance in Alzheimer’s disease (AD). Using data from a population-based study, persons with AD and depression (AD/D), AD alone and a control group of normal older adults were compared in two tests of verbal ability (category and letter fluency) and two tests of visuospatial skill (block design and clock drawing). As expected, there were clear AD-related deficits across all cognitive tasks. More importantly, the AD and AD/D groups were indistinguishable on all task variables. The lack of effects of depression was discussed relative to the view that those symptoms of this disease which are especially detrimental to cognitive functioning (e.g. concentration difficulties, lack of interest, loss of energy) may already be present in AD as a result of the neurodegenerative process.

Objective: To examine preclinical depressive symptoms 3 years before the diagnosis of AD. Methods: The authors compared incident AD patients and nondemented individuals in terms of baseline mood- and motivation-related symptoms of depression, and assessed whether depressive symptoms in preclinical AD are related to self-perceived memory problems. Participants came from a population-based longitudinal study on aging and dementia in Stockholm, Sweden. The sample consisted of 222 persons older than 74 years who were followed for a 3-year interval. Thirty-four individuals had developed AD at follow-up, whereas 188 remained nondemented. Dementia diagnosis was made according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised. Depressive symptoms were assessed by the Comprehensive Psychopathological Rating Scale. Results: The incident AD patients had more depressive symptoms than the nondemented persons at baseline. There was a dominance of motivation-related symptoms of depression (e.g., lack of interest, loss of energy, concentration difficulties) in preclinical AD. This association remained when adjusting for subjective memory complaints. Conclusions: Depressive symptoms are elevated preclinically in AD, and this elevation is not merely a by-product of self-perceived cognitive difficulties. Thus, depressive symptoms may be part of the preclinical phase in AD.

In a population-based study of persons between 75 and 96 years of age, normal old adults (n = 296), patients with Alzheimer's disease (AD; n = 45), and patients with concomitant AD and depression (AD-D; n = 9) were compared on free recall and recognition of slowly and rapidly presented words and digit span. With the exception of forward digit span, the normal old group outperformed the 2 AD groups across all tasks. In free recall, only the normal old group performed better as task pacing decreased; however, all groups benefited from more study time in recognition. This suggests that both AD and AD-D patients have deficits in the ability to use more study time for remembering. Of most importance, the 2 AD groups were indistinguishable for all task variables. This lack of comorbidity effects is discussed relative to the view that depression, much like many other individual-difference variables that affect memory performance in normal aging, may be overshadowed by the influence of the neurodegenerative process in AD.