Exercise Training for Persons with Alzheimer's Disease and Caregivers: A Review of Dyadic Exercise Interventions

Alzheimer's disease (AD) is the most common form of dementia and the prevalence will increase dramatically in the next decades. Although exercise has shown benefits for people with dementia due to AD as well as their caregivers, the impact of a dyadic exercise intervention including both groups as study participants remains to be determined. The authors review the current clinical evidence for dyadic exercise interventions, which are exercise regimens applied to both the person with dementia and the caregiver. A total of 4 controlled trials were reviewed. This review shows that dyadic exercise interventions are feasible and may produce a positive effect on functional independence and caregiver burden. However, there was insufficient evidence to support a benefit of dyadic exercise intervention on cognitive performance and on behavioral and neuropsychiatric symptoms in participants with dementia due to AD. A dyadic exercise intervention improves functional independence and caregiver burden. However, there is a need for well-designed randomized controlled clinical trials to confirm these benefits and to investigate several important points such as the effects of a dyadic exercise intervention on cognitive and noncognitive outcomes of AD, the optimal intensity of exercise training, and the cost effectiveness of such a program.     

Mild cognitive impairment: a neuropsychological perspective

Mild cognitive impairment (MCI) is a clinical diagnosis in which deficits in cognitive function are evident but not of sufficient severity to warrant a diagnosis of dementia. For the majority of patients, MCI represents a transitional state between normal aging and mild dementia, usually Alzheimer's disease. Multiple subtypes of MCI are now recognized. In addition to presentations featuring memory impairment, symptoms in other cognitive domains (eg, executive function, language, visuospatial) have been identified. Neuropsychological testing can be extremely useful in making the MCI diagnosis and tracking the evolution of cognitive symptoms over time. A comprehensive test battery includes measures of baseline intellectual ability, attention, executive function, memory, language, visuospatial skills, and mood. Informant-based measures of neuropsychiatric symptoms, behaviors, and competency in instrumental activity are also included. Careful assessment can identify subtle deficits that may otherwise elude detection, particularly in individuals of superior baseline intellectual ability. As we move closer to disease-modifying therapy for Alzheimer's disease, early identification becomes critical for identifying patients who have an opportunity to benefit from treatment.     

The cholinergic lesion of Alzheimer's disease: pivotal factor or side show?

A profound loss of cortical cholinergic innervation is a nearly invariant feature of advanced Alzheimer's disease (AD). The temporal course of this lesion and its relationship to other aspects of the disease have not yet been fully clarified. Despite assertions to the contrary, a review of the evidence suggests that a perturbation of cholinergic innervation is likely to be present even in the very early stages of AD. This cholinergic lesion is unlikely to be a major determinant of the clinical symptoms or of the neuropathological lesions. Nonetheless, it almost certainly contributes to the severity of the cognitive and behavioral deficits, especially in the areas of memory and attention. The cholinergic lesion may also influence the progression of the neuropathological process through complex interactions with amyloidogenesis, tau phosphorylation and neuroplasticity.     

Eyeblink Classical Conditioning Differentiates Normal Aging from Alzheimer's Disease

Eyeblink classical conditioning is a useful paradigm for the study of the neurobiology of learning, memory, and aging, which also has application in the differential diagnosis of neurodegenerative diseases expressed in advancing age. Converging evidence from studies of eyeblink conditioning in neurological patients and brain imaging in normal adults document parallels in the neural substrates of this form of associative learning in humans and non-human mammals. Age differences in the short-delay procedure (400 ms CS-US interval) appear in middle age in humans and may be caused at least in part by cerebellar cortical changes such as loss of Purkinje cells. Whereas the hippocampus is not essential for conditioning in the delay procedure, disruption of hippocampal cholinergic neurotransmission impairs acquisition and slows the rate of learning. Alzheimer's disease (AD) profoundly disrupts the hippocampaL cholinergic system, and patients with AD consistently perform poorly in eyeblink conditioning. We hypothesize that disruption of hippocampal cholinergic pathways in AD in addition to age-associated Purkinje cell loss results in severely impaired eyeblink conditioning. The earliest pathology in AD occurs in entorhinal cortical input to hippocampus, and eyeblink conditioning may detect this early disruption before declarative learning and memory circuits become impaired. A case study is presented in which eyeblink conditioning detected impending dementia six years before changes on other screening tests indicated impairment. Because eyeblink conditioning is simple, non-threatening, and non-invasive, it may become a useful addition to test batteries designed to differentiate normal aging from mild cognitive impairment that progresses to AD and AD from other types of dementia.     

Alzheimer's Disease Patients' Cognitive Status and Course Years Prior to Symptom Recognition

This is a prospective examination of the cognitive performance and cognitive course of persons in an asymptomatic “preclinical” phase who eventually developed Alzheimer's disease (AD). We compared performances on the Mayo Cognitive Factor Scales (MCFS) of 20 persons in a neurologically normal cohort who subsequently developed AD to the performances of 60 persons who remained free of dementia symptoms. For the AD patients, exams occurred prior to the appearance of dementia symptoms (an average of 4.2 and 1.5 years prior to symptom onset). Results reveal strong group differences on learning and retention, with eventual AD patients scoring lower than controls years prior to reporting symptoms of the disease. There was no significant interaction effect (group × testing session) for memory retention, suggesting that memory decline in this preclinical period may be too slow to be a useful indicator of future AD. A significant interaction (but no group effect) was seen for verbal comprehension.     

Alzheimer's disease patients' cognitive status and course years prior to symptom recognition

This is a prospective examination of the cognitive performance and cognitive course of persons in an asymptomatic "preclinical" phase who eventually developed Alzheimer's disease (AD). We compared performances on the Mayo Cognitive Factor Scales (MCFS) of 20 persons in a neurologically normal cohort who subsequently developed AD to the performances of 60 persons who remained free of dementia symptoms. For the AD patients, exams occurred prior to the appearance of dementia symptoms (an average of 4.2 and 1.5 years prior to symptom onset). Results reveal strong group differences on learning and retention, with eventual AD patients scoring lower than controls years prior to reporting symptoms of the disease. There was no significant interaction effect (group x testing session) for memory retention, suggesting that memory decline in this preclinical period may be too slow to be a useful indicator of future AD. A significant interaction (but no group effect) was seen for verbal comprehension.     

Eyeblink classical conditioning differentiates normal aging from Alzheimer’s disease

Eyeblink classical conditioning is a useful paradigm for the study of the neurobiology of learning, memory, and aging, which also has application in the differential diagnosis of neurodegenerative diseases expressed in advancing age. Converging evidence from studies of eyeblink conditioning in neurological patients and brain imaging in normal adults document parallels in the neural substrates of this form of associative learning in humans and non-human mammals. Age differences in the short-delay procedure (400 ms CS-US interval) appear in middle age in humans and may be caused at least in part by cerebellar cortical changes such as loss of Purkinje cells. Whereas the hippocampus is not essential for conditioning in the delay procedure, disruption of hippocampal cholinergic neurotransmission impairs acquisition and slows the rate of learning. Alzheimer’s disease (AD) profoundly disrupts the hippocampal cholinergic system, and patients with AD consistently perform poorly in eyeblink conditioning. We hypothesize that disruption of hippocampal cholinergic pathways in AD in addition to age-associated Purkinje cell loss results in severely impaired eyeblink conditioning. The earliest pathology in AD occurs in entorhinal cortical input to hippocampus, and eyeblink conditioning may detect this early disruption before declarative learning and memory circuits become impaired. A case study is presented in which eyeblink conditioning detected impending dementia six years before changes on other screening tests indicated impairment. Because eyeblink conditioning is simple, non-threatening, and non-invasive, it may become a useful addition to test batteries designed to differentiate normal aging from mild cognitive impairment that progresses to AD and AD from other types of dementia.     

Decision making and neuropsychiatry

Abnormal decision making is a central feature of neuropsychiatric disorders. Recent investigations of the neural substrates underlying decision making have involved qualitative assessment of the cognition of decision making in clinical lesion studies (in patients with frontal lobe dementia) and neuropsychiatric disorders such as mania, substance abuse and personality disorders. A neural network involving the orbitofrontal cortex, ventral striatum and modulatory ascending neurotransmitter systems has been identified as having a fundamental role in decision making and in the neural basis of neuropsychiatric diseases. This network accounts for the dissociations among decision-making deficits in different clinical populations. Ultimately, a more refined and sophisticated characterization of such deficits might guide the early diagnosis and cognitive and therapeutic rehabilitation of these patients.     

Neuropsychological Differences Between Frontotemporal Dementia and Alzheimer's Disease: A Review

This paper surveys the similarities and differences between frontotemporal dementia (FTD) and Alzheimer's disease (AD). The review covers findings primarily from neuropsychological studies on memory, language, attention/executive function, and visuospatial abilities. However, neuropsychiatric and neuroimaging data are also briefly discussed. Distinguishing features of both FTD and AD are described in order to present a comprehensive clinical picture of these dementing diseases, which is essential for the process of differential diagnosis. The cause of specific cognitive deficits is also considered. Our comprehensive review of the empirical literature reveals that AD is characterized by early memory loss and visuospatial problems, while among the main features of FTD are behavioral abnormalities and executive dysfunctions.     

Effects of two-year treatment with the cholinesterase inhibitor rivastigmine on behavioural symptoms in Alzheimer's disease

Alzheimer's disease (AD) is accompanied by prominent behavioural disturbances. They cause significant distress for both caregivers and patients and can play a major role in the decision to institutionalise AD patients. Recent evidence suggests that cholinergic deficiencies not only contribute to the memory and cognitive abnormalities of AD but are also responsible for some behavioural abnormalities seen over the course of the disease. In this study we assessed the ability of rivastigmine, a pseudo-irreversible cholinesterase inhibitor, to improve behavioural and psychopathologic symptoms in AD. The analysis included 34 patients present in the Germanarm of the international study B303 who received and completed long-term treatment with rivastigmine in the open-label study B305. Assessments of behaviour and psychopathological symptoms were performed using the behavioural component of the Clinicians Interview Based Impression of Change Plus (CIBIC-Plus). Results show that long-term treatment with rivastigmine can slow the progression of behavioural and psychopathological symptoms of AD. Behavioural symptoms showing stabilisation included aggressiveness, activity disturbances, hallucinations and paranoid features. Results also suggest that patients treated earlier with rivastigmine may attain a greater benefit compared with patients whose treatment is delayed 6 months. Further studies examining the effects of rivastigmine on behavioural disturbances in AD are therefore warranted.     

The cholinergic neurotransmitter system in human memory and dementia: A review

The present paper reviews three types of evidence implicating the role of acetylcholine in human memory and dementia: (1) neuropathological evidence that the cholinergic transmitter system is depleted in Alzheimer-type dementia; (2) psychopharmacological studies that have employed “cholinergic blockade” as a model of cholinergic depletion; and (3) clinical studies of cholinergic “replacement” therapy in Alzheimer-type dementia. The evidence that the cholinergic system is depleted in Alzheimer-type dementia has been complemented by the finding that cholinergic blockade in healthy subjects causes a substantial learning (or “acquisition”) deficit in episodic memory. The overall results of studies of replacement therapy have generally been disappointing, but a few have reported benefits in recall and recognition tests. The role of the cholinergic system in many aspects of memory remains to be elucidated; but it seems unlikely that cholinergic depletion accounts for all aspects of the memory disorder in Alzheimer-type dementia, and possibly the depletions of other neurotransmitters also contribute to the memory impairment.     

Can cognitive and behavioural disorders differentiate frontal variant-frontotemporal dementia from Alzheimer's disease at early stages?

Frontal variant-Frontotemporal dementia (fvFTD) and Alzheimer's disease (AD) patients matched for severity of dementia at the Clinical Dementia Rating (CDR) received neuropsychological testing in order to explore if the dysexecutive disorder might characterise fvFTD at early stage, when AD is dominated by the episodic memory defect. We also determined if the behavioural syndrome was more severe in fvFTD than AD, and if specific patterns of behavioural symptoms could differentiate the two types of dementia, using the Neuropsychiatry Inventory (NPI). AD patients performed worse than fvFTD not only in memory but also in executive tasks. Apathy and eating disorders proved to be more severe or frequent in fvFTD even if the two groups did not differ in the total NPI score. CDR score significantly correlated with the NPI score in fvFTD and with the MMSE in AD. Our data confirm that the memory disorders may differentiate the two types of dementia; however, the dysexecutive syndrome is as severe, and even more severe in AD. The severity of the behavioural syndrome is comparable in the two groups but the nature of the behavioural disorders may vary to some extent. We conclude that AD dementia at early stage is a behavioural-cognitive syndrome, while in fvFTD the behavioural disorders appear when the cognitive deficit is still relatively mild.     

Neuropsychological impairment in Parkinson's disease without dementia

Cognitive dysfunction in Parkinson's Disease (PD) has been consistently reported, but little is known about cognitive impairment in PD patients without dementia, and its association with clinical characteristics, neuropsychiatric disturbance and functional activities. Therefore, we evaluated 52 non-demented PD patients, 22 of them with mild cognitive impairment (PD-MCI) who were matched with 52 healthy controls. Our results confirm the existence of dysfunction in information processing speed, executive function, verbal memory and visuo-perceptual processing in PD. On the other hand, PD-MCI was associated with advanced age at the onset of PD, more neuropsychiatric symptoms, caregiver stress and functional problems. The study supports the hypothesis that specific neuropsychological impairments may act as modulators of functional impairment in PD, for instance slowness of information processing.     

Efficacy of Cognitive Rehabilitation Therapies for Mild Cognitive Impairment (MCI) in Older Adults: Working Toward a Theoretical Model and Evidence-Based Interventions

To evaluate the efficacy of cognitive rehabilitation therapies (CRTs) for mild cognitive impairment (MCI). Our review revealed a need for evidence-based treatments for MCI and a lack of a theoretical rehabilitation model to guide the development and evaluation of these interventions. We have thus proposed a theoretical rehabilitation model of MCI that yields key intervention targets–cognitive compromise, functional compromise, neuropsychiatric symptoms, and modifiable risk and protective factors known to be associated with MCI and dementia. Our model additionally defines specific cognitive rehabilitation approaches that may directly or indirectly target key outcomes–restorative cognitive training, compensatory cognitive training, lifestyle interventions, and psychotherapeutic techniques. Fourteen randomized controlled trials met inclusion criteria and were reviewed. Studies markedly varied in terms of intervention approaches and selected outcome measures and were frequently hampered by design limitations. The bulk of the evidence suggested that CRTs can change targeted behaviors in individuals with MCI and that CRTs are associated with improvements in objective cognitive performance, but the pattern of effects on specific cognitive domains was inconsistent across studies. Other important outcomes (i.e., daily functioning, quality of life, neuropsychiatric symptom severity) were infrequently assessed across studies. Few studies evaluated long-term outcomes or the impact of CRTs on conversion rates from MCI to dementia or normal cognition. Overall, results from trials are promising but inconclusive. Additional well-designed and adequately powered trials are warranted and required before CRTs for MCI can be considered evidence-based.     

The Differential Effects of Alzheimer's Disease and Lewy Body Pathology on Cognitive Performance: a Meta-analysis

Differential diagnosis of Alzheimer’s disease (AD) from normal aging and other dementia etiologies is imperative for disease specific treatment options and long-term care planning. Neuropathological confirmation is the gold standard for neurodegenerative disease diagnosis, yet most published studies examining the use of neuropsychological tests in the differential diagnosis of dementia rely upon clinical diagnostic outcomes. The present study undertook a meta-analytic review of the literature to identify cognitive tests and domains that allow for the differentiation of individuals with AD pathology from individuals with dementia with Lewy Bodies (DLB) pathology and pathology-free individuals. A comprehensive literature search yielded 14 studies that met the inclusion criteria for the present meta-analysis. Six studies comprised 222 decedents with AD compared to 433 normal controls, and eight studies comprised 431 cases of AD compared to 155 decedents with DLB. Results revealed that the effect of having neuropathologically confirmed AD versus DLB lowered performance in the memory domain, and having DLB decreased performance in the visuospatial domain. No single test differed significantly across the AD and DLB groups. For the AD and pathology free comparison, results indicated that that AD was associated with poorer performance on the memory and language domains. With respect to specific cognitive tests, AD produced lower scores on list learning tests, category fluency, and the Digit Symbol substitution test. The limited number of studies meeting inclusion criteria warrants formulation of guidelines for reporting in clinico-pathological studies; suggested guidelines are provided.     

Multiple combinations of co-factors produce variants of age-related cognitive decline: a theory.

A theory concerning the etiology of age-related cognitive decline, like Alzheimer's disease (AD), is presented. The view utilizes the idea that this form of dementia is a etiologically complex and heterogeneous brain disorder that is caused by various co-factors. A particular patient with AD would have some combination of these co-factors present but the exact type and combinations might be different from another patient. This theory could also be used to explain other forms of dementia and age-related cognitive decline and the differences in severity of memory impairments associated with each. The co-factors in the present model include genes, neurotransmitter changes, vascular abnormalities, stress hormones, circadian rhythms, head trauma, and seizures.     

Neuropsychological indicators of preclinical Alzheimer’s disease among depressed older adults

Older adults with major depressive disorder (MDD) may also have preclinical Alzheimer’s disease (AD). Differential diagnosis is quite challenging due to the overlapping symptoms of MDD and AD. In the current study, we predicted that impaired long-term memory (an area most affected in early AD), but not executive function (an area affected in MDD and AD), would distinguish older depressed patients who developed AD from those who did not. Patients (N = 120) assessed as having MDD but not dementia at baseline were administered tests of cognitive function and followed longitudinally for subsequent diagnosis of AD. Using structural equation modeling we found a latent construct of long-term memory to be associated with AD to a greater extent than executive functioning. Additional analyses to enhance clinical utility of findings indicated that individual tests of episodic memory were most predictive of AD status. Tests of long-term memory can be utilized by the clinician when assessing for preclinical AD among depressed elderly.     

Neuropsychological Characteristics of Dementia with Lewy Bodies and Parkinson’s Disease with Dementia: Differentiation, Early Detection, and Implications for “Mild Cognitive Impairment” and Biomarkers

Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are neurodegenerative conditions sharing a disorder of α-synuclein metabolism. Temporal differences in the emergence of symptoms and clinical features warrant the continued clinical distinction between DLB and PDD. While DLB and PDD groups’ neuropsychological profiles often differ from those in Alzheimer’s disease (AD), the diagnostic sensitivity, specificity, and predictive values of these profiles remain largely unknown. PDD and DLB neuropsychological profiles share sufficient similarity to resist accurate and reliable differentiation. Although heterogeneous cognitive changes (predominantly in memory and executive function) may manifest earlier and more frequently than previously appreciated in Parkinson’s disease (PD), and executive deficits may be harbingers of dementia, the enthusiasm to uncritically extend the concept of mild cognitive impairment (MCI) to PD should be tempered. Instead, future research might strive to identify the precise neuropsychological characteristics of the prodromal stages of PD, PDD, and DLB which, in conjunction with other potential biomarkers, facilitate early and accurate diagnosis, and the definition of neuroprotective, neurorestorative, and symptomatic treatment endpoints.     

Episodic memory effects of gamma frequency precuneus transcranial magnetic stimulation in Alzheimer's disease: A randomized multiple baseline study

Episodic memory decline is the prominent neuropsychological feature of typical Alzheimer's Disease (AD), for which current treatments have a limited clinical response. Recently, gamma entrainment therapy has been used as a non-invasive treatment in AD, providing evidence that it may have the potential to alleviate brain pathology and improve cognitive function in AD patients. At the same time, the precuneus (PC) has been recognized as a key area involved in AD related memory deficits and as a key node of the Default Mode Network. This study aimed to investigate the effectiveness of a 40 Hz Transcranial Magnetic Stimulation (TMS) intervention, delivered bilaterally to the precuneus for 10 days, in improving the patients' episodic memory performance. Secondary outcome variables investigated included general cognitive function, semantic and spatial memory, as well as attention and executive function. A concurrent multiple baseline design across five cases was employed. Four patients completed the study. Visual analysis combined with effect size indices were used to evaluate changes across phases. An increase in the average level of immediate recalled words was observed in three out of four patients. Effect size indices indicated significant improvement of attention skills in two patients. No treatment effect was observed for semantic and visual memory, or for executive function. An immediate treatment effect was observed in all patients' general cognitive function as assessed with the Alzheimer's Disease Assessment Scale (mean reduction of 5 points), which was maintained and improved further three months post-treatment. The neuropsychological evaluations indicated improved performance three months post-treatment in immediate and delayed recall, attention, phonological verbal fluency, anxiety, and neuropsychiatric symptoms. This study provides preliminary evidence for the efficacy of a novel non-pharmacological treatment using gamma-band TMS in addressing cognitive dysfunction in AD.     

Primary Progressive Aphasias and Their Contribution to the Contemporary Knowledge About the Brain-Language Relationship

Primary progressive aphasia (PPA), typically resulting from a neurodegenerative disease such as frontotemporal dementia/Pick Complex or Alzheimer’s disease, is a heterogeneous clinical condition characterized by a progressive loss of specific language functions with initial sparing of other cognitive domains. Based on the constellation of symptoms, PPA has been classified into a nonfluent, semantic, or logopenic variant. This review of the literature aims to characterize the speech and language impairment, cognition, neuroimaging, pathology, genetics, and epidemiology associated with each of these variants. Some therapeutic recommendations, theoretical implications, and directions for future research have been also provided.