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Mr. C, a 75-year-old man, noticed difficulty remembering names and adding numbers after wakening while on vacation. Although these problems were quite subtle, his wife was puzzled because he seemed to have no difficulty the day before. One week later, he noted that “something was wrong” but could not describe the changes in detail. He felt that his balance was “not right” and experienced difficulty keeping track of his golf scores. Over the next few months, he developed word-finding problems and had difficulty expressing himself. He was very forgetful, had trouble problem solving, was distractible, and was unable to do simple calculations. Whereas he had previously been very reserved, he started talking with others in a more open way than he would normally have done. He continued to complain of balance problems and started to notice changes in his handwriting.
Many older adults experience memory changes that can have a meaningful impact on their everyday lives, such as restrictions to lifestyle activities and negative emotions. Older adults also report a variety of positive coping responses that help them manage these changes. The purpose of this study was to determine how objective cognitive performance and self-reported memory are related to the everyday impact of memory change.
We examined these associations in a sample of 94 older adults (age 60–89, 52% female) along a cognitive ability continuum from normal cognition to mild cognitive impairment.
Correlational analyses revealed that greater restrictions to lifestyle activities (|rs| = .36–.66), more negative emotion associated with memory change (|rs| = .27–.76), and an overall greater burden of memory change on everyday living (|rs| = .28–.61) were associated with poorer objective memory performance and lower self-reported memory ability and satisfaction. Performance on objective measures of executive attention was unrelated to the impact of memory change. Self-reported strategy use was positively related to positive coping with memory change (|r| = .26), but self-reported strategy use was associated with more negative emotions regarding memory change (|r| = .23).
Given the prevalence of memory complaints among older adults, it is important to understand the experience of memory change and its impact on everyday functioning in order to develop services that target the specific needs of this population.
Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.
Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.
Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.
This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.
In order to characterize the nature and extent of neuropsychological dysfunction in primary lateral sclerosis (PLS), we studied prospectively cognitive, emotional, and behavioral functioning in PLS, and compared performances to functioning in amyotrophic lateral sclerosis (ALS).
Eighteen patients with PLS and 13 patients with ALS completed a neuropsychological test battery assessing both cognitive skills and emotional/behavioral functioning.
Both PLS and ALS groups scored broadly within normal limits (mean T-scores greater than 40) on all cognitive measures and no significant between-group differences were found with the exception of one variable. However, when examined on a case by case basis, the data revealed considerable heterogeneity amongst patients in both groups. Overall, 39% of PLS patients and 31% of ALS patients were considered cognitively impaired. A higher than expected frequency of abnormal scores was noted for several tests of executive function in both groups, and a majority of PLS patients also exhibited abnormal behavioural symptoms. There was no relationship in PLS or ALS groups between cognitive functioning and disease duration, current site of disease, site of onset, functional status, and respiratory variables. Comparison between the PLS and ALS groups indicated virtually no differences in cognitive test scores and overall emotional/behavioural symptoms.
We observed deficits in cognition and behaviour in a significant proportion of PLS patients which were comparable to those observed in ALS cases. Although deficits were not in the range of frontotemporal dementia, both ALS and PLS cases demonstrated deficits most prominently on tests of executive functioning.
Because individuals develop dementia as a manifestation of neurodegenerative or neurovascular disorder, there is a need to develop reliable approaches to their identification. We are undertaking an observational study (Ontario Neurodegenerative Disease Research Initiative [ONDRI]) that includes genomics, neuroimaging, and assessments of cognition as well as language, speech, gait, retinal imaging, and eye tracking. Disorders studied include Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, and vascular cognitive impairment. Data from ONDRI will be collected into the Brain-CODE database to facilitate correlative analysis. ONDRI will provide a repertoire of endophenotyped individuals that will be a unique, publicly available resource.
The terms “cortical” and “subcortical” dementia are controversial; however, the clinical distinction between them is real. For example, although Alzheimer's and Parkinson's disease (prototypical of cortical and subcortical dementia, respectively) share clinical features, they differ in the presence of aphasia, apraxia, and agnosia in Alzheimer's disease but not in Parkinson's dementia. We review our studies aimed at clarifying the mechanisms underlying the differences between these neurological disorders. Experimental paradigms adopted from animal models were used to study the functional anatomy and neuropsychological characteristics of Alzheimer's and Parkinson's disease. The tasks administered include delayed alternation (DA) and delayed response (DR), which are sensitive to frontal system damage, and tactile discrimination learning (TOL) and reversal (TRL) paradigms sensitive to parietal system damage. Alzheimer's patients were significantly impaired on all tasks whereas Parkinsonians with dementia were impaired only on DR and TRL. Consideration of neuroanatomical and neuropsychological mechanisms involved in DA, DR, TOL, and TRL appears to have sharpened the distinction between Alzheimer's and Parkinson's dementia. Dementia in Alzheimer's disease may involve dorsolateral frontal, orbitofrontal and parietal systems. In contrast, dementia in Parkinson's disease may involve prominent dorsolateral frontal system damage.
Retrograde amnesia was assessed in demented and non-demented Parkinson’s patients using a test of remote memory spanning the years from 1920-1979. Results indicated that the demented patients 1) scored significantly below normal controls and 2) had equal impairment for all time periods. This pattern was like that seen in other dementing illnesses (i.e., Huntington’s and Alzheimer’s diseases), but different from that in amnesic disorders, such as Korsakoff s syndrome. The data, therefore, suggest qualitative differences in pattern of remote memory loss between the dementias and amnesic syndromes.
99mTc-HM-PAO single photon emission computed tomography (SPECT) was used to image 30 patients referred for the assessment of dementia. SPECT images revealed various patterns of regional cerebral perfusion (rCBF) in the subgroups of patients with the clinical diagnoses of Alzheimer's disease (AD, n = 14), Pick's disease (n = 1), and multi-infarct dementia (n = 7). In three patients, SPECT clarified the clinical differential diagnostic possibilities. Using a relative rCBF quantification technique, the relationship between specific cognitive impairments and rCBF in the AD patients was determined. There was a significant correlation between language impairment and left hemisphere hypoperfusion, whereas, apraxia correlated with hypoperfusion in the left parietal region. Thus, HMPAO SPECT is useful as an aid in the differential diagnosis of dementia and the technique of relative rCBF quantification with SPECT may contribute to the understanding of the clinico-anatomical relations of cognitive deficits in dementia.
The value of CT as a routine screening procedure in the investigation of cognitive impairment is being increasingly challenged. To address this issue, we reviewed the records of 175 patients with intellectual deficits admitted to a Behavioural Neurology Unit over a two-year period. In the vast majority of cases, ie. 82%, the CT served essentially to confirm the clinical impression and added no new diagnostic information that impacted the management of the presenting problem. In 15% of cases the CT scan was helpful for diagnosis, especially in the differentiation between Alzheimer's disease and multi-infarct dementia.
Objective: To replicate a previous finding that the trajectory of the Neuropsychiatric Inventory (NPI) shifts in the sixth year of behavioural variant frontotemporal dementia (bvFTD). We evaluated longitudinal tracking with both the Frontal Behavioural Inventory (FBI) and NPI, comparing bvFTD against other dementias.Methods: Chart reviews over two to five years for patients with bvFTD (n=30), primary progressive aphasia (PPA, n=13) and Alzheimer’s disease (AD, n=118) at an urban Canadian tertiary clinic specializing in dementia. Linear regressions of the longitudinal data tested predictors of annualized rates of change (ROC) in NPI and FBI total and subscales for apathy and disinhibition among dementia groups. Results: The mode of the overall sample for the most advanced duration of illness observed was 5 years, with the median at 7 years. We did not find a crescendo-decrescendo pattern in scores although, for bvFTD and AD, high initial scores correlated with ensuing downward ROCs on the NPI and FBI. Educational level showed an influence on disinhibition ROCs. The FBI was no more revealing than the NPI for apathy and disinhibition scores in these dementias. Conclusions: A cognitive reserve effect on behavioural disturbance was supported but it may take longer than our 4 years of observing the clinical sample to record inflection points in the behavioural and psychiatric symptoms seen in bvFTD. The current data only imply that both apathy and disinhibition will diminish over the course of dementia.
The magnitude of the problems faced by an aging Canadian society has been clearly identified. Perhaps the single most important problem is the increasing incidence of dementia. Alzheimer's disease (AD) accounts for 50-60% of the dementias in later life within a spectrum of other contributing dementias. Regulatory approval has been given to Acetylcholinesterase inhibitors for the symptomatic treatment of mild to moderate AD, and conditional approval to memantine for the symptoms of moderate to severe AD. There has been no regulatory approval for the treatment of the degenerative dementias beyond AD. The very rapid progress in the past decade in biotechnology and in the molecular biology of the dementias is supporting a new generation of innovative treatment strategies that will more directly target the underlying disease pathogenic mechanisms. Such treatments will foreseeably include immunotherapies, anti-aggregants that may prevent misfolding and deposition of proteins, and neuroregenerative interventions. These Guidelines follow the 2nd Canadian Conference on the Development of Antidementia Therapies, held in 2004, which covered a range of design, methodological and ethical issues facing clinical researchers and regulatory authorities. They are intended to provide a common point of reference and guidance in Canada for therapeutic development of the dementias.
Frontotemporal dementia (FTD) is one of three neurobehavioural syndromes produced by frontotemporal lobar degeneration. Despite the importance of FTD as a cause of dementia, especially in younger age groups, and a rationale for therapies targeting serotonergic and dopaminergic systems, there have been no large scale treatment trials in FTD. Moreover, there is no consensus on standards to facilitate comparison across therapeutic trials. This paper reviews the literature on therapeutic trials in FTD and outlines general recommendations for standards related to the development of future treatment studies in this disorder. Drugs tested in FTD include trazodone, galantamine, idazoxan, lithium plus fluoxetine, lithium plus paroxetine, SSRIs, l-deprenyl, moclobemide, methylphenidate, piracetam, rivastigmine, donepezil, olanzapine, risperidone, amantadine, guanfacine, allopurinol, and bromocriptine. Improvement has been reported in FTD for all drugs except piracetam, guanfacine and galantamine, although there was improvement on galantamine in primary progressive aphasia. Whereas improvement has been reported for paroxetine and other SSRIs, as well as idazoxan and methylphenidate, paroxetine and idazoxan have also been reported to cause a decline in function, and a marginally significant decline has been reported for methylphenidate. In addition, patients with Pick's disease, which is part of the spectrum of frontotemporal lobar degeneration, showed improvement on calcium EDTA. Six studies are double-blind placebo-controlled trials: two reports of cases using idazoxan and group trials using trazodone, paroxetine, galantamine and methylphenidate. It is recommended that experts in FTD arrive at a consensus to define standards for all clinical trials in FTD. These should include standards for diagnostic criteria, tests of severity, experimental design, and outcome measures.
This chapter discusses the organization of human sleep by the brain mechanisms and specific sleep disorders that lead to disturbances in the brain mechanisms. Non-rapid eye movement (NREM) sleep is controlled by brainstem oscillators whose activation leads to the multiple physiological accompaniments of the NREM state. The dream is the unusual mental content that often accompanies REM sleep. As humans transition from wakefulness to sleep, characteristic physiological changes include decreases in respiratory rate, heart rate, and blood pressure. The domain of the insomnias benefits from thoughtful differential diagnosis, as the causation may be both multiple and obscure. The insomnia complaints that are comorbid with medical disorders include both sleep disturbances caused by medical symptoms, and also those sleep disturbances caused by the pathophysiology underlying the medical condition. Restless leg syndrome (RLS) and periodic limb movements of sleep (PLMS) are considered as sleep disorders.
This chapter describes hemiparesis followed by dementia using the case of a 73-year-old woman who presented to the emergency room with mild left hemiparesis since awakening the day before. Computed tomography (CT) scan showed a known old right parieto-temporal infarct and a right caudate nucleus lacune. Magnetic resonance imaging (MRI) done within 3 days of presentation show the same ischemic lesions without diffusion restriction, with mild leukoaraiosis and atrophy for age. Neuropsychological tests showed severe executive functions deficits, moderate to severe memory deficits, and mild visuoconstructive and ideomotor apraxia. The initial diagnostic impression was mixed dementia, although a purely vascular dementia could not be ruled out. Repeated mini-mental state examination (MMSE) showed decline over time, despite temporary improvement after initiation of a cholinesterase inhibitor, galantamine (Reminyl ER), 3 months after presentation. Blood pressure remained high during initial follow-up, requiring several anti-hypertensive medication adjustments.
This chapter describes right-sided numbness using the case of an 82-year-old woman who had a former history of hypertension, type 2 diabetes treated with oral hypoglycemic agents, rheumatoid arthritis, dysthymic disorder, and left dorsal herpes zoster with residual postherpetic neuralgia. The physical examination showed a conscious patient with moderate motor aphasia, right homonymous hemianopsia, and balanced faciobrachiocrural hemiparesis in association with hemihypoesthesia of the right hemibody. The brain magnetic resonance imaging (MRI) scan showed acute cerebral ischemia in the territory of the left middle cerebral artery. A diagnosis of cerebral infarction of cardioembolic origin was made. A final tentative diagnosis of vascular cognitive impairment that fulfilled criteria of multi-infarct dementia was established. Living performance after stroke was severely impaired and home assistance for daily living activities was needed. Treatment for the cognitive impairment includes speech therapy and physical rehabilitation.
Two components of verbal fluency performance—clustering
(i.e., generating words within subcategories) and switching
(i.e., shifting between subcategories)—were examined
in patients with dementia of the Alzheimer type (DAT),
patients with dementia with Parkinson's disease (DPD),
nondemented patients with Parkinson's disease (NPD),
and demographically matched controls. The DAT and DPD groups
were impaired in the number of words generated on both
phonemic and semantic fluency. The DAT group produced smaller
clusters on both tasks and switched less often on semantic
fluency than controls. The DPD group switched less often
on both tasks and produced smaller clusters on phonemic
fluency than controls. The NPD group was not impaired on
any fluency variable. Thus, the total number of words generated
on phonemic and semantic fluency did not discriminate the
dementia groups from their respective control groups, but
measures of clustering and switching did. This differential
pattern of performance provides evidence for the potential
usefulness of measures of switching and clustering in the
assessment of dementia. (JINS, 1998, 4,
Although roles have been proposed for both graphomotor
speed and learning in the execution of Digit Symbol, few
data have been available concerning performance across
the adult lifespan on the Symbol Copy, paired associates,
or free recall measures derived from Digit Symbol and recommended
in the WAIS–R–NI. We report findings on 177
healthy older adults (ages 50–90), providing normative
data by age group, education level, and gender. As previously
reported, Digit Symbol scores decline steeply with age
(r = −.64). Symbol Copy speed declines almost
as steeply (r = −.58). Incidental learning,
however, declines only modestly (r = −.26
on both measures). Symbol Copy is a far stronger correlate
of Digit Symbol (r = .72) than are paired associates
or free recall (r = .26 and r = .28,
respectively). The 2 incidental learning measures do, however,
offer valuable supplementary information as part of a comprehensive
individual assessment. When low Digit Symbol scores are
produced by slowing on Symbol Copy, further evaluation
of perceptual and motor speed and dexterity are indicated.
When low incidental learning scores are obtained, further
evaluation of memory is warranted. Qualitative analysis
of errors (e.g., rotations) made on the incidental learning
procedures may also be valuable. (JINS, 2000,