Mervin Blair

Diagnosis and treatment of dementia: 2. Diagnosis

Background: Dementia can now be accurately diagnosed through clinical evaluation, cognitive screening, basic laboratory evaluation and structural imaging. A large number of ancillary techniques are also available to aid in diagnosis, but their role in the armamentarium of family physicians remains controversial. In this article, we provide physicians with practical guidance on the diagnosis of dementia based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006. Methods: We developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that pertained to key diagnostic issues in dementia. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care. Results: Of the 1591 articles we identified on all aspects of dementia diagnosis, 1095 met our inclusion criteria; 620 were deemed to be of good or fair quality. From a synthesis of the evidence in these studies, we made 32 recommendations related to the diagnosis of dementia. There are clinical criteria for diagnosing most forms of dementia. A standard diagnostic evaluation can be performd by family physicians over multiple visits. It involves a clinical history (from patient and caregiver), a physical examination and brief cognitive testing. A list of core laboratory tests is recommended. Structural imaging with computed tomography or magnetic resonance imaging is recommended in selected cases to rule out treatable causes of dementia or to rule in cerebrovascular disease. There is insufficient evidence to recommend routine functional imaging, measurement of biomarkers or neuropsychologic testing. Interpretation: The diagnosis of dementia remains clinically integrative based on history, physical examination and brief cognitive testing. A number of core laboratory tests are also recommended. Structural neuroimaging is advised in selected cases. Other diagnostic approaches, including functional neuroimaging, neuropsychological testing and measurement of biomarkers, have shown promise but are not yet recommended for routine use by family physicians.

A longitudinal study of language decline in Alzheimer's disease and frontotemporal dementia

Language decline is usually the fastest and predominant change in primary progressive aphasia (PPA). In Alzheimers disease (AD), it is usually associated with global cognitive deficits. Decreased speech output, reduced conversational initiation, echolalia, and changes in the pragmatics of conversation are seen in the behavioral variant of frontotemporal dementia (FTD-bv), however, the evolution of language disturbance in FTD-bv patients is rarely examined systematically with a standardized language battery. We aimed to longitudinally track the nature of language change in FTD-bv, PPA, and AD using a standardized measure of language functioning. We also explored the nature of language deficits between semantic dementia (SD) patients and the fluent subgroup of PPA patients. The Western Aphasia Battery was administered to 105 AD, 20 FTD-bv, 54 PPA, and 10 SD patients on 2 occasions with approximately 1 year between assessments. Ninety-nine of these patients were examined an additional year. FTD-bv and PPA patients showed a faster language decline than AD patients. The eventual overlap in language functioning in FTD-bv and PPA suggests that these syndromes belong to the same spectrum of disorders. In conclusion, longitudinal language assessment provides us with a unique understanding of the evolution and progression of language deterioration in various dementias.

Neuropsychological testing and assessment for dementia

This evidence‐based review examines the utility of brief cognitive tests and neuropsychological testing (NPT) in the detection and diagnosis of mild cognitive impairment (MCI) and dementia. All patients presenting with cognitive complaints are recommended to have a brief screening test administered to document the presence and severity of memory/cognitive deficits. There is fair evidence to support the use of a range of new screening tests that can detect MCI and mild dementia with higher sensitivity (≥80%) than the Mini‐Mental State Exam (MMSE). NPT should be part of a clinically integrative approach to the diagnosis and differential diagnosis of dementia. It should be applied selectively to address specific clinical and diagnostic issues including: 1) The distinction between normal cognitive functioning in the aged, MCI and early dementia: there is fair evidence that NPT can document the presence of specific diagnostic criteria and provide additional useful information on the pattern of memory/cognitive impairment. 2) The evaluation of risk for Alzheimer disease (AD) or other types of dementia in persons with MCI: there is fair evidence that NPT measures or profiles can predict progression to dementia (predictive accuracy ranges from ∼80 to 100%, sensitivities from 53 to 80%, and specificities from 67 to 99%). 3) Differential diagnosis: There is fair evidence that NPT can complement clinical history and neuroimaging in determining the dementia etiology. Different dementia types have distinguishable NPT profiles though these may be stage‐dependent, and increased sensitivity may be at the expense of specificity. 4) When NPT is part of a comprehensive assessment, which also entails clinical interviews and consideration of other clinical data, there is good evidence that it can contribute to management decisions in MCI and dementia, including the determination of retained and impaired cognitive abilities, their functional and vocational impact, and opportunities for cognitive rehabilitation.

The diagnosis and course of frontotemporal dementia.

The course of frontotemporal dementia (FTD) is examined in a prospective, incipient clinical cohort. Three hundred nineteen patients were followed yearly for an average of 3.6 years. The relative frequencies at presentation were Behavioral variety (FTD-bv) 37.6%, Primary Progressive Aphasia (PPA) 31.6%, possible PPA 10.6%, Corticobasal Syndrome (CBDS) and Progressive Supranuclear Palsy (PSP) 8.1%, Semantic Dementia (SD) 6.6%, and possible FTD 5.3%. The age of onset was significantly lower in the FTD-bv and SD groups than in the rest, but survival and sex distribution was similar in all groups. The evolution is characterized by the appearance of additional FTD syndromes in two-thirds of the patients. A significant association of SD with FTD-bv and CBDS/PSP with PPA was found. The Frontal Behavioral Inventory was highly sensitive and specific for FTD-bv. Visuospatial function was preserved except in CBDS/PSP. The clinical diagnosis showed a positive predictive value of 87% against autopsy in 67 patients. Multiple syndromes increase the likelihood of FTD pathology. In conclusion, the clinical associations follow the tau-negative and tau-positive pathologic dichotomy to some extent, but there is too much overlap to consider the clinical groups or their associations separate diseases.

Corticobasal degeneration and progressive aphasia

Objective: To describe language impairment in the corticobasal degeneration syndrome (CBDS) presenting as either a cognitive or motor disorder, to compare the evolution of aphasia in CBDS with primary progressive aphasia (PPA), and to examine whether the side of maximal cerebral atrophy or akinesia reflects the severity of aphasia. Methods: We divided 40 patients with CBDS according to motor or cognitive onsets and conducted detailed language assessments with the Western Aphasia Battery (WAB). We analyzed scores according to the side of atrophy and motor rigidity. Longitudinal performance over three annual assessments was compared against matched patients with PPA and Alzheimer disease. Results: Language at baseline was more impaired in cognitive than motor-onset CBDS but there was no correlation between the side of atrophy or motor impairment and the WAB. Serial assessment (n = 19) showed a similar evolution of aphasia in cognitive-onset CBDS and PPA and delayed aphasia in motor-onset CBDS. Conclusion: Aphasia is common in the corticobasal degeneration syndrome but there is little correlation with the laterality of clinical deficits. Cognitive-onset corticobasal degeneration syndrome and primary progressive aphasia are similar such that their aphasia appears identical.

Quantitative and qualitative analyses of clock drawing in frontotemporal dementia and Alzheimer's disease

The clock drawing test (CDT) is a widely used cognitive screening test. It is useful in identifying focal lesions and cognitive deficits in dementia groups. Lately, several studies attempted its use to differentiate between dementia subtypes. Although many studies have examined the CDT in dementia populations, research into the use of clock drawing in frontotemporal dementia (FTD) is limited. We examined quantitative (global) and qualitative (specific error type) differences on the CDT between FTD (n = 36) and Alzheimers disease (AD; n = 25) patients and controls without dementia (n = 25). Results showed significantly lower overall scores in the dementia groups compared to the control group, whereas FTD patients scored significantly higher than the AD group. On qualitative analysis, the FTD group had fewer stimulus bound responses, conceptual deficits, and spatial or planning errors compared to the AD group. In conclusion, both global and error analysis of the CDT helped discriminate the FTD group from controls and AD patients.

Oxytocin for frontotemporal dementia: A randomized dose-finding study of safety and tolerability

Objective: To determine the safety and tolerability of 3 doses of intranasal oxytocin (Syntocinon; Novartis, Bern, Switzerland) administered to patients with frontotemporal dementia (FTD). Methods: We conducted a randomized, parallel-group, double-blind, placebo-controlled study using a dose-escalation design to test 3 clinically feasible doses of intranasal oxytocin (24, 48, or 72 IU) administered twice daily for 1 week to 23 patients with behavioral variant FTD or semantic dementia (clinicaltrials.gov registration number NCT01386333). Primary outcome measures were safety and tolerability at each dose. Secondary measures explored efficacy across the combined oxytocin vs placebo groups and examined potential dose-related effects. Results: All 3 doses of intranasal oxytocin were safe and well tolerated. Conclusions: A multicenter trial is warranted to determine the therapeutic efficacy of long-term intranasal oxytocin for behavioral symptoms in FTD. Classification of evidence: This study provides Class I evidence that for patients with FTD, intranasal oxytocin is not significantly associated with adverse events or significant changes in the overall neuropsychiatric inventory.

The mediating role of processing speed in the relationship between depressive symptoms and cognitive function in multiple sclerosis

ABSTRACT Introduction: Although disorders of mood and cognition are frequently observed in multiple sclerosis, their relationship remains unclear. We aimed to investigate whether this mood–cognition relationship is mediated by inefficient processing speed, a deficit typically associated with mood symptomatology in the psychiatric literature and a common deficit observed in multiple sclerosis patients. Method: In this study, comprehensive cognitive data and self-reported mood data were retrospectively analyzed from 349 patients with relapsing remitting multiple sclerosis. We performed a bootstrapping analysis to examine whether processing speed provided an indirect means by which depressive symptoms influenced cognitive functioning, specifically memory and executive function. Results: We observed that processing speed mediated the relationship between depressive symptoms and measures of memory and executive function. Interestingly, exploratory analyses revealed that this mediational role of processing speed was specific to MS patients who were younger, had a lower disability level, and had fewer years since MS diagnosis. Conclusions: Together, these findings have implications for mood and cognitive intervention with multiple sclerosis patients.

Depressive Symptoms Are Associated With More Negative Functional Outcomes Than Anxiety Symptoms in Persons With Multiple Sclerosis

Depression and anxiety are common among persons with multiple sclerosis (MS), and both negatively affect functional status. However, studies rarely account for overlap in depressive and anxiety symptoms on functional outcomes among people with MS. The authors aimed to examine the differential impact of depression and anxiety, measured by the Anxiety and Depression subscales of the Hospital Anxiety and Depression Scale (HADS-A and HADS-D), on functional outcomes among people with MS. Using a retrospective chart review of 128 people with MS, the authors used exploratory structural equation modeling to examine the relation of HADS-A and HADS-D to functional outcomes, namely employment status, fatigue (with the Fatigue Severity Scale), disability (with the Expanded Disability Status Scale [EDSS]), and cognition (with the Symbol Digit Modalities Test [SDMT]). After the authors controlled for the effects of covariates, HADS-A was negatively associated with EDSS (β=-0.22, p<0.05) and positively associated with vocation (β=0.23, p<0.05). In contrast, HADS-D was positively correlated with fatigue (β=0.37, p<0.05) and EDSS (β=0.26, p<0.05) and negatively correlated with vocation (β=-0.32, p<0.05) and SDMT (β=-0.28, p<0.05). HADS-A and HADS-D explained 5% of the variability in employment, 14.5% in fatigue, 1.6% in EDSS, and 4.3% in SDMT, beyond the effects of the covariates. Depressive symptoms have a significant negative impact on functional outcomes among people with MS, relative to anxiety symptoms. These findings support the importance of identifying and treating depressive symptoms among people with MS.

Short Report: Prevalence of Cognitive Impairment in Newly Diagnosed Relapsing-Remitting Multiple Sclerosis

Background Cognitive impairment is common in multiple sclerosis (MS) and can manifest early in the disease process, sometimes as early as the first demyelinating event. However, the frequency of cognitive impairment in a newly diagnosed MS population has not been evaluated comprehensively in a clinical population. We sought to examine the prevalence of cognitive impairment in relapsing-remitting MS (RRMS) within a year of diagnosis in a clinic where cognitive testing at diagnosis is part of routine practice. Methods A retrospective medical record review of persons with RRMS assessed in a cognitive MS clinic identified 107 patients assessed by the Minimal Assessment of Cognitive Function in Multiple Sclerosis battery within 1 year of a confirmed RRMS diagnosis. Results The cohort was predominantly female (n = 82 [76.6%]) and white (n = 93 [86.9%]). Only 36 patients (33.6%) were diagnosed as having RRMS based on a second clinical event. Processing speed was the most frequently impaired domain (n = 38 [35.5%]). Only 37 patients (34.6%) were within normal limits on all cognitive domains. Regarding mood symptoms, 25 patients (23.4%) were positive for depressive symptoms; 59 (55.1%), for anxiety. Severe fatigue was correlated with a lower score on the Symbol Digit Modalities Test (SDMT) (r = -0.380, P < .001), and higher depressive scores were correlated with lower performance on the SDMT (r = -0.397, P < .001) and the Paced Auditory Serial Addition Test (r = -0.254, P = .009). Conclusions Cognitive impairment, specifically processing speed, and mood symptoms are frequently present in persons with newly diagnosed RRMS.