Morris Freedman

Bilingualism as a protection against the onset of symptoms of dementia

This study examined the effect of lifelong bilingualism on maintaining cognitive functioning and delaying the onset of symptoms of dementia in old age. The sample was selected from the records of 228 patients referred to a Memory Clinic with cognitive complaints. The final sample consisted of 184 patients diagnosed with dementia, 51% of whom were bilingual. The bilinguals showed symptoms of dementia 4 years later than monolinguals, all other measures being equivalent. Additionally, the rate of decline in Mini-Mental State Examination (MMSE) scores over the 4 years subsequent to the diagnosis was the same for a subset of patients in the two groups, suggesting a shift in onset age with no change in rate of progression.

Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is increasingly recognized to be a multisystem disorder which includes both clinical and neuropathological features of a frontotemporal lobar degeneration (FTLD). In order to provide a common framework within which to discuss the characteristics of the cognitive and behavioural syndromes of ALS, and with which to conduct clinical and neuropathological research, an international research workshop on frontotemporal dementia (FTD) and ALS was held in London, Canada in June 2007. The recommendations arising from this research workshop address the requirement for a concise clinical diagnosis of the underlying motor neuron disease (Axis I), defining the cognitive and behavioural dysfunction (Axis II), describing additional non-motor manifestations (Axis III) and identifying the presence of disease modifiers (Axis IV).

Amnesia after anterior communicating artery aneurysm rupture

We studied 11 patients with amnesia and personality change after surgical repair of ruptured anterior communicating artery (ACoA) aneurysm. CT and clinical evidence suggested that infarction in the territory of the ACoA was responsible for amnesia and personality change. The medial septa1 nuclei, the paraventricular nucleus of the anterior hypothalamus, and the medial forebrain bundle are the primary areas of potential interest in these cases. Gross infarction in the frontal lobes is not a requirement for the syndrome.

Bilateral frontal lobe disease and selective delayed response deficits in humans.

The performance of patients with frontal lobe disease was compared with that of amnesic patients (with etiology of alcoholic Korsakoffs disease or surgically treated ruptured anterior communicating artery aneurysm) on tasks known to be sensitive to frontal lobe damage in nonhuman primates: delayed alternation (DA) and delayed response (DR). Alcoholic patients with no clinical memory impairment served as controls. Results showed that bilateral frontal lobe damage in humans is associated with impairment on both tasks. In addition, there was no relation between performances on DA and DR and performance on standardized tests of memory, a result strengthening the suggestion that the former tasks are not sensitive to anterograde amnesia in humans.

Atypical antipsychotic drugs in the treatment of behavioural and psychological symptoms of dementia: systematic review

Abstract Objective To review the role of oral atypical antipsychotic drugs in the management of the behavioural and psychological symptoms of dementia (BPSD). Data sources Medline, Embase, and the Cochrane Library. Reference lists were reviewed and experts were contacted to identify additional trials. Study selection Double blind randomised controlled trials that evaluated the four oral atypical antipsychotic therapies for BPSD. Review methods Two reviewers assessed trial validity independently. Data extraction Demographics of patients, study duration, dose of antipsychotic, primary end points, adverse events. Results 77 abstracts were reviewed. Five randomised trials (1570 patients) evaluating risperidone and olanzapine were identified. The quality of trials was generally good. Most participants were in an institution (> 96%), elderly (weighted mean 82.3 years), and had Alzheimers disease (76.3%). Trials lasted 6-12 weeks. Treatment with atypical antipsychotic drugs was superior to placebo for the primary end point in three of the five trials. Two trials comparing risperidone with haloperidol did not find any differences in the primary measures of efficacy. Adverse events were common and included extrapyramidal symptoms, somnolence, and abnormal gait. Conclusions Although atypical antipsychotic drugs are being used with increasing frequency, few randomised trials have evaluated their use for BPSD. Limited evidence supports the perception of improved efficacy and adverse event profiles compared with typical antipsychotic drugs.

Anatomic basis of transcortical motor aphasia

Analysis of language profiles and CT anatomy in transcortical motor aphasia (TCMA) suggests that the essential lesion is disruption of connections at sites between the supplementary motor area and the frontal perisylvian speech zone. If the lesion is extended, there may also be poor articulation (lesion deep to motor strip for face), impaired auditory comprehension (lesion in anterior head of caudate, anterior limb internal capsule, anterior putamen, and anterior portion of external capsule, claustrum, extreme capsule, and insula), or stuttering (lesion in pars opercularis and lower third of premotor region). This concept unifies disparate anatomic and psychophysiologic observations about three syndromes: classical TCMA, aphasia after left medial frontal infarction, and TCMA during recovery from Brocas aphasia.

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis

BACKGROUND Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. METHODS We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. FINDINGS Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1). INTERPRETATION Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. FUNDING Centres of Excellence in Neurodegeneration.

The contribution of autobiographical significance to semantic memory: evidence from Alzheimer's disease, semantic dementia, and amnesia.

In a previous study [Memory Cognit., in press], we demonstrated that some semantic concepts are more likely than others to be associated with specific personal memories, and that this autobiographical significance gives these concepts special status in long-term memory. In this paper, we explore the possible neural correlates of autobiographically significant semantic knowledge and examine whether or not autobiographical significance is a factor in determining patterns of semantic memory loss caused by brain damage. Using famous names that were rated on various attributes, including autobiographical significance, by control participants in a norming study [Memory Cognit., in press], we found that semantic dementia (SD) patients were more likely to recognize, identify and remember autobiographically significant episodes involving famous names that were rated high in autobiographical significance as compared to equally familiar names that were rated low. By contrast, people with Alzheimers disease (AD) and people with medial temporal lobe (MTL) amnesia did not exhibit this preference for names rated high in autobiographical significance. Furthermore, in tests of free recall, recognition, fame judgment and speeded reading, semantic dementia patients demonstrated a performance advantage for autobiographically significant famous names, whereas the other patient groups did not. These findings suggest a critical role for medial temporal regions in the mediation of autobiographical memory and the interaction between personal experience and semantic memory. Theoretical implications are discussed.

Different Patterns of Autobiographical Memory Loss in Semantic Dementia and Medial Temporal Lobe Amnesia: a Challenge to Consolidation Theory

Temporally graded retrograde memory loss, with a disproportionate impairment of recent relative to remote memories, is considered a hallmark of medial temporal lobe amnesia. According to consolidation theory, the hippocampal complex, which includes the hippocampal formation, parahippocampal gyrus, the entorhinal and perirhinal cortex, plays a time-limited role in memory, needed only until consolidation in the neocortex is complete (Squire, Psychological Review 1992; 99: 195–231). Recent support for this theory comes from findings of a reverse gradient in people with semantic dementia with neocortical degeneration but a relatively preserved hippocampal complex (Hodges and Graham, Neuropsychologia 1998; 36: 803–25). Consolidation theory is challenged by evidence that remote autobiographical memory is not always spared in amnesia (Nadel and Moscovitch, Current Opinion in Neurobiology 1997; 7: 217–27) and that semantic memory becomes highly personalized in semantic dementia (Snowden et al., Memory 1995; 3: 225–46). According to Nadel and Moscovitch, the hippocampal complex is needed to retain and retrieve detailed memories of autobiographical episodes no matter how old they are. To test consolidation theory against the opposing view, we investigated the role of the hippocampal complex in recent and remote autobiographical and personal semantic memory by contrasting the memory of a semantic dementia patient, EL, with that of an amnesic patient, KG, using family photographs as recall cues. KG demonstrated a complete loss of autobiographical episodes with a sparing of autobiographical facts; EL demonstrated well-preserved memory for episodes with a reverse gradient for personally relevant names. The influence of autobiographical significance on memory for names of public figures was examined further by comparing the effect that familiarity and recollection had on recognition of names of famous people and famous places. EL’s memory was influenced by autobiographical significance, whereas KC’s was not. We propose that the hippocampal complex plays a permanent role in the storage and retrieval of autobiographical episodes and that autobiographical significance may affect semantic representations.

Diagnosis and treatment of dementia: 3. Mild cognitive impairment and cognitive impairment without dementia.

Background: Mild cognitive impairment and cognitive impairment, no dementia, are emerging terms that encompass the clinical state between normal cognition and dementia in elderly people. Controversy surrounds their characterization, definition and application in clinical practice. In this article, we provide physicians with practical guidance on the definition, diagnosis and treatment of mild cognitive impairment and cognitive impairment, no 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 had mild cognitive impairment or cognitive impairment, no dementia, as the outcome. Subsequent to the conference, we searched for additional articles published between January 2006 and January 2008. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care. Results: We identified 2483 articles, of which 314 were considered to be relevant and of good or fair quality. From a synthesis of the evidence in these studies, we made 16 recommendations. In brief, family physicians should be aware that most types of dementia are preceded by a recognizable phase of mild cognitive decline. They should be familiar with the concepts of mild cognitive impairment and of cognitive impairment, no dementia. Patients with these conditions should be closely monitored because of their increased risk for dementia. Leisure activities, cognitive stimulation and physical activity could be promoted as part of a healthy lifestyle in elderly people and those with mild cognitive impairment. Vascular risk factors should be treated optimally. No other specific therapies can yet be recommended. Interpretation: Physicians will increasingly see elderly patients with mild memory loss, and learning an approach to diagnosing states such as mild cognitive impairment is now warranted. Close monitoring for progression to dementia, promotion of a healthy lifestyle and treatment of vascular risk factors are recommended for the management of patients with mild cognitive impairment.