A decade of pre-diagnostic assessment in a case of familial Alzheimer's disease: tracking progression from asymptomatic to MCI and dementia

Detailed study of the very earliest phases of Alzheimer's disease (AD) is seldom possible, especially those changes preceding the development of mild cognitive impairment (MCI), which may occur years before diagnosis. Knowledge of imaging and neuropsychological features of these early stages would add insight into this poorly understood phase of the disease. We present data from a subject who entered a longitudinal study of individuals at risk of familial Alzheimer's disease (FAD), as a healthy volunteer with no memory complaints, undergoing 12 assessments between 1992 and 2003. Longitudinal MRI, neuropsychological and clinical data are presented over the decade preceding this man's diagnosis, through the asymptomatic and prodromal preludes to his presentation with MCI and on to eventual conversion to AD.     

Association between Dementia Rating Scale performance and neurocognitive domains in Alzheimer''s disease

The Dementia Rating Scale (DRS; Mattis, 1976, 1988) is commonly used in the assessment of dementia, although little is known about the relationship of performance on this test to specific cognitive deficits in Alzheimer's disease (AD). Additionally, cognitive profiles have not been investigated across different levels of dementia as determined by the DRS. A sample of 133 individuals diagnosed with possible or probable AD was administered the DRS as part of a comprehensive neuropsychological evaluation. Composite scores for the cognitive domains of attention, executive functioning, visuospatial skills, language abilities, immediate recall, and delayed memory were derived by averaging demographically corrected T scores of key measures. Individual domain scores were also averaged to develop a global index score. Pearson correlations between composite and total DRS scores were highly significant (p<.001) for all domains and the global index score, with the exception of delayed memory, which showed a floor effect. When the sample was divided into mild and moderate-to-severe groups to examine the effects of disease severity on the relationship between the DRS and standard neurocognitive domain scores, the resulting mean neuropsychological profile scores were significantly different while maintaining a parallel pattern of impairment across domains. Results demonstrate the relationship between the DRS and standard cognitive domain functions, which appears to underscore the validity and robustness of the DRS in characterizing patterns of cognitive impairment across the AD spectrum.     

Cognitive decline in patients with familial Alzheimer's disease associated with E280a presenilin-1 mutation: a longitudinal study

Few longitudinal studies have been carried out to investigate the cognitive decline in early onset of familial Alzheimer's disease (FAD). In this study 12 patients with FAD (M age = 49.61 years, SD = 4.99), 10 patients with sporadic Alzheimer's disease (SAD) (M age = 71.40, SD =10.00), and 15 matched normal controls (M age = 45.01, SD = 7.24) were selected. A comprehensive neuropsychological battery was administered three times over a period of 18 months. Individuals designated as FAD met the criteria for dementia and were positive for the E280A presenilin 1 mutation. Participants with SAD met the criteria for dementia and were negative for the E280A presenilin 1 mutation. Normal control participants were the FAD patients' relatives, who were negative for the mutation. Two groups of neuropsychological instruments were administered: (1) The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological test battery, and (2) additional neuropsychological tests of abstraction and constructional abilities. Patients with FAD were significantly impaired on all measures at the first examination except for reading of words. While the performance of the normal controls remained unchanged over the 18 months for most neuropsychological tests, the patients with FAD displayed a decline in verbal memory, language, constructional and abstraction tests. The greatest decline was observed on the Mini-Mental State Exam scores. Patients with SAD demonstrated a similar pattern of cognitive decline, but the decline was faster in FAD than in SAD participants.     

Cognitive deficits in familial Alzheimer's disease associated with M239V mutation of presenilin 2

The neuropsychological assessment of non-demented subjects with gene mutation of familial Alzheimer's disease (AD) provides a model for exploring the early cognitive features of the disease. We evaluated 1 patient and 6 non-demented subjects belonging to a family with AD with M239V mutation of the presenilin 2 gene, aiming to verify the contribution of specific cognitive patterns to the characterization of familial AD. One patient, 3 non-demented subjects with M239V mutation and 3 subjects without mutation from the same family underwent neuropsychological testing. The patient's cognitive profile was characterized by anosognosia, visuospatial agnosia, apraxia and fluent aphasia. Of the 3 non-demented subjects with mutation, 1 showed no deficits, another constructive apraxia and the third spatial perception and memory deficits. The 3 subjects without mutation showed normal abilities. The cognitive deficits of the non-demented subjects with mutations indicate focal dysfunction of the posterior cortical areas, resembling the more extended parieto-occipito-temporal dysfunction of the demented patient. Such grading of visuospatial, praxis, and language impairments highlights a distinctive pattern related to the M239V mutation of the presenilin 2 gene.     

Selective attention deficits associated with mild cognitive impairment and early stage Alzheimer's disease in adults with Down syndrome

Adults with Down syndrome and early stage Alzheimer's disease showed decline in their ability to selectively attend to stimuli in a multitrial cancellation task. They also showed variability in their performance over the test trials, whereas healthy participants showed stability. These changes in performance were observed approximately 2 years prior to a physician's diagnosis of possible Alzheimer's disease, which was made when they were exhibiting declines in episodic memory suggestive of mild cognitive impairment. Performance on this task varied with the evolution of dementia, showed modestly good sensitivity and specificity, and was relatively easy to administer. Given these qualities this task could be a valuable addition to a neuropsychological battery intended for the assessment of mild cognitive impairment and Alzheimer's disease in adults with Down syndrome.     

抑郁症和早期阿尔茨海默病的记忆和执行功能

目的 研究抑郁症和早期阿尔茨海默病(AD)的神经心理学特征,试图运用神经心理学评估对两者进行鉴别。方法 对32例单相抑郁症、38例早期AD和34例对照进行WHO-UCLA词语学习、词语流畅、复杂图形和逻辑记忆的评估。结果 早期AD组神经心理学测验得分最低,抑郁症组次之,对照组最高,3组之间有显著性差异(P<0.01);抑郁症组仅表现为词语学习和逻辑记忆的自由回忆以及语义流畅的损害(P<0.05),而早期AD组表现为全面的认知功能损害(P<0.01);逐步判别分析提示,复杂图形延迟自由回忆、词语学习长时延迟自由回忆和语义流畅是区分抑郁症组和早期AD组的重要指标。结论 抑郁症和早期AD认知功能损害的特征不同,长时延迟自由回忆、再认和语义流畅能够区分早期AD和抑郁症。     

Two domains of anosognosia in Alzheimer''s disease.

OBJECTIVE: To examine the presence of different dimensions of unawareness in patients with probable Alzheimer's disease. METHODS: A consecutive series of 170 patients with probable Alzheimer's disease were assessed with the anosognosia questionnaire-dementia (AQ-D) which includes items related to cognitive deficits and behavioural problems. RESULTS: A factor analysis of the AQ-D produced two factors: a "cognitive unawareness" factor, which loaded on items of memory, spatial and temporal orientation, calculation, abstract reasoning, and praxis, and a "behavioural unawareness" factor which loaded on items of irritability, selfishness, inappropriate emotional display, and instinctive disinhibition. A stepwise forward regression analysis showed significant correlations between the cognitive unawareness factor and more severe cognitive deficits, delusions, and apathy, but less depression. On the other hand, the behavioural unawareness factor correlated significantly with higher mania and pathological laughing scores. Whereas the cognitive unawareness factor showed a significant correlation with cognitive tests assessing verbal comprehension and long term memory, and was significantly associated with a longer duration of illness, no significant correlations were found between the behavioural unawareness factor and the neuropsychological tasks. CONCLUSION: Unawareness of cognitive deficits and unawareness of behavioural problems may constitute independent phenomena in Alzheimer's disease. Whereas unawareness of cognitive deficits is related to the severity of intellectual impairment and the presence of delusional apathetic mood, unawareness of behavioural problems may be part of a disinhibition syndrome.     

Specific deficit of colour-colour short-term memory binding in sporadic and familial Alzheimer's disease

Short-term memory binding of visual features which are processed across different dimensions (shape-colour) is impaired in sporadic Alzheimer's disease, familial Alzheimer's disease, and in asymptomatic carriers of familial Alzheimer's disease. This study investigated whether Alzheimer's disease also impacts on within-dimension binding processes. The study specifically explored whether visual short-term memory binding of features of the same type (colour-colour) is sensitive to Alzheimer's disease. We used a neuropsychological battery and a short-term memory binding task to assess patients with sporadic Alzheimer's disease (Experiment 1), familial Alzheimer's disease (Experiment 2) due to the mutation E280A of the Presenilin-1 gene and asymptomatic carriers of the mutation. The binding task assessed change detection within arrays of unicoloured objects (Colour Only) or bicoloured objects the colours of which had to be remembered separately (Unbound Colours) or together (Bound Colours). Performance on the Bound Colours condition (1) explained the largest proportion of variance between patients (sporadic and familial Alzheimer's disease), (2) combined more sensitivity and specificity for the disease than other more traditional neuropsychological tasks, (3) identified asymptomatic carriers of the mutation even when traditional neuropsychological measures and other measures of short-term memory did not and, (4) contrary to shape-colour binding, correlated with measures of hippocampal functions. Colour-colour binding and shape-colour binding both appear to be sensitive to AD even though they seem to rely on different brain mechanisms.     

Neuropsychological markers for the diagnosis of Alzheimer's disease

Better knowledge of the preclinical phase of Alzheimer's disease and of the symptomatic pre-dementia stage designated "mild cognitive impairment" will require considerable progress in our understanding of neuropsychological processes. The results of studies suggest that impaired performance in memory tests may serve as a marker for Alzheimer's disease. The best current predictors include stringent tests of episodic memory and recognition tests. The early stages of Alzheimer's disease also seem to involve subtle deficits in semantic memory and attentional processes. Face recognition and denomination seem to be useful tools. Greater accuracy and precision in the transitional zone between healthy aging and the first manifestations of Alzheimer's disease will require work combining data on neuropsychological profiles and neuroimaging.     

Neuropsychological profiles of familial Alzheimer's disease associated with mutations in the presenilin 1 and amyloid precursor protein genes

Patients with familial Alzheimer's disease and a subset known to have presenilin mutations were compared with sporadic cases on a comprehensive battery of cognitive tests. These included measures of memory, intelligence, language and perception. The three group were very comparable, in terms of severity, on global measures of dementia. However, their profiles/patterns of cognitive impairment differed in two respects; the group with sporadic Alzheimer's disease were significantly more impaired on tests of object naming and object perception than either the group with familial Alzheimer's disease or group with familial Alzheimer's disease and presenilin mutations, yet they scored at a significantly higher level on the measure of verbal intelligence. This study provides further evidence of the heterogeneity of the disease process. Received: 25 April 2000 / Received in revised form: 26 June 2000 / Accepted: 14 July 2000     

Cognitive deficits associated with a recently reported familial neurodegenerative disease: familial encephalopathy with neuroserpin inclusion bodies

BACKGROUND: We recently discovered an autosomal dominant disease causing a progressive dementia. The disease is caused by a point mutation in the gene coding for the serine protease inhibitor (ie, serpin) neuroserpin. The mutation results in an unstable neuroserpin protein that readily aggregates into intraneuronal inclusions that we identify as Collins bodies. The bodies are distributed throughout the cerebral hemispheres but are significantly more numerous in the cortex and the substantia nigra. We have named the disease familial encephalopathy with neuroserpin inclusion bodies (FENIB). OBJECTIVES: To describe the cognitive and neurophysiological changes exhibited by individuals with FENIB and to correlate the phenotypic expression of the disease with the neuropathological findings. DESIGN: Multiple case studies using neuropsychological assessment, electroencephalography (EEG), magnetic resonance imaging (MRI), and single-photon emission computed tomographic (SPECT) studies of family members were performed. Using these measures, we also compared family members in whom the mutation is present with family members in whom the mutation was absent to control for nonspecific familial factors. SUBJECTS: Nine individuals (5 women, aged 31-64 years; 4 men, aged 43-67 years) from 2 generations of family members related to the first reliably identified individual with symptoms of this disease. Symptoms, by self-report and reports of other family members, ranged from asymptomatic to severe dementia. Six of the 9 individuals carried the disease mutation. RESULTS: All subjects with the mutation demonstrated some cognitive changes, with the greatest demonstrated by subjects older than 40 years. The changes included restricted attention, concentration, and response regulation functions, reduced controlled oral fluency (word-list generation), and restricted visuospatial organization. In general, recall memory was not as affected as other cognitive domains. The most severely affected subject demonstrated global dementia with prominent frontal lobe features. Findings on SPECT showed anomalies limited to frontal areas in the less affected subjects and more global, patchy areas of hypoperfusion in the more severely affected subjects. The 3 oldest and most affected subjects demonstrated slowing on EEG findings. The MRI findings were noncontributory except in the 2 most severe cases, which showed global cortical atrophy. CONCLUSIONS: Cognitive changes in mildly to moderately affected subjects were characterized by deficits in frontal and frontal-subcortical area-dependent processes. Continued progressive deterioration of cerebral functions with relative sparing of recall memory suggests a unique dementia associated with this disease.     

A decade of pre-diagnostic assessment in a case of familial Alzheimer’s disease: tracking progression from asymptomatic to MCI and dementia

Detailed study of the very earliest phases of Alzheimer’s disease (AD) is seldom possible, especially those changes preceding the development of mild cognitive impairment (MCI), which may occur years before diagnosis. Knowledge of imaging and neuropsychological features of these early stages would add insight into this poorly understood phase of the disease. We present data from a subject who entered a longitudinal study of individuals at risk of familial Alzheimer’s disease (FAD), as a healthy volunteer with no memory complaints, undergoing 12 assessments between 1992 and 2003. Longitudinal MRI, neuropsychological and clinical data are presented over the decade preceding this man’s diagnosis, through the asymptomatic and prodromal preludes to his presentation with MCI and on to eventual conversion to AD.     

Relation of anosognosia to frontal lobe dysfunction in Alzheimer''s disease.

A self-rating scale of memory functions was administered to 24 non-depressed patients with probable Alzheimer's disease, divided into two groups according to the overall severity of dementia (mild, mini-mental state (MMS) > 21; moderate, MMS between 10 and 20). These groups did not significantly differ in their self-rating of memory functions. The same questionnaire was submitted to a member of each patient's family, who had to rate the patient's memory. An "anosognosia score" was defined as the difference between patient's and family's ratings. This score was highly variable, and covered, in the two groups, the full range between complete awareness of deficits and total anosognosia. Correlations between the anosognosia score and several neuropsychological data were searched for. No significant correlation was found with either the Wechsler memory scale, the MMS, or linguistic abilities and gestures. In contrast, this score was highly correlated with the "frontal score", defined as the sum of scores on the Wisconsin card sorting test (WCST), verbal fluency, Luria's graphic series, and "frontal behaviours" (prehension, utilisation, imitation behaviours, inertia, indifference). Among these tests of executive functions, the highest correlation with the anosognosia score was obtained on the WCST. This suggests that anosognosia in Alzheimer's disease is not related to the degree of cognitive deterioration but results, at least in part, from frontal dysfunction.     

Early cognitive decline in Creutzfeldt-Jakob disease associated with human growth hormone treatment

BACKGROUND: Most cases of Creutzfeldt-Jakob disease (CJD) in recipients of human cadaveric growth hormone present with a cerebellar syndrome. Dementia is thought to occur late and as a minor feature of the illness. However, neuropsychology data published on these cases are largely qualitative and anecdotal. The first published case does include a neuropsychological assessment seven months after the onset of a cerebellar syndrome, showing evidence of intellectual decline. Subsequent reports hint that cognitive problems may be present in the initial stages of the illness. OBJECTIVE: To assess early cognition in Creutzfeldt-Jakob disease in recipients of pituitary derived human growth hormone. METHODS: Detailed neuropsychology assessment is reported at referral (mean 4.5 months from the onset of symptoms; range 4 to 6 months) in five patients with histologically proven human growth hormone derived CJD. RESULTS: All cases presented with a cerebellar syndrome and only one had noticed mild memory problems. On formal testing, however, four had demonstrable mild intellectual decline, as measured on the WAIS-R. One case showed selective visual memory impairment and frontal executive dysfunction. CONCLUSIONS: These findings suggest that, although not the presenting feature, mild cognitive decline may be evident in the early stages of CJD associated with human cadaveric growth hormone treatment.     

Self-consciousness and Alzheimer''s disease

OBJECTIVES: To propose a neuropsychological study of the various aspects of self-consciousness (SC) in Alzheimer's disease. METHODS: Forty-five patients with probable mild or moderate AD were included in the study. Severity of their dementia was assessed by the Mini Mental State (MMS). Fourteen questions were prepared to evaluate SC. RESULTS: No significant correlations were found between SC score and educational level, age, and duration of disease. A significant correlation was found between SC score and the severity of dementia, whereas frontal disturbances were just short of the significance threshold. The various aspects of SC were not impaired to the same degree. The most disturbed ones were awareness of cognitive deficiencies, moral judgements and prospective memory. The least disturbed aspects were awareness of identity and of mental representation of the body. Items relating to anosognosia and moral judgements were significantly correlated with the MMS score, whereas affective state, body representation disorders, prospective memory, and capacities for introspection were not related to the severity of the dementia. Consciousness of identity was sound, regardless of MMS score. CONCLUSIONS: AD clearly induces an heterogeneous impairment of SC. SC requires a convergence of many neural networks. In AD, neuronal alterations involve many cortical areas and information sent to the associative frontal cortex from memory, language and visuospatial areas is lacking or disturbed. Thus, the sequential order of successive stimuli cannot be maintained by the heteromodal associative cortex (dorsal convexity of the prefrontal cortex), and the supramodal associative cortex (located rostrally in the frontal lobes) is unable to provide reliable monitoring and assessment of simultaneous neural cognitive networks carrying insufficient and inadequate input. The core deficiency in AD patients might be impaired SC equated with the disability to maintain sequential and simultaneous "attention to life". The Self-Consciousness Questionnaire, a clinical scale providing multidimensional measurement, indicates that different aspects of consciousness are not correlated with overall cognitive deficiency as determined by the MMSE.     

A comparison of dementia in Alzheimer's disease and multiple sclerosis

We compared results of comprehensive neuropsychological testing in 42 patients with clinically diagnosed Alzheimer's disease (AD) and in an equal number of patients with clinically definite chronic-progressive multiple sclerosis. Age, sex, and education were controlled using demographically corrected T scores based on a large normal sample. Both groups showed significant impairment on the test battery, but the degree of dementia was more severe in the patients with AD. A deviation score analysis, controlling for overall level of cognitive impairment, revealed significant differences between the groups. Alzheimer's disease was associated with relatively greater impairment of learning, memory, and verbal skills, whereas the MS group showed greater relative impairment of attention, incidental memory, and psychomotor functions. These data suggest that both the degree and pattern of mental impairement differ in patients with AD and patients with multiple sclerosis. Our results support a distinction between "gray matter" and "white matter" dementia, and may help clarify the issue of "cortical" vs "subcortical" dementia by demonstrating neuropsychological differences based on secure neuropathologic distinctions.     

Material-specific memory loss in probable Alzheimer''s disease.

This study extends previous work analysing functional dissociations occurring in patients with Alzheimer's disease (AD) by demonstrating that material-specific memory loss is common. The pattern of neuropsychological dysfunction in 191 patients with probable AD was examined and 13% presented with material-specific memory loss. Thirteen patients had impaired immediate verbal recall, but normal non verbal recall and 12 had impaired non verbal recall and normal verbal memory. These patterns appeared to be related to a specific memory deficit and were probably not secondary to associated cognitive impairments. These data confirm earlier observations that the memory defect in AD can be material-specific, and suggest that these patterns of impairment should be viewed as a focal sparing of function.     

Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer's disease

Abnormally phosphorylated tau accumulates as neurofibrillary tangles and neuropil threads in older persons with and without Alzheimer's disease. The relationship between neurofibrillary tangles and neuropil threads and how they relate to cognitive function is unknown. This study investigated the relationship between phosphorylated tau lesions and cognitive function in 31 persons participating in the Religious Orders Study, a prospective, longitudinal clinicopathological study of aging and Alzheimer's disease. All subjects underwent detailed neuropsychological performance testing within a year of death and evidenced a spectrum of cognitive performance ranging from normal abilities to mild dementia. Measures of neurofibrillary tangle density and phosphorylated tau immunoreactive structures (predominantly neuropil threads) in the entorhinal and perirhinal cortices by quantitative image analysis were significantly correlated (r = 0.5). In multiple linear regression analyses controlling for age, sex, and education, parahippocampal neurofibrillary tangles and neuropil threads were significantly lower in persons without cognitive impairment compared to those with mild cognitive impairment and/or Alzheimer's disease. Further, neurofibrillary tangles were significantly correlated to measures of episodic memory but not other cognitive abilities; neuropil tangles were not significantly related to memory or other cognitive functions. These data indicate that phosphorylated tau pathology in the ventromedial temporal lobe develop prior to the onset of clinical dementia and their presence is associated with cognitive impairment, particularly impairment of episodic memory.     

Neuropsychological study of familial Alzheimer's disease caused by mutation E280A in the presenilin 1 gene

In Antioquia, Colombia, investigators have recently discovered the largest family with the E280A mutation in the presenilin 1 gene that causes one type of familial Alzheimer's disease (FAD). The current study compares two groups within this family: those diagnosed with Alzheimer's disease (AD) in its early stage (nine subjects) and relatives (carriers) who did not show any signs of dementia (nine subjects). A battery of the following neuropsychological tests was administered to subjects in both groups: the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), a Phonological Verbal Fluency test, the Visual "A" Cancellation Test, memory of three phrases, the Rey-Osterrieth Complex Figure, and the Trail Making Test Part A. Statistical analyses of the average test scores of each group showed that the AD group scored significantly (p < 0.01 or p < 0.05) lower on 29 of the 43 neuropsychological variables measured (67 percent). Therefore, this specific battery was useful in discriminating subjects with AD from their healthy relatives who are carriers of the disease. The AD group as a whole presented slight dementia with predominant deficits in memory, language, praxis, and attention. This profile is similar to those reported in subjects with sporadic AD in its early stage and confirms the findings found in other neuropsychological studies of subjects with FAD linked to mutations in chromosome 14.     

Recent advances in the neuropsychology of Alzheimer''s disease

1. Memory, language, and visuospatial impairments are prominent neuropsychological deficits in Alzheirner's disease.

2. The neuropsychological characteristics of Alzheimer's disease are unigue, and contrast with those of other brain diseases.

3. Neuropsychological study of patients with Alzheimer's disease may he useful in discovering the neuronal basis of cognitive processes, in differential diagnosis of dementia, and in evaluating treatment.