David S. Knopman

Personal ViewTracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers

In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimers disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.

Procedural learning is impaired in Huntington's disease : evidence from the serial reaction time task

The purpose of the study was to test the hypothesis that Huntingtons disease (HD) is associated with impairment of procedural learning. We identified 13 patients with mild to moderate HD whose manual performance was still sufficiently intact to assess learning on the serial reaction time (SRT) task. Twelve age-matched neurologically normal control subjects were studied as well. The SRT task was a four-choice reaction time task in which the stimuli followed a sequence (10 items in length) which repeated itself 10 times during each of the first four blocks of trials. During the fifth block of trials, the stimuli were random. Learning was manifested by a reduction in response latency over the first four blocks and an increase in response latency in the fifth (random) block. Learning in this task has been demonstrated in other amnesics of other etiologies. The HD patients were significantly impaired on sequence-specific learning, using the log-transformed reaction time data (P less than 0.004). In addition, in an individual-by-individual analysis, five of the HD patients and none of the control subjects failed to show sequence-specific learning, a difference in proportions that was significant (P less than 0.04). No feature of the standard cognitive or motor assessment of the HD patients was associated with efficacy of procedural learning. HD, including patients with mild disease, was associated with a deficit in procedural learning, consistent with the hypothesis that the striatum plays a critical role in supporting procedural learning.

Dementia lacking distinctive histologie features A common non‐Alzheimer degenerative dementia

From a series of 460 dementia patients referred to a regional brain bank, 14 (3%) patients had a pathologic diagnosis of primary degeneration of the brain involving multiple sites (frontoparietal cortex, striatum, medial thalamus, substantia nigra, and hypoglossal nucleus), with cell loss and astrocytosis. There were no neuronal inclusions and essentially no senile plaques. This entity, which we have termed “dementia lacking distinctive histology” (DLDH), presented with memory loss and personality changes, and led to death, usually within 2 to 7 years. Dysarthria and dysphagia were prominent in the later phases of the illness in most patients. The psychometric findings of some of the patients were consistent with a “frontal” lobe dementia. A few patients had prominent caudate atrophy on CT as well as neuropathologically. Eight of our patients had positive family histories for neurologic disease, mainly dementia. DLDH, in addition to Picks disease, is a major member of the frontal-lobe dementia group. In patients under age 70 years, the frontal lobe dementias represent an important diagnostic consideration.

Development of cognitive instruments for use in clinical trials of antidementia drugs: Additions to the Alzheimer's disease assessment scale that broaden its scope

The cognitive assessment protocol of the Alzheimers Disease Cooperative Study (ADCS) was designed to evaluate the reliability and validity of cognitive assessment measures that might be valuable additions to the Alzheimers Disease Assessment Scale (ADAS) or other concise batteries used in antidementia drug trials. As part of an overall ADCS protocol to develop new instruments to be used in trials of treatments for Alzheimers disease (AD), patients with mild to moderate AD and cognitively normal elderly were administered a battery of five tests at least three times over 1 year. The tests included word list learning with delayed free recall, a recognition memory test for faces, a series of letter and digit cancellation tests to measure concentration, tests of praxis, and a series of maze completion tasks designed to assess planning and executive function. A version of the digit cancellation task was reliable and sensitive to a broad range of dementia severity so that it could provide a useful addition to the present version of the ADAS. Performance on the word learning task with delayed recall and a subset of the mazes task were impaired even in mild AD, so these tasks may be useful in trials involving mild or at-risk subjects. Performances on the facial recognition task and on the praxis tasks were not related to dementia severity, so these tasks would not be useful to evaluate treatments. Therefore, the major outcome of this investigation was the identification of some potential addtions to the present ADAS that extend both the cognitive domains and the range of symptom severity covered.

Neurochemical dissociation of memory systems

The administration of scopolamine, an anticholinergic drug, reduced the ability to recall and recognize stimuli presented previously—abilities thought to require declarative memory. In contrast, measures of procedural memory were unaffected by scopolamine: performance on a serial reaction time task incorporating a repeating stimulus and response sequence showed no difference in acquisition and retention of the sequence after scopolamine or saline. These results suggest that the cholinergic system is required for declarative but not procedural memory.

Correlates of Cognitive Function in Middle-Aged Adults

The Atherosclerosis Risk in Communities Study administered cognitive function tests to more than 14,000 middle-aged adults in 1990–1992. The battery included the Delayed Word Recall test, the Digit Symbol Subtest of the Wechsler Adult Intelligence Scale-Revised, and the Controlled Oral Word Association (Word Fluency) test. Test performance was correlated positively with education level, negatively with age, was better in women than in men, and better in managers/professionals compared with other occupations. After controlling for these factors, race and community, the findings most consistent for both sexes were that Delayed Word Recall was negatively associated with depressive symptoms, diabetes, and fibrinogen level; the Digit Symbol Subtest was associated with marital status, negatively associated with depressive symptoms, smoking status, fibrinogen level, and carotid intima-media thickness, and positively associated with alcohol drinking and FEV1; and the Word Fluency test was positively associated with marital status, alcohol drinking, sports participation, and FEV1. Most of these cross-sectional results were in the predicted direction and have biologic plausibility, but mean differences between extreme categories were small (generally on the order of 0.1 to 0.2 of a standard deviation). Longitudinal study is warranted to evaluate whether small differences in middle-age lead to larger, clinically meaningful deficits with aging.

Longitudinal Study of Death and Institutionalization in Patients with Primary Degenerative Dementia

We studied the outcome of 101 patients with primary degenerative dementia. The patients were outpatients at the time of the initial evaluation, and all had family caregivers. There were substantial differences in mortality and institutionalization between the mild and advanced patients, as defined by scores on mental status examination. Similar differences in those two outcomes were also evident when the patients were stratified by scores on activities of daily living and disruptive behavior assessments. Thus, certain patient characteristics may be of value in predicting risk for institutionalization and death.

Patterns of care in the early stages of Alzheimer's disease : Impediments to timely diagnosis

OBJECTIVE: Description of factors associated with delay in diagnosis of Alzheimers disease (AD).

Implicit Learning of New Verbal Associations

Implicit learning of a series of new verbal associations was studied in four experiments. The first two experiments demonstrated that learning of a repeating sequence of verbal stimuli may occur without awareness, but only when the stimulus-response mapping requires an attention-demanding activity: Subjects who were unaware of the sequence learned when instructed to categorize the stimuli, but not when instructed simply to read them. However, in both situations, unaware subjects performed no better than untrained control subjects in expressing their knowledge of the sequence explicitly. In Experiments 3 and 4, subjects showed implicit learning when the task involved either motor responses to verbal stimuli or verbal responses to spatially arranged stimuli. These findings are discussed in terms of the conditions under which implicit learning can be obtained. First, they demonstrate implicit learning of a set of new associations in the verbal domain. Second, the data suggest that attention is important in implicit learning. Finally, the degree of interitem organization that is familiar preexperimentally seems to partially determine the amount of implicit learning.

Unaware learning versus preserved learning in pharmacologic amnesia: similarities and differences.

The differences between learning in lorazepam (LOR)--or scopolamine (SCOP)--induced amnesia and learning in unaware drug-free normal subjects were examined. The drugs produced impairment in free recall, but did not affect digit span or word retrieval. In a verbal version, but not a motor version, of the serial reaction time task, the subjects who received SCOP or higher dose LOR showed impairment of sequence-specific learning. Subjects who received placebo had no such impairment. In the stem completion paradigm, higher dose LOR, but not SCOP, impaired performance. In a tachistoscopic word identification task, neither drug interfered with repetition priming. Unaware learning and drug-induced amnesic learning were thus dissociable. These findings disconfirm the hypothesis that unaware learning and drug-induced amnesic learning are analogous.