Tiffany W. Chow

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.

Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease

Few studies evaluate neuropathological correlates of behavioral changes in Alzheimer disease (AD). We identified 31 autopsy patients with a diagnosis of definite AD. Behavioral changes were assessed with the Neuropsychiatric Inventory. Brain sections were collected from bilateral orbitofrontal and left anterior cingulate, superior temporal, inferior parietal, occipital, and hippocampal cortices for quantification of neurofibrillary tangles (NFTs) and diffuse and neuritic plaques. Sections from frontal, cingulate, and hippocampal cortices were reviewed for the presence of Lewy bodies (LBs). Hypothesis‐driven correlational analyses were performed by the bootstrap method. Subgroup analyses contrasted a group with high scores of one specific behavior to a group with low scores after equating groups for other behaviors. NFT burden in the left orbitofrontal cortex across all 31 patients significantly correlated with agitation scores (r = 0.41, p < 0.015) and NFTs correlated significantly (r = 0.66, p = 0.004) with higher agitation scores in the subgroup analysis. Left anterior cingulate NFTs, although not within our hypotheses, also showed a significant relationship to agitation within the subgroups (r = 0.76, p = 0.0003; Bonferroni p = 0.02). Seven patients, including three in the agitation subgroup, had cortical LBs. Aberrant motor behavior and NFT density in the left orbitofrontal cortex showed a significant relationship for the entire group (r = 0.38, p < 0.03) and for subgroups (r = 0.49, p = 0.04), whereas apathy and left anterior cingulate NFTs showed a significant relationship only for the entire group (r = 0.25, p ≤ 0.01). These observations suggest that agitation and aberrant motor behavior are correlates of greater NFT pathology in the orbitofrontal cortex in AD, whereas increasing apathy may relate to greater NFT burden in the anterior cingulate. Ann Neurol 2001;49:355–361

Diagnostic criteria for the behavioral variant of frontotemporal dementia (bvFTD): Current limitations and future directions

The most widely established diagnostic criteria for the behavioral variant of frontotemporal dementia have now been in use for almost a decade. Although consensus criteria have provided a much needed standard for frontotemporal dementia research, a growing body of evidence suggests that revisions are needed to improve their applicability. In this article, we discuss the limitations of current diagnostic criteria and propose the establishment of an international consortium to revise diagnostic and research criteria for the behavioral variant of frontotemporal dementia.

A Neurocomputational Model of Analogical Reasoning and its Breakdown in Frontotemporal Lobar Degeneration

Analogy is important for learning and discovery and is considered a core component of intelligence. We present a computational account of analogical reasoning that is compatible with data we have collected from patients with cortical degeneration of either their frontal or anterior temporal cortices due to frontotemporal lobar degeneration (FTLD). These two patient groups showed different deficits in picture and verbal analogies: frontal lobe FTLD patients tended to make errors due to impairments in working memory and inhibitory abilities, whereas temporal lobe FTLD patients tended to make errors due to semantic memory loss. Using the Learning and Inference with Schemas and Analogies model, we provide a specific account of how such deficits may arise within neural networks supporting analogical problem solving.

Abnormal network connectivity in frontotemporal dementia: Evidence for prefrontal isolation

INTRODUCTION Degraded social function, disinhibition, and stereotypy are defining characteristics of frontotemporal dementia (FTD), manifesting in both the behavioral variant of frontotemporal dementia (bvFTD) and semantic dementia (SD) subtypes. Recent neuroimaging research also associates FTD with alterations in the brains intrinsic connectivity networks. The present study explored the relationship between neural network connectivity and specific behavioral symptoms in FTD. METHODS Resting-state functional magnetic resonance imaging was employed to investigate neural network changes in bvFTD and SD. We used independent components analysis (ICA) to examine changes in frontolimbic network connectivity, as well as several metrics of local network strength, such as the fractional amplitude of low-frequency fluctuations, regional homogeneity, and seed-based functional connectivity. For each analysis, we compared each FTD subgroup to healthy controls, characterizing general and subtype-unique network changes. The relationship between abnormal connectivity in FTD and behavior disturbances was explored. RESULTS Across multiple analytic approaches, both bvFTD and SD were associated with disrupted frontolimbic connectivity and elevated local connectivity within the prefrontal cortex. Even after controlling for structural atrophy, prefrontal hyperconnectivity was robustly associated with apathy scores. Frontolimbic disconnection was associated with lower disinhibition scores, suggesting that abnormal frontolimbic connectivity contributes to positive symptoms in dementia. Unique to bvFTD, stereotypy was associated with elevated default network connectivity in the right angular gyrus. The behavioral variant was also associated with marginally higher apathy scores and a more diffuse pattern of prefrontal hyperconnectivity than SD. CONCLUSIONS The present findings support a theory of FTD as a disorder of frontolimbic disconnection leading to unconstrained prefrontal connectivity. Prefrontal hyperconnectivity may represent a compensatory response to the absence of affective feedback during the planning and execution of behavior. Increased reliance upon prefrontal processes in isolation from subcortical structures appears to be maladaptive and may drive behavioral withdrawal that is commonly observed in later phases of neurodegeneration.

Apathy Symptom Profile and Behavioral Associations in Frontotemporal Dementia vs Dementia of Alzheimer Type

BACKGROUND Apathy is a common and significant problem in patients with dementia, regardless of its cause. Observations about frontosubcortical circuit syndromes indicate that apathy may have affective, behavioral, or cognitive manifestations. OBJECTIVES To explore whether the apathy manifested in frontotemporal dementia (FTD), with its predominantly anterior brain neuropathologic features, differs from the apathy in dementia of Alzheimer type (DAT), with its predominantly hippocampal- and temporoparietal-based neuropathologic features, and to determine whether other behavioral disturbances reported in frontosubcortical circuit syndromes correlate with apathy. DESIGN Analyses included individual items within Neuropsychiatric Inventory subscale items. Items of the apathy/indifference subscale were designated by consensus as affective (lacking in emotions), behavioral (inactive, chores abandoned), or cognitive (no interest in the activities of others). Proportions of correlated nonapathy Neuropsychiatric Inventory items were calculated. SETTING Several neurology specialty clinics contributed to our data set. PARTICIPANTS A total of 92 participants with FTD and 457 with DAT. MAIN OUTCOME MEASURES The Neuropsychiatric Inventory was analyzed. RESULTS Apathy was more prevalent in patients with FTD than in those with DAT, but when present, the specific apathy symptoms associated with both types of dementia were rarely restricted to 1 of the 3 domains of apathy. Dysphoria concurrent with apathy was unique to the DAT group and negatively correlated in the FTD group. Participants with affective apathy more frequently copresented with an orbital frontosubcortical syndrome in FTD (impulsivity and compulsions). Affective apathy also copresented with uncooperative agitation, anger, and physical agitation in both types of dementia. CONCLUSIONS Apathy is common in patients with FTD and DAT, although it is more common in those with FTD. When present, it usually involves changes in affect, behavior, and cognition. It is associated with behaviors that have previously been shown to affect patient safety, independence, and quality of life.

Distraction during relational reasoning: The role of prefrontal cortex in interference control

We compared the reasoning performance of patients with frontal-variant frontotemporal lobar degeneration (FTLD) with that of patients with temporal-variant FTLD and healthy controls. In a picture analogy task with a multiple-choice answer format, frontal-variant FTLD patients performed less accurately than temporal-variant FTLD patients, who in turn performed worse than healthy controls, when semantic and perceptual distractors were present among the answer choices. When the distractor answer choices were eliminated, frontal-variant patients showed relatively greater improvement in performance. Similar patient groups were tested with a relational-pattern reasoning task that included manipulations of one or two relations and both perceptual and semantic extraneous information. Frontal-variant patients showed performance deficits on all tasks relative to the other subject groups, especially when distracted. These results demonstrate that intact prefrontal cortex (PFC) is necessary for controlling interference from perceptual and semantic distractors in order to reason from relational structure.

Variations in regional SPECT hypoperfusion and clinical features in frontotemporal dementia

Objective: To characterize the presenting clinical features for frontotemporal dementia (FTD) and contrast them with the degree of frontal and temporal hypoperfusion on SPECT imaging. Methods: The authors evaluated 74 patients who eventually met Consensus Criteria for the FTD form of frontotemporal lobar degeneration (excluding primary progressive aphasia and semantic dementia) on 2-year follow-up. On first presentation, these patients had undergone both an FTD Inventory for 12 features based on core and supportive Consensus Criteria and SPECT imaging. The initial clinical diagnostic features were contrasted with variations in regional SPECT hypoperfusion. Results: The patients with FTD had more hypoperfusion in the right frontal lobe than in other regions; the subgroup of 25 patients who met Consensus Criteria from the first presentation had the most right frontal hypoperfusion. Frontal lobe involvement was associated with significant apathy, whereas temporal lobe involvement was associated with hypomania-like behavior. Right frontal lobe hypoperfusion further predicted loss of insight, environmental dependency, and stereotyped behaviors. Other associations included left frontal hypoperfusion with a decline in personal hygiene and left temporal hypoperfusion with compulsions and mental rigidity. Conclusions: On first presentation, frontotemporal dementia (FTD) is disproportionately a right frontal disease evident on behavioral measures and on SPECT. Nonetheless, patients with FTD can initially present with further regional differences in clinical diagnostic features, such as apathy with bifrontal hypoperfusion and hypomania-like behaviors with anterior temporal involvement.

Relational Integration and Executive Function in Alzheimer's Disease.

Executive functions depend on the ability to represent relations between objects and events, and the prefrontal cortex provides the neural substrate for this capacity. Patients with probable Alzheimers disease (AD) and control participants were administered measures of working memory and reasoning that varied systematically in their relational complexity. AD patients showed impairment on reasoning measures that required the online integration of relations but performed as well as control participants on nonrelational items and items requiring the processing of only single relations. When AD patients were divided into subgroups based on their performance on relational reasoning measures, the subgroup that showed significant impairment on relational integration measures exhibited a neuropsychological profile consistent with prefrontal cortical dysfunction.

Clinicopathological concordance of dementia diagnoses by community versus tertiary care clinicians.

Subjects enrolled in the Autopsy Program at the University of Southern California Alzheimers Disease Research Center may receive clinical diagnoses from primary care providers in the community or from specialists in neurology. We reviewed the autopsy concordance rates for 463 subjects for diagnoses made by both groups of clinicians. Seventy-seven percent of the sample met neuropathological criteria for Alzheimers disease (AD). The overall diagnostic accuracy for this sample was 81 percent. Neurologists assessed 200 of the subjects (43 percent). The diagnostic accuracy for any clinical diagnosis among the non-neurologists was 84 percent, and 78 percent (p = 0.07) among neurologists. For AD, non-neurologists had a diagnostic concordance rate of 91 percent and neurologists 87 percent. Where neuropathological AD was missed, non-neurologists had failed to detect any cognitive impairment; neurologists had diagnosed Parkinsons disease (PD) and amyotrophic lateral sclerosis (ALS). Erroneous clinical diagnoses of AD missed dementia with Lewy bodies (DLB) or AD concurrent with Parkinsons disease (PD). Our findings identify specific foci for improving clinical diagnosis of dementia among all physicians managing dementia.